should we be concerned about herbal remedies

Journal of Ethnopharmacology 75 (2001) 141164

Should we be concerned about herbal remedies

Memory Elvin-LewisDepartment of Biology, Washington Uni6ersity, Box 1137, St. Louis, MO 63130-4899, USA

Received 24 November 2000; received in revised form 5 December 2000; accepted 5 December 2000

Abstract

During the latter part of this century the practice of herbalism has become mainstream throughout the world. This is due inpart to the recognition of the value of traditional medical systems, particularly of Asian origin, and the identification of medicinalplants from indigenous pharmacopeias that have been shown to have significant healing power, either in their natural state or asthe source of new pharmaceuticals. Generally these formulations are considered moderate in efficacy and thus less toxic than mostpharmaceutical agents. In the Western world, in particular, the developing concept that natural is better than chemical orsynthetic has led to the evolution of Neo-Western herbalism that is the basis of an ever expanding industry. In the US, oftenguised as food, or food supplements, known as nutriceuticals, these formulations are readily available for those that wish toself-medicate. Within this system, in particular, are plants that lack ethnomedical verification of efficacy or safety. Unfortunatelythere is no universal regulatory system in place that insures that any of these plant remedies are what they say they are, do whatis claimed, or most importantly are safe. Data will be presented in this context, outlining how adulteration, inappropriateformulation, or lack of understanding of plant and drug interactions have led to adverse reactions that are sometimeslife-threatening or lethal. 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Herbal remedies; Evolving pharmacopeias; Surveillance and research databases; Adverse effects; Regulatory challenges

www.elsevier.com/locate/jethpharm

1. Introduction

During the latter part of the 20th century herbalismhas become mainstream worldwide. This is due in partto the recognition of the value of traditional and indige-nous pharmacopeias, the incorporation of some derivedfrom these sources into pharmaceuticals (DeSmet et al.,1992a; DeSmet, 1997; Winslow and Kroll, 1998), theneed to make health care affordable for all, and theperception that natural remedies are somehow saferand more efficacious than remedies that are pharma-ceutically derived (Bateman et al., 1998; Murphy,1999). For a variety of reasons more individuals arenowadays preferring to take personal control over theirhealth, not only in the prevention of diseases but alsoto treat them. This is particularly true for a wide varietyof chronic or incurable diseases (cancer, diabetes,arthritis) or acute illnesses readily treated at home(common cold etc.) (Kincheloe, 1997). In this respectmany individuals have become disenchanted with the

worth of allopathic treatments, and the adverse effectsthat can be anticipated. They are seemingly unaware ofthe potential problems associated with herbal use or thefact that their limited diagnostic skills, or of thoseprescribing treatment for them, may prevent the detec-tion of serious underlying conditions like malignancies(Saxe, 1987; Youngkin and Israel, 1996; Donaldson,1998; Winslow and Kroll, 1998; Shaw et al., 1999;Stewart et al., 1999).

Most allopathic practitioners have traditionally con-sidered herbal treatments to be innocuous or alter-nately, potentially problematical. Three decades agoonly a few had any appreciation of the number ofremedies that had their origins in herbal medicine andmost had a vague impression of what herbalism, orother forms of alternate medicinal practices implied(Lipp, 1996). There was still a great deal of carry-overfrom the beginning of the 20th century when the intro-duction of wire services allowed for the disseminationof adverse effects of snake-root concoctions and thelike. As early as 1906, misbranding and adulterationwere disallowed in the US Herbal remedies, not a partof The Dispensatory of the United States of America,E-mail address: [email protected] (M. Elvin-Lewis).

0378-8741/01/$ - see front matter 2001 Elsevier Science Ireland Ltd. All rights reserved.PII: S 0 3 7 8 -8741 (00 )00394 -9

M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164142

were shunned as if the danger associated with oneremedy was common to all much like the notion that ifone mushroom is poisonous, all must be and by 1938,safety testing was mandated under the Federal Food,Drug and Cosmetic Act. By mid-century, pharmacog-nosy (study of plants affecting health) was a dyingscience. Dicta of the day, as outlined in a 1962 law(KefauverHarris Drug Amendments) required proofof safety and efficacy. This policy determined that onlychemically defined and clinically evaluated medicineshad value, and if pharmaceutically derived, must beprescribed by allopathic physicians. (Murphy, 1999).Licensure to practice in the US was confined to allo-pathic clinicians and others in naturopathy and home-opathy whose traditional use of herbs was well defined.Some leeway was also given to practicing traditionalhealers within Asian and indigenous communities. Onthe whole, other types of herbalists were not recognized(OHara et al., 1998).

Such was the case for decades, until the age ofAquarius arrived, and the return to nature was thedriving force of every flower child. In this wake,self-medication became the rule as old Europeanherbals and indigenous remedies were revisited, andwere used with impunity, without concern for adverseeffects. In addition, hallucinogens, particularly fromAmerican indigenous cultures, became popular as manytrying to escape the reality of a war-torn and hide-bound world, experimented with altered states. Soonhealth food stores appeared, specializing in unrefinedfood, organic-grown vegetables, herbs and herbalpreparations. With the opening up of Asian markets,other types of medicines were introduced, and werepermitted since they were considered already culturallyacceptable. A synthesis of all these types of herbalmedicinal practices evolved into what can be called,Neo-Western herbalism. Formulae found in this sys-tem are based upon both ethnomedical worth or aresimply serendipitous inventions of the formulator. Abelief of benefit over single-ingredient drugs is thecorner stone of this form of herbalism that subscribesto the notion that primary active ingredients in herbsare synergized by secondary compounds, and secondarycompounds mitigate the side effects caused by primaryactive ingredients (McPartland and Pruitt, 1999). Sinceit is possible for single taxa to contain a family ofrelated bioreactive compounds varying in potency, it islogical to presume that one or more of these willcontribute to the totality of the effects observed (Lewisand Elvin-Lewis 1994; Elvin-Lewis and Lewis, 1995). Itwould follow that when mixtures of several crude ex-tracts are used in formulations, enhancement of benefi-cial effects (or greater toxicity) is expected througheither synergistic amplification or diminishment of pos-sible adverse side effects. It is also presumed that theircombination could prevent the gradual decline in effi-

cacy that is frequently observed when single drugs aregiven over long periods of time (Borchers et al., 1997).Nowadays such remedies can be still found in ethnicand health food stores, but are also available in phar-macies and grocery stores. Unfortunately there is nouniversal regulatory system that ensures that theseremedies are what they say they are, do what isclaimed, or most importantly, are safe (Angell andKassirer, 1998; DeSmet, 1993; DeSmet et al., 1997).

