Post on 28-Mar-2023
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Copyright American Scientific Publishers
Copyright copy 2015 American Scientific PublishersAll rights reservedPrinted in the United States of America
ReviewJournal of
Nanoscience and NanotechnologyVol 15 4021ndash4038 2015
wwwaspbscomjnn
Low Doses of Traditional Nanophytomedicines for
Clinical Treatment Manufacturing Processes and
Nonlinear Response Patterns
Iris R Bell12lowast MD PhD Barbara Sarter34 PhD APRN FNP-C Leanna J Standish5 ND PhDPrasanta Banerji6 FMIH and Pratip Banerji6 MD(Hom)
1Department of Family and Community Medicine The University of Arizona College of Medicine
1450 N Cherry Avenue MS 245052 Tucson AZ 85719 USA2College of Nursing The University of Arizona 1305 N Martin Tucson AZ 85721 USA
3Hahn School of Nursing and Health Sciences University of San Diego
5998 Alcala Park San Diego CA 92110 USA4Bastyr UniversitymdashCalifornia 4106 Sorrento Valley Blvd San Diego CA 92121 USA
5Bastyr University 14500 Juanita Drive NE Kenmore WA 98028 USA6PBH Research Foundation 1031 Elgin Road (Lala Lajpat Rai Sarant) Kolkata 700020 West Bengal India
The purpose of the present paper is to (a) summarize evidence for the nanoparticle nature and bio-logical effects of traditional homeopathically-prepared medicines at low and ultralow doses (b) pro-vide details of historically-based homeopathic green manufacturing materials and methods relatingthem to top-down mechanical attrition and plant-based biosynthetic processes in modern nanotech-nology (c) outline the potential roles of nonlinear dose-responses and dynamical interactions withcomplex adaptive systems in generating endogenous amplification processes during low dose treat-ment Possible mechanisms of low dose effects for which there is evidence involving nanoparticlesandor homeopathically-manufactured medicines include hormesis time-dependent sensitizationand stochastic resonance All of the proposed mechanisms depend upon endogenous nonlinearamplification processes in the recipient organism in interaction with the salient albeit weak signalproperties of the medicine Conventional ligand-receptor mechanisms relevant to higher doses areless likely involved Effects especially for homeopathically-prepared nanophytomedicines includebidirectional host state-dependent changes in function Homeopathic clinicians report successfultreatment of serious infections and cancers Preclinical biological evidence is consistent with suchclaims Controlled biological data on homeopathically-prepared medicines indicate modulation ofgene expression and biological signaling pathways regulating cell cycles immune reactions andcentral nervous system function from studies on cells animals and human subjects As a 200-year old system of traditional medicine used by millions of people worldwide homeopathy offers apulsed low dose treatment strategy and strong safety record to facilitate progress in translationalnanomedicine with plants and other natural products In turn modern nanotechnology methodscan improve homeopathic manufacturing procedures characterize nanoparticle end-products anddescribe interactions of homeopathic nanophytomedicines with living systems at the nanoparticleand even individual organism level of detection Faster progress toward safe and effective person-alized nanophytomedicine treatments can result
Keywords Nanomedicine Nanoparticle Low Dose Phytomedicine Green ManufacturingHomeopathy Hormesis Time-Dependent Sensitization Stochastic ResonanceNonlinear Dynamics Complex Adaptive System Silica Self Assembly AdjuvantCancer Treatment
lowastAuthor to whom correspondence should be addressed
J Nanosci Nanotechnol 2015 Vol 15 No 6 1533-48802015154021018 doi101166jnn20159481 4021
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
CONTENTS1 Introduction 4022
2 Homeopathic Manufacturing Procedures for
Natural Nanomedicines 4024
21 Overview of Traditional Homeopathic
Medicine Manufacturing 4024
22 The Debate Over ldquoDilutionrdquo versus Homeopathic
Manufacturing Procedures 4026
3 Pulsed Dosing and Nonlinear Dose-Responses 4031
31 Dosing Homeopathic Nanoparticles 4031
32 Nonlinear Dose-Response Mechanisms 4032
4 Conclusions 4033
Acknowledgment 4034
References and Notes 4034
1 INTRODUCTIONThe purpose of the present paper is to (a) summarize evi-
dence for the nanoparticle nature and biological effects of
traditional homeopathically-prepared medicines at low and
ultralow doses (b) provide details of historically-based
homeopathic manufacturing materials and methods relat-
ing them to top-down mechanical attrition doping and
templating of nanosilica and plant-based biosynthetic pro-
cesses in modern nanotechnology (c) outline the potential
roles of nonlinear dose-responses of hormesis stochastic
resonance and nonlinear dynamical interactions with com-
plex adaptive systems in generating endogenous amplifi-
cation processes during low dose treatment
Many cultures worldwide have relied on bulk form
plant-based natural medicines for hundreds to thousands
of years for treating acute and chronic health problems
Traditional Chinese medicine Ayurvedic medicine and
Western herbalism are all examples of highly-developed
historical approaches to natural product-based treatment
for conditions ranging from infections to cancers1ndash6
Herbalists argue for use of the whole plant or traditionally-
used intact plant parts (eg roots stem bark leaves)
rather than chemically-isolated individual nutraceutical
ingredients in order to obtain gentler and synergistic
effects of multiple natural constituents7 interacting with
the individual as an integrated complex adaptive system8
However as modern researchers have taken a closer
look at the strengths and limitations of traditional phy-
tomedicines they often identify poor absorption lower
bioavailability and limited patient tolerability as barri-
ers to more widespread adoption of herbs for clinical
care
Nanotechnologists are currently beginning to exploit the
ability of nanoparticulate (NP) forms of traditional botan-
ical agents to dramatically improve absorption bioavail-
ability and reduce side effects9ndash17 Because of their tiny
size (eg a log unit smaller than the wavelength of vis-
ible light) many NPs can readily cross cell membranes
including blood-brain barrier1819 The therapeutic dose
ranges for nanoscale forms of many agents are lower by
orders of magnitude compared with their respective bulk
forms20ndash26 Modern NPs offer additional therapeutic advan-
tages over bulk forms such as better intracellular access22
and targeting of cancerous cells while sparing healthy cells
in the organism27ndash32 Nanoparticles made from botanical
and nutraceutical agents have particularly low toxicity and
favorable side effect profiles1633ndash35
At the same time translation from bench to bedside has
been slow36 Concerns about uncertain toxicity profiles of
manufactured NPs persist37 Plants and fungi are among
the natural products used to biosynthesize potentially safer
forms of certain NPs eg silver or gold38ndash42 Plant biosyn-
thesis helps avoid toxic reagents during green manufac-
turing of nanomedicines43 Similarly reducing and coating
the surface of otherwise more toxic NPs with benign sug-
ars such as lactose sucrose maltose or glucose appears
to attenuate toxicity for nanomedicine use44ndash46 This strat-
egy is important because of the ability of nanoparticles
to adsorb onto other materials involved in their produc-
tion given their highly reactive surfaces NP adsorbants
such as plants or sugars can not only modify the sur-
face charge and physicochemical properties of the resultant
NPs but also enhance the beneficial biological effects of
the nanoscale agent4047ndash49 Still widespread clinical appli-
cation of plant-synthesized NPs and nanophytomedicines
does not appear imminent Many practical and regulatory
hurdles lie ahead
Nanophytomedicines might otherwise appear to be new
and relatively untested forms of treatment However inves-
tigators have begun to identify specific nanoscale materials
in certain Chinese herbs5051 and Ayurvedic medicines52
In addition recent studies have demonstrated that the his-
torical manufacturing procedures for making homeopathic
medicines another traditional system of natural medicine
also generate polydisperse source nanoparticles of differ-
ent sizes from quantum dot (1ndash10 nm) to larger nanoscale
structures (Fig 1) Convergent evidence indicates that
homeopathic manufacturing methods mechanically gener-
ate top-down nanoscale particles of the original source
material1753ndash56 as well as silicasilicon from the inside
walls of the glass containers5557ndash61 Previous nanoscience
research suggests that interactions of homeopathic plant
mother tinctures with silica precursors and silicon-derived
materials in solution might also generate plant-modified
(coated doped or imprinted) andor plant self-assembled
silica NPs404362ndash65
The unique green top-down and bottom-up biosynthetic
manufacturing and pulsed low dosing methods of homeo-
pathic medicine combined with the large pharmacopoeias
for hundreds of natural medicines and already established
regulatory standards for these agents provide a possi-
ble foundation for accelerating progress in translational
nanophytomedicine Homeopaths have had over 200 years
of real-world experience and an estimated more than
500 million patients worldwide66 in the safe and effective
use of thousands of their nanoscale natural products ie
homeopathic medicines6768111ndash113117
4022 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Iris R Bell received her AB in Biology from Harvard University and completed her
PhD in Neuro- and Biobehavioral Sciences and MD (Medicine) from Stanford Univer-
sity She is Professor Emeritus in the Department of Family and Community Medicine at
the University of Arizona College of Medicine and Research Professor at the University of
Arizona College of Nursing Her main research interests supported by both National Insti-
tutes of health (NIH) and private foundation grants have focused on nonlinear complex
adaptive systems psychophysiological processes and basic science of complementary and
alternative medicine interventions in chronic disease She has more than 140 publications
and 30 book chapters Most recently she received competitive grant support to examine
the nanoparticle nature of classical homeopathic medicines and related natural products in
the treatment of cancer
Barbara Sarter is currently Professor in the School of Naturopathic Medicine at Bastyr
University California Previously she was Associate Professor at the University of South-
ern California Keck School of Medicine Dr Sarter organized the International Research
Consortium on the Banerji Protocols which is attempting to advance research on the
nano pharmacological approach using natural substances that is practiced at the PBH
Research Foundation in Kolkata India Her research background includes studies on nutri-
tional approaches for health promotion and natural substances for cancer treatment and
prevention
Leanna J Standish received her PhD in NeuroscienceBiopsychology from the Univer-
sity of Massachusetts and her ND (Naturopathic Medicine) from Bastyr University Dr
Standish is Research Professor for the School of Naturopathic Medicine at Bastyr Clinical
Professor for the School of Public Health at the University of Washington and Affili-
ate Research Professor in the University of Washingtonrsquos School of Medicinersquos radiology
department She is Board-certified in naturopathic oncology Dr Standish has also been
the medical director of the Bastyr Integrative Oncology Research Center (BIORC) and
a clinical research professor at the Bastyr University Research Institute She has served
as principal investigator on several National Institutes of Health (NIH) research grants
since 1994 Currently her research is focused on the Asian medicinal mushroom Tram-
etes versicolor in the treatment of breast and prostate cancer functional brain imaging in
the treatment of brain cancer and the development of integrative oncology outcomes studies New projects using IV
Resveratrol and IV Curcumin to treat cancer are being developed
Prasanta Banerji is Founder and Managing Trustee of the PBH Research Foundation
Fellow of the Mihijam Institute of Homeopathy and well known for establishing the
Banerji Protocols of treatment using Homeopathic Medicines internationally Research
areas include the treatment of every type of cancer and other serious illnesses which have
ensured replicability and helped produce vast amounts of data for meaningful research
which in turn has led to the acceptance at the Best Case Series program of the National
Cancer Institute (NCI) of USA He has been disseminating the protocols by lectures and
teaching seminars and has a number of published papers book chapters and books on the
subject
Pratip Banerji is Co-founder and Dy Managing Trustee of the Dr Prasanta Banerji
Homoeopathic Research Foundation (PBHRF) a consultant physician since 1991 with a
Bachelors Degree-BHMS from the Calcutta University He is also a Doctor of Medicine
MD(Hom) from the JRN Rajasthan Vidyapeeth (Deemed University) Udaipur in India
has played an important role in conducting research on the efficacy of treatment under the
Banerji Protocols The process of data accrual and documentation according to the highest
international standards was introduced by him This has made their research acceptable to
the international scientific community He has been disseminating the protocols by lectures
and teaching seminars and has a number of published papers book chapters and books on
the subject
J Nanosci Nanotechnol 15 4021ndash4038 2015 4023
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 1 Polydisperse size distribution of zinc metal nanoparticles of
homeopathically-prepared Zincum metallicum at 30C and 200C potencies
from two different manufacturers (SBL and WSI) Reprinted with per-
mission from [54] P S Chikramane et al Homeopathy 99 231 (2010)copy 2010 Churchill Livingstone
2 HOMEOPATHIC MANUFACTURINGPROCEDURES FOR NATURALNANOMEDICINES
21 Overview of Traditional Homeopathic MedicineManufacturing
Many skeptics globally reject homeopathy on the basis
of a concern about one aspect in the preparation of its
medicines without understanding specifics of what the
manufacturing procedures or rest of the field encompasses
Simplistic dismissal of an entire field risks missing the
relevance of this traditional approach to nanomedicine
in terms of actual manufacturing procedures range of
medicine doses used in treatment and 200 years of clin-
ical experience Homeopathic dosing methods are unique
and potentially informative for developing safer methods
for administering nanomedicines to patients in general
At the same time understanding homeopathic medicines
as crudely-made natural nanomedicines can also help clar-
ify the documented variability of basic preclinical and
clinical research findings69
The impact of integrating information from nan-
otechnology with homeopathy should lead to improved
consistency of data going forward The most controver-
sial principle of homeopathic medicine is the assertion
that serial dilutions of the bulk form of a natural prod-
uct to concentrations that are the reciprocal of Avogadrorsquos
number (110)minus23 nonetheless leave an active agent Until
the discovery of persistent source nanoparticles and silica
despite bulk form dilution53ndash55575960 there has been no
plausible physical mechanism to support such a claim
Homeopathic manufacturing methods are inherently
simple green and natural in their reagents with an
emphasis on mechanical attrition techniques andor plant
biosynthetic methods for generating nanoparticles in aque-
ous solutions at room temperature In nanotechnology it is
known that nanoparticles from mechanical attrition are pro-
duced by a top-down process using a mechanical device
generically described as a mill70ndash73 Notably extended peri-
ods of agitation by high energy ultrasonication of plant
starch in water alone can produce starch nanoparticles74
Samuel Hahnemann MD a physician-chemist and
founder of homeopathy originally designed his mechani-
cal techniques in the early 1800rsquos and refined them in his
writings until his death in 184375 His words (translated
from German) were75 ldquo This remarkable alterationin the properties of natural bodies is achieved throughmechanical action on their smallest particles by tritura-tion grinding in milk sugar and succussion agitation inethanol-distilled water solutions while these particles areseparated from one another by means of an interveningindifferent substance that is either dry or liquid rdquo
Thousands of different medicines each made with simi-
lar procedures from specific members of the plant mineral
and animal kingdoms contribute to the overall contempo-
rary homeopathic materia medica worldwide76ndash79 Homeo-
pathic manufacturing methods overlap crudely with those
of modern top-down nanoparticle mechanical attrition
manufacturing techniques and plant-based biosynthetic
bottom-up methods40627080 Plants are among the various
biological materials that can synthesize nanoparticles of
metals or silica from their precursors in solution However
neither homeopathic researchers nor commercial clinical
suppliers have usually provided the types of details neces-
sary to reliably replicate production of specific nanoparti-
cles of a given size shape distribution surface charge or
other properties relevant to their biological effects8182
Indeed homeopathic basic research reveals objectively-
measurable differences between verum medicines and
succussed controls8384 but variability of specific find-
ings from study to study85ndash88 UV-vis and Raman
spectroscopy8489 as well as thermoluminescence83 are
among the technologies that show differences between
verums and controls All three of these technologies are
also used to study properties of various modern manufac-
tured NPs90ndash92 Like nanoparticles93 at least three studies
on homeopathic medicines have shown aging effects of liq-
uid samples stored in glass619495 However aging status
of test solutions is rarely assessed or reported in homeo-
pathic studies
Variations in manufacturing methods and materials with
resultant variability of the test medicines could contribute
substantially to the situation of inconsistent research
findings96 Top down mechanical methods for NP produc-
tion are well-known to cause variable defects in the final
products7097 Homeopathic medicine research test mate-
rials are typically liquids which would be susceptible to
nonlinear NP aggregation processes that change their sur-
face chemistry reactivity98ndash101 On the other hand many
4024 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
commercial homeopathic clinical products are dried onto
lactose or lactose-sucrose pellets immediately after manu-
facturing a step that could stabilize and retain nanostruc-
tural integrity46102ndash106
Integrating modern nanoparticle manufacturing and
characterization methods107 and relevant bioassays108ndash110
could guide homeopathic manufacturers and researchers
to generate more reproducible products and experimental
findings Still some NP suspensions eg fullerene C60
NPs produced top-down by extended mixing in water and
sonication (agitation) can exhibit inherently uncontrolled
variability in batch-to-batch properties such as average par-
ticle sizes size distribution and ultraviolet visual spectro-
scopic patterns101 Mere dilution of fullerene C60 NPs can
also by itself introduce variability of colloidal properties
compared with a more concentrated parent suspension111
The fundamental steps for making all plant- and
most other natural source material derived homeopathic
medicines are
bull Preparation of an ethanolic herbal extract of the origi-
nal plant source or grinding and milling fresh raw plant or
mineral materials then added directly into ethanolic solu-
tions (manufacturers can differ on how homeopathic plant
medicines are prepared from raw materials)
bull For insoluble inorganic and organic source materials
such as metals and some mineral salts as well as cer-
tain plant and animal parts initial grinding and milling of
the natural raw source material in dry lactose for many
hours (termed ldquotriturationrdquo) Notably in nanotechnology
mechanical milling of lactose generates a variety of differ-
ent sized nanoparticles and nanocrystals of lactose itself112
Ball milling plant material for hours can generate silica
NPs71
bull Serial dilutions and multiple succussions per dilution
step (intense up and down agitation inside a glass con-
tainer) in liquid diluent typically ethanol-water or distilled
water
Common dilution ratios include 110 or 11001 part
source material to 9 parts diluent (X or D dose series) or
1 part source material to 99 parts diluent (C dose series)
Every insoluble source for a homeopathically-
prepared medicine begins by being ground up in lactose
for hours to make low potency dry dilutions (bulk mate-
rial diluted but not exceeding the reciprocal of Avogadrorsquos
number ie less than 24X or 12C potency)
Every dose of homeopathic medicines prepared past
the lowest dilutions is made by placing source material
into a glass container of ethanol-water solvent (typically
up to 90 vv ethanol but sometimes 0 20 43
or 70 ethanol) for making high potency dilutions (bulk
material diluted and exceeding the reciprocal of Avo-
gadrorsquos number ie higher than 24X or 12C potency) and
succussing (violently agitating) the flask or container 10
or more times after each ldquodilutionrdquo step53
From nanotechnology variations in ethanol con-
centration113ndash117 andor variations in dilution factors100111
can alter the resultant NP properties especially zeta poten-
tials and surface reactivity with other materials
Potentially parallel to the effects of multiple suc-
cussions in homeopathy a recent nanotechnology study
has shown that longer periods of ultrasound agitation of
plant starch granules in water can produce 30ndash100 nm sized
starch nanoparticles mechanically without any toxic chem-
ical treatment74 Longer periods of ultrasound agitation led
to progressively smaller sized starch NPs as small as 30 nm
after 90 minutes Notably increased numbers of succus-
sions can reportedly heighten the biological effects of a
given homeopathic medicine potency in an experimental
plant development model118
Moreover the extensive mechanical agitation of
liquid forms of the medicines (succussions) likely facil-
itates dispersion of any nanoparticle agglomerates or
aggregates that might form after initial production119
Homeopathic manufacturers may use manual pounding of
the glass container on a hard elastic surface vortexing or
sonication to perform their multiple agitations120
bull Final commercial products in ethanol-water solutions
are sprayed or poured and dried onto dry lactose (or
lactose-sucrose) pellets for ease of transport and dis-
pensing In homeopathic manufacturing only lactose and
sucrose are used Nanotechnologists have found that not
only lactose and sucrose but also fructose maltose glu-
cose and honey can all serve as biochemical reducing and
nanoparticle capping agents49121ndash124 as well as biological
carriers for nano-proteins105 and other NPs112
Modern homeopathic manufacturers each use variations
of the same original procedures and natural materials that
Hahnemann used However instead of manual mortar and
pestle grinding and agitation of subsequent ethanol-water
solutions within the glassware some homeopathic com-
panies utilize ball milling or similar methods to accom-
plish the grinding in lactose The methods for agitating the
ethanol-water solutions (succussions) also vary between
manufacturers Some perform manual succussions against
a hard elastic surface eg a book or even the palm of the
opposite hand Others have developed proprietary mechan-
ical arms to mimic the action of a human arm pounding the
glass container against a hard rubberized or elastic surface
with a relatively consistent arc and force Still others uti-
lize modern vortexing or sonication procedures to agitate
the solutions120125
For lower potencies manufacturers often use the Hah-
nemannian dilution method of removing one part of the
powder or solution from the previous triturated or suc-
cussed container placing it into a new container of 9 parts
or 99 parts either dry lactose (at the lowest potencies)
or ethanol-water solvent (for some low and all higher
potencies) For making higher potencies many manu-
facturers revert to the Korsakovian dilution method of
pouring off 9 parts (X potencies) or 99 parts (C poten-
cies) of the previously-succussed solution and repeatedly
J Nanosci Nanotechnol 15 4021ndash4038 2015 4025
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
refilling the same glass tube or container with fresh
solvent before resuming the next set of succussions
Thus certain lower homeopathic medicine potencies will
entail use of a new glass container for each prepara-
tion step whereas higher potencies often involve only a
single reused glass container for later preparation steps
Manufacturers may or may not specify their dilution
methods and materials for a given potency on their web-
sites Few commercial producers specify their glassware
sources despite its increasingly likely role in homeopathic
medicine production555759126127
The importance of these procedural details is that
at least 6 different laboratories have replicated evidence
for silica derivatives andor silicon in borosilicate or
soda lime glass-succussed but not plastic-succussed
liquid homeopathic medicines and succussed solvent
controls5557596189120128 Given recent evidence that spe-
cific glass materials from different manufacturers can
release different amounts of nanosilica and its precursors
into solution129 the sources sizes shapes and inner
surfaces of the glass containers themselves may con-
tribute indeterminate variables and variability to the
final products130 Any adsorption or binding of plant or
