EUROPSYC ATRIC ASPECTS 0POISO SAND TOXI S

Shreenath V. Doctor, M.D., Ph.D.

All substances are poisons; there is none which is not a poison. The right dose differ­entiates a poison and a remedy.

Paracelsus, sixteenth century

835

A poison is defined in this chapter as a material or sub­stance that is capable of producing a harmful response in

a biological life form, seriously injuring function that, ifcritical, results in the death of the organism. Toxins are

further categorized as poisons produced by various ani­mal, plant, fungal, and microbial species to which hu­mans are either intentionally or unintentionally exposed.Neurotoxic agents are poisons or toxins that specific allyproduce an adverse change in the structure and/or functionof the nervous system. Exposure to poisons and toxins,

particularly neurotoxic agents, often cause neuropsychi­atric manifestations. Several different classes of chemicalpoisons producing neuropsychiatric seq uelae are shownin Table 22-l.

Short-term or long-term exposure to neurotoxic chem­ical agents can result in various neuropsychiatric manifesta­tions, such as those shown in Tables 22-2 through 22-5 .

Exposures to neurotoxic agents may occur from theair, water, food, environmental surfaces, soil, microbes,fungi, plants, and animals or by envenomation via bitesand stings. In our industrialized society, the number of

new chem icals produced every year is estimated to be inthe thousands, and each has the potential for neuropsychi­atric sequelae. The multitude of adverse effects of the nu­merous inorganic JnJ organi c chem icals present in our en­vironment makes the subject of this chapter a broad topicarea. I discuss poisons and tox ins that have prom inentneuropsychiatric seque lae in humans and provide infor­mation, if available, on their exposure, absorption, mech­

anisms of action, diagnosis, and treatment of their effects .Included are biocides, chemicals deliberately placed in

our environment to selectively injure or kill microbes,plants, animals, and ocher forms of life. lntoxrcations dueto medications are beyond the scope of thi s chapter.

.858 The American Psychiatric Publ ishing Textbook of Neuropsychiatry and Behav ioral Neurosciences

T A BL E 22-13 . Psychoactive substances used in herbal preparations (continued)

Use Effects

Smoked or t ea as Hallucinogen

euphoriant

Chewed or tea as Hallucinogen

hallucinogen

Smoked as euphoriant Analgesic

Smoked as marijuana Mild euphoriant

substitute

Smoked or tea as tobacco Sedative

substitute

Smoked or tea as tobacco Anticholinergic

substitute or effects

hallucinogen

Smoked as tobacco Strong

st imu lant

Tea or capsules as sedative Sedative

Sm oked as opioid Possibly

substitute analgesic,

sedative

Smoked or tea as relaxant Sedative

Indole alkaloids

Active Ingredients

Rauwolfia Reserpin e

serpent ine

Datura s tramonium Atropine.

scopolam ine

Nicotiana species Ni co tine

Lactuca sat il/a Unknown

Valeriana offici/W.Lis Valepotriates,

volatile oils

roseus

Lophophora Mescaline

unlliamsi i

Argemone mexicana Protopine, berberine,

isoquinolines

Cytisus species Sparteine-

Catharanthus

Scientific name

Artemisia Thujone

abs inthium

Yohimbine Corynanthe Yohimbine Smoked or tea as Mild

[ohimbe stimulant hallucinogen

Wormwood

Wild lettuce

Prickly poppy

Valerian

Per iwinkle

Peyote

Scotch broom

Thorn-apple

Snakeroot

Tobacco

Ingredient

Source. Adapted from DeWitt Re. Dart RC: "Herbal and Indigenous Remedies, " in MedicalToxicology. Edited by Dart RC. Phil­adelphia, PA, Lippincott Williams & Wilkins, 2004, pp 1741-1747; Siegel RK: "Herbal Intoxication." Journal of the American

Medical Association 236:474-4 76. 1976 ,

MicrofungiMolds or rnicrofungi, in addition to mycotoxins, produce

medicinally useful ant ibiotics that include penicillin, ceph­

al osporin, erythromyc in, griseoful vin, and neomycin.

Molds also produce the potent immunosuppressants

cyclosporine and ta croli rnus used for organ transplantation

andcoumadin used commonly 3S an anticoagu lant and anti­

thrombotic agent. Also derived from mold are the structur­

ally complex ergot alkaloids (Figure 22-8), such as ergota­

mine, lysergic acid diethylam ide, and bromocriptine .

