Cmrmrnw5PtariesMedicinal Herbs in the United States: Research NeedsHazel B. Matthews,1 George W Lucier,1 and Kenneth D. Fisher2'National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; 2Office of Disease Prevention andHealth Promotion, Department of Health and Human Services, Washington, DC, USA

Virually all cultures have, throughout history, used a variety of plants or materials derived fromplants for the prevention and treatment of disease. Evidence of the beneficial therapeutic effects ofthese medial herbs is seen in their continued use. Additionally, the development of modernchemistry permitted the isolation of chemnicals from medicinal herbs that have served as drugs orstarting materials for the synthesis of many important drugs used today. Many more moderndrugs have been synthesized as a result of knowledge gained from studies of mechanisms ofactions of chemicals first isolated from medicinal herbs. Thus, medicinal herbs have played amajor role in the development of modern medicine and continue to be widely used in their origi-nal form. Whereas it is generally agreed that most medicinal herbs are safe under the conditionsused, some are toxic and should be avoided even though they are readily available, and othershave significant adverse side effects when misused. Also, little has been done to investigate poten-tial adverse effects that may be associated with extended or high-dose use of medicinal herbs.Thus, concern has been expressed that the lack of quality control used in the preparation of medi-cinal herbs, plus their unregulated sale and uninformed use, pose potential adverse health effectsfor consumers. There is also concer regarding potential herblherb or herbldrug interactions andpossible untoward health effects of medicinal herbs in sensitive subpopulations such as the youngand the elderly and certain genetically predisposed individuals. In this paper, we discuss theseconcerns at some length and make recommendations for additional research and education dis-cussed in the recent International Workshop to Evaluate Research Needs on the Use and Safety ofMedicinal Herbs. Key wordk; medicinal herbs, dietary supplements. Environ Health Perspect107:773-778 (1999). [Online 25 August 1999]hnp://ehpneatl.niehs.nih.gov/d,ocs/9991107p 773-778matthewslabstract htm!

Much ofwhat is today considered "alternativemedicine" in the more developed countrieswas, in the not too distant past, the only med-icine. Indeed, a major portion of the world'spopulation still depends almost exclusively onwhat many in the more developed countriesconsider alternative forms of treatment formost health-related problems. In most cul-tures, medicinal herbs have long constituted amajor component of these traditional or alter-native treatments. Knowledge of the thera-peutic properties of plants predates recordedhistory, and great respect was given to thosewho possessed and passed on this knowledgeto succeeding generations. When consumed,made into teas or infusions, or when applieddirectly to an injury, certain plants appearedto have almost magical healing properties.Thus, among the treasures sought by earlyexplorers was knowledge of the existence anduse of new medicinal plants. These plants andknowledge of their therapeutic uses werereturned to the home countries as part of thejustification of early explorations. Export ofmedicinal plants back to the home countriesplayed a major role in disseminating both theplants and knowledge of their medicinalproperties and helped to establish both earlytrade between countries and the basis ofmod-ern pharmaceuticals.

Knowledge gained from the use of medi-cinal herbs and their active ingredients serves

as the foundation for much of modern phar-macology. Drugs such as aspirin, digitalis,morphine, and quinine were all originallyisolated or synthesized from materials derivedfrom plants. Perhaps more important to thedevelopment of pharmacology has beenknowledge gained from studies of the mecha-nisms of action of naturally occurring chemi-cals derived from medicinal plants. Studies ofchemicals derived from plants have support-ed the development of new synthetic chemi-cals that account for a major portion of thedrugs used in modern medicine. This fact iswell recognized by today's biomedical com-munity that continues to send modernexplorers to the corners of the earth to findnew plant-related cures for our maladies.

The historic role of medicinal herbs inthe treatment and prevention of diseaseand their role as catalysts in the developmentof pharmacology do not, however, assuretheir safety for uncontrolled use by anuninformed public. Concern regarding thecurrent proliferation of widespread, uncon-trolled, and largely uninformed or misin-formed use of medicinal herbs was thesubject of a recent editorial in the NewEnglandJournal ofMedicine (NEJM) (1) anda series of articles in the Journal of theAmerican Medical Association (JAMA) (2).The recent International Workshop toEvaluate Research Needs on the Use and

Safety of Medicinal Herbs addressed theneed for additional research to support moreeffective and safe use of medicinal herbs (3).