other nanomedicine source materials might adsorb to the
inside container walls andor coat some of the nanosil-
ica (or vice versa) in solution and modify the biological
effects106131ndash133 Silica NPs can also serve as carriers with
organosilanes as possible building blocks for synthetic
nanomaterials templated around the specific medicine
source65134ndash136 Rough versus smooth NP surfaces137 and
different shapes138ndash140 as well as particle defects and sur-
face charge variations may contribute another source of
variability to the homeopathically-manufactured materials
The ability of silica crystals and nanoparticles to stim-
ulate vigorous immune system adjuvant activation is
well-documented in the nanomedicine literature30141ndash143
Thus the presence of variable amounts of nanosilica
and silicon-based strtuctures could amplify biological
effects of even a small amount of source materials141
but in a correspondingly variable manner144 Ethanol
itself can dope nanosilica to change its optical fluores-
cence properties116 Silica and some metal NPs can also
self-assemble larger nanostructures from 3-dimensional
structural and electromagnetic information from epitaxial
templates such as viruses proteins DNA plant steroids
cells or calcium phosphate nanoparticles in solution with
the silica65134145ndash152 No homeopathic studies to date have
examined the inside walls of the succussed glass containers
as a silicate-rich adsorptive and adhesive area for source
nanoparticles133153 nanobubbles from succusions53 and
their possible release with agitation
All homeopathic medicine preparation occurs at room
temperature though the specific ambient temperature
may vary between manufacturers in terms of indoor
room air conditioning or heating Homeopathic pharma-
copoeia regulatory standards in various countries spec-
ify the medicine sources lactose and ethanol reagents
and preparation steps at room temperature although no
pharmacopoeias currently dictate in their documentation
any specific particle sizes or characterization methods for
the final products Unlike Hahnemann some contempo-
rary homeopathic manufacturers use container materials
such as polypropylene or polyethylene rather than glass in
which to succuss their products59120 materials likely to
generate different types of nanostructures154ndash157 Nanotech-
nology research has repeatedly documented the ability of
variations of manufacturing parameters such as solvent
type and concentration reducing and capping agents pH
temperature sonication force and duration to modify the
resultant nanoparticles made4874112ndash114158159 Seemingly
trivial differences such as lactose on the surface of silver
NPs for instance increases their rate of uptake into cancer
cells48
22 The Debate Over ldquoDilutionrdquo versus HomeopathicManufacturing Procedures
The debate over the validity of homeopathy as a clini-
cal treatment stems primarily from the serial dilution steps
during manufacturing The claim of skeptics is that for
high potencies that is serial bulk form ldquoultra-dilutionsrdquo
past the reciprocal of Avogadrorsquos number (6times 1023mdashie
24X or 12C potencies and higher) homeopathic medicines
could only serve as biologically inert placebos They
rarely address the facts that (a) homeopaths also use
low potencies that are not ultra-diluted or (b) the objec-
tive laboratory data using different technologies show that
homeopathic medicines at low and high potencies dif-
fer from control materials with unique physico-chemical
patterns838489160161 Animal plant and cell culture stud-
ies also show biological activity of low and high potency
homeopathic medicines69 There are many scientific lim-
itations to such a globally dismissive assumption that all
homeopathic medicines are merely biologically inert plain
solvent (Table I)
First the simplistic negative argument might be rel-
evant if homeopathic medicines were only bulk form
drugs andor prepared by simple dilution On the con-
trary the objective empirical evidence suggests that
both low and high potencies of homeopathically-
prepared metal (gold silver copper zinc tin plat-
inum) plant (Pulsatilla Belladonna Colchicum) and
conventional medicines (Phenazepam Panovir) contain
source nanoparticles1754ndash56 Quantities of source NPs
across different manufacturers and batches are variable
and low but nevertheless present54 Other investiga-
tors have also identified reproducible differences at the
nanoscale between homeopathically-prepared medicines
and homeopathically-prepared solvent controls60 Low
doses of NPs are biologically much more active than are
low doses of the ldquosamerdquo source material in bulk form2226
4026 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells
animals and human subjects including control groups
Homeopathic phytomedicine Biological effects
Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222
Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223
Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet
irradiation225
Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of
activation of the cellular interferon system226
6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227
Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to
that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231
Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232
Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional
anxiolytic drug buspirone in mice186 233
Anti-cancer effects of 2C potency on HeLa cells120
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected
mice234 235
Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
J Nanosci Nanotechnol 15 4021ndash4038 2015 4027
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Complement Alternat Med 2012 519031 (2012)2 B Zhang X Wang and S Li Evid Based Complement Alternat
Med 2013 456747 (2013)
3 K Chan D Shaw M S Simmonds C J Leon Q Xu A Lu
I Sutherland S Ignatova Y P Zhu R Verpoorte E M
Williamson and P Duez J Ethnopharmacol 140 469 (2012)4 C L Quave M Pardo-de-Santayana and A Pieroni Evid Based
Complement Alternat Med 2012 156846 (2012)5 X Li G Yang X Li Y Zhang J Yang J Chang X Sun
X Zhou Y Guo Y Xu J Liu and A Bensoussan PLoS One8 e60338 (2013)
6 J Li L Gu H Zhang T Liu D Tian M Zhou and S Zhou
Lab Invest 93 354 (2013)7 E M Williamson Phytomedicine 8 401 (2001)8 K Niemeyer I R Bell and M Koithan J Herbal Medicine 3 112
(2013)9 Z Li X Wu J Li L Yao L Sun Y Shi W Zhang J Lin
D Liang and Y Li Int J Nanomedicine 7 2389 (2012)10 W Tan Y Li M Chen and Y Wang Int J Nanomedicine 6 1773
(2011)11 H B Nair B Sung V R Yadav R Kannappan M M Chaturvedi
and B B Aggarwal Biochem Pharmacol 80 1833 (2010)12 S Huang S J Chang M Yang J J Chen and W H Chang Int
J Nanomedicine 6 1365 (2011)13 R Mauludin R H Muller and C M Keck Int J Pharm 370 202
(2009)14 R Mauludin R H Muller and C M Keck Eur J Pharm Sci
36 502 (2009)15 A R Khuda-Bukhsh S S Bhattacharyya S Paul and
N Boujedaini Zhong Xi Yi Jie He Xue Bao 8 853 (2010)16 N Ahmad S Sharma M K Alam V N Singh S F Shamsi
B R Mehta and A Fatma Colloids Surf B Biointerfaces 81 81
(2010)17 R Barve and R Chaughule Journal of Nanostructure in Chemistry
3 18 (2013)18 C Buzea I I Pacheco and K Robbie Biointerphases 2 MR17
(2007)19 Y M Tsai C F Chien L C Lin and T H Tsai Int J Pharm
416 331 (2011)20 D J Prakash S Arulkumar and M Sabesan Pharmacognosy Res
2 330 (2010)21 S S Bhattacharyya S Paul and A R Khuda-Bukhsh Exp Biol
Med Maywood 235 678 (2010)22 A L Armstead and B Li Int J Nanomedicine 6 3281 (2011)23 M Diwan P Elamanchili M Cao and J Samuel Curr Drug
Deliv 1 405 (2004)24 Y S Chun S Bisht V Chenna D Pramanik T Yoshida S M
Hong R F de Wilde Z Zhang D L Huso M Zhao M A
Rudek V Stearns A Maitra and S Sukumar Carcinogenesis33 2242 (2012)
25 Z Ahmad and G K Khuller Expert Opin Drug Deliv 5 1323(2008)
26 A C Shirali M Look W Du E Kassis H W Stout-Delgado
T M Fahmy and D R Goldstein American Journal of Transplan-tation Official Journal of the American Society of Transplantationand the American Society of Transplant Surgeons 11 2582 (2011)
27 W Zhang Z Zhang and Y Zhang Nanoscale Res Lett 6 555(2011)
28 I H El-Sayed Curr Oncol Rep 12 121 (2010)29 K J Lim S Bisht E E Bar A Maitra and C G Eberhart
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4034 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
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1st Homeopathic Research Institute International HomeopathyResearch Conference Cutting Edge Research in HomeopathyBarcelona Spain (2013)
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Macromol Biosci 12 1459 (2012)138 V Biju T Itoh A Anas A Sujith and M Ishikawa Anal Bioanal
Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and
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J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
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Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
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Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
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Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
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5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
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Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
CONTENTS1 Introduction 4022
2 Homeopathic Manufacturing Procedures for
Natural Nanomedicines 4024
21 Overview of Traditional Homeopathic
Medicine Manufacturing 4024
22 The Debate Over ldquoDilutionrdquo versus Homeopathic
Manufacturing Procedures 4026
3 Pulsed Dosing and Nonlinear Dose-Responses 4031
31 Dosing Homeopathic Nanoparticles 4031
32 Nonlinear Dose-Response Mechanisms 4032
4 Conclusions 4033
Acknowledgment 4034
References and Notes 4034
1 INTRODUCTIONThe purpose of the present paper is to (a) summarize evi-
dence for the nanoparticle nature and biological effects of
traditional homeopathically-prepared medicines at low and
ultralow doses (b) provide details of historically-based
homeopathic manufacturing materials and methods relat-
ing them to top-down mechanical attrition doping and
templating of nanosilica and plant-based biosynthetic pro-
cesses in modern nanotechnology (c) outline the potential
roles of nonlinear dose-responses of hormesis stochastic
resonance and nonlinear dynamical interactions with com-
plex adaptive systems in generating endogenous amplifi-
cation processes during low dose treatment
Many cultures worldwide have relied on bulk form
plant-based natural medicines for hundreds to thousands
of years for treating acute and chronic health problems
Traditional Chinese medicine Ayurvedic medicine and
Western herbalism are all examples of highly-developed
historical approaches to natural product-based treatment
for conditions ranging from infections to cancers1ndash6
Herbalists argue for use of the whole plant or traditionally-
used intact plant parts (eg roots stem bark leaves)
rather than chemically-isolated individual nutraceutical
ingredients in order to obtain gentler and synergistic
effects of multiple natural constituents7 interacting with
the individual as an integrated complex adaptive system8
However as modern researchers have taken a closer
look at the strengths and limitations of traditional phy-
tomedicines they often identify poor absorption lower
bioavailability and limited patient tolerability as barri-
ers to more widespread adoption of herbs for clinical
care
Nanotechnologists are currently beginning to exploit the
ability of nanoparticulate (NP) forms of traditional botan-
ical agents to dramatically improve absorption bioavail-
ability and reduce side effects9ndash17 Because of their tiny
size (eg a log unit smaller than the wavelength of vis-
ible light) many NPs can readily cross cell membranes
including blood-brain barrier1819 The therapeutic dose
ranges for nanoscale forms of many agents are lower by
orders of magnitude compared with their respective bulk
forms20ndash26 Modern NPs offer additional therapeutic advan-
tages over bulk forms such as better intracellular access22
and targeting of cancerous cells while sparing healthy cells
in the organism27ndash32 Nanoparticles made from botanical
and nutraceutical agents have particularly low toxicity and
favorable side effect profiles1633ndash35
At the same time translation from bench to bedside has
been slow36 Concerns about uncertain toxicity profiles of
manufactured NPs persist37 Plants and fungi are among
the natural products used to biosynthesize potentially safer
forms of certain NPs eg silver or gold38ndash42 Plant biosyn-
thesis helps avoid toxic reagents during green manufac-
turing of nanomedicines43 Similarly reducing and coating
the surface of otherwise more toxic NPs with benign sug-
ars such as lactose sucrose maltose or glucose appears
to attenuate toxicity for nanomedicine use44ndash46 This strat-
egy is important because of the ability of nanoparticles
to adsorb onto other materials involved in their produc-
tion given their highly reactive surfaces NP adsorbants
such as plants or sugars can not only modify the sur-
face charge and physicochemical properties of the resultant
NPs but also enhance the beneficial biological effects of
the nanoscale agent4047ndash49 Still widespread clinical appli-
cation of plant-synthesized NPs and nanophytomedicines
does not appear imminent Many practical and regulatory
hurdles lie ahead
Nanophytomedicines might otherwise appear to be new
and relatively untested forms of treatment However inves-
tigators have begun to identify specific nanoscale materials
in certain Chinese herbs5051 and Ayurvedic medicines52
In addition recent studies have demonstrated that the his-
torical manufacturing procedures for making homeopathic
medicines another traditional system of natural medicine
also generate polydisperse source nanoparticles of differ-
ent sizes from quantum dot (1ndash10 nm) to larger nanoscale
structures (Fig 1) Convergent evidence indicates that
homeopathic manufacturing methods mechanically gener-
ate top-down nanoscale particles of the original source
material1753ndash56 as well as silicasilicon from the inside
walls of the glass containers5557ndash61 Previous nanoscience
research suggests that interactions of homeopathic plant
mother tinctures with silica precursors and silicon-derived
materials in solution might also generate plant-modified
(coated doped or imprinted) andor plant self-assembled
silica NPs404362ndash65
The unique green top-down and bottom-up biosynthetic
manufacturing and pulsed low dosing methods of homeo-
pathic medicine combined with the large pharmacopoeias
for hundreds of natural medicines and already established
regulatory standards for these agents provide a possi-
ble foundation for accelerating progress in translational
nanophytomedicine Homeopaths have had over 200 years
of real-world experience and an estimated more than
500 million patients worldwide66 in the safe and effective
use of thousands of their nanoscale natural products ie
homeopathic medicines6768111ndash113117
4022 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Iris R Bell received her AB in Biology from Harvard University and completed her
PhD in Neuro- and Biobehavioral Sciences and MD (Medicine) from Stanford Univer-
sity She is Professor Emeritus in the Department of Family and Community Medicine at
the University of Arizona College of Medicine and Research Professor at the University of
Arizona College of Nursing Her main research interests supported by both National Insti-
tutes of health (NIH) and private foundation grants have focused on nonlinear complex
adaptive systems psychophysiological processes and basic science of complementary and
alternative medicine interventions in chronic disease She has more than 140 publications
and 30 book chapters Most recently she received competitive grant support to examine
the nanoparticle nature of classical homeopathic medicines and related natural products in
the treatment of cancer
Barbara Sarter is currently Professor in the School of Naturopathic Medicine at Bastyr
University California Previously she was Associate Professor at the University of South-
ern California Keck School of Medicine Dr Sarter organized the International Research
Consortium on the Banerji Protocols which is attempting to advance research on the
nano pharmacological approach using natural substances that is practiced at the PBH
Research Foundation in Kolkata India Her research background includes studies on nutri-
tional approaches for health promotion and natural substances for cancer treatment and
prevention
Leanna J Standish received her PhD in NeuroscienceBiopsychology from the Univer-
sity of Massachusetts and her ND (Naturopathic Medicine) from Bastyr University Dr
Standish is Research Professor for the School of Naturopathic Medicine at Bastyr Clinical
Professor for the School of Public Health at the University of Washington and Affili-
ate Research Professor in the University of Washingtonrsquos School of Medicinersquos radiology
department She is Board-certified in naturopathic oncology Dr Standish has also been
the medical director of the Bastyr Integrative Oncology Research Center (BIORC) and
a clinical research professor at the Bastyr University Research Institute She has served
as principal investigator on several National Institutes of Health (NIH) research grants
since 1994 Currently her research is focused on the Asian medicinal mushroom Tram-
etes versicolor in the treatment of breast and prostate cancer functional brain imaging in
the treatment of brain cancer and the development of integrative oncology outcomes studies New projects using IV
Resveratrol and IV Curcumin to treat cancer are being developed
Prasanta Banerji is Founder and Managing Trustee of the PBH Research Foundation
Fellow of the Mihijam Institute of Homeopathy and well known for establishing the
Banerji Protocols of treatment using Homeopathic Medicines internationally Research
areas include the treatment of every type of cancer and other serious illnesses which have
ensured replicability and helped produce vast amounts of data for meaningful research
which in turn has led to the acceptance at the Best Case Series program of the National
Cancer Institute (NCI) of USA He has been disseminating the protocols by lectures and
teaching seminars and has a number of published papers book chapters and books on the
subject
Pratip Banerji is Co-founder and Dy Managing Trustee of the Dr Prasanta Banerji
Homoeopathic Research Foundation (PBHRF) a consultant physician since 1991 with a
Bachelors Degree-BHMS from the Calcutta University He is also a Doctor of Medicine
MD(Hom) from the JRN Rajasthan Vidyapeeth (Deemed University) Udaipur in India
has played an important role in conducting research on the efficacy of treatment under the
Banerji Protocols The process of data accrual and documentation according to the highest
international standards was introduced by him This has made their research acceptable to
the international scientific community He has been disseminating the protocols by lectures
and teaching seminars and has a number of published papers book chapters and books on
the subject
J Nanosci Nanotechnol 15 4021ndash4038 2015 4023
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 1 Polydisperse size distribution of zinc metal nanoparticles of
homeopathically-prepared Zincum metallicum at 30C and 200C potencies
from two different manufacturers (SBL and WSI) Reprinted with per-
mission from [54] P S Chikramane et al Homeopathy 99 231 (2010)copy 2010 Churchill Livingstone
2 HOMEOPATHIC MANUFACTURINGPROCEDURES FOR NATURALNANOMEDICINES
21 Overview of Traditional Homeopathic MedicineManufacturing
Many skeptics globally reject homeopathy on the basis
of a concern about one aspect in the preparation of its
medicines without understanding specifics of what the
manufacturing procedures or rest of the field encompasses
Simplistic dismissal of an entire field risks missing the
relevance of this traditional approach to nanomedicine
in terms of actual manufacturing procedures range of
medicine doses used in treatment and 200 years of clin-
ical experience Homeopathic dosing methods are unique
and potentially informative for developing safer methods
for administering nanomedicines to patients in general
At the same time understanding homeopathic medicines
as crudely-made natural nanomedicines can also help clar-
ify the documented variability of basic preclinical and
clinical research findings69
The impact of integrating information from nan-
otechnology with homeopathy should lead to improved
consistency of data going forward The most controver-
sial principle of homeopathic medicine is the assertion
that serial dilutions of the bulk form of a natural prod-
uct to concentrations that are the reciprocal of Avogadrorsquos
number (110)minus23 nonetheless leave an active agent Until
the discovery of persistent source nanoparticles and silica
despite bulk form dilution53ndash55575960 there has been no
plausible physical mechanism to support such a claim
Homeopathic manufacturing methods are inherently
simple green and natural in their reagents with an
emphasis on mechanical attrition techniques andor plant
biosynthetic methods for generating nanoparticles in aque-
ous solutions at room temperature In nanotechnology it is
known that nanoparticles from mechanical attrition are pro-
duced by a top-down process using a mechanical device
generically described as a mill70ndash73 Notably extended peri-
ods of agitation by high energy ultrasonication of plant
starch in water alone can produce starch nanoparticles74
Samuel Hahnemann MD a physician-chemist and
founder of homeopathy originally designed his mechani-
cal techniques in the early 1800rsquos and refined them in his
writings until his death in 184375 His words (translated
from German) were75 ldquo This remarkable alterationin the properties of natural bodies is achieved throughmechanical action on their smallest particles by tritura-tion grinding in milk sugar and succussion agitation inethanol-distilled water solutions while these particles areseparated from one another by means of an interveningindifferent substance that is either dry or liquid rdquo
Thousands of different medicines each made with simi-
lar procedures from specific members of the plant mineral
and animal kingdoms contribute to the overall contempo-
rary homeopathic materia medica worldwide76ndash79 Homeo-
pathic manufacturing methods overlap crudely with those
of modern top-down nanoparticle mechanical attrition
manufacturing techniques and plant-based biosynthetic
bottom-up methods40627080 Plants are among the various
biological materials that can synthesize nanoparticles of
metals or silica from their precursors in solution However
neither homeopathic researchers nor commercial clinical
suppliers have usually provided the types of details neces-
sary to reliably replicate production of specific nanoparti-
cles of a given size shape distribution surface charge or
other properties relevant to their biological effects8182
Indeed homeopathic basic research reveals objectively-
measurable differences between verum medicines and
succussed controls8384 but variability of specific find-
ings from study to study85ndash88 UV-vis and Raman
spectroscopy8489 as well as thermoluminescence83 are
among the technologies that show differences between
verums and controls All three of these technologies are
also used to study properties of various modern manufac-
tured NPs90ndash92 Like nanoparticles93 at least three studies
on homeopathic medicines have shown aging effects of liq-
uid samples stored in glass619495 However aging status
of test solutions is rarely assessed or reported in homeo-
pathic studies
Variations in manufacturing methods and materials with
resultant variability of the test medicines could contribute
substantially to the situation of inconsistent research
findings96 Top down mechanical methods for NP produc-
tion are well-known to cause variable defects in the final
products7097 Homeopathic medicine research test mate-
rials are typically liquids which would be susceptible to
nonlinear NP aggregation processes that change their sur-
face chemistry reactivity98ndash101 On the other hand many
4024 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
commercial homeopathic clinical products are dried onto
lactose or lactose-sucrose pellets immediately after manu-
facturing a step that could stabilize and retain nanostruc-
tural integrity46102ndash106
Integrating modern nanoparticle manufacturing and
characterization methods107 and relevant bioassays108ndash110
could guide homeopathic manufacturers and researchers
to generate more reproducible products and experimental
findings Still some NP suspensions eg fullerene C60
NPs produced top-down by extended mixing in water and
sonication (agitation) can exhibit inherently uncontrolled
variability in batch-to-batch properties such as average par-
ticle sizes size distribution and ultraviolet visual spectro-
scopic patterns101 Mere dilution of fullerene C60 NPs can
also by itself introduce variability of colloidal properties
compared with a more concentrated parent suspension111
The fundamental steps for making all plant- and
most other natural source material derived homeopathic
medicines are
bull Preparation of an ethanolic herbal extract of the origi-
nal plant source or grinding and milling fresh raw plant or
mineral materials then added directly into ethanolic solu-
tions (manufacturers can differ on how homeopathic plant
medicines are prepared from raw materials)
bull For insoluble inorganic and organic source materials
such as metals and some mineral salts as well as cer-
tain plant and animal parts initial grinding and milling of
the natural raw source material in dry lactose for many
hours (termed ldquotriturationrdquo) Notably in nanotechnology
mechanical milling of lactose generates a variety of differ-
ent sized nanoparticles and nanocrystals of lactose itself112