2. Evolving pharmacopeias

2.1. Major types of herbal medicine

Four general types of Herbal Medicine exist whichare Asian, European, Indigenous and Neo-Western.Many like the Asian and European systems go backthousands of years, appear in pharmacopeia, and withsuch a tradition of use are better understood than thoseof indigenous origins that are often only orally orsecondarily recorded (DeSmet et al., 1992a; DeSmet,1992b).

2.2. Indigenous herbalism

Indigenous medicinal systems are the most diverseand are still practiced where such cultures are intact,but are continuously evolving as contact with othercultures continues. The knowledge may reside exclu-sively with traditional healers, or be generally known.Information regarding parameters of efficacy and toxic-ity can vary since claims are primarily anecdotal. Usu-ally regional variations to formulae exist, and plantsselected can be quite specific, generic, or inadvertentlyadulterated. It usually follows that when a remedy iswidespread in acceptance its efficacy and safety has asound therapeutic basis. It is these plants, in particular,that can be found in Neo-Western herbalism.

2.3. Asian medicinal systems

The most established types of herbalism are those ofAsian origin, particularly from India (Aryuvedic,Unani, Siddha), China (Wu-Hsing) and Japan(Kampo), and today they still follow the ideas ofdiagnosis and treatment known for millennia (Kanba etal., 1998; Wong et al., 1998; Vogel, 1991). Most ofthe remedies are mixtures of plants, sometimes alsocontaining animal parts and minerals and are formu-lated to achieve expected therapeutic goals. They areoften referred to as drugs. In these remedies it is notunusual to find more than one plant whose componentshave complementary effects that seemingly work to-gether to enhance the therapeutic value or other prop-erties of the mixture. This is also true for Indian dental

M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 143

preparations that follow traditional formulations(Elvin-Lewis, 1987, 1989). Under ideal conditions,care is taken by traditionally trained practitioners tocarefully identify the ingredients, to harvest the plantsat very specific times to insure appropriate levels ofbioreactivity, to prepare the remedies under strictrules, and to prescribe them to achieve an appropriateclinical response. In spite of the fact that parametersof use may be known to the practitioner, includingside effects that can be expected, packaging insertsaccompanying commercial products rarely cite thesenor do they always accurately represent the contents.Also, there is a general acceptance in Asian countries,particularly India, for patients to seek concurrenttreatment through more than one Indian MedicinalSystem as well as allopathy, or in Chinese herbalismto fraudulently incorporate pharmaceuticals in someremedies. This only compounds issues related torecognizing the source of potential side effects, and itis uncommon for them to be reported at all. More-over, without enforceable regulatory systems to gov-ern the activities of practitioners and formulators,unexpected adverse reactions are always likely. In thisrespect, formulations may be inappropriately made,prescribed, or taken. Formulation diversity, due toadvertent substitutions, can also exist in preparationswith the same name. These changes are not alwaysobvious. Examples can be found in Aryuvedic prepa-rations formulated in southern India, where tradi-tional Himalayan plants are unavailable. Withoutappropriate prescription labeling, adulterations are aparticular problem in Asian medicines, and formula-tions have been found to contain substitutions ofplant ingredients, dangerous levels of toxic plant com-ponents, unapproved ingredients like pharmaceuticalsand heavy metals in addition to other toxic and aller-genic substances (Anonymous, 1989; Chan et al.,1993; Chan, 1997; Drew and Myers, 1997; Ernst,1997; Ko, 1998). For example, although strictly notherbal remedies, lead has been found in a Laotianpreparation known as Pay-loo-ah, a Korean remedy,hai ge fen, containing clam shell powder (Borins,1998) and in Indian traditional cosmetics used as eye-liners (surma) (Shaw et al., 1997).

Chinese herbal medicines are typically unpalatableand can induce nausea and vomiting. Most reportedadverse effects on the heart have been associated withAconitum poisonings and certain topical skin prepara-tions that can also cause liver damage (Chan, 1997;Drew and Myers, 1997; Ko, 1998; Armstrong andErnst, 1999). In addition, pain or asthma remediescontaining Datura metel are recognized to cause anti-cholinergic effects leading to reduced visceral activity.Liquorice, by affecting the sodium/potassium balance,can cause water retention. More serious are condi-tions like jaundice and brain damage due to neonatal

remedies containing berberine, additive or toxic effectsdue to undeclared pharmaceuticals like mefenamicacid and diazepam (Gertner et al., 1995), heavy metaladulterations (Schaumburg and Berger, 1992; Kew etal., 1993; Sheerin et al., 1994), or when inadvertentadulterations with Podophyllum emodi instead oflondancao (Gentiana spp.) have elicited severe life-threatening events (Chan, 1997; Drew and Myers,1997). Highly concentrated alkaloid preparations liketetrahydropalmatine, a potent neuroreactive, can befound in Jin Bu Huan. This Chinese patent medicineused as a painkiller, has been associated with seriousadverse reactions episodes in children and adults.Symptoms occurring in long-term users range fromacute toxicity, lethargy, muscle weakness, respiratorycompromise, bradycardia and coma, to extreme fa-tigue, fever, jaundice and hepatitis. These events werereported in the Communicable Disease Centers Mor-bidity and Mortality Weekly Reports (Anonymous,1993a,b), and by Horowitz et al. (1996).

Ginseng preparations imported from China must al-ways be suspect since not only can the content of theginsenosides vary (Consumer Reports, 1995), butcommercial formulations can be adulterated with po-tent and dangerous plants like mandrake (Mandrogoraofficinarum) containing scopolamine and Rauwolfiaserpentina containing reserpine and stimulants likecaffeine from Cola spp. (Drew and Myers, 1997). Cer-tain Chinese remedies may be named the same butare formulated differently depending upon the uniquecondition of the patient; such is the case with Chineseherbal preparations called Eternal Life. Without ap-propriate labeling of its ingredients it is almost impos-sible to identify the source of any adverse effectsassociated with its use (Sanders et al., 1995).