Chemically synt h e sized analogues of spec ific less

toxic and nonhallucinogenic ergot alkaloids continue to

be medically useful in uterine stimulation, to inhibit pro­

lactin production, to control po stpartum hemorrhage , to

treat migraine headaches and Parkinson's d isease, and to

stimulate cerebral and peripheral metabolism [Benn ettand Klich 2003) .

Molds or microfungi produce three types of illness: al­

lergy, toxicity, and infection . Consistent with the objective

of this chapter, only the toxic effects of microfungi are

covered . The toxic effects of mold or micro fungi are

caused by mycoroxins, Mycotoxins, produced by filamen­

tous fungi, are low-molecular-weight secondary metabo­

lites not critical to fungal cell processes that are e xtremely

toxic in low concentrations. These metabolites ar e chem­

ically heterogeneous yet grouped together solely because

of their abil ity to cau se disease and death in humans and

other vertebrates (Bennett and Klich 2003) . Mycotoxins

seem to give mold a competit ive advantage in the biologi­

cal struggle over other mold species, bacteria, and other

organisms competing for the same ecological niche. Ap ­

proximately 400 known rnycotoxins exist, of which only a

do zen grou ps of rnycotoxin s are well known. Exposure to

rnycotoxins can occur through ingestion, inhalation, and

859

TABLE 22-/4 . Majo r halluc inogenic plants a nd the ir acti ve components-------------- - ----

Plant

Cannabis sativa

Lophophora unlliamsii

Piptadenia species

Mimosa species

Virola species

Banisleriopsis species

Peganum harmala

Tabemaruhe iboga

Ipomoea uiolacea

Turbina corymbosa

Datura species

M ethysticodendron amesianum

Amanita muscaria

Family

Cannabinaceae

Cactaceae

Legum inosae

Legurninosae

Myristicaceae

Malpighiaceae

Zygophyllaceae

Apocynaceae

Can volvu laceae

Convolvulaceae

Solanaceae

Solanaceae

Agaricaceae

Active component

Tetra hydrocannabinol

Mescaline

Substituted tryptamincs

Substituted tryptarnines

Substituted tryptamines

Harmaline, harmine

Harmal ine, harmine

Ibogaine

D-Lysergic acid amide, D-isoly sergic acid amide

D-Lysergic acid amide, n-Isolvsergic acid amide

Scopo larnine

Scopola mine

Panrherine, iborenic acid

Psilocybe mexicana Agaricaceae

Source. Adapted from Farnsworth 1986.

dermal exposure of viable or nonviable mold spores, spore

fragments, and mycelia. Mycotoxins are lipid soluble and

readily absorbed by the intestinal lining, airways, and skin.

The public has an increased awareness of and interest

in mycotoxins because of both their presence in water­

damaged homes and buildings in which mold is present

and their production and deliberate use by terrorists.

Commonly found mycotoxins include allatoxins,

which are very potent carcinogens, and hepatotoxins pro­

duced by the Aspergillus species; ochratoxins, which are

nephrotoxic and carcinogenic. produced by several species

of Aspergillus and Penicillium; sterigmatocystin, which is

immunosuppressive and a liver carcinogen , produced byspecies of Aspergillus, particularly AspergiUrLS versicolor;and trichothecenes, which are produced primarily by spe­

cies of Stachybotrys and Fusarium. Physicians have re­

cently become more aware of the effects of rnycoroxins. In

1994, attention focused on a cluster of 10 cases of infants

with acute idiopathic pulmonary hemorrhage and hemosi­

derosis. A case-control study comparing chose to infants

with 30 age-matched control infants from the same area of

Cleveland, Ohio, reported that the infants with acute pul­

monary hemorrhage resided in homes with water damage

and resultant mold infestation. Because of the rapid

growth of the lungs in an infant, the effects of inhaled my­

cotoxins in infants were severe (Kilburn 2003a) . As a re­

sult, the American Academy of Pediatrics currently recom­

mends that physicians ask parents about mold exposure.