Ball milling plant material for hours can generate silica
NPs71
bull Serial dilutions and multiple succussions per dilution
step (intense up and down agitation inside a glass con-
tainer) in liquid diluent typically ethanol-water or distilled
water
Common dilution ratios include 110 or 11001 part
source material to 9 parts diluent (X or D dose series) or
1 part source material to 99 parts diluent (C dose series)
Every insoluble source for a homeopathically-
prepared medicine begins by being ground up in lactose
for hours to make low potency dry dilutions (bulk mate-
rial diluted but not exceeding the reciprocal of Avogadrorsquos
number ie less than 24X or 12C potency)
Every dose of homeopathic medicines prepared past
the lowest dilutions is made by placing source material
into a glass container of ethanol-water solvent (typically
up to 90 vv ethanol but sometimes 0 20 43
or 70 ethanol) for making high potency dilutions (bulk
material diluted and exceeding the reciprocal of Avo-
gadrorsquos number ie higher than 24X or 12C potency) and
succussing (violently agitating) the flask or container 10
or more times after each ldquodilutionrdquo step53
From nanotechnology variations in ethanol con-
centration113ndash117 andor variations in dilution factors100111
can alter the resultant NP properties especially zeta poten-
tials and surface reactivity with other materials
Potentially parallel to the effects of multiple suc-
cussions in homeopathy a recent nanotechnology study
has shown that longer periods of ultrasound agitation of
plant starch granules in water can produce 30ndash100 nm sized
starch nanoparticles mechanically without any toxic chem-
ical treatment74 Longer periods of ultrasound agitation led
to progressively smaller sized starch NPs as small as 30 nm
after 90 minutes Notably increased numbers of succus-
sions can reportedly heighten the biological effects of a
given homeopathic medicine potency in an experimental
plant development model118
Moreover the extensive mechanical agitation of
liquid forms of the medicines (succussions) likely facil-
itates dispersion of any nanoparticle agglomerates or
aggregates that might form after initial production119
Homeopathic manufacturers may use manual pounding of
the glass container on a hard elastic surface vortexing or
sonication to perform their multiple agitations120
bull Final commercial products in ethanol-water solutions
are sprayed or poured and dried onto dry lactose (or
lactose-sucrose) pellets for ease of transport and dis-
pensing In homeopathic manufacturing only lactose and
sucrose are used Nanotechnologists have found that not
only lactose and sucrose but also fructose maltose glu-
cose and honey can all serve as biochemical reducing and
nanoparticle capping agents49121ndash124 as well as biological
carriers for nano-proteins105 and other NPs112
Modern homeopathic manufacturers each use variations
of the same original procedures and natural materials that
Hahnemann used However instead of manual mortar and
pestle grinding and agitation of subsequent ethanol-water
solutions within the glassware some homeopathic com-
panies utilize ball milling or similar methods to accom-
plish the grinding in lactose The methods for agitating the
ethanol-water solutions (succussions) also vary between
manufacturers Some perform manual succussions against
a hard elastic surface eg a book or even the palm of the
opposite hand Others have developed proprietary mechan-
ical arms to mimic the action of a human arm pounding the
glass container against a hard rubberized or elastic surface
with a relatively consistent arc and force Still others uti-
lize modern vortexing or sonication procedures to agitate
the solutions120125
For lower potencies manufacturers often use the Hah-
nemannian dilution method of removing one part of the
powder or solution from the previous triturated or suc-
cussed container placing it into a new container of 9 parts
or 99 parts either dry lactose (at the lowest potencies)
or ethanol-water solvent (for some low and all higher
potencies) For making higher potencies many manu-
facturers revert to the Korsakovian dilution method of
pouring off 9 parts (X potencies) or 99 parts (C poten-
cies) of the previously-succussed solution and repeatedly
J Nanosci Nanotechnol 15 4021ndash4038 2015 4025
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
refilling the same glass tube or container with fresh
solvent before resuming the next set of succussions
Thus certain lower homeopathic medicine potencies will
entail use of a new glass container for each prepara-
tion step whereas higher potencies often involve only a
single reused glass container for later preparation steps
Manufacturers may or may not specify their dilution
methods and materials for a given potency on their web-
sites Few commercial producers specify their glassware
sources despite its increasingly likely role in homeopathic
medicine production555759126127
The importance of these procedural details is that
at least 6 different laboratories have replicated evidence
for silica derivatives andor silicon in borosilicate or
soda lime glass-succussed but not plastic-succussed
liquid homeopathic medicines and succussed solvent
controls5557596189120128 Given recent evidence that spe-
cific glass materials from different manufacturers can
release different amounts of nanosilica and its precursors
into solution129 the sources sizes shapes and inner
surfaces of the glass containers themselves may con-
tribute indeterminate variables and variability to the
final products130 Any adsorption or binding of plant or
other nanomedicine source materials might adsorb to the
inside container walls andor coat some of the nanosil-
ica (or vice versa) in solution and modify the biological
effects106131ndash133 Silica NPs can also serve as carriers with
organosilanes as possible building blocks for synthetic
nanomaterials templated around the specific medicine
source65134ndash136 Rough versus smooth NP surfaces137 and
different shapes138ndash140 as well as particle defects and sur-
face charge variations may contribute another source of
variability to the homeopathically-manufactured materials
The ability of silica crystals and nanoparticles to stim-
ulate vigorous immune system adjuvant activation is
well-documented in the nanomedicine literature30141ndash143
Thus the presence of variable amounts of nanosilica
and silicon-based strtuctures could amplify biological
effects of even a small amount of source materials141
but in a correspondingly variable manner144 Ethanol
itself can dope nanosilica to change its optical fluores-
cence properties116 Silica and some metal NPs can also
self-assemble larger nanostructures from 3-dimensional
structural and electromagnetic information from epitaxial
templates such as viruses proteins DNA plant steroids
cells or calcium phosphate nanoparticles in solution with
the silica65134145ndash152 No homeopathic studies to date have
examined the inside walls of the succussed glass containers
as a silicate-rich adsorptive and adhesive area for source
nanoparticles133153 nanobubbles from succusions53 and
their possible release with agitation
All homeopathic medicine preparation occurs at room
temperature though the specific ambient temperature
may vary between manufacturers in terms of indoor
room air conditioning or heating Homeopathic pharma-
copoeia regulatory standards in various countries spec-
ify the medicine sources lactose and ethanol reagents
and preparation steps at room temperature although no
pharmacopoeias currently dictate in their documentation
any specific particle sizes or characterization methods for
the final products Unlike Hahnemann some contempo-
rary homeopathic manufacturers use container materials
such as polypropylene or polyethylene rather than glass in
which to succuss their products59120 materials likely to
generate different types of nanostructures154ndash157 Nanotech-
nology research has repeatedly documented the ability of
variations of manufacturing parameters such as solvent
type and concentration reducing and capping agents pH
temperature sonication force and duration to modify the
resultant nanoparticles made4874112ndash114158159 Seemingly
trivial differences such as lactose on the surface of silver
NPs for instance increases their rate of uptake into cancer
cells48
22 The Debate Over ldquoDilutionrdquo versus HomeopathicManufacturing Procedures
The debate over the validity of homeopathy as a clini-
cal treatment stems primarily from the serial dilution steps
during manufacturing The claim of skeptics is that for
high potencies that is serial bulk form ldquoultra-dilutionsrdquo
past the reciprocal of Avogadrorsquos number (6times 1023mdashie
24X or 12C potencies and higher) homeopathic medicines
could only serve as biologically inert placebos They
rarely address the facts that (a) homeopaths also use
low potencies that are not ultra-diluted or (b) the objec-
tive laboratory data using different technologies show that
homeopathic medicines at low and high potencies dif-
fer from control materials with unique physico-chemical
patterns838489160161 Animal plant and cell culture stud-
ies also show biological activity of low and high potency
homeopathic medicines69 There are many scientific lim-
itations to such a globally dismissive assumption that all
homeopathic medicines are merely biologically inert plain
solvent (Table I)
First the simplistic negative argument might be rel-
evant if homeopathic medicines were only bulk form
drugs andor prepared by simple dilution On the con-
trary the objective empirical evidence suggests that
both low and high potencies of homeopathically-
prepared metal (gold silver copper zinc tin plat-
inum) plant (Pulsatilla Belladonna Colchicum) and
conventional medicines (Phenazepam Panovir) contain
source nanoparticles1754ndash56 Quantities of source NPs
across different manufacturers and batches are variable
and low but nevertheless present54 Other investiga-
tors have also identified reproducible differences at the
nanoscale between homeopathically-prepared medicines
and homeopathically-prepared solvent controls60 Low
doses of NPs are biologically much more active than are
low doses of the ldquosamerdquo source material in bulk form2226
4026 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells
animals and human subjects including control groups
Homeopathic phytomedicine Biological effects
Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222
Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223
Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet
irradiation225
Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of
activation of the cellular interferon system226
6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227
Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to
that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231
Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232
Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional
anxiolytic drug buspirone in mice186 233
Anti-cancer effects of 2C potency on HeLa cells120
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected
mice234 235
Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
J Nanosci Nanotechnol 15 4021ndash4038 2015 4027
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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Homeopathy Hahnemann Clinic Publishing Grass Valley CA
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K Linde R Ludtke F Musial R van Wijk C Witt
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323 67 (2003)84 M Rao R Roy and I R Bell Materials Letters 62 1487 (2008)85 S Baumgartner The state of basic research on homeopathy
New Directions in Homeopathy Research edited by C Witt and
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and U Wolf ScientificWorldJournal 10 49 (2010)96 D Nani M Brizzi L Lazzarato and L Betti Forsch Komple-
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Properties and Applications 2nd ed World Scientific New Jersey
(2011)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4035
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
98 H L Xin and H Zheng Nano Lett 12 1470 (2012)99 G E Batley J K Kirby and M J McLaughlin Acc Chem Res
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(2011)101 X Chang and P J Vikesland Langmuir 29 9685 (2013)102 M Fatnassi C Tourne-Peteilh T Mineva J M Devoisselle
P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
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AAPS Pharm Sci Tech 11 959 (2010)105 M A Tavares Cardoso M Talebi P A Soares C U Yurteri and
J R van Ommen Int J Pharmaceutics 414 1 (2011)106 Y Chaikin O Kedem J Raz A Vaskevich and I Rubinstein
Anal Chem (2013)107 N C Bell C Minelli J Tompkins M M Stevens and A G
Shard Langmuir 28 10860 (2012)108 A E James and J D Driskell Analyst (2013)109 C D Walkey and W C Chan Chem Soc Rev 41 2780 (2012)110 X Chang L K Duncan J Jinschek and P J Vikesland Langmuir
28 7622 (2012)111 X Chang and P J Vikesland Environ Pollut 181C 51 (2013)112 V Caron J F Willart R Lefort P Derollez F Danede and
M Descamps Carbohydr Res 346 2622 (2011)113 A R Abbasi and A Morsali Ultrason Sonochem 19 540 (2012)114 J W Yoo D S Yun and H J Kim J Nanosci Nanotechnol
6 3343 (2006)115 K R Moonoosawmy and P Kruse J Am Chem Soc 132 1572
(2010)116 Y Yang A L Yang R Q Yang G J Yuan and Y L Shi J
Nanosci Nanotechnol 11 9717 (2011)117 X Li O Niitsoo and A Couzis J Colloid Interface Sci 394 26
(2013)118 L Betti G Trebbi O Kokornaczyk D Nani M Peruzzi and
M Brizzi Int J High Dilution Res 12 127 (2013)119 C Tang T Zhou J Yang Q Zhang F Chen Q Fu and L Yang
Colloids Surf B Biointerfaces 86 189 (2011)120 S S Bhattacharyya S K Mandal R Biswas S Paul S Pathak
N Boujedaini P Belon and A R Khuda-Bukhsh Exp Biol MedMaywood 233 1591 (2008)
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Perez Trends Biotechnol 31 240 (2013)122 K K Katti V Kattumuri S Bhaskaran K V Katti and
R Kannan International Journal of Green NanotechnologyBiomedicine 1 B53 (2009)
123 V Snitka D O Naumenko L Ramanauskaite S A Kravchenko
and B A Snopok J Colloid Interface Sci 386 99 (2012)124 C Zhu S Guo Y Fang and S Dong ACS Nano 4 2429 (2010)125 J L Demangeat P Gries B Poitevin J J Droesbeke T M Zahaf
F C Pierart and R N Miller Appl Magn Reson 26 465 (2004)126 S Cartwright Pyridinium-N-phenolates as molecular probes
of serially diluted and agitated solutions Preliminary results
1st Homeopathic Research Institute International HomeopathyResearch Conference Cutting Edge Research in HomeopathyBarcelona Spain (2013)
127 D J Anick and J A Ives Homeopathy 96 189 (2007)128 C Witt R Ludtke T E Weisshuhn and S N Willich Forschende
Komplementarmedizinund Klassische Naturheilkunde 12 6 (2005)129 L Liu T W Randolph and J F Carpenter J Pharm Sci
101 2952 (2012)130 Y Shimotsuma M Sakakura K Miura J Qiu P G Kazansky
K Fujita and K Hirao J Nanosci Nanotechnol 7 94 (2007)131 C G Pack M R Song E J Lee M Hiroshima K H Byun
J S Kim and Y Sako J Control Release (2012)132 T K Barik B Sahu and V Swain Parasitol Res 103 253 (2008)
133 S Kiel O Grinberg N Perkas J Charmet H Kepner and
A Gedanken Beilstein J Nanotechnol 3 267 (2012)134 A Cumbo B Lorber P F Corvini W Meier and P Shahgaldian
Nat Commun 4 1503 (2013)135 H K Baca E C Carnes C E Ashley D M Lopez C Douthit
S Karlin and C J Brinker Biochim Biophys Acta 1810 259
(2011)136 R Zhu W Zhao M Zhai F Wei Z Cai N Sheng and Q Hu
Anal Chim Acta 658 209 (2010)137 A Schrade V Mailander S Ritz K Landfester and U Ziener
Macromol Biosci 12 1459 (2012)138 V Biju T Itoh A Anas A Sujith and M Ishikawa Anal Bioanal
Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and
M Sharon Colloids Surf B Biointerfaces 109 25 (2013)140 D Menon A Basanth A Retnakumari K Manzoor and S V
Nair J Biomed Nanotechnol 8 901 (2012)141 T Wang H Jiang Q Zhao S Wang M Zou and G Cheng Int
J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
I Forster Nanotoxicology 5 326 (2011)143 D Mahony A S Cavallaro F Stahr T J Mahony S Z Qiao
and N Mitter Small 9 3138 (2013)144 W J Sandberg M Lag J A Holme B Friede M Gualtieri
M Kruszewski P E Schwarze T Skuland and M Refsnes PartFibre Toxicol 9 32 (2012)
145 B Kaehr J L Townson R M Kalinich Y H Awad B S
Swartzentruber D R Dunphy and C J Brinker Proc Natl AcadSci USA 109 17336 (2012)
146 H K Baca E Carnes S Singh C Ashley D Lopez and C J
Brinker Acc Chem Res 40 836 (2007)147 X Li J Zhang and H Gu Langmuir 28 2827 (2012)148 D C Wang G Y Chen K Y Chen and C H Tsai IET
Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
Stat Nonlin Soft Matter Phys 84 061705 (2011)150 C Groger K Lutz and E Brunner Cell Biochem Biophys 50 23
(2008)151 P A Williamson P J Blower and M A Green Chem Commun
Camb 47 1568 (2011)152 Y Park S Kim J Moon J C Lee and Y Kim J Nanosci
Nanotechnol 12 1444 (2012)153 J M Almeida L De Boni W Avansi C Ribeiro E Longo A C
Hernandes and C R Mendonca Opt Express 20 15106 (2012)154 A Pawlak Colloid and Polymer Science 291 773 (2013)155 H Duran M Steinhart H J Butt and G Floudas Nano Lett
11 1671 (2011)156 S Jain H Goossens M van Duin and P Lemstra Polymer
46 8805 (2005)157 R A Roberts T Shen I C Allen W Hasan J M DeSimone
and J P Ting PLoS One 8 e62115 (2013)158 B Ruan and M Jacobi Nanoscale Research Letters 7 127 (2012)159 T A Hassan V K Rangari R K Rana and S Jeelani Ultrason
Sonochem 20 1308 (2013)160 V Elia and M Niccoli Annals of the New York Academy of Sci-
ences 879 241 (1999)161 K Lenger R P Bajpai and M Spielmann Cell Biochem Biophys
(2013)162 C E McNamee and K Higashitani Langmuir 29 5013 (2013)163 E Taran Y Kanda I U Vakarelski and K Higashitani J Colloid
Interface Sci 307 425 (2007)164 J Lim K Hippalgaonkar S C Andrews A Majumdar and
P Yang Nano Lett 12 2475 (2012)165 L Montagnier J Aissa S Ferris J-L Montagnier and C Lavallee
Interdisciplinary Sci Comput Life Sci 1 81 (2009)166 P Bellavite P Magnani E Zanolin and A Conforti Evid Based
Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
ogy 89 338 (1986)184 Z Ahmad R Pandey S Sharma and G K Khuller Indian J
Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Iris R Bell received her AB in Biology from Harvard University and completed her
PhD in Neuro- and Biobehavioral Sciences and MD (Medicine) from Stanford Univer-
sity She is Professor Emeritus in the Department of Family and Community Medicine at
the University of Arizona College of Medicine and Research Professor at the University of
Arizona College of Nursing Her main research interests supported by both National Insti-
tutes of health (NIH) and private foundation grants have focused on nonlinear complex
adaptive systems psychophysiological processes and basic science of complementary and
alternative medicine interventions in chronic disease She has more than 140 publications
and 30 book chapters Most recently she received competitive grant support to examine
the nanoparticle nature of classical homeopathic medicines and related natural products in
the treatment of cancer
Barbara Sarter is currently Professor in the School of Naturopathic Medicine at Bastyr
University California Previously she was Associate Professor at the University of South-
ern California Keck School of Medicine Dr Sarter organized the International Research
Consortium on the Banerji Protocols which is attempting to advance research on the
nano pharmacological approach using natural substances that is practiced at the PBH
Research Foundation in Kolkata India Her research background includes studies on nutri-
tional approaches for health promotion and natural substances for cancer treatment and
prevention
Leanna J Standish received her PhD in NeuroscienceBiopsychology from the Univer-
sity of Massachusetts and her ND (Naturopathic Medicine) from Bastyr University Dr
Standish is Research Professor for the School of Naturopathic Medicine at Bastyr Clinical
Professor for the School of Public Health at the University of Washington and Affili-
ate Research Professor in the University of Washingtonrsquos School of Medicinersquos radiology
department She is Board-certified in naturopathic oncology Dr Standish has also been
the medical director of the Bastyr Integrative Oncology Research Center (BIORC) and
a clinical research professor at the Bastyr University Research Institute She has served
as principal investigator on several National Institutes of Health (NIH) research grants
since 1994 Currently her research is focused on the Asian medicinal mushroom Tram-
etes versicolor in the treatment of breast and prostate cancer functional brain imaging in
the treatment of brain cancer and the development of integrative oncology outcomes studies New projects using IV
Resveratrol and IV Curcumin to treat cancer are being developed
Prasanta Banerji is Founder and Managing Trustee of the PBH Research Foundation
Fellow of the Mihijam Institute of Homeopathy and well known for establishing the
Banerji Protocols of treatment using Homeopathic Medicines internationally Research
areas include the treatment of every type of cancer and other serious illnesses which have
ensured replicability and helped produce vast amounts of data for meaningful research
which in turn has led to the acceptance at the Best Case Series program of the National
Cancer Institute (NCI) of USA He has been disseminating the protocols by lectures and
teaching seminars and has a number of published papers book chapters and books on the
subject
Pratip Banerji is Co-founder and Dy Managing Trustee of the Dr Prasanta Banerji
Homoeopathic Research Foundation (PBHRF) a consultant physician since 1991 with a
Bachelors Degree-BHMS from the Calcutta University He is also a Doctor of Medicine
MD(Hom) from the JRN Rajasthan Vidyapeeth (Deemed University) Udaipur in India
has played an important role in conducting research on the efficacy of treatment under the
Banerji Protocols The process of data accrual and documentation according to the highest
international standards was introduced by him This has made their research acceptable to
the international scientific community He has been disseminating the protocols by lectures
and teaching seminars and has a number of published papers book chapters and books on
the subject
J Nanosci Nanotechnol 15 4021ndash4038 2015 4023
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 1 Polydisperse size distribution of zinc metal nanoparticles of
homeopathically-prepared Zincum metallicum at 30C and 200C potencies
from two different manufacturers (SBL and WSI) Reprinted with per-
mission from [54] P S Chikramane et al Homeopathy 99 231 (2010)copy 2010 Churchill Livingstone
2 HOMEOPATHIC MANUFACTURINGPROCEDURES FOR NATURALNANOMEDICINES
21 Overview of Traditional Homeopathic MedicineManufacturing
Many skeptics globally reject homeopathy on the basis
of a concern about one aspect in the preparation of its
medicines without understanding specifics of what the
manufacturing procedures or rest of the field encompasses
Simplistic dismissal of an entire field risks missing the
relevance of this traditional approach to nanomedicine
in terms of actual manufacturing procedures range of
medicine doses used in treatment and 200 years of clin-
ical experience Homeopathic dosing methods are unique
and potentially informative for developing safer methods
for administering nanomedicines to patients in general
At the same time understanding homeopathic medicines
as crudely-made natural nanomedicines can also help clar-
ify the documented variability of basic preclinical and
clinical research findings69
The impact of integrating information from nan-
otechnology with homeopathy should lead to improved
consistency of data going forward The most controver-
sial principle of homeopathic medicine is the assertion
that serial dilutions of the bulk form of a natural prod-
uct to concentrations that are the reciprocal of Avogadrorsquos
number (110)minus23 nonetheless leave an active agent Until
the discovery of persistent source nanoparticles and silica
despite bulk form dilution53ndash55575960 there has been no
plausible physical mechanism to support such a claim
Homeopathic manufacturing methods are inherently
simple green and natural in their reagents with an
emphasis on mechanical attrition techniques andor plant
biosynthetic methods for generating nanoparticles in aque-
ous solutions at room temperature In nanotechnology it is
known that nanoparticles from mechanical attrition are pro-
duced by a top-down process using a mechanical device
generically described as a mill70ndash73 Notably extended peri-
ods of agitation by high energy ultrasonication of plant
starch in water alone can produce starch nanoparticles74
Samuel Hahnemann MD a physician-chemist and
founder of homeopathy originally designed his mechani-
cal techniques in the early 1800rsquos and refined them in his
writings until his death in 184375 His words (translated
from German) were75 ldquo This remarkable alterationin the properties of natural bodies is achieved throughmechanical action on their smallest particles by tritura-tion grinding in milk sugar and succussion agitation inethanol-distilled water solutions while these particles areseparated from one another by means of an interveningindifferent substance that is either dry or liquid rdquo
Thousands of different medicines each made with simi-
lar procedures from specific members of the plant mineral
and animal kingdoms contribute to the overall contempo-
rary homeopathic materia medica worldwide76ndash79 Homeo-
pathic manufacturing methods overlap crudely with those
of modern top-down nanoparticle mechanical attrition
manufacturing techniques and plant-based biosynthetic
bottom-up methods40627080 Plants are among the various
biological materials that can synthesize nanoparticles of
metals or silica from their precursors in solution However
neither homeopathic researchers nor commercial clinical
suppliers have usually provided the types of details neces-
sary to reliably replicate production of specific nanoparti-
cles of a given size shape distribution surface charge or
other properties relevant to their biological effects8182