2.4. European herbalism

European Traditional Medicine has its roots mostlyin antiquated Mediterranean civilizations and has overthe centuries evolved in its utilization of both Eu-ropean and plants from abroad. In the Middle Agesthe color or shape of a plant denoted a cosmic clueto its medical usefulness, and hence the Doctrine ofSignatures was a criterion by which many plants wereselected, e.g. heart-shaped leaf as a heart remedy, yel-low plant parts for treating hepatitis, etc. By the 19thcentury, some of these medicinal plants hadbecome part of the pharmacopeias of allopathy,naturopathy and homeopathy, and their therapeuticbasis investigated by medicinal chemists and pharma-cognosists. Usually when compounds are isolated, andsometimes totally synthesized, their pharmaceuticaluses are more carefully regulated; aspirin, of course,being an early exception (DeSmet, 1993; DeSmet etal., 1997).


2.5. Neo-Western herbalism

In its totality European Traditional Medicine hasmatured along with American herbal introductions intoNeo-Western herbalism. In this system single plantpreparations that have been either selected from formu-lations found in ancient pharmacopeias or derived frommedicinal plants valued in other cultures, includingthose of indigenous origin, are sold alone or as mix-tures in an assortment of combinations. For example,one of the most popular plants in use in Europe todayis Echinacea with its origins in North American (Mid-western) indigenous medicine (Lewis and Elvin-Lewis,1977). Also, novel formulations can be devised withoutethnomedical data to support their merit, or represent amixture of plants known to a variety of medicinalsystems (DeSmet, 1995a). To promote the sale of aparticular product, examples exist where supportingethnomedical data are purposely vague, obtuse, or con-trived. While such mixtures may potentiate a remedysmedicinal value, it is also possible that these combina-tions could promote adverse effects not known whenindividual plant components are used. Without tradi-tional parameters to guide the consumer, the benefits orrisks to these newly contrived formulations are cur-rently unknown.

While most British, European and Asian herbalistsare formally trained within the context of known phar-macopeias or curricula, American herbalists can vary intheir instruction, some being self-taught, while othersundertake training in various types of apprenticeshipprograms. However, like allopathic clinicians, bothnaturopathic and homeopathic clinicians undergo clas-sical training and in the US and Canada some schoolsof naturopathy also teach homeopathy as a sub-spe-cialty. Both of these disciplines utilize specifically for-mulated medications that are understood forparameters of use. However, philosophies of diagnosisand treatment differ. Naturopathy, based on hydrother-apy and dietary treatment, currently prescribes formu-lations containing plant extracts or phytochemicals atpharmacognostically determined levels of efficacy. Thephilosophy of treatment is two-fold and includes bothcurative and maintenance (normalization) aspects.Homeopathic formulations (that contain plant extractsand other substances) are compounded under the phi-losophy that substances that cause specific toxic effectscan, at extremely dilute concentrations, reduce similareffects elicited by disease states. While homeopathicremedies are often considered to only elicit placebo-likeactions, practitioners recognize their worth, and under-stand that these remedies are not only bioreactive butmay also elicit minor adverse effects like rashes, nausea,vomiting, agitation, shaking and allergic reactions(Shaw et al., 1997; Glisson et al., 1999).

3. Regulatory challenges

3.1. Asia

Overall, the incidence of serious adverse reactions issignificantly lower with most of these therapeutic reme-dies when compared to pharmaceutically derived drugs.However, the need still exists to more closely monitorpractitioners and formulators of any traditionalmedicine, including those of Asian origin, so thatmedicinal irregularities and unethical practices are re-duced. Also, Chinese herbal prescriptions are individu-alized and when dispensed are not usually labeled, andshould adverse effects arise, identification of their con-tents is difficult unless the patient has been provided awritten copy of the formulation. Presuming that theformulation contains the plants described, verificationmay be impossible after processing has occurred.Should traditional remedies be prepared in an Asiancountry, and imported, the task of insuring safety iseven more difficult since the notion of incorporatingpotentially toxic herbs or heavy metals may not beconsidered harmful in the country of origin (Natori,1980; Anonymous, 1989; Shaw et al., 1997).

3.2. Europe

Unfortunately, regulatory standards vary from coun-try to country, and thus claims of content, efficacy, andsafety of any herbal remedy cannot always be assured.Germany is the leader in evolving rational regulatorypolicies (Benzi and Ceci, 1997). There, plant remediesare carefully delineated and registered in Commission EMonographs with known risk/benefit/drug interactionscited, and consistency of bioreactive compounds chemi-cally defined as phytopharmaceuticals (Blumenthal etal., 1998). More detail is provided in the 50 mono-graphs published by the European Scientific Coopera-tive on Phytotherapy and 10 additional monographsare underway (Blumenthal, 1999). While self-medica-tion is the norm, prescriptions for some medications arealso mandated. Most European countries are evolvingsimilar policies (Benzi and Ceci, 1997), although in theUnited Kingdom only some herbal preparations fallunder such strict regulatory guidelines (Mills, 1995).

3.3. US

In the US regulatory mechanisms regarding herbal-ism were non-existent until only a few years ago, andeven then and now they still lack true enforcementcapability. FDA Commissioner Kessler voiced concernsregarding safety in 1993 and proposed removal ofherbal products without proven safety and efficacy. Asa reaction to this proposal the Dietary SupplementHealth and Education Act (DSHEA) was inaugurated


in 1994. Under this act many botanical medicinesdefined as a vitamin, a mineral, an herb or otherbotanical (or) amino acid are now sold under the guiseof food or dietary supplement (Brevoort, 1998; Mur-phy, 1999). As long as no medical claims are present onthe label they are exempt from strict pharmaceuticalregulations. Any display literature must further claimthat the product has not been reviewed by the FDA oris not intended for medication. Also in 1997, a FederalCommission on Dietary Supplements was establishedthat recommended that manufacturers provide science-base evidence to consumers. To some physicians likeAngell and Kassirer (1998), these guidelines, and vagueor oblique claims related to the maintenance of goodhealth, still begs the issue regarding proven safety orefficacy. They emphasize that since these herbal reme-dies are not classified as medications they are not underFDA scrutiny. Without being appropriately evaluatedfor content, safety or efficacy it is difficult to determineparameters of use. However, should adverse reactionsbecome apparent, the FDA could investigate and inter-vene to remove the product (Murphy, 1999). Moreover,the FTC (Federal Trade Commission) is active in defin-ing the regulatory framework for advertising claims fordietary supplements. The legal and regulatory aspectsof these US government agencies in overseeing the herband dietary supplement industry from the perspectiveof the Consumer Healthcare Products Association hasbeen recently reviewed and is a useful reference to thoserequiring details of such aspects (Soller, 2000).