Use of Medicinal Herbs in theUnited StatesThere is little question that many medicinalherbs have preventive and/or therapeuticeffects. Thus, like any therapeutic agent,when overdosed or incorrectly used, they alsohave the potential to induce adverse effects.The likelihood of adverse effects increaseswhen the production and sale of such prod-ucts is largely uncontrolled and the consumeris not adequately informed as to their properuses. These concerns have been the majorfocus of the recent articles (1,2) and the work-shop mentioned above. In their editorial inNEJM, Angell and Kassirer (1) discussed thesignificance of the large and rapidly increasinguse of medicinal herbs in the United States.They expressed concern for possible risksassociated with widespread use of prepara-tions that have not been scientifically tested.They also pointed out that, while most herbalremedies are probably harmless, some may bequite toxic, and the consumer is largely unin-formed as to possible adverse effects. In hisguest editorial in JAMA, Wayne Jonas (4),former Director of the National Institutes ofHealth Office of Alternative Medicine,endeavored to look at both sides of the issueand stressed the fact that there are positiveand negative aspects of both alternative andconventional medicine. He pointed out thatconventional medicine excels in the use of sci-entific methods to authenticate its benefits,whereas alternative medicine depends largelyon anecdotal reports. He cautioned, however,that the beneficial effects of medicinal herbsmay vary because of the lack of standardiza-tion in collection and processing. Thus, whileacknowledging the beneficial effects of alter-native medicine, Jonas (4) urged increasedresearch to confirm the beneficial and safeuses and further research into the mechanismsthat account for the therapeutic effects ofalternative treatments. In the same issue ofJAMA, Fontanarosa and Lundberg (5) pointedout that, although millions of patients use

Address correspondence to H.B. Matthews,NIEHS (B3-10), PO Box 12233, ResearchTriangle Park, NC 27709-2233 USA. Telephone:(919) 541-3252. Fax: (919) 541-4632. E-mail:matthews@niehs.nih.govReceived 23 February 1999; accepted 7 May 1999.

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alternative practices such as medicinal herbs,these practices have not been subjects of prop-erly designed and conducted randomized con-trol trials. Thus, consumers are spending bil-lions of dollars annually for remedies that mayor may not be effective and, in most cases, arenot reimbursed by insurance. Fontanarosaand Lundberg (5) also pointed out that, insome incidences, the alternative methods usedmay, in fact, be contraindicated.

The use of medicinal herbs in the UnitedStates, which was quite common in the nine-teenth century and early in the twentiethcentury, dedined with increased knowledgeof the germ theory of disease and theincreased availability of synthetic drugs. Therecent resurgence in the use of medicinalherbs is speculated to be due to some disillu-sionment with conventional medicine and itsincreased costs plus changes in health caredelivery systems that make them moreimpersonal. There has also been increasedinterest in the use of "natural" alternatives inthe mistaken impression that natural prod-ucts are always safe. Marketing and use ofthese "natural" alternatives were greatly facili-tated by the passage of the DietarySupplement Health and Education Act of1994 (DSHEA) (6). The DSHEA includedmedicinal herbs and other botanical productsin the definition of dietary supplements.Thus, unless approved by the Food and DrugAdministration (FDA), specific preventativeor therapeutic claims cannot be made formedicinal herbs. Evidence of preventiveand/or therapeutic effects can, however, bestrongly inferred. (Medicinal herbs are morewidely used in many other developed coun-tries, such as Germany, than in the UnitedStates. They are frequently prescribed bydoctors, and their costs are often covered byinsurance. However, many of the productsthat are readily available through a variety ofretail outlets in the United States are moreclosely controlled and are available only byprescription in many European countries.)

As a result of increased interest and pro-motion and limited control, approximately40% of the U.S. population is reported touse some sort of dietary supplement.Medicinal herbs now constitute the mostrapidly growing segment of the total U.S.pharmaceutical market. According to thePresidential Commission on DietarySupplement Labels, some 1,500-1,800botanical products are sold in the UnitedStates as dietary supplements or ethnic med-icinals (7). These formulations are beingconsumed by tens of millions of U.S. citi-zens for both treatment and prevention of awide variety of health-related problems.Estimates of the market value of herbal med-icines in this country vary, but all sourcesagree it is a multibillion dollar industry.

Concerns Regarding the Useof Medicinal Herbs

A major portion of the world's populationdepends almost exclusively on herbal prod-ucts and other alternative methods as theprimary defense against or treatment for dis-ease and various organic disorders. Further,many botanical products continue to be usedtoday in a manner identical or very similarto that used for thousands of years. Thislong history of use lends credibility to sup-port the beneficial effects of herbal medi-cines in the prevention and treatment of dis-ease. However, although most botanicalproducts are probably safe under most con-

ditions, some are known to be toxic at highdoses and others may have potentiallyadverse effects under some conditions. Thatis, it must be assumed that if they have bene-ficial therapeutic effects, the chemicals inmedicinal herbs, just as those in syntheticdrugs, also have the potential to cause

adverse effects. The intensity of adverseeffects would be expected to vary with dose,responses of sensitive individuals based on