Psilocybin

Mycor oxins appear in water-damaged homes and

buildings be cause intrusion of water into houses, offices,

and buildings leads to the growth of mold. Building ma­

terials, including wood and wood products, insulation

materials, carpet, fabric and upholstery, drywall, and cel­

lulose substrates (including paper and paper products,

cardboard, ceiling til es, and wallpaper) , are suitable nu­

trient sources for fungal growth. Health symptoms asso­

ciated with mold infestation or water damage in a build­

ing involve multiple organs such as upper and lower

respiratory tracts, gastrointestinal tract, urinary tract, cir­

culatory system, and the central and peripheral nervous

systems. Studies have shown adverse effects on the ner­

vous system in humans exposed to mold in buildings with

water damage. Mycotoxins, which art" prominent neuro­

toxins or product" neuropsychiatric effects , inelude the

ergot alkaloids, trichothccenes, fumonisins , patulin, and

trernorgens (Figure 22-9).

N e uro psychia t r ic manifestations. The neuropsychi­atric manifestations of rnycotoxins were first noted in the

Middle Ages, when outbreaks of ergotism were caused by

eating wheat or rye contaminated with the mold Clavi­

ceps purpurea, which produced ergot alkaloids and hallu­

cinogens such as lysergic acid diethylamide , resulting in

the deaths of thousands of people in Europe. Human

ergotism manifests in a disorder characterized by mania,

hallucinations, d elusions, severe peripheral paresthesias,

860 Th e American Psychiatr ic Pub lish ing Textbook of Neuropsych iatry and Be haviora l Neurosciences

Source . Adapted from Spoerke DG, Hall AH: "Plants and Mushrooms of Abuse." Emergency Medicine Clinics of North America8:579-593, 1990.

TAB LE 22- 15 . Plants of abuse

Plant Part used Toxic agent

Argyreia nervosa Seed Ergoline hallucinogens

Atropa bel1adonna Seed Tropane alkaloids

Banisteriopsis species Various Harmaline (hallucinogen)

Cola nitida Seed Caffeine

Datura spe cies Seed Tropane alkaloids

Hyoscyamus niger Whole plant Tropane alkaloids

llex paraguariensis Leaf Caffeine

Lophophora

Mandragora officinarum Whole plant Tropane alkaloids

Methysticodendron amesianurn Stem/l eaf Tropane alkaloids

Mimosa hostilis Root Phenylamine hallucinogens

Olmedioperebea sclerophylla Fruit Unknown hallucinogen

Passijlora incarnate Stem/leaf Harma line (hallu cinogen)

Peganum harmala Seed Harmaline (hallucinogen)

Piper methysticum Root Methystlcin/kawain

Piptadenia colubrinll See d Phenylamine hallucinogens

Piptadenia excelsa Seed Phenylarn ine hallucinogens

Piptadenia macrocarpa Seed Phenylam ine hallucinogens

Piptadenia peregrina Seed/bark Phenylamine hallucinogens

Salvia divinorum Leaf Unknown hallucinogen

Sophora. secundillora Seed Cytosine (stimulant)

Tabemanthe iboga Root Ibogaine (hallucinogen)

Trichocereus pachanoi Cactus Mescaline

Virola calophylla Bark Phenylarnine hallucinogens

convulsions , violent muscle spasms, vomiting, diarrhea ,abdominal pain, coronary vasoconstriction, peripheralvasoconstriction, and gangrene (Bennett and Klich 2003).

Indoor molds present following water damage includePenicillium, Aspergillus, Cladosporium, Alternaria, S/achy·botrys, and Fusarium species . Each is capable of producingvarying amounts of mycotoxins, including the neurotoxicergot alkaloids, trichotheccncs, and trernorgens. How­ever, the health effects of an exposure to building-related

mold are difficult to assess be cause the exposures areinevitably from multiple species, each producing mu lti­ple mycotoxins, and con sequently, healt h effects o f expo­sure are termed a mixed-mold mycOtDXiCOSlS (G ray et al.2003) .