Attempts are being made to bring some sense out ofthis current regulatory chaos since it is in the bestinterest of everyone to do so. In this regard, pharma-cognosists and natural products chemists have onceagain become active in trying to understand the thera-peutic basis of herbal remedies and toxicologists areaddressing issues of the origins of potential adverseeffects as incidences of associated use or abuse becomeevident. As a complement to these efforts a number oforganizations are preparing monographs to delineatedetails of herbs that are popularly used as phy-tomedicines and medicinal plant preparations so thattheir recognition as official medicines may result(McGuffin et al., 1997). The most ambitious is that ofthe American Herbal Pharmacopeia and TherapeuticCompendium with plans to publish at least 2000 mono-graphs of this nature. Also, the herb trade in recogniz-ing its responsibility to provide appropriate guidelines,has recently published through the American ProductsHerbal Association (AHPA) The Botanical SafetyHandbook, 2nd edition (1998). The FDA accepts thisorganizations Herbs of Commerce as the authoritativetext for label nomenclature related to available herbalproducts. To aid pharmacists in understanding risksand benefits of herbal products, the United States Phar-macopeia (USP) is also compiling standard mono-

graphs for herbal dietary supplements and dispensatoryinformation (DI). They have already published 11monographs and an additional 12 are under prepara-tion. In order to set standards to document the qualityof herbal products, and outline the therapeutic parame-ters for safe and effective use, publication of the WHOMonographs on Selected Medicinal Plants is on-going(Akerele, 1993). Volume 1 (1999) contains 28 mono-graphs on 31 plant species and Volume 2 to be pub-lished in 2000, an additional 29 monographs(Blumenthal, 1999).

Furthermore, the FDA is considering reviewing cer-tain botanicals via the IND/NDA (Investigational NewDrug/New Drug Application) process. Presently thereare at least 50 botanicals or botanical formulas holdingactive IND applications. Priority will be given to thosewith a long-history of safety, particularly for short-termuse since information is unlikely to be adequate tosupport claims of safety for long-term use. In somecases issues related to accompanying chemistry andtoxicological data remain to be resolved (Murphy,1999). Recently, a Federal Commission on DietarySupplements has been established (1997) recommendsthat manufacturers provide science-based evidence toconsumers. Also to support evaluation of herbalmedicines and other non-traditional remedies the Na-tional Institutes of Health (Bethesda, MD) formed theOffice of Alternative Medicine in 1992 that has recentlybeen up-graded to the National Center for Complemen-tary and Alternative Medicine (Murphy, 1999). Eventu-ally, these initiatives and others evolving elsewhere, areexpected to provide needed information to validate thistype of therapy. To aid in this endeavor two searchabledatabases generated by the US National Institutes ofHealth on dietary supplements exist. The InternationalBibliographic Information on Dietary Supplements(IBIDS) can be accessed at the ODS website http://odp.od.nih.gov/ods. Currently, IBIDS contains 400 000citations and abstracts of published international, scien-tific literature on dietary supplements, including vita-mins, minerals, and botanicals and is updatedquarterly. Scheduled to go online in 2001, CARDS(Computer Access to Research on Dietary Supple-ments) will identify ongoing, federally funded researchon dietary supplements and individual nutrients (CAM,2000). Within this context clinical evaluation protocolsshould include those outlined in Table 1.

3.4. Canada

In Canada similar regulatory mechanisms are beinginstituted and in March of 1999, an Office of NaturalHealth Products was created to assure that Canadianconsumers have access to a full range of safe healthproducts. The Office will undertake or coordinate allthe regulatory functions within the life-cycle of natural


health products from pre-market assessment forproduct licensing through licensing of establishments,post-approval monitoring and the compliance and en-forcement tools appropriate with ensuring health pro-tection. This will include the development ofappropriate training standards of manufacturing anddistribution establishments. Within this context, crite-ria to determine the applicability of efficacy as reflectedin labeling claims will be established and informationdisseminated to allow the Canadian consumer to makeinformed self-care decisions. Accommodations will bemade for aboriginal healers. Currently, Health Canadapolicy allows an individual to import a 3 month supplyof a drug product for their own personal use that is notsubject to these evolving regulatory policies (Koryrskyj,1977).

4. Surveillance of adverse effects through databases

Regardless of the type of herbalism being practicedsome adverse reactions are more easily recognizablethan others. Postulates have been proposed by Hughes(1995) to define if adverse effects are linked to a druguse. According to Stewart (1990), DeSmet (1995b),events that are pharmacologically predictable are oftendose-dependant and thus preventable by dose reduc-tion, or if allergenic, by elimination. However, in spiteof the mode of application, individual differences inphysiology may elicit a variety of idiosyncratic local orsystemic reactions, including those that are life threat-ening. Age may also be a factor and those remediesmost frequently used by the elderly may elicit varyingresponses (Ernst, 1999). Similarly, long-term use canproduce predictable reactions or consist of delayedeffects such as carcinogenicity and teratogenicity. Tobetter understand the scope of these problems andbring them forward to the public DeSmet (1995b)

proposed that forms of herbal post marketing surveil-lances be conducted to detect serious adverse reactions,quantify their incidence and identify contributive andmodifying factors. Obviously, the success of such en-deavors depends on those willing to voluntarily andspontaneously report such events to appropriate healthcare officials, pharmocologists (http,//www.faseb.org/aspet/H&MIG3.htmc top), regulatory bodies (FDAMEDWATCH (http,//www.vmcfscan.fda.gov/dms/aems.html)), and responsible parties in the herb tradeindustry itself, like the American Botanical Council(http,//www.herbs.org), who are collating these data forpublic dissemination (Winslow and Kroll, 1998).