genetic predisposition, diet, drug interac-tions, and other factors. Because medicinalherbs are not prescribed by physicians or dis-pensed by pharmacists, reports of theiradverse effects are largely anecdotal. Thus,documentation of adverse effects associatedwith the use of medicinal herbs is largelylimited to those reports associated with over-

dose and allergic reactions.A number of plants that have been or are

currently used as medicinal herbs are alsoknown to be ineffective or toxic and are notrecommended for use. The English transla-tion of The Complete German Commission EMonographs: Therapeutic Guide to HerbalMedicines (8) lists more than 100 such inef-fective or toxic herbs that have been usedmedicinally but are no longer recommended.Many are still available, however, and are

found in retail outlets along with safe andeffective medicinal herbs. There have been a

number of cases of injury and even deathresulting from misuse, contamination,and/or adulteration of medicinal herbs (9).Also, because they are not regulated for con-

tent or efficacy, it is not possible to knowhow often medicinal herbs fail to contain theadvertised active ingredient and thus have no

effect. It is also impossible to determinewhen a product might have contained sub-stances that resulted in subtle adverse effectsthat were not reported. Similarly, it is quitepossible that the placebo effect resultingfrom widespread advertising, popular pro-

motion, and the natural tendency of mostcommon maladies to run their course

accounts for much of the beneficial effectsachieved with some products.

Other concerns regarding the use of med-icinal herbs include the possibility ofherb/herb or herb/drug interactions andallergic reactions (7-9). Any pharmacologi-cally active agent has the potential to result insynergistic or antagonistic interaction whenconsumed with other pharmacologicallyactive compounds. This is no less the case formedicinal herbs. Medicinal herbs that havesimilar or opposite therapeutic effects asdrugs or those that inhibit the metabolism ofdrugs are the most likely candidates foradverse interactions. Depending on the inter-action involved, the action of a syntheticdrug may be enhanced or suppressed by co-administration of an herb and vice versa.Because interactions are not systematicallydocumented and such reports are largelyanecdotal, concern has been expressedregarding potential interactions involvingprescription drugs. Warfarin, for example, isadministered to delay blood clot formationand could be potentiated by co-administra-tion of feverfew, garlic, ginkgo, ginger, orginseng, which have similar actions (10).Taken together, warfarin and one or more ofthese herbs might cause the patient to hem-orrhage. St. John's wort, which is known toenhance photosensitivity (11), should not beused with other known photosensitizers (e.g.,tetracycline). Additionally, St. John's wort isknown to inhibit monoamine oxidase andmay thus enhance the action of othermonoamine oxidase inhibitors or serotoninreuptake inhibitors (1J). Valerian is not rec-ommended for use with barbiturates becauseit has been demonstrated to prolong barbitu-rate-induced sleeping times (12). Concernfor the possibility of adverse drug/herb reac-tions is heightened by the fact that the poten-tial for such interactions is not described onthe package inserts for most prescriptiondrugs, and herbal remedies do not requirepackage inserts. Thus, because the consumeris uninformed and many patients do notinform their physicians that they are alsousing medicinal herbs, the potential foradverse interaction is increased.

Recommendations for the use of pre-scribed drugs (i.e., dose, manner, and fre-quency of administration and the period forwhich they are taken) are reviewed and con-trolled by the prescribing physician. Becausethey are usually self-prescribed by the con-sumer, this is frequently not the case withmedicinal herbs. Further, the extended pre-clinical and clinical testing to assure the safe-ty of prescription drugs before they arereleased to the market is not required formedicinal herbs. Little is known aboutchronic toxicities that might be associatedwith their prolonged use. There has beenminimal research to address possible adversereproductive, immunologic, or neurologic

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effects or even systemic toxicity and/orcarcinogenicity that might be associated withhigh doses or prolonged use of these prod-ucts (10). This concern was frequentlyexpressed at the International Workshop toEvaluate Research Needs on the Use andSafety of Medicinal Herbs, where it wasstrongly emphasized that medicinal herbscannot be assumed safe because they are"natural" (3). Many natural products arequite toxic or carcinogenic. For example,strychnine (one of the most toxic chemicalsknown), aflatoxin (which is both toxic andcarcinogenic), and pulegone (a toxic aborti-facient) are all "natural" (8,9). Pulegone isfound in the medicinal herb pennyroyal,which can be found in many outlets formedicinal herbs. Medicinal herbs contain avariety of chemicals that are toxic when con-sumed at high doses and for which little isknown about their chronic toxicity. Becausethe DSHEA exempts dietary supplementssuch as medicinal herbs from testing (6), thepublic may be unknowingly exposed tochemicals with the potential to induce a vari-ety of toxicities and/or carcinogenicity onchronic use. Further, because such testing isexpensive and is not required, it is unlikelyto be performed by the producers or distrib-utors of these products. This does not meanthat the industry is not interested in the safe-ty of their products. Rather, as bestdescribed by Loren Israelson (3), aspokesperson for the herbal industry, there isa financial disincentive for the industry tosupport such research. Because these prod-ucts cannot be patented, funding researchinto their chronic effects would not conferany proprietary right to the company thatsupported the work. Thus, research fundedby one company could be used equally wellby their competitors.