Indeed homeopathic basic research reveals objectively-
measurable differences between verum medicines and
succussed controls8384 but variability of specific find-
ings from study to study85ndash88 UV-vis and Raman
spectroscopy8489 as well as thermoluminescence83 are
among the technologies that show differences between
verums and controls All three of these technologies are
also used to study properties of various modern manufac-
tured NPs90ndash92 Like nanoparticles93 at least three studies
on homeopathic medicines have shown aging effects of liq-
uid samples stored in glass619495 However aging status
of test solutions is rarely assessed or reported in homeo-
pathic studies
Variations in manufacturing methods and materials with
resultant variability of the test medicines could contribute
substantially to the situation of inconsistent research
findings96 Top down mechanical methods for NP produc-
tion are well-known to cause variable defects in the final
products7097 Homeopathic medicine research test mate-
rials are typically liquids which would be susceptible to
nonlinear NP aggregation processes that change their sur-
face chemistry reactivity98ndash101 On the other hand many
4024 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
commercial homeopathic clinical products are dried onto
lactose or lactose-sucrose pellets immediately after manu-
facturing a step that could stabilize and retain nanostruc-
tural integrity46102ndash106
Integrating modern nanoparticle manufacturing and
characterization methods107 and relevant bioassays108ndash110
could guide homeopathic manufacturers and researchers
to generate more reproducible products and experimental
findings Still some NP suspensions eg fullerene C60
NPs produced top-down by extended mixing in water and
sonication (agitation) can exhibit inherently uncontrolled
variability in batch-to-batch properties such as average par-
ticle sizes size distribution and ultraviolet visual spectro-
scopic patterns101 Mere dilution of fullerene C60 NPs can
also by itself introduce variability of colloidal properties
compared with a more concentrated parent suspension111
The fundamental steps for making all plant- and
most other natural source material derived homeopathic
medicines are
bull Preparation of an ethanolic herbal extract of the origi-
nal plant source or grinding and milling fresh raw plant or
mineral materials then added directly into ethanolic solu-
tions (manufacturers can differ on how homeopathic plant
medicines are prepared from raw materials)
bull For insoluble inorganic and organic source materials
such as metals and some mineral salts as well as cer-
tain plant and animal parts initial grinding and milling of
the natural raw source material in dry lactose for many
hours (termed ldquotriturationrdquo) Notably in nanotechnology
mechanical milling of lactose generates a variety of differ-
ent sized nanoparticles and nanocrystals of lactose itself112
Ball milling plant material for hours can generate silica
NPs71
bull Serial dilutions and multiple succussions per dilution
step (intense up and down agitation inside a glass con-
tainer) in liquid diluent typically ethanol-water or distilled
water
Common dilution ratios include 110 or 11001 part
source material to 9 parts diluent (X or D dose series) or
1 part source material to 99 parts diluent (C dose series)
Every insoluble source for a homeopathically-
prepared medicine begins by being ground up in lactose
for hours to make low potency dry dilutions (bulk mate-
rial diluted but not exceeding the reciprocal of Avogadrorsquos
number ie less than 24X or 12C potency)
Every dose of homeopathic medicines prepared past
the lowest dilutions is made by placing source material
into a glass container of ethanol-water solvent (typically
up to 90 vv ethanol but sometimes 0 20 43
or 70 ethanol) for making high potency dilutions (bulk
material diluted and exceeding the reciprocal of Avo-
gadrorsquos number ie higher than 24X or 12C potency) and
succussing (violently agitating) the flask or container 10
or more times after each ldquodilutionrdquo step53
From nanotechnology variations in ethanol con-
centration113ndash117 andor variations in dilution factors100111
can alter the resultant NP properties especially zeta poten-
tials and surface reactivity with other materials
Potentially parallel to the effects of multiple suc-
cussions in homeopathy a recent nanotechnology study
has shown that longer periods of ultrasound agitation of
plant starch granules in water can produce 30ndash100 nm sized
starch nanoparticles mechanically without any toxic chem-
ical treatment74 Longer periods of ultrasound agitation led
to progressively smaller sized starch NPs as small as 30 nm
after 90 minutes Notably increased numbers of succus-
sions can reportedly heighten the biological effects of a
given homeopathic medicine potency in an experimental
plant development model118
Moreover the extensive mechanical agitation of
liquid forms of the medicines (succussions) likely facil-
itates dispersion of any nanoparticle agglomerates or
aggregates that might form after initial production119
Homeopathic manufacturers may use manual pounding of
the glass container on a hard elastic surface vortexing or
sonication to perform their multiple agitations120
bull Final commercial products in ethanol-water solutions
are sprayed or poured and dried onto dry lactose (or
lactose-sucrose) pellets for ease of transport and dis-
pensing In homeopathic manufacturing only lactose and
sucrose are used Nanotechnologists have found that not
only lactose and sucrose but also fructose maltose glu-
cose and honey can all serve as biochemical reducing and
nanoparticle capping agents49121ndash124 as well as biological
carriers for nano-proteins105 and other NPs112
Modern homeopathic manufacturers each use variations
of the same original procedures and natural materials that
Hahnemann used However instead of manual mortar and
pestle grinding and agitation of subsequent ethanol-water
solutions within the glassware some homeopathic com-
panies utilize ball milling or similar methods to accom-
plish the grinding in lactose The methods for agitating the
ethanol-water solutions (succussions) also vary between
manufacturers Some perform manual succussions against
a hard elastic surface eg a book or even the palm of the
opposite hand Others have developed proprietary mechan-
ical arms to mimic the action of a human arm pounding the
glass container against a hard rubberized or elastic surface
with a relatively consistent arc and force Still others uti-
lize modern vortexing or sonication procedures to agitate
the solutions120125
For lower potencies manufacturers often use the Hah-
nemannian dilution method of removing one part of the
powder or solution from the previous triturated or suc-
cussed container placing it into a new container of 9 parts
or 99 parts either dry lactose (at the lowest potencies)
or ethanol-water solvent (for some low and all higher
potencies) For making higher potencies many manu-
facturers revert to the Korsakovian dilution method of
pouring off 9 parts (X potencies) or 99 parts (C poten-
cies) of the previously-succussed solution and repeatedly
J Nanosci Nanotechnol 15 4021ndash4038 2015 4025
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
refilling the same glass tube or container with fresh
solvent before resuming the next set of succussions
Thus certain lower homeopathic medicine potencies will
entail use of a new glass container for each prepara-
tion step whereas higher potencies often involve only a
single reused glass container for later preparation steps
Manufacturers may or may not specify their dilution
methods and materials for a given potency on their web-
sites Few commercial producers specify their glassware
sources despite its increasingly likely role in homeopathic
medicine production555759126127
The importance of these procedural details is that
at least 6 different laboratories have replicated evidence
for silica derivatives andor silicon in borosilicate or
soda lime glass-succussed but not plastic-succussed
liquid homeopathic medicines and succussed solvent
controls5557596189120128 Given recent evidence that spe-
cific glass materials from different manufacturers can
release different amounts of nanosilica and its precursors
into solution129 the sources sizes shapes and inner
surfaces of the glass containers themselves may con-
tribute indeterminate variables and variability to the
final products130 Any adsorption or binding of plant or
other nanomedicine source materials might adsorb to the
inside container walls andor coat some of the nanosil-
ica (or vice versa) in solution and modify the biological
effects106131ndash133 Silica NPs can also serve as carriers with
organosilanes as possible building blocks for synthetic
nanomaterials templated around the specific medicine
source65134ndash136 Rough versus smooth NP surfaces137 and
different shapes138ndash140 as well as particle defects and sur-
face charge variations may contribute another source of
variability to the homeopathically-manufactured materials
The ability of silica crystals and nanoparticles to stim-
ulate vigorous immune system adjuvant activation is
well-documented in the nanomedicine literature30141ndash143
Thus the presence of variable amounts of nanosilica
and silicon-based strtuctures could amplify biological
effects of even a small amount of source materials141
but in a correspondingly variable manner144 Ethanol
itself can dope nanosilica to change its optical fluores-
cence properties116 Silica and some metal NPs can also
self-assemble larger nanostructures from 3-dimensional
structural and electromagnetic information from epitaxial
templates such as viruses proteins DNA plant steroids
cells or calcium phosphate nanoparticles in solution with
the silica65134145ndash152 No homeopathic studies to date have
examined the inside walls of the succussed glass containers
as a silicate-rich adsorptive and adhesive area for source
nanoparticles133153 nanobubbles from succusions53 and
their possible release with agitation
All homeopathic medicine preparation occurs at room
temperature though the specific ambient temperature
may vary between manufacturers in terms of indoor
room air conditioning or heating Homeopathic pharma-
copoeia regulatory standards in various countries spec-
ify the medicine sources lactose and ethanol reagents
and preparation steps at room temperature although no
pharmacopoeias currently dictate in their documentation
any specific particle sizes or characterization methods for
the final products Unlike Hahnemann some contempo-
rary homeopathic manufacturers use container materials
such as polypropylene or polyethylene rather than glass in
which to succuss their products59120 materials likely to
generate different types of nanostructures154ndash157 Nanotech-
nology research has repeatedly documented the ability of
variations of manufacturing parameters such as solvent
type and concentration reducing and capping agents pH
temperature sonication force and duration to modify the
resultant nanoparticles made4874112ndash114158159 Seemingly
trivial differences such as lactose on the surface of silver
NPs for instance increases their rate of uptake into cancer
cells48
22 The Debate Over ldquoDilutionrdquo versus HomeopathicManufacturing Procedures
The debate over the validity of homeopathy as a clini-
cal treatment stems primarily from the serial dilution steps
during manufacturing The claim of skeptics is that for
high potencies that is serial bulk form ldquoultra-dilutionsrdquo
past the reciprocal of Avogadrorsquos number (6times 1023mdashie
24X or 12C potencies and higher) homeopathic medicines
could only serve as biologically inert placebos They
rarely address the facts that (a) homeopaths also use
low potencies that are not ultra-diluted or (b) the objec-
tive laboratory data using different technologies show that
homeopathic medicines at low and high potencies dif-
fer from control materials with unique physico-chemical
patterns838489160161 Animal plant and cell culture stud-
ies also show biological activity of low and high potency
homeopathic medicines69 There are many scientific lim-
itations to such a globally dismissive assumption that all
homeopathic medicines are merely biologically inert plain
solvent (Table I)
First the simplistic negative argument might be rel-
evant if homeopathic medicines were only bulk form
drugs andor prepared by simple dilution On the con-
trary the objective empirical evidence suggests that
both low and high potencies of homeopathically-
prepared metal (gold silver copper zinc tin plat-
inum) plant (Pulsatilla Belladonna Colchicum) and
conventional medicines (Phenazepam Panovir) contain
source nanoparticles1754ndash56 Quantities of source NPs
across different manufacturers and batches are variable
and low but nevertheless present54 Other investiga-
tors have also identified reproducible differences at the
nanoscale between homeopathically-prepared medicines
and homeopathically-prepared solvent controls60 Low
doses of NPs are biologically much more active than are
low doses of the ldquosamerdquo source material in bulk form2226
4026 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells
animals and human subjects including control groups
Homeopathic phytomedicine Biological effects
Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222
Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223
Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet
irradiation225
Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of
activation of the cellular interferon system226
6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227
Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to
that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231
Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232
Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional
anxiolytic drug buspirone in mice186 233
Anti-cancer effects of 2C potency on HeLa cells120
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected
mice234 235
Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
J Nanosci Nanotechnol 15 4021ndash4038 2015 4027
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4029
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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Copyright American Scientific Publishers
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P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
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4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
ogy 89 338 (1986)184 Z Ahmad R Pandey S Sharma and G K Khuller Indian J
Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 1 Polydisperse size distribution of zinc metal nanoparticles of
homeopathically-prepared Zincum metallicum at 30C and 200C potencies
from two different manufacturers (SBL and WSI) Reprinted with per-
mission from [54] P S Chikramane et al Homeopathy 99 231 (2010)copy 2010 Churchill Livingstone
2 HOMEOPATHIC MANUFACTURINGPROCEDURES FOR NATURALNANOMEDICINES
21 Overview of Traditional Homeopathic MedicineManufacturing
Many skeptics globally reject homeopathy on the basis
of a concern about one aspect in the preparation of its
medicines without understanding specifics of what the
manufacturing procedures or rest of the field encompasses
Simplistic dismissal of an entire field risks missing the
relevance of this traditional approach to nanomedicine
in terms of actual manufacturing procedures range of
medicine doses used in treatment and 200 years of clin-
ical experience Homeopathic dosing methods are unique
and potentially informative for developing safer methods
for administering nanomedicines to patients in general
At the same time understanding homeopathic medicines
as crudely-made natural nanomedicines can also help clar-
ify the documented variability of basic preclinical and
clinical research findings69
The impact of integrating information from nan-
otechnology with homeopathy should lead to improved
consistency of data going forward The most controver-
sial principle of homeopathic medicine is the assertion
that serial dilutions of the bulk form of a natural prod-
uct to concentrations that are the reciprocal of Avogadrorsquos
number (110)minus23 nonetheless leave an active agent Until
the discovery of persistent source nanoparticles and silica
despite bulk form dilution53ndash55575960 there has been no
plausible physical mechanism to support such a claim
Homeopathic manufacturing methods are inherently
simple green and natural in their reagents with an
emphasis on mechanical attrition techniques andor plant
biosynthetic methods for generating nanoparticles in aque-
ous solutions at room temperature In nanotechnology it is
known that nanoparticles from mechanical attrition are pro-
duced by a top-down process using a mechanical device
generically described as a mill70ndash73 Notably extended peri-
ods of agitation by high energy ultrasonication of plant
starch in water alone can produce starch nanoparticles74
Samuel Hahnemann MD a physician-chemist and
founder of homeopathy originally designed his mechani-
cal techniques in the early 1800rsquos and refined them in his
writings until his death in 184375 His words (translated
from German) were75 ldquo This remarkable alterationin the properties of natural bodies is achieved throughmechanical action on their smallest particles by tritura-tion grinding in milk sugar and succussion agitation inethanol-distilled water solutions while these particles areseparated from one another by means of an interveningindifferent substance that is either dry or liquid rdquo
Thousands of different medicines each made with simi-
lar procedures from specific members of the plant mineral
and animal kingdoms contribute to the overall contempo-
rary homeopathic materia medica worldwide76ndash79 Homeo-
pathic manufacturing methods overlap crudely with those
of modern top-down nanoparticle mechanical attrition
manufacturing techniques and plant-based biosynthetic
bottom-up methods40627080 Plants are among the various
biological materials that can synthesize nanoparticles of
metals or silica from their precursors in solution However
neither homeopathic researchers nor commercial clinical
suppliers have usually provided the types of details neces-
sary to reliably replicate production of specific nanoparti-
cles of a given size shape distribution surface charge or
other properties relevant to their biological effects8182
Indeed homeopathic basic research reveals objectively-
measurable differences between verum medicines and
succussed controls8384 but variability of specific find-
ings from study to study85ndash88 UV-vis and Raman
spectroscopy8489 as well as thermoluminescence83 are
among the technologies that show differences between
verums and controls All three of these technologies are
also used to study properties of various modern manufac-
tured NPs90ndash92 Like nanoparticles93 at least three studies
on homeopathic medicines have shown aging effects of liq-
uid samples stored in glass619495 However aging status
of test solutions is rarely assessed or reported in homeo-
pathic studies
Variations in manufacturing methods and materials with
resultant variability of the test medicines could contribute
substantially to the situation of inconsistent research
findings96 Top down mechanical methods for NP produc-
tion are well-known to cause variable defects in the final
products7097 Homeopathic medicine research test mate-
rials are typically liquids which would be susceptible to
nonlinear NP aggregation processes that change their sur-
face chemistry reactivity98ndash101 On the other hand many
4024 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
commercial homeopathic clinical products are dried onto
lactose or lactose-sucrose pellets immediately after manu-
facturing a step that could stabilize and retain nanostruc-
tural integrity46102ndash106
Integrating modern nanoparticle manufacturing and
characterization methods107 and relevant bioassays108ndash110
could guide homeopathic manufacturers and researchers
to generate more reproducible products and experimental
findings Still some NP suspensions eg fullerene C60
NPs produced top-down by extended mixing in water and
sonication (agitation) can exhibit inherently uncontrolled
variability in batch-to-batch properties such as average par-
ticle sizes size distribution and ultraviolet visual spectro-
scopic patterns101 Mere dilution of fullerene C60 NPs can
also by itself introduce variability of colloidal properties
compared with a more concentrated parent suspension111
The fundamental steps for making all plant- and
most other natural source material derived homeopathic
medicines are
bull Preparation of an ethanolic herbal extract of the origi-
nal plant source or grinding and milling fresh raw plant or
mineral materials then added directly into ethanolic solu-
tions (manufacturers can differ on how homeopathic plant
medicines are prepared from raw materials)
bull For insoluble inorganic and organic source materials
such as metals and some mineral salts as well as cer-
tain plant and animal parts initial grinding and milling of
the natural raw source material in dry lactose for many
hours (termed ldquotriturationrdquo) Notably in nanotechnology
mechanical milling of lactose generates a variety of differ-
ent sized nanoparticles and nanocrystals of lactose itself112
Ball milling plant material for hours can generate silica
NPs71
bull Serial dilutions and multiple succussions per dilution
step (intense up and down agitation inside a glass con-
tainer) in liquid diluent typically ethanol-water or distilled
water
Common dilution ratios include 110 or 11001 part
source material to 9 parts diluent (X or D dose series) or
1 part source material to 99 parts diluent (C dose series)
Every insoluble source for a homeopathically-
prepared medicine begins by being ground up in lactose
for hours to make low potency dry dilutions (bulk mate-
rial diluted but not exceeding the reciprocal of Avogadrorsquos
number ie less than 24X or 12C potency)
Every dose of homeopathic medicines prepared past
the lowest dilutions is made by placing source material
into a glass container of ethanol-water solvent (typically
up to 90 vv ethanol but sometimes 0 20 43
or 70 ethanol) for making high potency dilutions (bulk
material diluted and exceeding the reciprocal of Avo-
gadrorsquos number ie higher than 24X or 12C potency) and
succussing (violently agitating) the flask or container 10
or more times after each ldquodilutionrdquo step53
From nanotechnology variations in ethanol con-
centration113ndash117 andor variations in dilution factors100111
can alter the resultant NP properties especially zeta poten-
tials and surface reactivity with other materials
Potentially parallel to the effects of multiple suc-
cussions in homeopathy a recent nanotechnology study
has shown that longer periods of ultrasound agitation of
plant starch granules in water can produce 30ndash100 nm sized
starch nanoparticles mechanically without any toxic chem-
ical treatment74 Longer periods of ultrasound agitation led
to progressively smaller sized starch NPs as small as 30 nm
after 90 minutes Notably increased numbers of succus-
sions can reportedly heighten the biological effects of a
given homeopathic medicine potency in an experimental
plant development model118
Moreover the extensive mechanical agitation of
liquid forms of the medicines (succussions) likely facil-
itates dispersion of any nanoparticle agglomerates or
aggregates that might form after initial production119
Homeopathic manufacturers may use manual pounding of
the glass container on a hard elastic surface vortexing or
sonication to perform their multiple agitations120
bull Final commercial products in ethanol-water solutions
are sprayed or poured and dried onto dry lactose (or
lactose-sucrose) pellets for ease of transport and dis-
pensing In homeopathic manufacturing only lactose and
sucrose are used Nanotechnologists have found that not
only lactose and sucrose but also fructose maltose glu-
cose and honey can all serve as biochemical reducing and
nanoparticle capping agents49121ndash124 as well as biological
carriers for nano-proteins105 and other NPs112
Modern homeopathic manufacturers each use variations
of the same original procedures and natural materials that
Hahnemann used However instead of manual mortar and
pestle grinding and agitation of subsequent ethanol-water
solutions within the glassware some homeopathic com-
panies utilize ball milling or similar methods to accom-
plish the grinding in lactose The methods for agitating the
ethanol-water solutions (succussions) also vary between
manufacturers Some perform manual succussions against
a hard elastic surface eg a book or even the palm of the
opposite hand Others have developed proprietary mechan-
ical arms to mimic the action of a human arm pounding the
glass container against a hard rubberized or elastic surface
with a relatively consistent arc and force Still others uti-
lize modern vortexing or sonication procedures to agitate
the solutions120125
For lower potencies manufacturers often use the Hah-
nemannian dilution method of removing one part of the
powder or solution from the previous triturated or suc-
cussed container placing it into a new container of 9 parts
or 99 parts either dry lactose (at the lowest potencies)
or ethanol-water solvent (for some low and all higher
potencies) For making higher potencies many manu-
facturers revert to the Korsakovian dilution method of
pouring off 9 parts (X potencies) or 99 parts (C poten-
cies) of the previously-succussed solution and repeatedly
J Nanosci Nanotechnol 15 4021ndash4038 2015 4025
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
refilling the same glass tube or container with fresh
solvent before resuming the next set of succussions
Thus certain lower homeopathic medicine potencies will
entail use of a new glass container for each prepara-