With the number of mixed plant formulations nowmarketed in the US alone, it is particularly importantto refer to web sites that can provide on an on-goingbasis useful information on current adverse reactions.Overall, the US is still a long way from the develop-ment of standardized herbal drugs, called phytophar-maceuticals, which have been formulated (in a fashion)to ensure a reproducible effect by undergoing suitablemeans of identification and clinical evaluations toachieve international approval. Obviously these areneeded steps if allopathic acceptance is to follow (An-gell and Kassirer, 1998). In the interim, information isaccumulating that is providing appropriate ways tounderstand herbal therapies and can be elicited frominternet sources like the National Center for Comple-mentary and Alternative Medicine (http,//nc-cam.nih.gov), American Botanical Council(www.herbalgram.org), US Food and Drug Adminis-tration (www.fda.gov), and the US Pharmacopeia(www.U.S.p.org) (Murphy, 1999).

5. Bridging the gap between herbalism and allopathy

Most importantly, it is now recognized that allo-pathic clinicians have little training in understandinghow various forms of herbalism and self-medicationsare impacting on the health of their patients, who areoften, also under prescriptive medication. However, asawareness of potential interactions with allopathictreatments and herbal remedies increases, many clini-cians and hospitals are eliciting this information onadmission questionnaires (Murphy, 1999). To ensurethat patients will be forthcoming with the information,it is recommended that such solicitations be carefullyworded so as not to be judgmental. This is essentialsince a patients response to treatment, particularly in aclinical trial, could be distorted when concurrent useswith herbal remedies are not revealed (Kassler et al.,1991; Buchness, 1998; Donaldson, 1998).

To increase the sensitivity of future practitioners, anumber of US medical schools are developing coursesin Complementary and Alternative Medicine, including

Table 1Proposed clinical evaluation protocol for the development of anherbal drug

Confirm ethnomedical value in country of originNote all parameters of use particularly among children, the aged

or others with underlying disease statesReview traditional formulations to understand rationale of useKnow variations to standard formulations and reasons for

additions or substitutionsConduct controlled clinical trial with formulation considered to

be the bestIdentify bioreactive components to insure standardization of

contentConduct toxicological studies to understand safe parameters of

useConduct placebo-based clinical trials following appropriate

guidelines for patient entry, evaluations of efficacy etc. tocomply with regulations where product is to be sold


some exposure to herbal medicinal practices. At thispoint these curricula vary and are by no means univer-sal. As a complement to this effort, the need to offercontinuing education courses for physicians, nurses,pharmacists, nutritionists and the like should be pro-moted (Dalen, 1998).

6. Pharmacokinetic behavior of plant-derived drugs

Studies on plant-derived drugs primarily with quinineand sparteine have provided a better understanding offactors affecting the pharmacokinetic behavior of drugswithin human populations. It has been recognized, forinstance, that age effects storage and clearance ratesjust as the ability to metabolically oxidize certain com-pounds can be genetically determined and racially fo-cused. Diseases affecting the kidney and liver can alterthe clearance rates of certain compounds or exacerbateunderlying conditions. Infections like malaria can actu-ally raise the plasma levels of the medication (quinine)just as low protein diets can alter urine pH, which whenalkaline, can slow its renal clearance. Smoking or cer-tain drug interactions can also effect oral or metabolicclearance rates. Normal ovarian function can be alteredby use of Vitex agnus castus (Cahill et al., 1994). Allthese activities can impact either beneficial or adverseeffect of drugs and/or herbal therapies (DeSmet andBrouwers, 1997).

7. Herbal drug transmission in utero or throughmothers milk

It is well known that transmission of particular drugsin utero to the fetus or through breast milk to an infantcan take place. Evidence is accumulating that this isalso true should mothers use certain herbal remediesduring pregnancy or while nursing their babies. Effectsmay be transient, grave, or fatal. The fetus is in partic-ular jeopardy should herbs with teratogenic, carcino-genic, toxic or abortifacient properties be employed.For example, constituents like salicylates are potentiallyteratogenic and embryocidal, even if applied externallyin Oil of Wintergreen. Ingestion of sassafras (Sassafrasalbidum), tea popular in the US for its flavor and use asa diuretic (DArcy, 1993), might also pose problems tothe fetus. This is suggested by studies in mice wheretransplacental carcinogenesis has been found to occurfollowing treatment with sassafras and is possiblycaused by its major carcinogenic component, safrole(DeSmet, 1992b). Neonatal jaundice has been traced tothe use of goldenseal and barberry and its hydrastinecontent. Also, since feverfew (Tanacetum parthenium) isa traditional inducer of menses, its use to treatheadaches during pregnancy should be avoided

(OHara et al., 1998). Infant deaths due to veno-occlu-sive disease have been associated with the consumptionof pyrrolizidine alkaloid containing teas or cough reme-dies during pregnancy (Roulet et al., 1988; Winship,1991). Since there is a risk of bleeding disorders beingtransmitted to the fetus or breast feeding infant hep-arin-containing herbs should also be avoided duringpregnancy or lactation (Ernst, 1997). Due to its do-paminergic actions, the same is true for use of chaste-berry fruit (Vitex agnus-castus Boehnert, 1997). Birthweights are also lower in women chewing the stimulant,khat (Catha edulis) during pregnancy (Ghani et al.,1987). At parturition, blue cohosh (Caulophyllum thal-ictroides), used to promote uterine contractions shouldbe avoided since a neonate developed acute myocardialinfarction, associated with profound congestive heartfailure and shock. The infant remained critically ill forseveral weeks but survived. This event was believed dueto vasoactive glycosides, a toxic alkaloid, and sparteinefound in the plant (Jones and Lawson, 1998).