A significant body of literature exists regarding the neu­ropsychiatric and neuropsychological effects of mixed­mold exposure in the form of independent case series . In­

dependent studies of more than ] ,600 patients with ill ef­fects associated with fungal exposure were presented at the21st Annual Symposium on Man and H is Environment inDallas, Texas, in 2003. Two case series of 48 and 150 mold­exposed patients found significant fatigue and weakness in70% and 100% of patients, respectively, and neurocognitive

dysfunction, including memory loss, irritability, anxiety, anddepression, in more than 40% of the patients in both series .Classic man ifestation s of neurotoxicity, including numb­ness, tingling, and tremor, were observed in a significantnumber of the patien ts (Liebcnnan 2003; Rea et al. 2003).

/OHHO-P

l~oHo

/CH3

~--.,...-CH2 - CH2 - N,CH3

NH

Psilocybin

Ho

Psilocin

F I G U R E 22-7 . Chemical structures of psilocybin and psilocin.

86 1

Ergotamine 2-Bromo-a-ergocryptine lysergic acid diethylamide

FI G U RE 22-8 . Chemical structures of pharm acologically active ergot alkalo ids der ived from mold .

862 The American P ~ychiatric Publ ishing Textbook of Neu ro ps ychi a t r y an d Behavio r a l N e uroscie nce s

COOHO~ I

'\:CCH2CHCH2COOH

6 OH OH

Fumonisin B1

Penitrem A1Rl=CIR2=OHR3=-H

Penitrem B1Rl =.H

R2=-HR3=-H

Patulin

Verruculogen

Territrem B

Trichethecene (T-2) toxin

F IG U R E 22-9 . Chemical stru ctur-es of some representative rnycotoxins with reported neurotoxicity.

A study by Campbell and colleagues (2003) evaluated 119mixed-mold-exposed patients who had multiorgan symp­

toms and peripheral neuropathy. Subjective complaints in­

cluded severe fatigue, decreased muscle strength, sleep dis­turbances, numbness and tingling of extremities with and

without tremors of the fingers and hands, and severe head­ache. Object ively, 99 (83%) of these individuals had abnor­mal nerv e conduction velocit ies in association with autoan­

tibodies against nine neural antigens, whereas the rem aining

20 (17 %) had normal test result s (Campbell et al. 2004) . A

st udy of 43 mixed-mold-exposed pat ients found that they

performed significantly worse (P<O.oOOI) than 202 controlsubjects on lTIany neuropsychiatric tests, including balance

sway speed, blinking reflex, color perception, reaction

times, and left grip strength (Gray et al. 2003) .

Quantitative EEG studies in 182 patients with docu­mented mold ex posure also noted significant differencesin brain waves, with hypoactivation of the frontal cortex

and narrowed frequency bands (Crago et al. 2003). Inthese 182 patients, increased severity of mold exposure,by either increased duration of exposure, increased de n­

sity of spores in air, or presence of a more toxigenic spe­

c ies, was significantly associated with more abnorm al

quantitative EEG results as well as worse scores on CO

centrarion, motor skills, and verbal skills tests (Crago et al,2003) . Triple-headed single photon emission computed

tomography (SPECT) brain scans identified neurotoxicpatterns in 26 of 30 (87%) mold-exposed patients (Simonand Rea 2003). Assessment of the autonomic nervousfunction in 60 mixed-mold-exposed patients by iriscorderfound that 95% had abnormal autonomic responses of thepupil compared with the population reference range. Vi­sual contrast sensitivity studies had significantly abnormalresults in indoor mold-exposed patients (Rea et al. 2003).

Additional studies have reported that compared withthe general population reference range, mold-exposed pa­tients perform significantly worse on tests of attention, bal­ance, reaction time, verbal recall, concentration, memory,and finger tapping (Didricksen 2003; Gordon et al. 1999;Kilburn 2003a, 2003b) . Studies of children and adults whowere exposed to indoor molds found significantly more neu­rophysiological abnormalities than in control subjects, in­cluding abnormal EEG findings and abnormal brain stem,visual, and somatosensory evoked potentials (Anyanwu etal. 2003a, 2003b; Baldo et al. 2002; Campbell et al. 2003).