Other concerns regarding the marketingand use of medicinal herbs voiced both in theliterature and at the recent workshop arethose of standardization and stability (1-3).Unlike pharmaceuticals, botanical productsare complex mixtures in which the activeingredients may not be known or may consti-tute only a small percent of the total product.Some products are, in fact, believed toachieve their beneficial effects through thecombined actions of several ingredient chem-icals, each of which accounts for a very smallportion of the total product. Quality controlissues are further complicated by the mannerin which these products are produced. Thatis, unlike synthetic drugs that are producedin highly purified form, medicinal herbs aregathered in the wild or grown in relativelysmall plots. Thus, the active ingredients mayvary significantly with the part of the plantused, the season in which they are harvested,and/or the growing conditions (e.g., weather,

soil, etc.). When these facts are combinedwith the fact that these dried plant parts arepurchased locally by dealers who sell them tothe larger distributor, who in turn may fur-ther market or formulate and distribute thefinal product, the potential for misidentifica-tion or cross contamination is apparent.Because little is done to monitor the concen-tration of active ingredients or the possibilityof cross contamination through these steps,the content of active ingredients in a givenproduct may vary significantly from one lotto another.

As described by Joe Betz at the recentInternational Workshop to EvaluateResearch Needs on the Use and Safety ofMedicinal Herbs, sophisticated analyticalprocedures have and are being developed inthis country and elsewhere to analyze thecontents of medicinal herbs. Quality controlguidelines based on methods described inpharmacopoeias from more than a dozennations have been described in a recent docu-ment prepared by the World HealthOrganization (WXHO) (13). A recent effortby the U.S. Pharmacopeia has provided moredetailed methods for the standardization ofspecific medicinal herbs and dietary supple-ments (14). Monographs for the specificherbs addressed are being published as theyare developed. These methods are only rec-ommended, however, and are not requiredfor any of the products addressed.

As mentioned above, the active ingredi-ents of herbal formulations usually constitutea small fraction of the total product. In somecases, the active ingredient(s) are unknown oronly partially characterized. In other cases,beneficial effects are attributed to a combina-tion of active ingredients. Because the stabilityof chemicals varies according to individualstructures of the chemicals and the formula-tion in which they are found, the stability ofactive ingredients of medicinal herbs is also amatter of concern. However, the active ingre-dients of many medicinal herbs are unknown,and for others our knowledge of active ingre-dients is incomplete. Thus, expiration dates,when present for medicinal herbs, may not bemeaningful. Because there has been relativelylittle research to establish the active ingredi-ent(s) of most medicinal herbs or to docu-ment their shelf life, the efficacy of a particu-lar preparation may vary significantly withtime or from one brand to another. For thosepreparations in which the active ingredientsare known, methods are available or could berelatively easily developed to determine theirshelf life. However, this work is not requiredand is not being widely employed to assureproducts of consistent content and quality.

Representatives of the herbal industrywho attended the International Workshopon Evaluating Research Needs on the Use

and Safety of Medicinal Herbs agreed thatthe industry must provide safe products andthat current approaches for standardizationare inadequate (3). They emphasized that themore responsible members of the industryare working to improve and standardize theirproducts. There is general recognition, how-ever, that some members of this diverse andfragmented industry are marketing over theInternet, through direct sales catalogs, andeven in service stations. This lack of industryregulation permitted under the DSHEAallows marketing of products of both ques-tionable quality and content by individualswhose financial interests may, in some cases,override their interest in the safety and effica-cy of their product. Descriptions of theseproducts outlandishly infer everything fromincreased virility and vitality to a state ofecstasy. In some cases, all three conditionsand more are promised if one consumes asingle pill that is claimed to contain a half-dozen or more herbal products.

The ease of marketing dietary supple-ments and the lack of regulatory control ofsuch marketing are illustrated by an articlepublished in the Wall Street Journal (15). Inthis case, an individual who was interested instarting a business did so by simply obtaininga source of dietary supplements and market-ing over the Internet. His initial product wasthe testosterone precursor androstenedionethat he had formulated into tablets and thenmarketed as "The Stud Pill for Men." Thisindividual's research for the efficacy and safe-ty of this product was limited to a cursory lit-erature search and no laboratory work. Noapproval or control by regulatory agencieswas necessary. His success ($30,000 gross inthe first month) was such that this individualis now selling a weaker formulation ofandrostenedine for women as the "PassionPill for Women" and a formulation ofephedra, found in the herbal product MaHuang, as "HerbalTrim." Again, researchwas limited to a brief review of the literature.The literature clearly states that profoundtoxicity and a number of deaths have beenattributed to the use of ephedra or MaHuang, and a number of adverse effects havebeen reported for testosterone precursors.These facts apparently did not deter his profitmotive. This example of effective marketing,in the absence of regulatory control, is pro-jected to result in $500,000 gross sales ofthese products by this individual in his firstyear in business (15).