Also consumption by a mother of senna laxative,with rhein, was reported as having elicited catharsis inher nursing infant (Faber and Strenge-Hess, 1988).Comfrey tea, now banned, contains a potentially harm-ful pyrrolizidine alkaloid, echimidine known to havehepatotoxic, genotoxic and carcinogenic properties isalso excreted in breast milk (Winship, 1991). In oneinstance a veno-occlusive hepatic illness resemblingBuddChiari syndrome was linked to the consumptionof a tea containing flowers of Tussilago farfara androots of Petasites officinalis (Radix petasitidis) (Rouletet al., 1988; Spang, 1989), and in another, senecionine,a pyrrolizidine alkaloid present in an herbal coughremedy was responsible for this fatal illness (Fox et al.,1978).

8. Allergic reactions

Allergic reactions that can occur with herbal use aremanifested in a variety of forms (Rieder, 1994). BothType I immediate hypersensitivity reactions leading torhinitis, headache, dermatitis (hives), and/or anaphylac-tic shock are commonly induced by cross-reactionsamong Asteraceous (daisy family) plants taken inter-nally, whereas delayed Type IV, contact dermatitis ismore prevalent when topical applications are used(Gordon, 1999). Within this family, wide cross-reac-tions are known and a major sensitizing plant in the USis ragweed (Ambrosia spp.), it follows that patients withknown sensitivity to ragweed should avoid Asteraceousherbal teas like chamomile (Chamaemelum nobile)(Lewis, 1992b) or other remedies containing flowerheads and pollen, and particularly in concentratedforms such as bee pollen (propolis) preparations. Whenused as a vulnerary agent, rare allergic reactions and


contact irritation have been reported; and it is espe-cially to be avoided in ocular preparations (OHara etal., 1998). Also royal jelly, a thick mixture of honey andpollen naturally contaminated with pollen allergens hasbeen repeatedly linked to cases of severe bronchospasm(Perharic et al., 1993). In Europe, where ragweed isunknown or uncommon, chamomile was once consid-ered safe for use as a tea or in a variety of medications,unless of course one is allergic to the wormwoods(Artemisia) of Spain and elsewhere (Subiza et al., 1989)or other Asteraceae (Hausen, 1981, 1996). Recently anumber of reports from throughout Europe suggestthat sensitization can take place and allergic reactionsmay be manifest systemically (Rodriguez-Serna et al.,1998) as dermatitis (Subiza et al., 1989; Paulsen et al.,1993; Bossuyt and Dooms-Goossens, 1994; Pereira etal., 1997; Foti et al., 2000; Giordano-Labadie et al.,2000), or when used in an enema during labor, as fatalanaphylaxis (Jensen-Jarolim et al., 1998). Recently tworeports from Australia regarding Echinacea-inducedanaphylaxis (Mullins, 1998; Myer and Wohlmuth 1998)elicit further concerns regarding the use of asteraceousplants in complementary medicine. In this context,contact with feverfew (Tanacetum parthenium) mayelicit contact dermatitis (Hausen, 1981) and in herbalpreparations can be contraindicative to those allergic toother members of the Asteraceae. For example, should,a sensitized patient use a feverfew preparation to treatheadache their condition could be amplified rather thanreduced (OHara et al., 1998). Also yohimbine has beenreported as causing a lupus-like syndrome (Sandler andAronson, 1993). Recently a number of adverse reportshave been associated with flavonoids used in Europeanherbal preparations (Ernst, 1998), e.g. cyanidanol elicit-ing hemolytic anemia (Gandolfo et al., 1992), cirkancausing chronic diarrhea (Maechel, 1992), sciadopitysincausing severe nephropathy (Lin and Ho, 1994) andcolitis from a phlebotonic French drug, cyclo-3 fortcontaining Ruscus aculeatus, hersperidin methyl chal-cone, ascorbic acid (Beaugerie et al., 1994).

Essential oil delayed-hypersensitivity can be relatedto episodes of aphthous stomatitis (canker sores), whenother predisposing factors like atopy and stress are inplace. In a preliminary study of eight patients withaphthous stomatitis, of 34 essential oils or their compo-nents tested, 30 of these substances proved to elicitsome reactivity in one or more patients, whereas fourcontrol patients were unreactive. Using lymphoblastictransformation to test hypersensitivity, a major excitingagent was found to be eugenol found in spices (oil ofcloves), herbs, foods (artichokes), flavorings, cosmetics,fragnances and medicinals. Walnut, anise, dill, pepper-mint, caraway, and lavender were also significant elici-tors (Elvin-Lewis et al., 1985) in addition to cashew nutand its urushiol (Lewis and Elvin-Lewis, 1977). L-car-vone in many mint and peppermint oils has also been

implicated in contact allergies (Paulsen et al., 1993) andcheilitis induced by use of toothpaste (Hausen, 1984).In another study when patch testing (Standard Eu-ropean Series) was used to test 20 patients with apht-hous stomatitis, a positive reaction to a number of foodsubstances were also considered clinically relevant andavoidance of the offending allergens recommend(Nolan et al., 1991).

It is also possible that inhalation of some of theessential oils including lavender, jasmine and rosewoodused in perfumes or as an ingredient in aromatherapycan elicit similar allergic reactions in the nasal passagesand respiratory tract, (Schaller and Korting, 1995; Sel-vaag et al., 1995a; Sugiura et al., 2000). Aromathera-pists may also be at risk of developing dermatitis fromcontinued contact with these oils (Selvaag et al., 1995b).Dermatological conditions associated with contact ofallergenic plants and their products have been recentlyreviewed by Sassevile (1999).

9. Dental products

Adverse effects of dental products containing plantcomponents are rare, but are worthwhile considering(Ocasio et al., 1999). These formulations often includenatural sources of calcium carbonate that can vary inabrasivity, and when derived from seashells may con-tain high amounts of mercury. It is not unusual forAsian herbal dentifrices to be packaged in lead tubingand it is unclear how many are still being sold in thisway.