tion step whereas higher potencies often involve only a
single reused glass container for later preparation steps
Manufacturers may or may not specify their dilution
methods and materials for a given potency on their web-
sites Few commercial producers specify their glassware
sources despite its increasingly likely role in homeopathic
medicine production555759126127
The importance of these procedural details is that
at least 6 different laboratories have replicated evidence
for silica derivatives andor silicon in borosilicate or
soda lime glass-succussed but not plastic-succussed
liquid homeopathic medicines and succussed solvent
controls5557596189120128 Given recent evidence that spe-
cific glass materials from different manufacturers can
release different amounts of nanosilica and its precursors
into solution129 the sources sizes shapes and inner
surfaces of the glass containers themselves may con-
tribute indeterminate variables and variability to the
final products130 Any adsorption or binding of plant or
other nanomedicine source materials might adsorb to the
inside container walls andor coat some of the nanosil-
ica (or vice versa) in solution and modify the biological
effects106131ndash133 Silica NPs can also serve as carriers with
organosilanes as possible building blocks for synthetic
nanomaterials templated around the specific medicine
source65134ndash136 Rough versus smooth NP surfaces137 and
different shapes138ndash140 as well as particle defects and sur-
face charge variations may contribute another source of
variability to the homeopathically-manufactured materials
The ability of silica crystals and nanoparticles to stim-
ulate vigorous immune system adjuvant activation is
well-documented in the nanomedicine literature30141ndash143
Thus the presence of variable amounts of nanosilica
and silicon-based strtuctures could amplify biological
effects of even a small amount of source materials141
but in a correspondingly variable manner144 Ethanol
itself can dope nanosilica to change its optical fluores-
cence properties116 Silica and some metal NPs can also
self-assemble larger nanostructures from 3-dimensional
structural and electromagnetic information from epitaxial
templates such as viruses proteins DNA plant steroids
cells or calcium phosphate nanoparticles in solution with
the silica65134145ndash152 No homeopathic studies to date have
examined the inside walls of the succussed glass containers
as a silicate-rich adsorptive and adhesive area for source
nanoparticles133153 nanobubbles from succusions53 and
their possible release with agitation
All homeopathic medicine preparation occurs at room
temperature though the specific ambient temperature
may vary between manufacturers in terms of indoor
room air conditioning or heating Homeopathic pharma-
copoeia regulatory standards in various countries spec-
ify the medicine sources lactose and ethanol reagents
and preparation steps at room temperature although no
pharmacopoeias currently dictate in their documentation
any specific particle sizes or characterization methods for
the final products Unlike Hahnemann some contempo-
rary homeopathic manufacturers use container materials
such as polypropylene or polyethylene rather than glass in
which to succuss their products59120 materials likely to
generate different types of nanostructures154ndash157 Nanotech-
nology research has repeatedly documented the ability of
variations of manufacturing parameters such as solvent
type and concentration reducing and capping agents pH
temperature sonication force and duration to modify the
resultant nanoparticles made4874112ndash114158159 Seemingly
trivial differences such as lactose on the surface of silver
NPs for instance increases their rate of uptake into cancer
cells48
22 The Debate Over ldquoDilutionrdquo versus HomeopathicManufacturing Procedures
The debate over the validity of homeopathy as a clini-
cal treatment stems primarily from the serial dilution steps
during manufacturing The claim of skeptics is that for
high potencies that is serial bulk form ldquoultra-dilutionsrdquo
past the reciprocal of Avogadrorsquos number (6times 1023mdashie
24X or 12C potencies and higher) homeopathic medicines
could only serve as biologically inert placebos They
rarely address the facts that (a) homeopaths also use
low potencies that are not ultra-diluted or (b) the objec-
tive laboratory data using different technologies show that
homeopathic medicines at low and high potencies dif-
fer from control materials with unique physico-chemical
patterns838489160161 Animal plant and cell culture stud-
ies also show biological activity of low and high potency
homeopathic medicines69 There are many scientific lim-
itations to such a globally dismissive assumption that all
homeopathic medicines are merely biologically inert plain
solvent (Table I)
First the simplistic negative argument might be rel-
evant if homeopathic medicines were only bulk form
drugs andor prepared by simple dilution On the con-
trary the objective empirical evidence suggests that
both low and high potencies of homeopathically-
prepared metal (gold silver copper zinc tin plat-
inum) plant (Pulsatilla Belladonna Colchicum) and
conventional medicines (Phenazepam Panovir) contain
source nanoparticles1754ndash56 Quantities of source NPs
across different manufacturers and batches are variable
and low but nevertheless present54 Other investiga-
tors have also identified reproducible differences at the
nanoscale between homeopathically-prepared medicines
and homeopathically-prepared solvent controls60 Low
doses of NPs are biologically much more active than are
low doses of the ldquosamerdquo source material in bulk form2226
4026 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells
animals and human subjects including control groups
Homeopathic phytomedicine Biological effects
Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222
Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223
Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet
irradiation225
Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of
activation of the cellular interferon system226
6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227
Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to
that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231
Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232
Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional
anxiolytic drug buspirone in mice186 233
Anti-cancer effects of 2C potency on HeLa cells120
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected
mice234 235
Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
J Nanosci Nanotechnol 15 4021ndash4038 2015 4027
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
References and Notes1 X Wang X Xu W Tao Y Li Y Wang and L Yang Evid Based
Complement Alternat Med 2012 519031 (2012)2 B Zhang X Wang and S Li Evid Based Complement Alternat
Med 2013 456747 (2013)
3 K Chan D Shaw M S Simmonds C J Leon Q Xu A Lu
I Sutherland S Ignatova Y P Zhu R Verpoorte E M
Williamson and P Duez J Ethnopharmacol 140 469 (2012)4 C L Quave M Pardo-de-Santayana and A Pieroni Evid Based
Complement Alternat Med 2012 156846 (2012)5 X Li G Yang X Li Y Zhang J Yang J Chang X Sun
X Zhou Y Guo Y Xu J Liu and A Bensoussan PLoS One8 e60338 (2013)
6 J Li L Gu H Zhang T Liu D Tian M Zhou and S Zhou
Lab Invest 93 354 (2013)7 E M Williamson Phytomedicine 8 401 (2001)8 K Niemeyer I R Bell and M Koithan J Herbal Medicine 3 112
(2013)9 Z Li X Wu J Li L Yao L Sun Y Shi W Zhang J Lin
D Liang and Y Li Int J Nanomedicine 7 2389 (2012)10 W Tan Y Li M Chen and Y Wang Int J Nanomedicine 6 1773
(2011)11 H B Nair B Sung V R Yadav R Kannappan M M Chaturvedi
and B B Aggarwal Biochem Pharmacol 80 1833 (2010)12 S Huang S J Chang M Yang J J Chen and W H Chang Int
J Nanomedicine 6 1365 (2011)13 R Mauludin R H Muller and C M Keck Int J Pharm 370 202
(2009)14 R Mauludin R H Muller and C M Keck Eur J Pharm Sci
36 502 (2009)15 A R Khuda-Bukhsh S S Bhattacharyya S Paul and
N Boujedaini Zhong Xi Yi Jie He Xue Bao 8 853 (2010)16 N Ahmad S Sharma M K Alam V N Singh S F Shamsi
B R Mehta and A Fatma Colloids Surf B Biointerfaces 81 81
(2010)17 R Barve and R Chaughule Journal of Nanostructure in Chemistry
3 18 (2013)18 C Buzea I I Pacheco and K Robbie Biointerphases 2 MR17
(2007)19 Y M Tsai C F Chien L C Lin and T H Tsai Int J Pharm
416 331 (2011)20 D J Prakash S Arulkumar and M Sabesan Pharmacognosy Res
2 330 (2010)21 S S Bhattacharyya S Paul and A R Khuda-Bukhsh Exp Biol
Med Maywood 235 678 (2010)22 A L Armstead and B Li Int J Nanomedicine 6 3281 (2011)23 M Diwan P Elamanchili M Cao and J Samuel Curr Drug
Deliv 1 405 (2004)24 Y S Chun S Bisht V Chenna D Pramanik T Yoshida S M
Hong R F de Wilde Z Zhang D L Huso M Zhao M A
Rudek V Stearns A Maitra and S Sukumar Carcinogenesis33 2242 (2012)
25 Z Ahmad and G K Khuller Expert Opin Drug Deliv 5 1323(2008)
26 A C Shirali M Look W Du E Kassis H W Stout-Delgado
T M Fahmy and D R Goldstein American Journal of Transplan-tation Official Journal of the American Society of Transplantationand the American Society of Transplant Surgeons 11 2582 (2011)
27 W Zhang Z Zhang and Y Zhang Nanoscale Res Lett 6 555(2011)
28 I H El-Sayed Curr Oncol Rep 12 121 (2010)29 K J Lim S Bisht E E Bar A Maitra and C G Eberhart
Cancer Biology and Therapy 11 464 (2011)30 M K Al-Sadoon M A Abdel-Maksoud D M Rabah and
G Badr Cell Physiol Biochem 30 653 (2012)31 L Harhaji A Isakovic N Raicevic Z Markovic B Todorovic-
Markovic N Nikolic S Vranjes-Djuric I Markovic and
V Trajkovic Eur J Pharmacol 568 89 (2007)32 J Meng J Xing Y Wang J Lu Y Zhao X Gao P C Wang
L Jia and X Liang Nanoscale 3 4713 (2011)
4034 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
33 S Barua R Konwarh S S Bhattacharya P Das K S Devi T K
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Homeopathy Hahnemann Clinic Publishing Grass Valley CA
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Nanotechnol 13 377 (2013)92 D Mendoza-Anaya C Angeles P Salas R Rodriguez and V M
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(2011)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4035
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
98 H L Xin and H Zheng Nano Lett 12 1470 (2012)99 G E Batley J K Kirby and M J McLaughlin Acc Chem Res
(2012)100 I A Mudunkotuwa and V H Grassian J Environ Monit 13 1135
(2011)101 X Chang and P J Vikesland Langmuir 29 9685 (2013)102 M Fatnassi C Tourne-Peteilh T Mineva J M Devoisselle
P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
103 T Niwa and K Danjo Eur J Pharm Sci (2013)104 N Genina H Raikkonen J Heinamaki P Veski and J Yliruusi
AAPS Pharm Sci Tech 11 959 (2010)105 M A Tavares Cardoso M Talebi P A Soares C U Yurteri and
J R van Ommen Int J Pharmaceutics 414 1 (2011)106 Y Chaikin O Kedem J Raz A Vaskevich and I Rubinstein
Anal Chem (2013)107 N C Bell C Minelli J Tompkins M M Stevens and A G
Shard Langmuir 28 10860 (2012)108 A E James and J D Driskell Analyst (2013)109 C D Walkey and W C Chan Chem Soc Rev 41 2780 (2012)110 X Chang L K Duncan J Jinschek and P J Vikesland Langmuir
28 7622 (2012)111 X Chang and P J Vikesland Environ Pollut 181C 51 (2013)112 V Caron J F Willart R Lefort P Derollez F Danede and
M Descamps Carbohydr Res 346 2622 (2011)113 A R Abbasi and A Morsali Ultrason Sonochem 19 540 (2012)114 J W Yoo D S Yun and H J Kim J Nanosci Nanotechnol
6 3343 (2006)115 K R Moonoosawmy and P Kruse J Am Chem Soc 132 1572
(2010)116 Y Yang A L Yang R Q Yang G J Yuan and Y L Shi J
Nanosci Nanotechnol 11 9717 (2011)117 X Li O Niitsoo and A Couzis J Colloid Interface Sci 394 26
(2013)118 L Betti G Trebbi O Kokornaczyk D Nani M Peruzzi and
M Brizzi Int J High Dilution Res 12 127 (2013)119 C Tang T Zhou J Yang Q Zhang F Chen Q Fu and L Yang
Colloids Surf B Biointerfaces 86 189 (2011)120 S S Bhattacharyya S K Mandal R Biswas S Paul S Pathak
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R Kannan International Journal of Green NanotechnologyBiomedicine 1 B53 (2009)
123 V Snitka D O Naumenko L Ramanauskaite S A Kravchenko
and B A Snopok J Colloid Interface Sci 386 99 (2012)124 C Zhu S Guo Y Fang and S Dong ACS Nano 4 2429 (2010)125 J L Demangeat P Gries B Poitevin J J Droesbeke T M Zahaf
F C Pierart and R N Miller Appl Magn Reson 26 465 (2004)126 S Cartwright Pyridinium-N-phenolates as molecular probes
of serially diluted and agitated solutions Preliminary results
1st Homeopathic Research Institute International HomeopathyResearch Conference Cutting Edge Research in HomeopathyBarcelona Spain (2013)
127 D J Anick and J A Ives Homeopathy 96 189 (2007)128 C Witt R Ludtke T E Weisshuhn and S N Willich Forschende
Komplementarmedizinund Klassische Naturheilkunde 12 6 (2005)129 L Liu T W Randolph and J F Carpenter J Pharm Sci
101 2952 (2012)130 Y Shimotsuma M Sakakura K Miura J Qiu P G Kazansky
K Fujita and K Hirao J Nanosci Nanotechnol 7 94 (2007)131 C G Pack M R Song E J Lee M Hiroshima K H Byun
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133 S Kiel O Grinberg N Perkas J Charmet H Kepner and
A Gedanken Beilstein J Nanotechnol 3 267 (2012)134 A Cumbo B Lorber P F Corvini W Meier and P Shahgaldian
Nat Commun 4 1503 (2013)135 H K Baca E C Carnes C E Ashley D M Lopez C Douthit
S Karlin and C J Brinker Biochim Biophys Acta 1810 259
(2011)136 R Zhu W Zhao M Zhai F Wei Z Cai N Sheng and Q Hu
Anal Chim Acta 658 209 (2010)137 A Schrade V Mailander S Ritz K Landfester and U Ziener
Macromol Biosci 12 1459 (2012)138 V Biju T Itoh A Anas A Sujith and M Ishikawa Anal Bioanal
Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and
M Sharon Colloids Surf B Biointerfaces 109 25 (2013)140 D Menon A Basanth A Retnakumari K Manzoor and S V
Nair J Biomed Nanotechnol 8 901 (2012)141 T Wang H Jiang Q Zhao S Wang M Zou and G Cheng Int
J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
I Forster Nanotoxicology 5 326 (2011)143 D Mahony A S Cavallaro F Stahr T J Mahony S Z Qiao
and N Mitter Small 9 3138 (2013)144 W J Sandberg M Lag J A Holme B Friede M Gualtieri
M Kruszewski P E Schwarze T Skuland and M Refsnes PartFibre Toxicol 9 32 (2012)
145 B Kaehr J L Townson R M Kalinich Y H Awad B S
Swartzentruber D R Dunphy and C J Brinker Proc Natl AcadSci USA 109 17336 (2012)
146 H K Baca E Carnes S Singh C Ashley D Lopez and C J
Brinker Acc Chem Res 40 836 (2007)147 X Li J Zhang and H Gu Langmuir 28 2827 (2012)148 D C Wang G Y Chen K Y Chen and C H Tsai IET
Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
Stat Nonlin Soft Matter Phys 84 061705 (2011)150 C Groger K Lutz and E Brunner Cell Biochem Biophys 50 23
(2008)151 P A Williamson P J Blower and M A Green Chem Commun
Camb 47 1568 (2011)152 Y Park S Kim J Moon J C Lee and Y Kim J Nanosci
Nanotechnol 12 1444 (2012)153 J M Almeida L De Boni W Avansi C Ribeiro E Longo A C
Hernandes and C R Mendonca Opt Express 20 15106 (2012)154 A Pawlak Colloid and Polymer Science 291 773 (2013)155 H Duran M Steinhart H J Butt and G Floudas Nano Lett
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and J P Ting PLoS One 8 e62115 (2013)158 B Ruan and M Jacobi Nanoscale Research Letters 7 127 (2012)159 T A Hassan V K Rangari R K Rana and S Jeelani Ultrason
Sonochem 20 1308 (2013)160 V Elia and M Niccoli Annals of the New York Academy of Sci-
ences 879 241 (1999)161 K Lenger R P Bajpai and M Spielmann Cell Biochem Biophys
(2013)162 C E McNamee and K Higashitani Langmuir 29 5013 (2013)163 E Taran Y Kanda I U Vakarelski and K Higashitani J Colloid
Interface Sci 307 425 (2007)164 J Lim K Hippalgaonkar S C Andrews A Majumdar and
P Yang Nano Lett 12 2475 (2012)165 L Montagnier J Aissa S Ferris J-L Montagnier and C Lavallee
Interdisciplinary Sci Comput Life Sci 1 81 (2009)166 P Bellavite P Magnani E Zanolin and A Conforti Evid Based
Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
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and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
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Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
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Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
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N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
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23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
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85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
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J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
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A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
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235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
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(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
commercial homeopathic clinical products are dried onto
lactose or lactose-sucrose pellets immediately after manu-
facturing a step that could stabilize and retain nanostruc-
tural integrity46102ndash106
Integrating modern nanoparticle manufacturing and
characterization methods107 and relevant bioassays108ndash110
could guide homeopathic manufacturers and researchers
to generate more reproducible products and experimental
findings Still some NP suspensions eg fullerene C60
NPs produced top-down by extended mixing in water and
sonication (agitation) can exhibit inherently uncontrolled
variability in batch-to-batch properties such as average par-
ticle sizes size distribution and ultraviolet visual spectro-
scopic patterns101 Mere dilution of fullerene C60 NPs can
also by itself introduce variability of colloidal properties
compared with a more concentrated parent suspension111
The fundamental steps for making all plant- and
most other natural source material derived homeopathic
medicines are
bull Preparation of an ethanolic herbal extract of the origi-
nal plant source or grinding and milling fresh raw plant or
mineral materials then added directly into ethanolic solu-
tions (manufacturers can differ on how homeopathic plant
medicines are prepared from raw materials)
bull For insoluble inorganic and organic source materials
such as metals and some mineral salts as well as cer-
tain plant and animal parts initial grinding and milling of
the natural raw source material in dry lactose for many
hours (termed ldquotriturationrdquo) Notably in nanotechnology
mechanical milling of lactose generates a variety of differ-
ent sized nanoparticles and nanocrystals of lactose itself112
Ball milling plant material for hours can generate silica
NPs71
bull Serial dilutions and multiple succussions per dilution
step (intense up and down agitation inside a glass con-
tainer) in liquid diluent typically ethanol-water or distilled
water
Common dilution ratios include 110 or 11001 part
source material to 9 parts diluent (X or D dose series) or
1 part source material to 99 parts diluent (C dose series)
Every insoluble source for a homeopathically-
prepared medicine begins by being ground up in lactose
for hours to make low potency dry dilutions (bulk mate-
rial diluted but not exceeding the reciprocal of Avogadrorsquos
number ie less than 24X or 12C potency)
Every dose of homeopathic medicines prepared past
the lowest dilutions is made by placing source material
into a glass container of ethanol-water solvent (typically
up to 90 vv ethanol but sometimes 0 20 43
or 70 ethanol) for making high potency dilutions (bulk
material diluted and exceeding the reciprocal of Avo-
gadrorsquos number ie higher than 24X or 12C potency) and
succussing (violently agitating) the flask or container 10
or more times after each ldquodilutionrdquo step53
From nanotechnology variations in ethanol con-
centration113ndash117 andor variations in dilution factors100111
can alter the resultant NP properties especially zeta poten-
tials and surface reactivity with other materials
Potentially parallel to the effects of multiple suc-
cussions in homeopathy a recent nanotechnology study
has shown that longer periods of ultrasound agitation of
plant starch granules in water can produce 30ndash100 nm sized
starch nanoparticles mechanically without any toxic chem-
ical treatment74 Longer periods of ultrasound agitation led
to progressively smaller sized starch NPs as small as 30 nm
after 90 minutes Notably increased numbers of succus-
sions can reportedly heighten the biological effects of a
given homeopathic medicine potency in an experimental
plant development model118
Moreover the extensive mechanical agitation of
liquid forms of the medicines (succussions) likely facil-
itates dispersion of any nanoparticle agglomerates or
aggregates that might form after initial production119
Homeopathic manufacturers may use manual pounding of
the glass container on a hard elastic surface vortexing or
sonication to perform their multiple agitations120
bull Final commercial products in ethanol-water solutions
are sprayed or poured and dried onto dry lactose (or
lactose-sucrose) pellets for ease of transport and dis-
pensing In homeopathic manufacturing only lactose and
sucrose are used Nanotechnologists have found that not
only lactose and sucrose but also fructose maltose glu-
cose and honey can all serve as biochemical reducing and
nanoparticle capping agents49121ndash124 as well as biological
carriers for nano-proteins105 and other NPs112
Modern homeopathic manufacturers each use variations
of the same original procedures and natural materials that
Hahnemann used However instead of manual mortar and
pestle grinding and agitation of subsequent ethanol-water
solutions within the glassware some homeopathic com-
panies utilize ball milling or similar methods to accom-
plish the grinding in lactose The methods for agitating the
ethanol-water solutions (succussions) also vary between
manufacturers Some perform manual succussions against
a hard elastic surface eg a book or even the palm of the
opposite hand Others have developed proprietary mechan-
ical arms to mimic the action of a human arm pounding the
glass container against a hard rubberized or elastic surface
with a relatively consistent arc and force Still others uti-
lize modern vortexing or sonication procedures to agitate
the solutions120125
For lower potencies manufacturers often use the Hah-
nemannian dilution method of removing one part of the
powder or solution from the previous triturated or suc-
cussed container placing it into a new container of 9 parts
or 99 parts either dry lactose (at the lowest potencies)
or ethanol-water solvent (for some low and all higher
potencies) For making higher potencies many manu-
facturers revert to the Korsakovian dilution method of
pouring off 9 parts (X potencies) or 99 parts (C poten-
cies) of the previously-succussed solution and repeatedly
J Nanosci Nanotechnol 15 4021ndash4038 2015 4025
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
refilling the same glass tube or container with fresh
solvent before resuming the next set of succussions
Thus certain lower homeopathic medicine potencies will
entail use of a new glass container for each prepara-
tion step whereas higher potencies often involve only a
single reused glass container for later preparation steps
Manufacturers may or may not specify their dilution
methods and materials for a given potency on their web-
sites Few commercial producers specify their glassware
sources despite its increasingly likely role in homeopathic
medicine production555759126127
The importance of these procedural details is that
at least 6 different laboratories have replicated evidence
for silica derivatives andor silicon in borosilicate or
soda lime glass-succussed but not plastic-succussed
liquid homeopathic medicines and succussed solvent
controls5557596189120128 Given recent evidence that spe-
cific glass materials from different manufacturers can
release different amounts of nanosilica and its precursors
into solution129 the sources sizes shapes and inner
surfaces of the glass containers themselves may con-
tribute indeterminate variables and variability to the
final products130 Any adsorption or binding of plant or
other nanomedicine source materials might adsorb to the
inside container walls andor coat some of the nanosil-
ica (or vice versa) in solution and modify the biological
effects106131ndash133 Silica NPs can also serve as carriers with
organosilanes as possible building blocks for synthetic
nanomaterials templated around the specific medicine
source65134ndash136 Rough versus smooth NP surfaces137 and
different shapes138ndash140 as well as particle defects and sur-
face charge variations may contribute another source of
variability to the homeopathically-manufactured materials
The ability of silica crystals and nanoparticles to stim-
ulate vigorous immune system adjuvant activation is
well-documented in the nanomedicine literature30141ndash143
Thus the presence of variable amounts of nanosilica
and silicon-based strtuctures could amplify biological
effects of even a small amount of source materials141
but in a correspondingly variable manner144 Ethanol
itself can dope nanosilica to change its optical fluores-
cence properties116 Silica and some metal NPs can also
self-assemble larger nanostructures from 3-dimensional
structural and electromagnetic information from epitaxial
templates such as viruses proteins DNA plant steroids
cells or calcium phosphate nanoparticles in solution with
the silica65134145ndash152 No homeopathic studies to date have
examined the inside walls of the succussed glass containers
as a silicate-rich adsorptive and adhesive area for source
nanoparticles133153 nanobubbles from succusions53 and
their possible release with agitation
All homeopathic medicine preparation occurs at room
temperature though the specific ambient temperature
may vary between manufacturers in terms of indoor
room air conditioning or heating Homeopathic pharma-
copoeia regulatory standards in various countries spec-
ify the medicine sources lactose and ethanol reagents
and preparation steps at room temperature although no