As a result of the actions of those whoare willing to take advantage of the freedomto market dietary supplements permitted bythe DSHEA, the more responsible membersof the dietary supplement industry run therisk that consumers might lose confidencein reputable products. Consumers could be

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injured by the unscrupulous sale of misfor-mulated or adulterated products. Under theDSHEA there is little that can be done toregulate such uncontrolled and possiblyeven unscrupulous marketing. However,recent guidelines from the Federal TradeCommission (16) requiring truthfulness andaccuracy in advertising of these productsmay curtail some of the more outlandishclaims currently being made.

Workshop speakers suggested that betterstandardization and quality control may bepositive aspects of the recent entry of themajor pharmaceutical companies into themedicinal herb market. Mass marketing bythe major pharmaceutical companies is alsolikely to place economic pressure on sup-pliers who do not have the resources tomaintain the good-manufacturing practicesnecessary to assure quality control and stan-dardized products.

A downside of the entrance of the majorpharmaceutical companies into the medicinalherb market is that many people who wouldnot have otherwise used medicinal herbs willbe encouraged to use products that have notbeen proven effective in normal healthy indi-viduals. Increased self-medication also increas-es the chance of adverse reactions to theseproducts as well as adverse drug/herb orherb/herb interactions. The end result will bemillions of dollars spent and not compensatedby insurance for litde or no beneficial effect.

A final concern regarding the use ofmedicinal herbs is that of risks posed to sen-sitive subpopulations. As discussed above,the fact that medicinal herbs are natural doesnot make them safe. The chemicals in medi-cinal herbs may be formed naturally in theplant, but they are not natural to the humanbody. Any compound with a therapeuticeffect has the potential to be incorrectly pre-scribed or overdosed. Increased sensitivity ofsubpopulations is most frequently attributedto slower metabolism of the compoundadministered or to an allergic response.Thus, it follows that individuals such as thedeveloping fetus, young children, and theelderly, who are more sensitive to the effectsof pharmaceuticals, will also be at greaterrisk to adverse health effects associated withmedicinal herbs. Additional sensitive indi-viduals are seen among those genetic sub-populations that metabolize foreign com-pounds less rapidly than the general popula-tion. Members of each of these variousgroups may be harmed by what is for mostof the population the recommended dose ofa drug or herb. Sensitive subpopulations arealso at greater risk of adverse herb/drug orherb/herb interactions.

Allergic reactions are not readily predict-ed and may occur in response to any of alarge number of agents including synthetic

and natural drugs. Allergic responses to syn-thetic drugs are frequently detected in thecourse of preclinical testing, and this infor-mation is provided to the patient and physi-cian. Additional information is obtained onsynthetic drugs when patients are monitoredby the prescribing physicians and dispensingpharmacists. Adverse responses and allergicreactions are noted and reported to thepharmaceutical companies who have theresponsibility to include this information inthe package insert for the respective drug.Consumers are thus informed and fore-warned of the possibility of adverse reac-tions and are more likely to recognize thesereactions when they occur. Because medici-nal herbs are not subject to similar testingand monitoring and they usually do notcontain package inserts, the consumer maybe unaware that a decline in his or herhealth is actually an adverse or hypersensi-tive response to the herbal medication.

Problem Areas,Recommendations,and ActionsStandardizationNumerous speakers and participants at therecent International Workshop to EvaluateResearch Needs on the Use and Safety ofMedicinal Herbs emphasized that herbalmedicines are poorly defined mixtures inwhich the active principal has frequently notbeen identified. Analysis of available medici-nal herb preparations indicate that both theingredients, active and otherwise, may varygreatly from one preparation to another. Thelack of standardization is illustrated by an arti-cle in Consumer Reports (17) that describedthe analysis of 10 preparations of ginseng forcontent of the possible active ingredients, gin-senosides. The analysis indicated that the con-tents of ginseng per capsule, when measuredby weight, varied by more than 6-fold, andthe ginsenosides per capsule varied by morethan 20-fold. Further, the content of ginseno-sides did not necessarily vary in proportion tothe weight of ginseng in the capsule. In addi-tion to better standardization of the products,work is needed to confirm the stability of theactive ingredient(s) of medicinal herbs. In theabsence of adequate standardization and qual-ity control, both consumers and responsibleproducers of medicinal herbs are at risk.Consumers must have a consistent product ofhigh quality to effectively achieve safe, benefi-cial effects from one formulation to another.Responsible producers are at risk when incon-sistent or ineffective products damage the rep-utation of the industry.