Aside from hypersensitivity reactions to flavoringagents that are primarily essential oils, or myrrh that isoften used as a breathe freshener, long-term exposureto other components may elicit more serious effects(Elvin-Lewis, 1987, 1989; Elvin-Lewis and Lewis, 1995).For example, American and Canadian dental productscontaining blood-root (Sanguinaria canadensis) extract,frequently promoted by dentists, have recently beenshown to induce a sanguinaria-associated leukoplakiasyndrome (hyperorthokeratosis, epithelial atrophy, andepithelial atypia/mild dysplasia) that in one instancewas also contiguous to a squamous cell sarcoma(Damm et al., 1999). Although these observations havebeen vigorously defended as being spurious (Munro etal., 1999) the fact remains that sanguinaria extract hasrecently been removed from the Viadent formulation!The flat structure of the alkaloids (sanguinarine andcherylethrine) and their ability to intercalate with DNAwere known at the time of formulation 15 years agoand were predictive of potential carcinogenicity (Cul-venor, 1983a,b). The concern of pyrrolizidine alkaloidmutagenicity (Yamanaka et al., 1979; Takanashi et al.,1980) was provided to the company but since results ofAmes and other mutagenicity tests were reported as


equivocal, the sale of the formulation was allowed. Thecompany and its Expert Panel of advisors (as relatedto me) considered the tingling or irritating sensationreported by some users to be associated with the flavor-ing agent. They did not consider, as relevant, the factthat users of an African chewing stick, Fagara xan-thoxyloides containing related alkaloids, also reportedsimilar effects (El-Said et al., 1971). (How this type ofchronic irritation predisposed to the precancerous le-sions is unknown.) While many pharmacognosists, andmyself, continued to be concerned about accumulativecarcinogenic effects, a few considered the amount of thecompounds in the formulations to be of little conse-quence. To date, almost 100 cases of leukoplakia havebeen reported in long-term users. This has resulted in arecent reformulation of the product and the removal ofthe offending alkaloids. Little is known about the con-sequences of use elsewhere in the body, but these arehighly bioreactive alkaloids. It is recognized that dentalproducts are swallowed during oral hygiene and that, atleast with fluoride; they can be absorbed beneficiallyinto the bones and teeth. It is important to also empha-size that there was no ethnodental validation to supportthe development of the product in the first place, inspite of claims to the contrary, unless of course onewere to rely on anecdotal information from one horsetrainer that used blood-root to remove plaque fromhorses teeth!

Adverse effects of other popular herbal dental prod-ucts are unknown. It is prudent to read the labels andbe aware of the plant products that they contain sincemany, especially if claimed to be of Ayurvedic origin,are mixtures of numerous substances with quantities ofeach ingredient unrevealed. However, such productsshould be avoided if information regarding their abilityto be locally irritating (a possible predisposing factorfor cancer), evoke contact dermatitis, or systemicallybioreactive is brought forward. This is a concern withTea Tree Oil, (Melaleuca alternifolia) found in herbaldental products. It is antiseptic but the oil can belocally irritating and elicits contact dermatitis (Knightand Hausen, 1994; Blushan and Beck, 1997; Greig etal., 1999), vulvovaginitis (Varma et al., 2000), and ifingested is toxic to the central nervous system (Rubel etal., 1998; Bruynzeel, 1999). Neem (Azadirachta indica)used a chewing-stick or as an oil-extract in dentalproducts might also potentially elicit problems. Neem isvalued for its antimicrobial and anti-inflammatory ef-fects and for its ability to ameliorate gingivitis (Elvin-Lewis, in press). However, little is known regarding theexact nature of the neem components it contains suchas the highly regarded insecticide and anti-feedent,azadirachtin. Although early Ames tests have beenreported as negative, its structure suggests it may bepotentially carcinogenic. It is known to elicit disruptivechanges in metaphase chromosomes in both insects and

mice (Rosenkranz and Klopman, 1995; Awasthy et al.,1999). Neem oil, bark and leaf extracts are particularlybioreactive and are currently being evaluated for a widerange of medicinal uses (Van der Nat et al., 1991),including hypoglycemic action (Chakraborty and Pod-der, 1984), and because of immunomodulatory effects,also for contraceptive and abortifacient activities(Mukherhee et al., 1996; Talwar et al., 1997a,b). Leafextracts have also been shown to adversely affect thy-roid function in mice, (Panda and Kar, 2000). If theideal neem dentifrice is to be formulated then com-pounds that promote dental health should be retainedand others that could potentially elicit adverse effectseliminated (Elvin-Lewis, in press).

10. Problems associated with long-term use

Today, many herbal remedies are being used prophy-lactically to maintain or enhance good health or pre-vent certain conditions from occurring. Since many ofthese herbal medications are popular and promoted asboth safe and efficacious, it is not always possible forthe long-term user to understand why this practicecould be harmful. Symptoms can vary from trivial tosevere and are particularly disconcerting when theyeffect the heart, blood pressure, liver, gastrointestinaltract and nervous or endocrine systems (Table 2). Note-worthy are effects associated with ginseng, golden seal,milk thistle, cassia, saw-palmetto, valerian, and a vari-ety of stimulants (DArcy, 1993; Anonymous, 1995a;Ernst, 1998; OHara et al., 1998) including those thatcontain caffeine, like guarana (Paullinia cupana) ormate (Ilex paraguariensis). The latter beverage has alsobeen implicated in inducing oral cancers (Victora et al.,1990), but clear correlative evidence has yet to beforthcoming. Another herbal stimulant, Ma Huang,containing ephedrine, has been reported to cause hallu-cinations and paranoia (Anonymous, 1996; Doyle andKargin, 1996). Also anthranoid laxatives such as aloe,cascara, rhubarb, and senna, commonly considered assafe, may be a risk factor for colorectal cancer if usedon a long-term basis (Siegers et al., 1992). Similarly,abuse of these laxatives can increase the loss of serumK, thereby potentiating the effects of cardiac glycosidesand antiarrhythmic agents (Blumenthal, 2000). The useof astragulus root (Astragulus membranaceus), a majorimmunostimulating herb of Chinese medicine, may becontraindicative when patients are undergoing im-munosuppressive therapy (DeSmet and DArcy, 1996).Also, black cohosh (Cimicifuga racemosa) used forgynecologic disorders (Liske, 1998) and to treatrheumatism, can when taken in large doses or forprolonged periods cause nausea, vomiting and gas-troenteritis (Saxe, 1987). Similar conditions have alsobeen reported for blue cohosh (Caulophyllum thalic-

M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164150T

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Table 3Hepatotoxicity related to herbal remedies