pharmacopoeias currently dictate in their documentation
any specific particle sizes or characterization methods for
the final products Unlike Hahnemann some contempo-
rary homeopathic manufacturers use container materials
such as polypropylene or polyethylene rather than glass in
which to succuss their products59120 materials likely to
generate different types of nanostructures154ndash157 Nanotech-
nology research has repeatedly documented the ability of
variations of manufacturing parameters such as solvent
type and concentration reducing and capping agents pH
temperature sonication force and duration to modify the
resultant nanoparticles made4874112ndash114158159 Seemingly
trivial differences such as lactose on the surface of silver
NPs for instance increases their rate of uptake into cancer
cells48
22 The Debate Over ldquoDilutionrdquo versus HomeopathicManufacturing Procedures
The debate over the validity of homeopathy as a clini-
cal treatment stems primarily from the serial dilution steps
during manufacturing The claim of skeptics is that for
high potencies that is serial bulk form ldquoultra-dilutionsrdquo
past the reciprocal of Avogadrorsquos number (6times 1023mdashie
24X or 12C potencies and higher) homeopathic medicines
could only serve as biologically inert placebos They
rarely address the facts that (a) homeopaths also use
low potencies that are not ultra-diluted or (b) the objec-
tive laboratory data using different technologies show that
homeopathic medicines at low and high potencies dif-
fer from control materials with unique physico-chemical
patterns838489160161 Animal plant and cell culture stud-
ies also show biological activity of low and high potency
homeopathic medicines69 There are many scientific lim-
itations to such a globally dismissive assumption that all
homeopathic medicines are merely biologically inert plain
solvent (Table I)
First the simplistic negative argument might be rel-
evant if homeopathic medicines were only bulk form
drugs andor prepared by simple dilution On the con-
trary the objective empirical evidence suggests that
both low and high potencies of homeopathically-
prepared metal (gold silver copper zinc tin plat-
inum) plant (Pulsatilla Belladonna Colchicum) and
conventional medicines (Phenazepam Panovir) contain
source nanoparticles1754ndash56 Quantities of source NPs
across different manufacturers and batches are variable
and low but nevertheless present54 Other investiga-
tors have also identified reproducible differences at the
nanoscale between homeopathically-prepared medicines
and homeopathically-prepared solvent controls60 Low
doses of NPs are biologically much more active than are
low doses of the ldquosamerdquo source material in bulk form2226
4026 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells
animals and human subjects including control groups
Homeopathic phytomedicine Biological effects
Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222
Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223
Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet
irradiation225
Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of
activation of the cellular interferon system226
6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227
Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to
that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231
Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232
Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional
anxiolytic drug buspirone in mice186 233
Anti-cancer effects of 2C potency on HeLa cells120
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected
mice234 235
Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
J Nanosci Nanotechnol 15 4021ndash4038 2015 4027
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4029
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
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Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
refilling the same glass tube or container with fresh
solvent before resuming the next set of succussions
Thus certain lower homeopathic medicine potencies will
entail use of a new glass container for each prepara-
tion step whereas higher potencies often involve only a
single reused glass container for later preparation steps
Manufacturers may or may not specify their dilution
methods and materials for a given potency on their web-
sites Few commercial producers specify their glassware
sources despite its increasingly likely role in homeopathic
medicine production555759126127
The importance of these procedural details is that
at least 6 different laboratories have replicated evidence
for silica derivatives andor silicon in borosilicate or
soda lime glass-succussed but not plastic-succussed
liquid homeopathic medicines and succussed solvent
controls5557596189120128 Given recent evidence that spe-
cific glass materials from different manufacturers can
release different amounts of nanosilica and its precursors
into solution129 the sources sizes shapes and inner
surfaces of the glass containers themselves may con-
tribute indeterminate variables and variability to the
final products130 Any adsorption or binding of plant or
other nanomedicine source materials might adsorb to the
inside container walls andor coat some of the nanosil-
ica (or vice versa) in solution and modify the biological
effects106131ndash133 Silica NPs can also serve as carriers with
organosilanes as possible building blocks for synthetic
nanomaterials templated around the specific medicine
source65134ndash136 Rough versus smooth NP surfaces137 and
different shapes138ndash140 as well as particle defects and sur-
face charge variations may contribute another source of
variability to the homeopathically-manufactured materials
The ability of silica crystals and nanoparticles to stim-
ulate vigorous immune system adjuvant activation is
well-documented in the nanomedicine literature30141ndash143
Thus the presence of variable amounts of nanosilica
and silicon-based strtuctures could amplify biological
effects of even a small amount of source materials141
but in a correspondingly variable manner144 Ethanol
itself can dope nanosilica to change its optical fluores-
cence properties116 Silica and some metal NPs can also
self-assemble larger nanostructures from 3-dimensional
structural and electromagnetic information from epitaxial
templates such as viruses proteins DNA plant steroids
cells or calcium phosphate nanoparticles in solution with
the silica65134145ndash152 No homeopathic studies to date have
examined the inside walls of the succussed glass containers
as a silicate-rich adsorptive and adhesive area for source
nanoparticles133153 nanobubbles from succusions53 and
their possible release with agitation
All homeopathic medicine preparation occurs at room
temperature though the specific ambient temperature
may vary between manufacturers in terms of indoor
room air conditioning or heating Homeopathic pharma-
copoeia regulatory standards in various countries spec-
ify the medicine sources lactose and ethanol reagents
and preparation steps at room temperature although no
pharmacopoeias currently dictate in their documentation
any specific particle sizes or characterization methods for
the final products Unlike Hahnemann some contempo-
rary homeopathic manufacturers use container materials
such as polypropylene or polyethylene rather than glass in
which to succuss their products59120 materials likely to
generate different types of nanostructures154ndash157 Nanotech-
nology research has repeatedly documented the ability of
variations of manufacturing parameters such as solvent
type and concentration reducing and capping agents pH
temperature sonication force and duration to modify the
resultant nanoparticles made4874112ndash114158159 Seemingly
trivial differences such as lactose on the surface of silver
NPs for instance increases their rate of uptake into cancer
cells48
22 The Debate Over ldquoDilutionrdquo versus HomeopathicManufacturing Procedures
The debate over the validity of homeopathy as a clini-
cal treatment stems primarily from the serial dilution steps
during manufacturing The claim of skeptics is that for
high potencies that is serial bulk form ldquoultra-dilutionsrdquo
past the reciprocal of Avogadrorsquos number (6times 1023mdashie
24X or 12C potencies and higher) homeopathic medicines
could only serve as biologically inert placebos They
rarely address the facts that (a) homeopaths also use
low potencies that are not ultra-diluted or (b) the objec-
tive laboratory data using different technologies show that
homeopathic medicines at low and high potencies dif-
fer from control materials with unique physico-chemical
patterns838489160161 Animal plant and cell culture stud-
ies also show biological activity of low and high potency
homeopathic medicines69 There are many scientific lim-
itations to such a globally dismissive assumption that all
homeopathic medicines are merely biologically inert plain
solvent (Table I)
First the simplistic negative argument might be rel-
evant if homeopathic medicines were only bulk form
drugs andor prepared by simple dilution On the con-
trary the objective empirical evidence suggests that
both low and high potencies of homeopathically-
prepared metal (gold silver copper zinc tin plat-
inum) plant (Pulsatilla Belladonna Colchicum) and
conventional medicines (Phenazepam Panovir) contain
source nanoparticles1754ndash56 Quantities of source NPs
across different manufacturers and batches are variable
and low but nevertheless present54 Other investiga-
tors have also identified reproducible differences at the
nanoscale between homeopathically-prepared medicines
and homeopathically-prepared solvent controls60 Low
doses of NPs are biologically much more active than are
low doses of the ldquosamerdquo source material in bulk form2226
4026 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells
animals and human subjects including control groups
Homeopathic phytomedicine Biological effects
Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222
Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223
Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet
irradiation225
Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of
activation of the cellular interferon system226
6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227
Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to
that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231
Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232
Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional
anxiolytic drug buspirone in mice186 233
Anti-cancer effects of 2C potency on HeLa cells120
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected
mice234 235
Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
J Nanosci Nanotechnol 15 4021ndash4038 2015 4027
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4029
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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mentmed 14 301 (2007)97 G Cao and Y Wang Nanostructures and Nanomaterials Synthesis
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Copyright American Scientific Publishers
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P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
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Nair J Biomed Nanotechnol 8 901 (2012)141 T Wang H Jiang Q Zhao S Wang M Zou and G Cheng Int
J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
I Forster Nanotoxicology 5 326 (2011)143 D Mahony A S Cavallaro F Stahr T J Mahony S Z Qiao
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M Kruszewski P E Schwarze T Skuland and M Refsnes PartFibre Toxicol 9 32 (2012)
145 B Kaehr J L Townson R M Kalinich Y H Awad B S
Swartzentruber D R Dunphy and C J Brinker Proc Natl AcadSci USA 109 17336 (2012)
146 H K Baca E Carnes S Singh C Ashley D Lopez and C J
Brinker Acc Chem Res 40 836 (2007)147 X Li J Zhang and H Gu Langmuir 28 2827 (2012)148 D C Wang G Y Chen K Y Chen and C H Tsai IET
Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
Stat Nonlin Soft Matter Phys 84 061705 (2011)150 C Groger K Lutz and E Brunner Cell Biochem Biophys 50 23
(2008)151 P A Williamson P J Blower and M A Green Chem Commun
Camb 47 1568 (2011)152 Y Park S Kim J Moon J C Lee and Y Kim J Nanosci
Nanotechnol 12 1444 (2012)153 J M Almeida L De Boni W Avansi C Ribeiro E Longo A C
Hernandes and C R Mendonca Opt Express 20 15106 (2012)154 A Pawlak Colloid and Polymer Science 291 773 (2013)155 H Duran M Steinhart H J Butt and G Floudas Nano Lett
11 1671 (2011)156 S Jain H Goossens M van Duin and P Lemstra Polymer
46 8805 (2005)157 R A Roberts T Shen I C Allen W Hasan J M DeSimone
and J P Ting PLoS One 8 e62115 (2013)158 B Ruan and M Jacobi Nanoscale Research Letters 7 127 (2012)159 T A Hassan V K Rangari R K Rana and S Jeelani Ultrason
Sonochem 20 1308 (2013)160 V Elia and M Niccoli Annals of the New York Academy of Sci-
ences 879 241 (1999)161 K Lenger R P Bajpai and M Spielmann Cell Biochem Biophys
(2013)162 C E McNamee and K Higashitani Langmuir 29 5013 (2013)163 E Taran Y Kanda I U Vakarelski and K Higashitani J Colloid
Interface Sci 307 425 (2007)164 J Lim K Hippalgaonkar S C Andrews A Majumdar and
P Yang Nano Lett 12 2475 (2012)165 L Montagnier J Aissa S Ferris J-L Montagnier and C Lavallee
Interdisciplinary Sci Comput Life Sci 1 81 (2009)166 P Bellavite P Magnani E Zanolin and A Conforti Evid Based
Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
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Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
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(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table I Biological effects of exemplar homeopathically-manufactured (nano)phytomedicines at homeopathically-manufactured potencies on cells
animals and human subjects including control groups
Homeopathic phytomedicine Biological effects
Aconitum napellus In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Aloe vera 3X 6X 12X 30X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Arnica montana 30C potency reduced genotoxicity of sonication stress in mice222
Combination homeopathic product including Arnica 3X potency blocked experimentally-induced edema in rat paws223
Combination homeopathic product including Arnica 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
30C potency upregulated DNA repair genes compared with controls in E coli bacterial model exposed to ultraviolet
irradiation225
Asclepias vincetoxicum 6X 10X 30X potencies as part of a combination homeopathic product demonstrated antiviral activity independent of
activation of the cellular interferon system226
6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Bryonia alba In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
4X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
Calendula officinalis Combination homeopathic product including Calendula 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Chelidonium majus 30C and 200C potencies caused significant amelioration of p-DAB induced hepatocarcinogenesis227
Coffea cruda 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C potency caused increased power in slow wave delta sleep of rats compared with controls230 effect was similar to
that of bulk form caffeine 200C potency affected only electroencephalographic synchronization231
Conium maculatum 30X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Eupatorium perfoliatum 3X potency as part of combination homeopathic product significantly reduced viral infectivity of multiple human
viruses220
4X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
30C potency caused a maximum 60 inhibition of parasitemia in a rodent model for malaria infection232
Euphorbium officinarum 6X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Gelsemium sempervirens Reduced anxiety-related behaviors in open field testing at 5C 9C and 30C potencies comparable to conventional
anxiolytic drug buspirone in mice186 233
Anti-cancer effects of 2C potency on HeLa cells120
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Hydrastis canadensis 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 694 and 1 M (1000C) potency reduced metastases of melanoma-affected
mice234 235
Hypericum perforatum Combination homeopathic product including Hypericum 4X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
J Nanosci Nanotechnol 15 4021ndash4038 2015 4027
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4029
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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mentmed 14 301 (2007)97 G Cao and Y Wang Nanostructures and Nanomaterials Synthesis
Properties and Applications 2nd ed World Scientific New Jersey
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Copyright American Scientific Publishers
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P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
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Shard Langmuir 28 10860 (2012)108 A E James and J D Driskell Analyst (2013)109 C D Walkey and W C Chan Chem Soc Rev 41 2780 (2012)110 X Chang L K Duncan J Jinschek and P J Vikesland Langmuir
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and B A Snopok J Colloid Interface Sci 386 99 (2012)124 C Zhu S Guo Y Fang and S Dong ACS Nano 4 2429 (2010)125 J L Demangeat P Gries B Poitevin J J Droesbeke T M Zahaf
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S Karlin and C J Brinker Biochim Biophys Acta 1810 259
(2011)136 R Zhu W Zhao M Zhai F Wei Z Cai N Sheng and Q Hu
Anal Chim Acta 658 209 (2010)137 A Schrade V Mailander S Ritz K Landfester and U Ziener
Macromol Biosci 12 1459 (2012)138 V Biju T Itoh A Anas A Sujith and M Ishikawa Anal Bioanal
Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and
M Sharon Colloids Surf B Biointerfaces 109 25 (2013)140 D Menon A Basanth A Retnakumari K Manzoor and S V
Nair J Biomed Nanotechnol 8 901 (2012)141 T Wang H Jiang Q Zhao S Wang M Zou and G Cheng Int
J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
I Forster Nanotoxicology 5 326 (2011)143 D Mahony A S Cavallaro F Stahr T J Mahony S Z Qiao
and N Mitter Small 9 3138 (2013)144 W J Sandberg M Lag J A Holme B Friede M Gualtieri
M Kruszewski P E Schwarze T Skuland and M Refsnes PartFibre Toxicol 9 32 (2012)
145 B Kaehr J L Townson R M Kalinich Y H Awad B S
Swartzentruber D R Dunphy and C J Brinker Proc Natl AcadSci USA 109 17336 (2012)
146 H K Baca E Carnes S Singh C Ashley D Lopez and C J
Brinker Acc Chem Res 40 836 (2007)147 X Li J Zhang and H Gu Langmuir 28 2827 (2012)148 D C Wang G Y Chen K Y Chen and C H Tsai IET
Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
Stat Nonlin Soft Matter Phys 84 061705 (2011)150 C Groger K Lutz and E Brunner Cell Biochem Biophys 50 23
(2008)151 P A Williamson P J Blower and M A Green Chem Commun
Camb 47 1568 (2011)152 Y Park S Kim J Moon J C Lee and Y Kim J Nanosci
Nanotechnol 12 1444 (2012)153 J M Almeida L De Boni W Avansi C Ribeiro E Longo A C
Hernandes and C R Mendonca Opt Express 20 15106 (2012)154 A Pawlak Colloid and Polymer Science 291 773 (2013)155 H Duran M Steinhart H J Butt and G Floudas Nano Lett
11 1671 (2011)156 S Jain H Goossens M van Duin and P Lemstra Polymer
46 8805 (2005)157 R A Roberts T Shen I C Allen W Hasan J M DeSimone
and J P Ting PLoS One 8 e62115 (2013)158 B Ruan and M Jacobi Nanoscale Research Letters 7 127 (2012)159 T A Hassan V K Rangari R K Rana and S Jeelani Ultrason
Sonochem 20 1308 (2013)160 V Elia and M Niccoli Annals of the New York Academy of Sci-
ences 879 241 (1999)161 K Lenger R P Bajpai and M Spielmann Cell Biochem Biophys
(2013)162 C E McNamee and K Higashitani Langmuir 29 5013 (2013)163 E Taran Y Kanda I U Vakarelski and K Higashitani J Colloid
Interface Sci 307 425 (2007)164 J Lim K Hippalgaonkar S C Andrews A Majumdar and
P Yang Nano Lett 12 2475 (2012)165 L Montagnier J Aissa S Ferris J-L Montagnier and C Lavallee
Interdisciplinary Sci Comput Life Sci 1 81 (2009)166 P Bellavite P Magnani E Zanolin and A Conforti Evid Based
Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
ogy 89 338 (1986)184 Z Ahmad R Pandey S Sharma and G K Khuller Indian J
Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
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Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Table I Continued
Homeopathic phytomedicine Biological effects
Lycopodium clavatum 1 M (1000C) potency reduced metastases of melanoma-affected mice234
200C potency reduces cytogenetic damage from exposure to chemical carcinogens in mice236
Nux vomica 30C potency increased total sleep time on polysomnographic recordings and short-term nonlinear effects on
electroencephalographic slow wave sleep of young adults with histories of coffee-induced insomnia228 229
30C 200C and 1000C potencies restored righting reflex sooner than untreated controls in mice injected with ethanol
4gkg challenge237
30C potency caused transient reduced coherence of electroencephalographic signals in otherwise healthy rats238
Phytolacca decandra Homeopathic mother tincture reduces proliferation activates caspase-mediated signaling and reactive oxygen species
generation with DNA damage in A375 cancer cells but not healthy lymphocytes239
200C potency exhibited inhibitory effects on 2 different breast cancer cell lines compared with solvent controls with
no difference in survival of healthy breast tissue cells from solvent controls240
3X 11X 19X 27X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated
release of pro- and anti-inflammatory cytokines by human white blood cells221
Pulsatilla nigricans 3X potency produced greater anxiolytic effects than 6X potency or bulk diazepam drug in mice on a common measure
of anxiety (elevated plus maze and open field test)241
6C 12C and 30C potencies by olfactory sniff administration produced significant effects on waking spectral alpha
electroencephalographic magnitudes in healthy young adults with constitutional traits of Pulsatilla patients controlled
for placebo sniffs242
Ruta graveolens 200C potency significantly increased lifespan of mice with transplanted Ehrlich Ascites Carcinoma and Daltonrsquos
Lymphoma Ascites induced-tumors by 497234 243
Ruta 6C in combination with Calcarea phosphorica 3X induced survival-signaling pathways in normal lymphocytes but
apoptosis-signaling pathways in human brain cancer cells194
Secale cornutum 30C potency induced changes in histological cytogenetical signal and pro-apoptotic proteins and other biomarkers of
skin papilloma in mice244
Symphytum officinale 6C potency enhanced bone formation around titanium implants in rats compared with controls245
Combination homeopathic product including Symphytum 6X potency stimulated fibroblast migration and promoted
experimental wound closure significantly better than succussed control solvent Unsuccussed solvent had no effect on
cell migration224
Taraxacum officinalis 1X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Thuja occidentalis Potency induced apoptosis in Daltonrsquos Lymphoma Ascites cells235 and 1 M (1000C) potency reduced metastases of
melanoma-affected mice234
In combination potentized medicine Canova induced macrophage biochemical activity resulting in reactive oxygen
species and nitric oxide production217
In combination potentized medicine Canova induced decreased interleukin-2 and interleukin-4 production and
differential expression of 147 genes in mouse macrophages218
In combination potentized medicine Canova reduced adverse effects of cyclophosphamide on white blood cell counts
micronucleus and DNA damage in non-human primates219
3X potency as part of a combination homeopathic product versus 20 ethanol control stimulated release of pro- and
anti-inflammatory cytokines by human white blood cells221
Viscum album 8X 16X 24X potencies as part of a combination homeopathic product versus 20 ethanol control stimulated release
of pro- and anti-inflammatory cytokines by human white blood cells221
Moreover in a recent paper from Langmuir Chikra-mane et al53 used manufactured gold nanoparticles to
demonstrate that applying Hahnemannian homeopathic
manufacturing methods makes the difference Performing
serial dilution after trituration in lactose and succussion
in 90 vv ethanol solvent of modern manufactured gold
nanoparticles causes a heterogeneous distribution and lay-
ering of the nanoparticles in part because of nanobub-
bles surrounding the NPs and rising toward the liquid-air
interface Consequently the nanoparticles are then trans-
ferred from container to container over the course of bulk
form dilutions albeit in variable amounts (Fig 2) Bulk
form materials were removed during homeopathic serial
ldquodilutionsrdquo but the nanoparticles triturated in lactose and
succussed in ethanolic solutions persisted across serial
container transfers
Korsakovian homeopathic manufacturing methods
within the same glassware container also may involve
source NP- and silica-related interactions For instance
separate from homeopathic research Kiel et al have
shown that agitation of salt solutions can concomitantly
generate and embed salt nanoparticles on glass or poly-
mer surfaces133 Furthermore the repeated agitation and
pouring of solvent solutions in and out of the same con-
tainer during homeopathic Korsakovian steps would add
capillary forces for charged particle attachment to some
silicate surfaces117 Such inner silica surfaces would be
progressively roughened and partially worn down by the
4028 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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Copyright American Scientific Publishers
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P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
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R Kannan International Journal of Green NanotechnologyBiomedicine 1 B53 (2009)
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4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
ogy 89 338 (1986)184 Z Ahmad R Pandey S Sharma and G K Khuller Indian J
Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Figure 2 Retention and transfer of gold source nanoparticles from container to container during homeopathic manufacturing procedures Lactose
trituration and succussion together offset serial ldquodilutionrdquo effect for NPs but not bulk form materials Reprinted with permission from [53] P S
Chikramane et al Langmuir 28 15864 (2012) copy 2012 American Chemical Society TL = Top layer ML =Middle layer ICP-MS = Inductively-
coupled plasma-mass spectroscopy
Notes This study found that nanobubbles formed during succussions can contribute to heterogeneous accumulation of the nanoparticles toward the
top layer of solution (froth flotation) if the metal nanoparticles were first mechanically ground in lactose per homeopathic manufacturing procedures
Middle layers in solution and bulk material contained lower and much less consistent quantities of the original gold nanoparticles
effects of the many cumulative succussions of the liquids
within the same glass container117162ndash164
At this point three different research groups have pre-
sented either electron microscopic evidence or dynamic
light scattering (DLS) data documenting persistent
nanoparticle forms of source materials in homeopathically-
manufactured medicines54ndash56 A fourth research group has
demonstrated that homeopathic ethanolic plant mother
tinctures of Gelsemium Hydrastis Phytolacca and Thujacan each biosynthesize well-characterized silver nanopar-
ticles from aqueous silver nitrate precursor40 The resul-
tant plant-modified silver NPs had different and distinct
patterns of sizes on electron microscopy dynamic light
scattering characteristics zeta potentials and biological
activity against E Coli bacteria and melanoma cancer cells
on in vitro testing40
Such findings follow repeated evidence involving mul-
tiple different types of spectroscopy thermoluminescence
and other technology that homeopathically-prepared mate-
rials in potencies differ objectively from plain or succussed
solvent controls838494160165 These verum medicines
also retain the unique ldquofingerprintsrdquo of their original
source materials on thermoluminescence testing83 Simi-
larly in nanoscience research specific metal nanoparticles
eg iron or copper NPs can enhance their thermolumi-
nescence response compared with pure silica samples92
Second the empirical evidence from multiple inde-
pendent laboratories has shown not only clinical ben-
efits but also objective changes in biological markers
in cells animals and human subjects at both low and
high potencies compared with controls166167 Table I
summarizes exemplar controlled studies using objec-
tive biomarkers of homeopathic phytomedicine effects
Skeptics rarely address the controlled cellular animal
or physiological evidence showing biological effects of
homeopathic medicines167ndash169 They also fail to distinguish
between lower and higher potencies in terms of the plausi-
bility argument Variability in findings from study to study
would be expected based on the crude traditional manu-
facturing procedures However negative findings in some
studies would not exclude the presence of NPs with bio-
logical activity in other positive studies on homeopathic
medicines The issue becomes an empirical question for
objective characterization of NPs and biological activity of
the same materials in a given study
Third numerous randomized clinical trials and asso-
ciated meta-analyses have many methodological flaws
including the obviously-inappropriate application of meta-
analysis to validate or invalidate an entire system of
medicine by combining only 8 studies across all pos-
sible diagnoses homeopathic medicines and providers
let alone study designs170 External and model validity
of study designs are also often overlooked in RCTs of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
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Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
homeopathy171 The scientific answers obtained to date
are that homeopathic medicines are not and do not
act like conventional bulk form drugs The reader is
referred to other resources for a more detailed discus-
sion of the debates over the validity and plausibility of
homeopathy167169172173
It is no longer sufficient however to use the circular
argument that any study demonstrating positive biological
or clinical effects is a fluke because of the lack of any plau-
sible active agent in homeopathically-prepared medicines
Plausible active and measurable NPs of source and silica
are present53ndash5659120165 Because of their heightened bio-
logical reactivity doses of nano-forms of plants drugs and
antigens can be far lower than for bulk forms of the same
materials to achieve comparable effects2026143 Thus low
Figure 3 Bimodal pathway for biological effects of nanoparticles or other agents based on dose level (NP= Nanoparticle)Notes Low doses of an agent can still exert salient biological signaling effects that the organism amplifies nonlinearly via a cascade of endogenous
adaptive responses across its network (see Section 32) Low doses of exogenous nanoparticles would serve as a mild stressor250 or danger signal whose
effects are amplified by the salience of the specific NPs as a threat to the organism overall Stochastic resonance using the pre-existing biological
ldquonoiserdquo pattern of disease in the organism is one of several processes by which the subthreshold signal amplification could occur
doses of homeopathically-manufactured NPs per se do not
preclude the potential for significant biological effects
The more interesting questions are currently at the
basic science and preclinical phasesmdashhow are the
homeopathically-prepared nanophytomedicines and other
NPs biologically active (Table I)174 How might they work
to stimulate systemic healing in an organism175 Then
how could additional research optimize the benefits for
clinical care What factors can inactivate homeopathically-
prepared medicines (eg heating direct sunlight certain
electromagnetic fields)95176 Despite its past controversial
history homeopathic medicine is positioned to contribute
valuable insights and guidance into how to make and use
nanophytomedicines and other natural NPs for safe and
effective care including in infections and cancer
4030 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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L Jia and X Liang Nanoscale 3 4713 (2011)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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(2011)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4035
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
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P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
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J R van Ommen Int J Pharmaceutics 414 1 (2011)106 Y Chaikin O Kedem J Raz A Vaskevich and I Rubinstein
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R Kannan International Journal of Green NanotechnologyBiomedicine 1 B53 (2009)
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and B A Snopok J Colloid Interface Sci 386 99 (2012)124 C Zhu S Guo Y Fang and S Dong ACS Nano 4 2429 (2010)125 J L Demangeat P Gries B Poitevin J J Droesbeke T M Zahaf
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of serially diluted and agitated solutions Preliminary results
1st Homeopathic Research Institute International HomeopathyResearch Conference Cutting Edge Research in HomeopathyBarcelona Spain (2013)
127 D J Anick and J A Ives Homeopathy 96 189 (2007)128 C Witt R Ludtke T E Weisshuhn and S N Willich Forschende
Komplementarmedizinund Klassische Naturheilkunde 12 6 (2005)129 L Liu T W Randolph and J F Carpenter J Pharm Sci
101 2952 (2012)130 Y Shimotsuma M Sakakura K Miura J Qiu P G Kazansky
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133 S Kiel O Grinberg N Perkas J Charmet H Kepner and
A Gedanken Beilstein J Nanotechnol 3 267 (2012)134 A Cumbo B Lorber P F Corvini W Meier and P Shahgaldian
Nat Commun 4 1503 (2013)135 H K Baca E C Carnes C E Ashley D M Lopez C Douthit
S Karlin and C J Brinker Biochim Biophys Acta 1810 259
(2011)136 R Zhu W Zhao M Zhai F Wei Z Cai N Sheng and Q Hu
Anal Chim Acta 658 209 (2010)137 A Schrade V Mailander S Ritz K Landfester and U Ziener
Macromol Biosci 12 1459 (2012)138 V Biju T Itoh A Anas A Sujith and M Ishikawa Anal Bioanal
Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and
M Sharon Colloids Surf B Biointerfaces 109 25 (2013)140 D Menon A Basanth A Retnakumari K Manzoor and S V
Nair J Biomed Nanotechnol 8 901 (2012)141 T Wang H Jiang Q Zhao S Wang M Zou and G Cheng Int
J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
I Forster Nanotoxicology 5 326 (2011)143 D Mahony A S Cavallaro F Stahr T J Mahony S Z Qiao
and N Mitter Small 9 3138 (2013)144 W J Sandberg M Lag J A Holme B Friede M Gualtieri
M Kruszewski P E Schwarze T Skuland and M Refsnes PartFibre Toxicol 9 32 (2012)
145 B Kaehr J L Townson R M Kalinich Y H Awad B S
Swartzentruber D R Dunphy and C J Brinker Proc Natl AcadSci USA 109 17336 (2012)
146 H K Baca E Carnes S Singh C Ashley D Lopez and C J
Brinker Acc Chem Res 40 836 (2007)147 X Li J Zhang and H Gu Langmuir 28 2827 (2012)148 D C Wang G Y Chen K Y Chen and C H Tsai IET
Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
Stat Nonlin Soft Matter Phys 84 061705 (2011)150 C Groger K Lutz and E Brunner Cell Biochem Biophys 50 23
(2008)151 P A Williamson P J Blower and M A Green Chem Commun
Camb 47 1568 (2011)152 Y Park S Kim J Moon J C Lee and Y Kim J Nanosci
Nanotechnol 12 1444 (2012)153 J M Almeida L De Boni W Avansi C Ribeiro E Longo A C
Hernandes and C R Mendonca Opt Express 20 15106 (2012)154 A Pawlak Colloid and Polymer Science 291 773 (2013)155 H Duran M Steinhart H J Butt and G Floudas Nano Lett
11 1671 (2011)156 S Jain H Goossens M van Duin and P Lemstra Polymer
46 8805 (2005)157 R A Roberts T Shen I C Allen W Hasan J M DeSimone
and J P Ting PLoS One 8 e62115 (2013)158 B Ruan and M Jacobi Nanoscale Research Letters 7 127 (2012)159 T A Hassan V K Rangari R K Rana and S Jeelani Ultrason
Sonochem 20 1308 (2013)160 V Elia and M Niccoli Annals of the New York Academy of Sci-
ences 879 241 (1999)161 K Lenger R P Bajpai and M Spielmann Cell Biochem Biophys
(2013)162 C E McNamee and K Higashitani Langmuir 29 5013 (2013)163 E Taran Y Kanda I U Vakarelski and K Higashitani J Colloid
Interface Sci 307 425 (2007)164 J Lim K Hippalgaonkar S C Andrews A Majumdar and
P Yang Nano Lett 12 2475 (2012)165 L Montagnier J Aissa S Ferris J-L Montagnier and C Lavallee
Interdisciplinary Sci Comput Life Sci 1 81 (2009)166 P Bellavite P Magnani E Zanolin and A Conforti Evid Based
Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
ogy 89 338 (1986)184 Z Ahmad R Pandey S Sharma and G K Khuller Indian J
Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Homeopaths have spent over 200 years using thousands
of these different natural nanoscale medicines many of
them plant-derived to treat a full range of acute and
chronic conditions in millions of patients The short- and
long-term safety data and patient acceptability of these
medicines are very favorable67177 The data suggest that
the doses of the homeopathically-made nanoparticles are
low and clinicians typically use each dose in a care-
fully timed and pulsed manner The goal of homeopathic
treatment is to stimulate innate healing processes systemi-
cally in the organism not to enforce local ligand-receptor
effects for local symptom suppression (Fig 3) Looking
for simple ligand-receptor mechanisms for isolated symp-
toms may not be productive
Conversely modern nanotechnology and particle char-
acterization and testing tools offer essential methods
for updating the 200-year-old manufacturing techniques
standardizing products and optimizing therapeutic effec-
tiveness of homeopathic medicines The absence of a way
to detect characterize and measure the active constituents
in homeopathic medicines has historically stymied high
quality clinical research The translation of NP technol-
ogy to homeopathic medicine will improve homeopathic
medicine research Conversely the translation of homeo-
pathic principles and practices will hasten important dis-
coveries in the emerging field of nanomedicine
3 PULSED DOSING AND NONLINEARDOSE-RESPONSES
31 Dosing Homeopathic NanoparticlesThere is already positive objective evidence from several
laboratories that source NPs and silicate nanostructures
are present in homeopathically-manufactured medicines
Other independent properly controlled studies using state-
of-the-science technologies such as transmission electron
microscopy dynamic light scattering zeta potentials and
nanoparticle tracking analysis will offer additional data on
identifying and characterizing the NPs40107 when present
assuming that future studies support the already accumu-
lating evidence for the presence of different sizes and
quantities of nanoparticles in homeopathically-prepared
medicines dosing regimens and safety are key issues Here
the extensive clinical experience of homeopaths comes
into play and could facilitate progress on NP dosing in
nanomedicine overall
While homeopathic NP sizes may be polydisperse
homeopathic medicine source NP doses are low and very
low mostly likely in the picograms up to 4 nanogram
milliliter range5354 In different studies silicon mea-
surements in homeopathically-prepared medicines have
ranged from 24 parts per million55 to 19ndash23 parts per
million59 and 1ndash4 mgmL57 No studies to date have
examined the potential amplification or interaction of
the source NPs with silica and silicon NPs in these
medicines Evidence from nanotechnology research sug-
gests that ensembles or multiple sizes of the same
material may contribute self-similar178 self-amplifying
effects179180 Silica and silicon nanostructures will also
add non-specific amplifying capabilities30143181 but may
also serve as drug delivery vehicles modified or imprinted
by the natural source materials for the specific medicine
Some homeopathically-prepared materials can emit mea-
surable unique electromagnetic signals165
Overall the convergent evidence suggests that phys-
ical chemistry and electron microscopic methods used
to detect nanoparticles can also distinguish specific
homeopathically-prepared medicines from solvent con-
trols Thus from nanomedicine we learn that Raman
and UV-vis spectroscopy182 and thermoluminescence92
together with other composition and particle charac-
terization techniques54 might translate ultimately into
quality control standards for homeopathic manufacturing
procedures
Moreover homeopaths emphasize the pulsed spac-
ing of repeat doses Patients typically take homeopathic
medicines by dissolving the sugar pellets under the tongue
but olfactory and dermal routes of administration are also
possible75 A subset of homeopathic clinicians favor dis-
pensing the medicine in liquid form or redissolving the
pellets in water and succussing the material immediately
prior to oral administration The latter strategy likely redis-
perses any nanostructures into smaller sizes119129
The frequency of repeat dosing is inversely related
to the homeopathic potency Thus in an acute illness
or many cancers a patient might take a homeopathic
medicine at a 6C potency every 2ndash4 hours whereas
they might take a 30C potency of the same medicine
every 8ndash12 hours If they were taking the medicine for a
slower-paced chronic disease at a higher potency such as
200C dosing might occur as infrequently as once every
few months or longer One animal study of four dif-
ferent homeopathic medicines (plants Gelsemium Sem-pervirens Cannabis Indica mushroomfungus AgaricusMuscarius and carbon Graphites) showed that the dura-
tion of their effects on restraint stress-induced catalepsy
was longer at the 200C potency than the 30C potency183
This type of prolonged action is reminiscent of reduced
doses and widely-spaced dosing regimens possible with
nano-forms of conventional drugs eg in tuberculosis ani-
mal models25184 in a transplant graft survival drug26 or
an autoimmune type 1 diabetes animal model185
Although cell plant and animal studies suggest the
likelihood that consecutive potencies exhibit a highly
nonlinear sometimes sinusoidal dose-response pattern
(Fig 4)56186ndash191 most clinicians rely on certain potencies
eg 6C 12C 30C 200C and employ their own empir-
ical systems for determining the choice of a low or high
potency for a given patient One protocol-based system
for cancer treatment reports a systematic determination of
J Nanosci Nanotechnol 15 4021ndash4038 2015 4031
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
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(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
Figure 4 Nonlinear sinusoidal dose-response curve for metabolic demethylation of veratric acid by bacterial cells Rhodococcus erythropolis to
homeopathically-manufactured formaldehyde potencies (doses) Reprinted with permission from [188] E Malarczyk et al Nonlinear Biomed Phys5 9 (2011) copy 2011 Biomed Central Ltd FA= Formaldehyde n=Number of homeopathic manufacturing cycles completed with each cycle involving
a dilution step at a ratio of 1100 followed by multiple succussions Incubation for 6 hours Ethanol concentration was 75 vv Both water and
ethanol control solutions were also succussed
Note Potencies higher than 12C are considered ldquohighrdquo in that bulk materials are likely diluted out of solution
a diagnosis-based low or high potency selection approach
for each medicine192ndash194 but clinical studies to evaluate
these potency selection issues are as yet not published
Given the evidence that different nanoparticle and clus-
ter sizes of the ldquosamerdquo composition material can lead to
differential nonlinear effect patterns30158195ndash197 it will be
crucial for future homeopathic research studies to test con-
currently (a) the nanoparticle characteristics and (b) bio-
logical effects of consecutive potencies
Finding source and silica NPs in homeopathic medicines
is an important advance in bringing this traditional sys-
tem of medicine into better scientific focus A body
of research already shows objective biological effects of
homeopathically-prepared plant-based medicines in cells
animals and human subjects at both lower and higher
potencies (Table I) However despite the enhanced bio-
logical reactivity of nanoparticle forms of natural mate-
rials such as plants the question of low dose effects
remains The next research challenge for the field is to
relate the available data to nonlinear endogenous ampli-
fication mechanisms underlying low dose effects of both
NPs and homeopathic medicines175198ndash200
32 Nonlinear Dose-Response MechanismsThe convergent thinking about how pulsed low doses of
homeopathic nanomedicines might restore health focuses
on the endogenous amplification capacity of the organ-
ism as a complex adaptive system175200 Complex adaptive
systems exhibit nonlinear dynamics self-organization and
emergent properties201 Disease and aging lead to a loss
of dynamical complexity202 Properly timed low intensity
stimuli can initiate a cascade of nonlinear adaptive bio-
logical events to restore systemic complexity especially in
the stress response networks of the body203
Various investigators have proposed three specific per-
haps overlapping mechanisms175 These all depend upon
interactions of a low dose of the salient homeopathic
nanomedicine with the history and state of the organism
(Table II) Endogenous amplification occurs as an inher-
ent aspect of the organismrsquos adaptive response capacity
The mechanisms include hormesis time-dependent sensi-
tization and stochastic resonance All three mechanisms
include the potential to reverse the direction of the sys-
temrsquos dynamics from a diseased pattern back toward a
healthier pattern It is beyond the scope of the present
paper to address the relevant issues and data in detail
However Table II provides a summary of definitions and
relevant citations for further reading The reader is referred
to the additional papers to consider this important topic in
greater depth200203
Nonlinear dose-response relationships involve both
enhanced magnitude and reversed direction of effects that
are disproportionate to the size and nature of the input
signal A unique aspect of nanoscale forms of herbs and
medicines compared with their respective bulk forms is
the multiple perhaps interacting ways in which response
amplification can occur Below is an overall summary of
possibilities175
Nanoparticle-dependent amplificationbull Heightened bioavailability and biological super-potenteffects at low doses2026 because of small size large surface
area and altered surface charge properties
4032 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
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Anal Chem (2013)107 N C Bell C Minelli J Tompkins M M Stevens and A G
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1st Homeopathic Research Institute International HomeopathyResearch Conference Cutting Edge Research in HomeopathyBarcelona Spain (2013)
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Nat Commun 4 1503 (2013)135 H K Baca E C Carnes C E Ashley D M Lopez C Douthit
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Macromol Biosci 12 1459 (2012)138 V Biju T Itoh A Anas A Sujith and M Ishikawa Anal Bioanal
Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and
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J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
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M Kruszewski P E Schwarze T Skuland and M Refsnes PartFibre Toxicol 9 32 (2012)
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146 H K Baca E Carnes S Singh C Ashley D Lopez and C J
Brinker Acc Chem Res 40 836 (2007)147 X Li J Zhang and H Gu Langmuir 28 2827 (2012)148 D C Wang G Y Chen K Y Chen and C H Tsai IET
Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
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and J P Ting PLoS One 8 e62115 (2013)158 B Ruan and M Jacobi Nanoscale Research Letters 7 127 (2012)159 T A Hassan V K Rangari R K Rana and S Jeelani Ultrason
Sonochem 20 1308 (2013)160 V Elia and M Niccoli Annals of the New York Academy of Sci-
ences 879 241 (1999)161 K Lenger R P Bajpai and M Spielmann Cell Biochem Biophys
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Interdisciplinary Sci Comput Life Sci 1 81 (2009)166 P Bellavite P Magnani E Zanolin and A Conforti Evid Based
Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
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Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
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Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
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Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
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Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
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23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
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Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
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A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
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(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
Table II Possible mechanisms for nonlinear dose-response amplification for homeopathically-manufactured nanoparticles All of these mechanisms
require interaction of low doses with the organism as a complex adaptive system
Proposed mechanism Definition
Hormesis246 Nonlinear dose-response relationship in which low doses stimulate and high doses inhibit function
Nanoparticles can cause hormesis206
Time-dependent sensitization (TDS)203 Nonlinear amplification and oscillatory process that can be initiated and elicited by intermittent repeated
(pulsed) doses of the same or a cross-sensitized drug stressor or other agent
Relies on the passage of time between doses for the organism to amplify biological and behavioral
responses247 Homeopathic medicines can cause TDS248
Stochastic resonance (SR)199 Nonlinear amplification of the effects of a weak or small signal by the concomitant presence of noise in the
system249
In the case of disease the dysfunctions that characterize the unique manifestations of the emergent
system-wide disease in the individual organism constitute the endogenous biological ldquonoiserdquo
The small SR signal would be a pulsed low dose of a salient homeopathically-prepared nanomedicine175
bull Nonspecific amplification of biologicalreactivity30142143181 if nano-silica and nano-silicon presentfrom multiple succussions in glass59125 (or nano-forms of
polypropylene or polyethylene if succussed in plastic)120
bull Self-similar antenna179204 and amplification205 functionsof different sizes of the same source nanomaterial andor
nanosilicasilicon functionalized by plant or animal DNA
and proteins in a single homeopathically-prepared nat-
ural medicine Homeopathically-prepared nanomedicines
use the whole plant not purified single components and
generate multiple different sized NPs54
Organism-based amplification of dose effectsbull Hormesismdashfor reversal of response direction using low
doses in a complex adaptive system206
bull Time-dependent sensitizationmdashfor elicitation of an
endogenously amplified response after initiation by the
same or another cross-sensitized agent or stressor reversal
of direction can occur with overly frequent dosing203207
bull Stochastic resonancemdashfor salience of the low dose as
a meaningful weak signal embedded in the larger back-
ground biological noise of the disease dysfunctions with
emergent properties across the organism as a complex
adaptive system208209
4 CONCLUSIONSThe direct nanoscience evidence for NPs in homeo-
pathicallyndashprepared medicines is promising but