Recommendations. Where methods forsuch quality assurance are available, theyshould be employed industry wide. When

such methods are lacking, research should beundertaken by both the industry and govern-ment to identify, certify, and quantify activeingredients and to determine and recom-mend optimum doses of medicinal herbs.

Formulations of medicinal herbs shouldbe standardized, to the extent possible, todeliver a known amount of the active ingre-dient(s) in a recommended dose. Where theyare known, the stability of the active ingredi-ents should be determined, and all packagesshould carry meaningful expiration dates.

Package inserts that contain dear instruc-tions regarding doses and possible contraindi-cations should be prepared and required formedicinal herbs.

Action. As discussed earlier, 'WHO (13)has developed basic methods for the analysis ofmedicinal herbs, and the U.S. Pharmacopeia(14) is developing and publishing recom-mended methods for specific herbal formula-tions. As described by Joe Betz and WilliamR. Obermeyer at the workshop, research atthe FDA is currently addressing the need forimproved methods to ensure the content andquality of medicinal herbs. Jill Ellis of theNational Nutritional Foods Association andLoren Israelsen, of the Utah NaturalProducts Alliance, two representatives of themedicinal herb industry in attendance at theworkshop, emphasized that many compo-nents of the industry are working to betterstandardize their products. The entry of themajor pharmaceutical houses into the medic-inal herb market is speculated to result inmore consistent formulations.

Consumer EducationThe American public, overall, comprises awell-educated and sophisticated group ofconsumers. However, any consumer groupmust base buying decisions on availableinformation. In the case of medicinal herbs,information about health benefits has beenlargely limited to that provided by a relative-ly few advocates of their use and marketersof these products. Thus, most of the avail-able information has been limited to thepositive aspects associated with the use ofmedicinal herbs, with little, if any, discus-sion of possible adverse effects. The generalpublic is largely unaware that adverse healtheffects associated with the use of medicinalherbs have been attributed to everythingfrom overdosing to contaminated formula-tions to the inherent toxicity of the herb ofchoice. The public is also largely unawarethat much of the literature regarding thebeneficial effects of these compounds isanecdotal, may be greatly exaggerated orincorrect, and has yet to be confirmedthrough clinical trials. Most of the clinicaltrials that have been conducted have beenconducted in other countries, and in most

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cases, the results have not been translatedinto English or evaluated by U.S. regulatoryofficials. Thus, when it comes to medicinalherbs, the American public may not be well-educated consumers.

Recommendations. Because these prod-ucts are not proprietary but are being con-sumed by a large segment of the public, fed-eral funds should be used to develop, evalu-ate, and distribute the most authoritativeinformation available regarding the efficacyand safety of herbal formulations.

Research conducted in other countriesshould be translated and evaluated by federalregulatory agencies. The most accurate dataregarding both beneficial and adverse effectsshould be used to prepare informative pack-age inserts to be included with all formula-tions of medicinal herbs. Package insertsshould be updated as additional informationbecomes available.

Action. The National Institutes of Health(NIH) Office of Dietary Supplements (ODS)was established by the DSHEA (6). The pur-poses of the ODS were defined in the law andinclude the following:

to more fully explore the potential role of dietarysupplements as a significant component of effortsto improve health care, and to promote the sci-entific study of dietary supplements in maintain-ing health and preventing chronic diseases andother health-related conditions.

Working with representatives of the scientif-ic community, consumers, and industry, theODS has developed a Strategic Plan thatincludes five equally weighed goals and relat-ed objectives (18). The Strategic Plan goalsinclude the following:* Evaluate the role of dietary supplements inthe prevention of disease and reduction ofrisk factors associated with disease

* Evaluate the role of dietary supplements inphysical and mental health and in perfor-mance

* Explore the biochemical and cellular effectsof dietary supplements on biological sys-tems and their physiological impact acrossthe life cycle

* Improve scientific methodology as relatedto the study of dietary supplements

* Inform and educate scientists, health careproviders, and the public about the bene-fits and risks of dietary supplements.

Additional information on ODS efforts tosupport research, improve education, anddisseminate knowledge is available on theODS web site (19).