Lieberman (2003) presented a case series of 12 patientswho developed tremors following documented heavymixed-indoor-mold exposure. Numerous articles have re­

ported domestic dogs developing tremors following inges­tion of moldy food (Boysen et al, 2002; Naude et al. 2002).Tremorgens are mycotoxins that contain an indole moiety,presumably derived from tryptophan, and that producetremors or seizures in animals consuming toxic amounts ofcontaminated foodstuffs (Peterson et al. 1982) . Molds ofthe genera Penicillium and Aspergillus produce most of the

tremorgenic rnycotoxins. At least five groups oftremorgensexist, including the penirre ms, verruculogens, paspali­trerns, fumitremorgins, and tryptoquivaline group. Themore common tremorgens-penitrems and verruculo­gens-grow in moldy refrigerated foods, cottage cheese,and cream cheese as well as moldy peanuts and grain.

Me chan ism s of action. Verruculogens increase thespontaneous release of glutamate and aspartate by 1,300%and 1,200%, respectively, but not that of y-aminobutyricacid (GABA) from cerebrocortical synaptosornes in sheep(Bradford et al. 1990). The st imu Ius for the releaseappears to be subcortical (Peterson et 011. 1982). TerritrernB, produced by the common fungus Aspergillus terreus,can, like an organophosphate pesticide, irreversibly bind toand inhibit the enzyme acetylcholinesterase (Chen et al.1999) . Similarly, the potent tremorgenic mycotoxin furni­tremorgin A produces violent clonic-tonic convulsions ,nystagmus, miosis, bradycardia, and arrhythmia consistentwith excessive cholinergic stimulation (Nishiyama andKuga 1986) . Fumonisins and fumonisin analogues disruptformation of complex sphingolipids through inhibition ofceramide synthase, with resultant apoptosis (Desai et al,

863

2002) and disruption of folate transport , which canpotentially result in human neural tube defects [Marasa set al. 2004). Paxilline, a trernorgenic alkaloid mycotcxi nproduced by Penicillium paxilline, is a reversible inhib­itor of cerebellar inositol l,4,S-triphosphate receptorthat decreases the extent of inositol 1,4,S-triphosphate­induced calcium release (Longland et al. 2000).

Penirrern A, produced by the common Penicilliumand Aspergillus genera. can cause severe generalizedtremors and ataxia that persist for up to 48 hours, and itaffects the cerebellar region: initial exposure to penitrern

A results in a three- to fourfold increase in cerebellar cor­tical blood flow. Mitochondrial swelling occurs in cere­bellar stellate and basket cells . Purkinje's cells develop in­tense cytoplasmic condensation with eosinophilia thatresembles "ischemic cell change, " whereas many otherPurkinjes cells show marked watery swelling. Astrocytesswell from hypertrophy of organelles, and discrete foci ofnecrosis appear in the granule cell layer, while permeabil­ity of overlying meningeal vessels becomes evident. Allchanges are more severe in vermis and paravermis, withno morphological changes in other brain regions. The af­finities of penitrem A for high-conductance calcium­dependent potassium channels and for GABA receptorsand resultant cxcttotoxity appear to be important under­lying factors for these changes (Cavanagh et a!. 1998) .Penitrern A increased the spontaneous release of endoge­nous glutamate, GABA, and aspartate by 213%, 455%,and 277%, respectively, from cerebrocorticalsynapto­somes. In neurons, pen itrem A increased the resting po­tential , end-plate potential, duration of depolarization,and presynaptic transmitter releas e (Norris et al. 1980).

Diagnosis. It is important to elicit a patient's history ofexposure to mold whether in the workplace or at home.A neuropsychiatrist should evaluate patients exposed tomixed mold carefully, particularly if neurocognitivesymptoms and neuropsychiatric symptoms arise afterindoor exposure to high levels of mixed mold . Forpatients who have had substantial exposure to mold, abattery of tests has been developed that includes visualcontrast sensitivity and pupillometry to assist in deter­mining autonomic nervous system functioning. The eval­uation should include;) neuropsychiatric examinationand a comprehensive metabolic panel that includes elec­trolytes, blood glucose, liver and kidney function tests,immune tests for autoantibodies, antibodies to the moldor mycotoxin, complement, gamma globulins, and lym­phocyte panels. EEG and brain imaging such as MRI andSPECT are helpful tools in determination of neurologicalinjury. Presence of rnycotoxins or metabolites in the urineusually confirms the diagnosis (Curtis et al. 2004).

864 T h e Am e rican Psych ia t r ic P ub lish ing Textbo ok of Neuropsyc hiatry and Be havio ra l Ne uro scie nce s

Treatment . The most important facet of treatment

involves preventing any further exposure of the patient to

mold. The potent toxicity of these agents warrants prudent

prevention of exposures when lev els of mold species

indoors exceed outdoor levels by any significant amount .