admittedly limited to date Other nanotechnology lab-
oratories have the necessary equipment to replicate
extend or refute the studies already published Highly
sensitive detection methods for low and very low con-
centrations of NPs but high levels of nonlinear biological
amplification are needed However the overlaps between
mechanical attrition methods for generating NPs and
manufacturing homeopathic medicines in their initial
steps are obvious Some homeopathic manufacturers even
use the same modern ball andor cylinder milling equip-
ment that contemporary nanotechnologists themselves
use to make contemporary nanomaterials from insoluble
sources (httphahnemannlabscompreparationhtml
accessed 051513)7173112 Thus triturated lower potency
homeopathically-prepared medicines most certainly con-
tain top-down NPs and perhaps micro-sized particles
coated with lactose55 Traditionally-made succussed
higher potency homeopathically-prepared liquid medicines
contain not only natural source NPs5455 but also sili-
cates from the glassware in amounts not seen in plastic
containers55575961
Why should nanoscientists invest time and effort to
understand homeopathic NPs and their mechanisms of
action in living systems We return to the fact that these
types of natural nanomedicines have had extensive field-
testing for safety across millions of patients in real-world
clinical practice for over 200 years Official pharma-
copoeias in many countries already contain monograph
documentation for the manufacture of well over 1000
different natural agents including hundreds of nanophy-
tomedicines all made with green manufacturing methods
Homeopaths have additionally field tested several thou-
sand more custom-prepared agents from the plant min-
eral and animal kingdoms7778210 In short homeopathy
like other traditional systems of medicine has already
been in phase 4-like post-marketing real-world use for
hundreds of years This status existed long before contem-
porary Western medicine formalized ldquonewrdquo drug develop-
ment phases for their own clinical agents211
Homeopathic NP doses are very low usually far below
the recognized cut-offs for toxic effects The pulsed
spaced infrequent repetitions of doses are another time-
tested clinical strategy that ensures little risk for
cumulative toxicity over time67 Nonlinear endogenous
amplification mechanisms are likely involved in the clini-
cal response These are vitally important considerations as
modern nanomedicine experts attempt to translate promis-
ing nanomedicines into clinical practice in a more expedi-
tious manner
The present discussion raises many questions but ones
that are amenable to experimental testing and verifica-
tion For example in addition to state-dependent nonlinear
responses in the recipient organism do variations in
J Nanosci Nanotechnol 15 4021ndash4038 2015 4033
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
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6 J Li L Gu H Zhang T Liu D Tian M Zhou and S Zhou
Lab Invest 93 354 (2013)7 E M Williamson Phytomedicine 8 401 (2001)8 K Niemeyer I R Bell and M Koithan J Herbal Medicine 3 112
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B R Mehta and A Fatma Colloids Surf B Biointerfaces 81 81
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Rudek V Stearns A Maitra and S Sukumar Carcinogenesis33 2242 (2012)
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
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J Nanosci Nanotechnol 15 4021ndash4038 2015 4035
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
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4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
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J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
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Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
nanoparticle quantities sizes shapes structural defects
and surface charges of these top-down homeopathic
nanoparticles and particle dynamics in solution98212ndash214
account for some replication problems in previous home-
opathic research as they can in other nanoscience
studies100101111
Also is the serial dilution process even necessary
to make homeopathically-effective nanophytomedicines
Perhaps Hahnemann needed to introduce ldquodilutionrdquo for
mechanical separation of the nanoparticles with lac-
tose or ethanol-water diluents simply to reduce the risk
of agglomeration and aggregation but the ideal is for
the higher potencies to contain a very low but mea-
surable and consistent quantity of polydisperse NPs
Repeated succussions would likely parallel extended peri-
ods of sonication in modern NP manufacturing proce-
dures for dispersion of larger nanostructures of different
sizes74119 potentially adding more nanosilica and nanosil-
icon as carriers134 surface imprinted structures134136 and
biological amplifiers141 Are there alternative green tech-
niques for accomplishing this same goal more reliably in
the era of contemporary nanotechnology
In conclusion the identification of nanoscale struc-
tures in traditional phytomedicine systems from tradi-
tional Chinese medicine to Ayurveda to homeopathy
opens the door to important advances in integrative health-
care The extensive histories of real-world clinical appli-
cations in these traditional fields especially homeopathy
can contribute a wealth of practical insights for guid-
ing translation of numerous natural nanophytomedicines
from bench to bedside58210215 Of the traditional sys-
tems of medicine homeopathy previously one of the
most controversial brings the most extensive experience
in manufacturing top-down and possibly biosynthesized
nanophytomedicines from members of many different
plant families77210 Modern nanotechnology can add great
sophistication to nanoparticle generation characterization
and biological testing techniques for homeopathically-
prepared nanomedicines107109216 In turn homeopathy
stands ready to point toward potential strategies and mech-
anisms for safe and effective use of pulsed low dose
nanomedicines in therapeutic contexts
Competing InterestsDr Bell is a consultant to Standard HomeopathicHylands
Inc a US-based manufacturer of homeopathic medicines
Acknowledgment This study was supported in part
by National Center for Complementary and Alternative
Medicine grant T32 AT01287 (PI IRB)
References and Notes1 X Wang X Xu W Tao Y Li Y Wang and L Yang Evid Based
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Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
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Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
33 S Barua R Konwarh S S Bhattacharya P Das K S Devi T K
Maiti M Mandal and N Karak Colloids Surf B Biointerfaces105 37 (2013)
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W Zheng Int J Nanomedicine 7 835 (2012)48 I Sur D Cam M Kahraman A Baysal and M Culha Nanotech-
nology 21 175104 (2010)49 S M Meshram S R Bonde I R Gupta A K Gade and M K
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Brothers D J Anick J Centeno M A Namboodiri and W B
Jonas Homeopathy 99 15 (2010)58 I R Bell G E Schwartz N N Boyer M Koithan and A J
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cal attrition Synthesis Functionalization and Surface Treatment ofNanoparticles edited by M I Baraton American Scientific Pub-
lisher Valencia CA (2002) pp 1
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mentmed 14 301 (2007)97 G Cao and Y Wang Nanostructures and Nanomaterials Synthesis
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J Nanosci Nanotechnol 15 4021ndash4038 2015 4035
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Low Dose Traditional Nanophytomedicines Bell et al
98 H L Xin and H Zheng Nano Lett 12 1470 (2012)99 G E Batley J K Kirby and M J McLaughlin Acc Chem Res
(2012)100 I A Mudunkotuwa and V H Grassian J Environ Monit 13 1135
(2011)101 X Chang and P J Vikesland Langmuir 29 9685 (2013)102 M Fatnassi C Tourne-Peteilh T Mineva J M Devoisselle
P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
103 T Niwa and K Danjo Eur J Pharm Sci (2013)104 N Genina H Raikkonen J Heinamaki P Veski and J Yliruusi
AAPS Pharm Sci Tech 11 959 (2010)105 M A Tavares Cardoso M Talebi P A Soares C U Yurteri and
J R van Ommen Int J Pharmaceutics 414 1 (2011)106 Y Chaikin O Kedem J Raz A Vaskevich and I Rubinstein
Anal Chem (2013)107 N C Bell C Minelli J Tompkins M M Stevens and A G
Shard Langmuir 28 10860 (2012)108 A E James and J D Driskell Analyst (2013)109 C D Walkey and W C Chan Chem Soc Rev 41 2780 (2012)110 X Chang L K Duncan J Jinschek and P J Vikesland Langmuir
28 7622 (2012)111 X Chang and P J Vikesland Environ Pollut 181C 51 (2013)112 V Caron J F Willart R Lefort P Derollez F Danede and
M Descamps Carbohydr Res 346 2622 (2011)113 A R Abbasi and A Morsali Ultrason Sonochem 19 540 (2012)114 J W Yoo D S Yun and H J Kim J Nanosci Nanotechnol
6 3343 (2006)115 K R Moonoosawmy and P Kruse J Am Chem Soc 132 1572
(2010)116 Y Yang A L Yang R Q Yang G J Yuan and Y L Shi J
Nanosci Nanotechnol 11 9717 (2011)117 X Li O Niitsoo and A Couzis J Colloid Interface Sci 394 26
(2013)118 L Betti G Trebbi O Kokornaczyk D Nani M Peruzzi and
M Brizzi Int J High Dilution Res 12 127 (2013)119 C Tang T Zhou J Yang Q Zhang F Chen Q Fu and L Yang
Colloids Surf B Biointerfaces 86 189 (2011)120 S S Bhattacharyya S K Mandal R Biswas S Paul S Pathak
N Boujedaini P Belon and A R Khuda-Bukhsh Exp Biol MedMaywood 233 1591 (2008)
121 O V Kharissova H V Dias B I Kharisov B O Perez and V M
Perez Trends Biotechnol 31 240 (2013)122 K K Katti V Kattumuri S Bhaskaran K V Katti and
R Kannan International Journal of Green NanotechnologyBiomedicine 1 B53 (2009)
123 V Snitka D O Naumenko L Ramanauskaite S A Kravchenko
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of serially diluted and agitated solutions Preliminary results
1st Homeopathic Research Institute International HomeopathyResearch Conference Cutting Edge Research in HomeopathyBarcelona Spain (2013)
127 D J Anick and J A Ives Homeopathy 96 189 (2007)128 C Witt R Ludtke T E Weisshuhn and S N Willich Forschende
Komplementarmedizinund Klassische Naturheilkunde 12 6 (2005)129 L Liu T W Randolph and J F Carpenter J Pharm Sci
101 2952 (2012)130 Y Shimotsuma M Sakakura K Miura J Qiu P G Kazansky
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167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
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and J A Ives Global Advances in Health and Medicine in Press
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A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
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Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
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A J Brooks Homeopathy 101 182 (2012)
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230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
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Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
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234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
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(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
98 H L Xin and H Zheng Nano Lett 12 1470 (2012)99 G E Batley J K Kirby and M J McLaughlin Acc Chem Res
(2012)100 I A Mudunkotuwa and V H Grassian J Environ Monit 13 1135
(2011)101 X Chang and P J Vikesland Langmuir 29 9685 (2013)102 M Fatnassi C Tourne-Peteilh T Mineva J M Devoisselle
P Gaveau F Fayon and B Alonso Phys Chem Phys 14 12285(2012)
103 T Niwa and K Danjo Eur J Pharm Sci (2013)104 N Genina H Raikkonen J Heinamaki P Veski and J Yliruusi
AAPS Pharm Sci Tech 11 959 (2010)105 M A Tavares Cardoso M Talebi P A Soares C U Yurteri and
J R van Ommen Int J Pharmaceutics 414 1 (2011)106 Y Chaikin O Kedem J Raz A Vaskevich and I Rubinstein
Anal Chem (2013)107 N C Bell C Minelli J Tompkins M M Stevens and A G
Shard Langmuir 28 10860 (2012)108 A E James and J D Driskell Analyst (2013)109 C D Walkey and W C Chan Chem Soc Rev 41 2780 (2012)110 X Chang L K Duncan J Jinschek and P J Vikesland Langmuir
28 7622 (2012)111 X Chang and P J Vikesland Environ Pollut 181C 51 (2013)112 V Caron J F Willart R Lefort P Derollez F Danede and
M Descamps Carbohydr Res 346 2622 (2011)113 A R Abbasi and A Morsali Ultrason Sonochem 19 540 (2012)114 J W Yoo D S Yun and H J Kim J Nanosci Nanotechnol
6 3343 (2006)115 K R Moonoosawmy and P Kruse J Am Chem Soc 132 1572
(2010)116 Y Yang A L Yang R Q Yang G J Yuan and Y L Shi J
Nanosci Nanotechnol 11 9717 (2011)117 X Li O Niitsoo and A Couzis J Colloid Interface Sci 394 26
(2013)118 L Betti G Trebbi O Kokornaczyk D Nani M Peruzzi and
M Brizzi Int J High Dilution Res 12 127 (2013)119 C Tang T Zhou J Yang Q Zhang F Chen Q Fu and L Yang
Colloids Surf B Biointerfaces 86 189 (2011)120 S S Bhattacharyya S K Mandal R Biswas S Paul S Pathak
N Boujedaini P Belon and A R Khuda-Bukhsh Exp Biol MedMaywood 233 1591 (2008)
121 O V Kharissova H V Dias B I Kharisov B O Perez and V M
Perez Trends Biotechnol 31 240 (2013)122 K K Katti V Kattumuri S Bhaskaran K V Katti and
R Kannan International Journal of Green NanotechnologyBiomedicine 1 B53 (2009)
123 V Snitka D O Naumenko L Ramanauskaite S A Kravchenko
and B A Snopok J Colloid Interface Sci 386 99 (2012)124 C Zhu S Guo Y Fang and S Dong ACS Nano 4 2429 (2010)125 J L Demangeat P Gries B Poitevin J J Droesbeke T M Zahaf
F C Pierart and R N Miller Appl Magn Reson 26 465 (2004)126 S Cartwright Pyridinium-N-phenolates as molecular probes
of serially diluted and agitated solutions Preliminary results
1st Homeopathic Research Institute International HomeopathyResearch Conference Cutting Edge Research in HomeopathyBarcelona Spain (2013)
127 D J Anick and J A Ives Homeopathy 96 189 (2007)128 C Witt R Ludtke T E Weisshuhn and S N Willich Forschende
Komplementarmedizinund Klassische Naturheilkunde 12 6 (2005)129 L Liu T W Randolph and J F Carpenter J Pharm Sci
101 2952 (2012)130 Y Shimotsuma M Sakakura K Miura J Qiu P G Kazansky
K Fujita and K Hirao J Nanosci Nanotechnol 7 94 (2007)131 C G Pack M R Song E J Lee M Hiroshima K H Byun
J S Kim and Y Sako J Control Release (2012)132 T K Barik B Sahu and V Swain Parasitol Res 103 253 (2008)
133 S Kiel O Grinberg N Perkas J Charmet H Kepner and
A Gedanken Beilstein J Nanotechnol 3 267 (2012)134 A Cumbo B Lorber P F Corvini W Meier and P Shahgaldian
Nat Commun 4 1503 (2013)135 H K Baca E C Carnes C E Ashley D M Lopez C Douthit
S Karlin and C J Brinker Biochim Biophys Acta 1810 259
(2011)136 R Zhu W Zhao M Zhai F Wei Z Cai N Sheng and Q Hu
Anal Chim Acta 658 209 (2010)137 A Schrade V Mailander S Ritz K Landfester and U Ziener
Macromol Biosci 12 1459 (2012)138 V Biju T Itoh A Anas A Sujith and M Ishikawa Anal Bioanal
Chem 391 2469 (2008)139 S Pandey M Thakur R Shah G Oza A Mewada and
M Sharon Colloids Surf B Biointerfaces 109 25 (2013)140 D Menon A Basanth A Retnakumari K Manzoor and S V
Nair J Biomed Nanotechnol 8 901 (2012)141 T Wang H Jiang Q Zhao S Wang M Zou and G Cheng Int
J Pharm 436 351 (2012)142 M Winter H D Beer V Hornung U Kramer R P Schins and
I Forster Nanotoxicology 5 326 (2011)143 D Mahony A S Cavallaro F Stahr T J Mahony S Z Qiao
and N Mitter Small 9 3138 (2013)144 W J Sandberg M Lag J A Holme B Friede M Gualtieri
M Kruszewski P E Schwarze T Skuland and M Refsnes PartFibre Toxicol 9 32 (2012)
145 B Kaehr J L Townson R M Kalinich Y H Awad B S
Swartzentruber D R Dunphy and C J Brinker Proc Natl AcadSci USA 109 17336 (2012)
146 H K Baca E Carnes S Singh C Ashley D Lopez and C J
Brinker Acc Chem Res 40 836 (2007)147 X Li J Zhang and H Gu Langmuir 28 2827 (2012)148 D C Wang G Y Chen K Y Chen and C H Tsai IET
Nanobiotechnol 5 132 (2011)149 S Relaix R L Leheny L Reven and M Sutton Phys Rev E
Stat Nonlin Soft Matter Phys 84 061705 (2011)150 C Groger K Lutz and E Brunner Cell Biochem Biophys 50 23
(2008)151 P A Williamson P J Blower and M A Green Chem Commun
Camb 47 1568 (2011)152 Y Park S Kim J Moon J C Lee and Y Kim J Nanosci
Nanotechnol 12 1444 (2012)153 J M Almeida L De Boni W Avansi C Ribeiro E Longo A C
Hernandes and C R Mendonca Opt Express 20 15106 (2012)154 A Pawlak Colloid and Polymer Science 291 773 (2013)155 H Duran M Steinhart H J Butt and G Floudas Nano Lett
11 1671 (2011)156 S Jain H Goossens M van Duin and P Lemstra Polymer
46 8805 (2005)157 R A Roberts T Shen I C Allen W Hasan J M DeSimone
and J P Ting PLoS One 8 e62115 (2013)158 B Ruan and M Jacobi Nanoscale Research Letters 7 127 (2012)159 T A Hassan V K Rangari R K Rana and S Jeelani Ultrason
Sonochem 20 1308 (2013)160 V Elia and M Niccoli Annals of the New York Academy of Sci-
ences 879 241 (1999)161 K Lenger R P Bajpai and M Spielmann Cell Biochem Biophys
(2013)162 C E McNamee and K Higashitani Langmuir 29 5013 (2013)163 E Taran Y Kanda I U Vakarelski and K Higashitani J Colloid
Interface Sci 307 425 (2007)164 J Lim K Hippalgaonkar S C Andrews A Majumdar and
P Yang Nano Lett 12 2475 (2012)165 L Montagnier J Aissa S Ferris J-L Montagnier and C Lavallee
Interdisciplinary Sci Comput Life Sci 1 81 (2009)166 P Bellavite P Magnani E Zanolin and A Conforti Evid Based
Complement Alternat Med 2011 362517 (2011)
4036 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
ogy 89 338 (1986)184 Z Ahmad R Pandey S Sharma and G K Khuller Indian J
Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Bell et al Low Dose Traditional Nanophytomedicines
167 P Bellavite M Marzotto S Chirumbolo and A Conforti FrontBiosci Schol Ed 3 1363 (2011)
168 P Bellavite and A Signorini The Emerging Science of Homeopa-
thy Complexity Biodynamics and Nanopharmacology 2nd ed
North Atlantic Books Berkeley (2002) p 408169 P Bellavite R Ortolani F Pontarollo G Pitari and A Conforti
Evid Based Complement Alternat Med 4 149 (2007)170 R Ludtke and A L Rutten J Clin Epidemiol 61 1197 (2008)171 G Bornhoumlft S Maxion-Bergemann U Wolf G S Kienle
A Michalsen H C Vollmar S Gilbertson and P F Matthiessen
BMC Med Res Methodol 6 56 (2006)172 P W Gold S Novella R Roy D Marcus I Bell N Davidovitch
and A Saine Homeopathy 97 28 (2008)173 L Rutten R T Mathie P Fisher M Goossens and M van
Wassenhoven Med Health Care Philos (2012)174 P Endler K Thieves C Reich P Matthiessen L Bonamin
C Scherr and S Baumgartner Homeopathy 99 25 (2010)175 I R Bell B Sarter M Koithan L J Standish P Banerji and
P Banerji Journal of Nanomedicine and Nanotechnology 4 179
(2013)176 S Weber P C Endler S U Welles E Suanjak-Traidl W Scherer-
Pongratz M Frass H Spranger G Peithner and H Lothaller
Homeopathy 97 3 (2008)177 C M Witt R Ludtke N Mengler and S N Willich BMC Public
Health 8 413 (2008)178 D Timmerman and T Gregorkiewicz Nanoscale Res Lett 7 389
(2012)179 C Hoppener Z J Lapin P Bharadwaj and L Novotny Phys Rev
Lett 109 017402 (2012)180 J Cervera J A Manzanares and S Mafe Nanotechnology
22 435201 (2011)181 M K Al-Sadoon D M Rabah and G Badr Cellular Immunology
284 129 (2013)182 R Intartaglia A Barchanski K Bagga A Genovese G Das
P Wagener E Di Fabrizio A Diaspro F Brandi and
S Barcikowski Nanoscale 4 1271 (2012)183 N C Sukul S K Bala and B Bhattacharyya Psychopharmacol-
ogy 89 338 (1986)184 Z Ahmad R Pandey S Sharma and G K Khuller Indian J
Chest Dis Allied Sci 48 171 (2006)185 J Sugarman S Tsai P Santamaria and A Khadra Immunol Cell
Biol 91 350 (2013)186 P Magnani A Conforti E Zanolin M Marzotto and P Bellavite
Psychopharmacology Berl 210 533 (2010)187 D Bousta R Soulimani I Jarmouni P Belon J Falla
N Froment and C Younos J Ethnopharmacol 74 205 (2001)188 E Malarczyk M Pazdzioch-Czochra M Graz J Kochmanska-
Rdest and A Jarosz-Wilkolazka Nonlinear Biomed Phys 5 9(2011)
189 E Malarczyk J Kochmanska-Rdest and A Jarosz-Wilkolazka
Nonlinear Biomed Phys 3 10 (2009)190 F A Wiegant H A Prins and R Van Wijk Dose Response 9 209
(2011)191 M E Hyland and G T Lewith Homeopathy The Journal of the
Faculty of Homeopathy 91 145 (2002)192 P Banerji and P Banerji The Banerji Protocols A New Method of
Treatment with Homeopathic Medicine Prasanta Banerji Kolkata
India (2013)193 P Banerji D R Campbell and P Banerji Oncol Rep 20 69
(2008)194 S Pathak A S Multani P Banerji and P Banerji Int J Oncol
23 975 (2003)195 E Roduner Chemical Society Reviews 35 583 (2006)196 R C Murdock L Braydich-Stolle A M Schrand J J Schlager
and S M Hussain Toxicol Sci 101 239 (2008)197 K S Rao K El-Hami T Kodaki K Matsushige and K Makino
J Colloid Interface Sci 289 125 (2005)
198 E J Calabrese and W B Jonas Hum Exp Toxicol 29 531 (2010)199 J L Torres and M A G Ruiz British Homoeopathic Journal
85 134 (1996)200 I R Bell and M Koithan BMC Complement Altern Med 12 191
(2012)201 M Koithan I R Bell K Niemeyer and D Pincus Forschende
Komplementarmedizinund Klassische Naturheilkunde 19 7 (2012)202 A L Goldberger C K Peng and L A Lipsitz Neurobiol Aging
23 23 (2002)203 I R Bell and G E Schwartz Frontiers in Bioscience Scholar
Ed 5 685 (2013)204 E B Urena M P Kreuzer S Itzhakov H Rigneault R Quidant
D Oron and J Wenger Adv Mater 24 OP314 (2012)205 J Wang Small 1 1036 (2005)206 I Iavicoli E J Calabrese and M A Nascarella Dose Response
8 501 (2010)207 S M Antelman and A R Caggiula Critical Reviews in Neurobi-
ology 10 101 (1996)208 D N Guerra T Dunn and P Mohanty Nano Lett 9 3096 (2009)209 D K Karig P Siuti R D Dar S T Retterer M J Doktycz and
M L Simpson Nano Communication Networks 2 39 (2011)210 J Scholten Wonderful Plants Stichting Alonnissos Utrecht The
Netherlands (2013)211 V Foslashnneboslash S Grimsgaard H Walach C Ritenbaugh A J
Norheim H MacPherson G Lewith L Launsoslash M Koithan
T Falkenberg H Boon and M Aickin BMC Med Res Methodol7 7 (2007)
212 V Bendre M Gautam R Carr J Smith and A Malloy J BiomedNanotechnol 7 195 (2011)
213 S H Jung C Chen S H Cha B Yeom J H Bahng
S Srivastava J Zhu M Yang S Liu and N A Kotov J AmChem Soc 133 10688 (2011)
214 M Wright Methods Mol Biol 906 511 (2012)215 I R Bell B Sarter M Koithan P Banerji P Banerji S Jain
and J A Ives Global Advances in Health and Medicine in Press
(2013)216 J P Bourdineaud R Rossignol and D Brethes Int J Biochem
Cell Biol 45 16 (2013)217 C C de Oliveira S M de Oliveira L M Godoy J Gabardo and
F Buchi Dde J Infect 52 420 (2006)218 C C de Oliveira S M de Oliveira V M Goes C M Probst
M A Krieger and F Buchi Dde J Cell Biochem 104 1364
(2008)219 M F Leal L M Antunes M F Lamarao C E da Silva I D
da Silva P P Assumpcao E F Andrade A P Rezende A A
Imbeloni J A Muniz G R Pinto A Smith Mde and R R
Burbano Food Chem Toxicol 50 4412 (2012)220 B Glatthaar-Saalmuller Can J Physiol Pharmacol 85 1084
(2007)221 C Ramachandran P K Nair R T Clement and S J Melnick
J Altern Complement Med 13 403 (2007)222 J Chakrabarti S J Biswas and A R Khuda-Bukhsh Indian
J Exp Biol 39 1235 (2001)223 S Lussignoli S Bertani H Metelmann P Bellavite and
A Conforti Complementary Therapies in Medicine 7 225 (1999)224 K Hostanska M Rostock J Melzer S Baumgartner and
R Saller BMC Complement Altern Med 12 100 (2012)225 S Das S K Saha A De D Das and A R Khuda-Bukhsh Zhong
Xi Yi Jie He Xue Bao 10 337 (2012)226 M Oberbaum B Glatthaar-Saalmuller P Stolt and M Weiser
J Altern Complement Med 11 855 (2005)227 S J Biswas and A R Khuda-Bukhsh BMC Complement Altern
Med 2 4 (2002)228 I R Bell A Howerter N Jackson M Aickin C M Baldwin
and R R Bootzin Sleep Med 12 505 (2011)229 I R Bell A Howerter N Jackson M Aickin R R Bootzin and
A J Brooks Homeopathy 101 182 (2012)
J Nanosci Nanotechnol 15 4021ndash4038 2015 4037
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
240 M Frenkel B M Mishra S Sen P Yang A Pawlus L Vence
A Leblanc L Cohen and P Banerji Int J Oncol 36 395 (2010)241 R Lakshmipathy Prabhu A Ruckmani D Venkatesan N Mad-
husudhanan and R Pavithra Homeopathy 101 171 (2012)242 I R Bell A J Brooks A Howerter N Jackson and G E
Schwartz Homeopathy 100 203 (2011)243 K Preethi S Ellanghiyil G Kuttan and R Kuttan Integr Cancer
Ther 11 172 (2012)244 A R Khuda-Bukhsh S S Bhattacharyya S Paul S Dutta
N Boujedaini and P Belon Evid Based Complement Alternat Med2011 286320 (2011)
245 R Spin-Neto M M Belluci C E Sakakura G Scaf M T
Pepato and E Marcantonio Jr Homeopathy 99 249 (2010)246 R Van Wijk and F A Wiegant Hum Exp Toxicol 29 561
(2010)247 S M Antelman J Levine and S Gershon Molecular Psychiatry
5 350 (2000)248 I R Bell D A Lewis 2nd S E Lewis G E Schwartz A J
Brooks A Scott and C M Baldwin International Journal ofNeuroscience 114 1195 (2004)
249 M D McDonnell and D Abbott PLoS Comput Biol 5 e1000348(2009)
250 D Napierska V Rabolli L C Thomassen D Dinsdale C Prin-
cen L Gonzalez K L Poels M Kirsch-Volders D Lison J A
Martens and P H Hoet Chem Res Toxicol 25 828 (2012)
Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015
Delivered by Publishing Technology to Iris BellIP 107258215 On Tue 21 Apr 2015 181555
Copyright American Scientific Publishers
Low Dose Traditional Nanophytomedicines Bell et al
230 G Ruiz-Vega L Perez-Ordaz P Proa-Flores and Y Aguilar-Diaz
British Homoeopathic Journal 89 122 (2000)231 G Ruiz-Vega L Perez-Ordaz O Leon-Hueramo E Cruz-
Vazquez and N Sanchez-Diaz Homeopathy The Journal of theFaculty of Homeopathy 91 80 (2002)
232 G Lira-Salazar E Marines-Montiel J Torres-Monzon
F Hernandez-Hernandez and J S Salas-Benito Homeopathy95 223 (2006)
233 P Bellavite A Conforti M Marzotto P Magnani M Cristofoletti
D Olioso and M E Zanolin Evid Based Complement AlternatMed 2012 954374 (2012)
234 S Es G Kuttan P Kc and R Kuttan Asian Pac J Cancer Prev8 390 (2007)
235 E S Sunila R Kuttan K C Preethi and G Kuttan Evid BasedComplement Alternat Med 6 257 (2009)
236 S Pathak N Bhattacharjee J K Das S C Choudhury S R
Karmakar P Banerjee S Paul A Banerjee and A R Khuda-
Bukhsh Forsch Komplementmed 14 148 (2007)237 A Sukul P Sarkar S P Sinhababu and N C Sukul Br Home-
opath J 89 73 (2000)238 G Ruiz and J L Torres British Homoeopathic Journal 86 201
(1997)239 S Ghosh K Bishayee A Paul A Mukherjee S Sikdar
D Chakraborty N Boujedaini and A R Khuda-Bukhsh Journalof Integrative Medicine 11 116 (2013)
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Received 25 June 2013 Accepted 12 November 2013
4038 J Nanosci Nanotechnol 15 4021ndash4038 2015