An excellent source of informationregarding the use and safety of medicinalherbs has recently been translated fromGerman into English (8). This text, translat-ed by the American Botanical Council, pro-vides a wealth of information on a multitudeof herbal formulations. The Botanical Safety

Handbook (11), another recently publishedresource that contains a great deal of valuableinformation, includes a listing of herbs byLatin binomial, based in part on toxicologicconsiderations and profiles of commonlyused herbal medicines. A third useful refer-ence is the Physicians Desk Reference (PDR)for Herbal Medicines (20). This publicationpresents a comprehensive listing of medicinalherbal products. Each entry provides infor-mation and data on source, identity, formu-lation, dosages, contraindications, and druginteractions where known. The entries alsoinclude references to published studies.Information on benefits and risks associatedwith the use of herbal supplements hasrecently been made available on the Internetfrom the FDA through the Center for FoodSafety and Applied Nutrition's dietary sup-plements web site (21) and through theNIH's National Center for Complementaryand Alternative Medicine (22).

Not all consumers have access to theserelatively expensive books or to the Internet.Further, information for all supplements isnot available or may be incomplete. Thus,when it is available, information regardingrecommended uses, doses, and possible con-traindications would be most assessable ifrequired on a package insert with the respec-tive product.

Herb/Drug and Herb/HerbInteractionsSeveral speakers and discussants at theInternational Workshop to EvaluateResearch Needs on the Use and Safety ofMedicinal Herbs expressed concern regard-ing the simultaneous use of more than oneherbal product and/or the use of herbalproducts in combination with pharmaceuti-cals and/or alcohol. Documented incidencesof adverse effects, some leading to death,were recounted by discussants at the work-shop. Most of these incidences were associat-ed with abuse. However, unrestrained mar-keting and fraudulent advertising set thestage for such adverse interactions. Patientsfrequently do not inform their physiciansthat they are also using herbal remedies.Thus, when a physician prescribes a drughaving the same or an opposite pharmaco-logic action, there is potential for adverseinteraction. In other cases these productsmay be marketed as a combination of herbalcompounds to be used as a means of obtain-ing extra energy, virility, or other desiredstate and thus set the stage for abuse andadverse interactions when combined withillicit drugs and alcohol.

Recommendation. An initiative is neededin the medical community and among theproducers and marketers of medicinal herbsto identify and document herb/drug and

herb/herb interactions. Information obtainedfrom this initiative should be provided toboth the herbal and pharmaceutical indus-tries and required on package inserts with therespective products.

Action. A number of health care profes-sionals who have treated patients experienc-ing adverse interactions have endeavored tobring this information to the attention of thepublic. However, these efforts are as yet gain-ing little attention from regulatory agenciesor the industry (11).

Potential Toxicity Associated withHigh Dose or Prolonged UsePrescription drugs come with carefully writ-ten instructions regarding their use and possi-ble contraindications. The time over whichthese products are used is limited by the expi-ration of the prescription, and prescriptionsare not renewed without the recommendationof a physician. Over-the-counter drugs arenot available until extended use has provedthem safe at the recommended dose, butmedicinal herbs, most ofwhich have not beentested in clinical trials, are readily available toa largely uninformed public. Little is knownregarding the potential of these compounds toincrease the risk of immunotoxicity, neuro-toxicity, birth defects, reproductive problems,or cancer with extended use.

Recommendations. Because medicinalherbs are not without therapeutic effect,they, like other pharmaceuticals, will betoxic at some dose. Medicinal herbs shouldthus be tested to characterize both theiracute and chronic toxicities.

Action. In a continuing effort to addressthose compounds to which the public isexposed, the National Toxicology Program iscurrently designing and initiating studies toidentify and characterize adverse effects thatmay be associated with prolonged or highdoses of some of the more popular medicinalherbs. Results of these studies will be peerreviewed and made available as soon as theyare completed.

Sensitive SubpopulationsIt has long been known that the developingfetus, the young, and the elderly may be moresensitive to the effects of certain drugs thanthe general population. There is also increas-ing evidence for other sensitive subpopula-tions as a result of genetic predisposition. Inmost instances, sensitive subpopulations showan elevated or adverse response as a result ofcompromised capacity to metabolize therespective drug. Also, individuals of all agesmay have allergic reactions to botanical prod-ucts. Because medicinal herbs are therapeu-tically active and metabolized in mannerssimilar to synthetic drugs, similar adversereactions to medicinal herbs can be expected

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in sensitive subpopulations. However, suchadverse reactions and allergic responses havenot been well documented, and informationregarding possible adverse responses is notusually provided to the consumer. In somecases, the public has actually been misledwhen medicinal herbs have been marketed assafe to all ages because they are natural.

Recommendation. Research and data col-lected from consumers should be compiledand analyzed to identify sensitive subpopula-tions based on age, sex, nutritional habits,allergic responses, and the presence of specificgenes that may predispose consumers to anelevated or toxic response to medicinal herbs.

Action. Little is being done to addressthe needs of sensitive subpopulations at thistime or to publicize the fact that they may beat risk. Once comprehensive studies to char-acterize the pharmacologic effects of individ-ual agents are completed, it will be possibleto design better studies to address this issue.