AN IM A L T OXINS

Animals capable of secreting a poison by biting or stinging

are termed venomous . Animals referred to as poisonous are

organisms whose tissues , in part or in entirety, are toxic.

Venoms are complex mixtures of enzymes and proteins

(Table 22-16) with various components that are neuro­

toxins, myotoxins, hemostatic system toxins, hernorrha­

gins, nephrotoxi ns, card iotoxins, and nccrotoxins (Ellen­

horn 1997; Ru ssell 1983; White 2004a). Venomous

snakes cause more than 30,000 deaths worldwide each

year. Most deaths caused by snakebites in the United

States are due to rattlesnake bites. Of the five families of

venomous snakes, only Elapidae, or elapids, which include

cobras , mambas, sea snakes, kraits, and death adders, and

Viperidae, or vipers, which inclu de Russell's viper and pit

vipers, produce significant neurotoxic symptoms (White

2004b, 2004c). Effects of bites from these snakes include

flaccid neurotox ic paralysis that is usually the result of

neuromuscular junction pre- and postsynaptic neurotox­

ins, which eet systernicall y rather th an locally, affecting

voluntary and respiratory muscle. Flaccid paralysis is pro­

gressive and may take from I to ] 2 hours to become evi­

dent . The paralysis of the cranial nerves is often seen first,

with partial ptosis, followed by complete ophthalmople­

gia , loss of facial tone, dysarthria, and dysphagia. The

pupils may become dilated and unresponsive to light, fol­

lowed by progressive weakness of the limbs and bulbar

function. The acc essory muscles of respiration may

become more prominent, and the patient may become

more agit ated or drowsy as hypoxia ensues. The dia­

phragm is freque ntl y th e last muscle affected and, even

so, may not be fully affected for 24 hours . Without timely

intubat ion and ventilation to secure the airway, complete

respiratory paralysis and death follow (White 20043) .

Treatment of venomous snakebites includes diagnosis

and history surrounding the incid e nt involving the bite.

Diagnostic tests should include urine output, complete

blood count , electrolytes and renal fun cti on, creatine ki­nase and liver function tests, and coagulation studies. Op­

timal management for major envenomation with respira­

tory support may require treatment in an int ensive care

unit. Medical management includes administration of an­

tivenorns, local wound care, supportive measures, admin­

istration of antibiotics, and tetanus prophylaxi s (Ellen­horn 1997; Nelson 1989; White 20043) .

TAB LE 2 2-1 6 . C omposition o f snake venoms

Acetylcholinesterase

L-Amino acid oxidase

Arginine ester hydrolase

Collagenase

DNase

Hyaluronidase

Lactate dehydrogenase

Nicotinamide adenine dinucleotide (NAD)-

nucleotidase

5' -Nucleotidase

Phosphodiesterase

Phospholipase A2 (A)

Phospholipase B

Phospholipase C

Phosphomonoesterase

Proteolytic enzymes

RNase

Thrornbinlike, enzyme

Source. Adapted from Ellenboro MJ: Ellenhorn's Medical

Toxicology: DiagllOsis and Treatment of Human Poisoning. Bal­timore, MD, Williams & Wilkins, 1997; Russell FE: SnakeVenom Poisoning. Great Neck, NY, Scholiom International,

1983.

CHEMICAL WARFARE AGENTS

Around the world, terrorism has become a stark reality.

News reports steadily remind us of groups of te rrorists

that are intent on harming or killing civilians or noncom­

batants for fanatical causes . Terrorist atta cks in the

United States including those of September 11, 2001, on

th e World Trade Center and the Pentagon, attacks in

more than 250 other countries, and, most recently, chlo­

rine gas attacks in Iraq in 2007 have led the United States

into an era of awareness and resolve to prepare for future

attacks. With certainty that terrorism will continue, the

use of chemical agents and toxin s purposefully to induce

fear in, injure, or kill both civilian and military personnel

has become a realistic concern.

N ERVE A GENTS

Nerve agents are particularly potent organophosphatesused for chemical warfare (Figure 22-10). Nerve agents

encompass a variety of compounds that have the capacity

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