SummaryMedicinal herbs are some of our oldest med-icines. The fact that they continue to be usedby millions of people is testament to boththeir real and perceived beneficial effects.Their increasing use in recent years is clearevidence of public interest in having alterna-tives to conventional medicine. However,the fact that medicinal herbs are "natural"does not assure their safety. They have notbeen tested in the manner required for con-ventional pharmaceuticals. Thus, there islimited data to confirm their efficacy andlittle or no scientific data regarding possible

adverse effects associated with high doses orchronic use or the hyperresponsiveness ofsensitive subpopulations. There is also con-siderable concern regarding the lack of stan-dardization of herbal preparations and theinadequacy of consumer information. Muchneeded testing for safety and efficacy cannotbe mandated under the present laws regulat-ing the industry. Given the economic disin-centive for significant expenditures for suchresearch, the industry is unlikely to conductthis research. Many of the concerns regard-ing standardization and consumer informa-tion could be addressed through reassess-ment of the DSHEA. However, if testing ofmedicinal herbs for efficacy and safety is tobe conducted, it will probably have to besupported by the government. Results oftesting, assessment of data from other coun-tries, and documentation of adverse effectsresulting from interactions and hypersensi-tive responses should provide information toconsumers in the form of package insertswith all products.

REFERENCES AND NOTES

1. Angell M, Kassirer, JP. Alternative medicine-the risksof untested and unregulated remedies. N EngI J Med339:839-841 (1998).

2. Journal of the American Medical Association (JAMA)280 (1998).

3. NIEHS news: herbal health. Environ Health Perspect106:A590-A592 (1998).

4. Jonas WB. Alternative medicine-learning from thepast, examining the present, advancing to the future.JAMA 280:1616-1618 (1998).

5. Fontanarosa PB, Lundberg GD. Alternative medicinemeets science. JAMA 280:1618-1619 (1998).

6. Bass IS, Young AL. Dietary Supplement Health and

Education Act: A Legislative History and Analysis.Washington, DC:The Food and Drug Law Institute, 1996.

7. Commission on Dietary Supplement Labels. Report of theCommission on Dietary Supplement Labels, Report to thePresident, Congress, and The Secretary of theDepartment of Health and Human Services. Washington,DC:U.S. Government Printing Office, 1997.

8. The Complete German Commission E Monographs:Therapeutic Guide to Herbal Medicines (Blumenthal M, ed).Boston, MA:lntergrative Medicine Communications, 1998.

9. De Smet PRGM, Keller K, Hansel R, Chandler, RF, eds.Adverse Effects of Herbal Drugs, Vol 1, 2 and 3. Berlin/Heidelerg/New York:Springer-Verlag, 1997.

10. Miller LG. Herbal medicinals: selected clinical consider-ations focusing on known or potential drug-herb interac-tions. Arch Intern Med 158:2200-2211 (1998).

11. McGuffin M, Hobbs C, Upton R, Goldberg A. BotanicalSafety Handbook. Boca Raton, FL:CRC Press, 1997.

12. Capasso A, DeFeo V, DeSimon F, Sorrentino L. Pharma-cological effects of aqueous extracts from Valerianaadscendens. Physiother Res Int 10:145-151 (1996).

13. WHO. Quality Control Methods for Medicinal PlantMaterials. Geneva:World Health Organization, 1998.

14. Shrinivasan V. Personal communication, 1998.15. Sharp R. With web site, smart ads, supplier, one man

scores big on a "stud pill." Wall Street Journal (27January):1 (1999).

16. Federal Trade Commission. Dietary Supplements: AnAdvertising Guide for Industry. Available: http://www.ftc.gov/bcp/conline/pubs/buspubs/dietsupp.htm[cited 29 June 1999].

17. Herbal roulette. Consumer Reports 60(11)8:69-705 (1995).18. Office of Dietary Supplements. Merging Quality Science

with Supplement Research: A Strategic Plan for theOffice of Dietary Supplements. NIH Publ 99-4356.Bethesda, MD:National Institutes of Health, 1998.Available: http:i/odp.od.nih.gov/ods/about/plan.html [cited27 May 1999].

19. Office of Dietary Supplements Home Page. Available:http://odp.od.nih.gov/ods/ [cited 29 June 1999].

20. Fleming T, ed. PDR for Herbal Medicines. Montvale,NJ:Medical Economics Company, 1998.

21. U.S. Food and Drug Administration. An FDA Guide toDietary Supplements. Available: http:llvm.cfsan.fda.gov/-dms/fdsupp.html [cited 29 June 1999].

22. National Institutes of Health. National Center forComplementary and Alternative Medicine Home Page.Available: http://nccam.nih.gov/ [cited 29 June 1999].

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