Herb or taxa ReferencesType ofcompound

Pyrrolizidine Senecio, Crotalaria, Symphytum, Winship, 1991; Hill et al., 1951; Bras et al., 1954; Fox et al., 1978; Lyford et al.,Heliotropium 1976alkaloids

Mentha puleguim, Hedeoma pulegoidesMonoterpene Sullivan et al., 1979; Anderson et al., 1996(pennyroyal)(puleguim)

Teucrium poliumm (gemander)Diterpenoid Larrey et al., 1992; World Health Organization, 1992; DArcy, 1993

DeSmet et al., 1996Anthren Cassia angustifolia (senna)

Jin Bu Huan concentrated alkaloidLevotetrahydrop- Anonymous, 1993a,b; Horowitz et al., 1996almitine

Atractylate Georgiou et al., 1988; Stickel et al., 2000; Hamouda et al., 2000Atraclylis gummifera

Safrole Sassafras albidum Segelman et al., 1976; Liu et al., 1999; Burkey et al., 2000

Larrea tridentata (chaparral)Nordihydroguair- Anonymous, 1992; Sheikh et al., 1997; Batchelor et al., 1995etic acid

Strahl et al., 1998; Ruze, 1990Piper methysticum (kava)UnknownBenninger et al., 1999Chelidonium majus

troides) (Saxe, 1987), in addition to adverse effects tothe newborn when used to promote labor (Jones andLawson, 1998).

11. Effects on internal organs

Detoxification and clearance of poisonous substancesfrom the body are primarily a function of the liver andkidneys and they are often the first to be affected bytoxic herbs (Larrey, 1994; DeSmet et al., 1996; Kaplow-itz, 1997; Nortier et al., 1999; Stickel et al., 2000).Sometimes the causes are more obtuse, as when kavauser developed a necrotizing hepatitis (Strahl et al.,1998), but not the usual kava dermatology of yellowand scaling skin associated with long-term use (Ruze,1990). Equally perplexing are the number of cases ofacute hepatitis following the use of greater celadine(Chelidonium majus) for treating biliary and gastricdisorders (Benninger et al., 1999), or the one case ofnecrotizing hepatitis possibly associated with use oflesser or common celidine (Strahl et al., 1998). Simi-larly, May apple (Podophyllum peltatum) used as a livertonic has been found to cause nausea, vomiting, inflam-mation and edema of the bowel, diarrhea, elevated liverenzymes and hematologic abnormalities (Saxe, 1987).Table 3 lists some of these or other herbs most prob-lematical to the liver.

Over 100 hepatotoxic pyrrolizidine alkaloids arefound within species of the Asteraceae, Borginaceae,and Fabaceae. Such plants are consumed as food, formedicinal purposes, or as contaminants of other agri-cultural crops (FDA/CFSAN AEMS Search Results,2000). Pyrrolizidine alkaloids and others, equally

heinous are particularly harmful to the liver and lungs,causing veno-occlusive disease (Winship, 1991). Whilethe disease is relatively rare in the US and is usuallyrelated to the consumption of herbal remedies (Sprang,1989) mass human poisonings have occurred elsewherefrom ingestion of seeds with these alkaloids contami-nating cereal crops (Chauvin et al., 1994; Drew andMyers, 1997). Abdominal pain, vomiting, and the de-velopment of ascites characterize this condition. Pa-tients may recover if the alkaloid intake is discontinuedand the liver damage not too severe, otherwise deathcan follow. In Jamaica, for example, endemic veno-oc-clusive disease, has been linked to the consumption ofSenecio or Crotalaria spp. as bush teas (Hill et al.,1951; Bras et al., 1954). Comfrey teas have now beenbanned in the US due to this serious side effect (Ridker,1989). Some, like chaparral tea for example, should beavoided during cancer treatments or when underlyingdiseases of the liver are known. A retrospective studyon adverse effects of herbal medicines by the NationalPoisons Unit (London) led the authors (Perharic et al.,1994) to recommend that routine liver function tests bedone on individuals using Chinese herbal remedies.This is important since so many cases of liver damageleading to acute liver failure have been associated withthe use of Chinese herbal remedies for the treatment ofskin disorders (Shaw et al., 1997; Armstrong and Ernst,1999).

Care should also be taken when using herbal medica-tions to treat cardiovascular problems (Mashour et al.,1998). While some may be worthwhile, many containnatural cardiac glycosides, blood thinners, or affectblood pressure and are not only bioreactive on theirown but can work with prescribed medications to po-


tentiate or diminish their action (Catania, 1998). Forexample, ginger contains a potent inhibitor of throm-boxan synthetase (Backon, 1986) that prolongs bleedingtime. According to Miller (1998) its use could result inadverse implications for pregnant patients or those onconcomitant warfarin therapy. It is noteworthynonetheless, that ginger is still a favored remedy totreat nausea from morning or motion sickness. Fever-few (Tanacetum parthenium) has the potential of poten-tiating platelet inhibitors and its use as a headacheremedy should be avoided during therapy with blood-thinning agents (OHara et al., 1998). It is also recom-mended that heparin-like herbs not be taken duringpregnancy or lactation, since cranial bleeding or otherassociated effects could be induced in the fetus ornursing infant, respectively (Pansatiankul andRatanasir, 1992; Pansatinkul and McKnanee, 1993). Anumber of cases of allergy and anaphylactic shock(Jaspersen-Schib et al., 1996) and one case of hepaticinjury (Takegoshi et al., 1986) have been associatedwith the use of horse chestnut species to treat chronicvenous insufficiency (Ernst, 1999) (Table 4).

12. Effects under predisposing conditions

Patients taking herbs for various purposes may alsopredispose themselves to unwanted conditions prior tosurgery, when pregnant, if atopic, or under treatmentfor other conditions, including those that require psy-choactive medications. Deaths due to medication ofgenerally recognized as safe herbs are extremely rare.

These events are more likely due to adulterants in theformulations, to unknown interactions in complex mix-tures, as a result of undisclosed pharmaceutical interac-tions, to inappropriate dosage or use, or to underlyingfactors associated with the specific patient (OHara etal., 1998; FDA/CFSAN AEMS Search Results, 2000).A variety of serious reactions due to use alone, withother herbal medications, or with pharmaceutical drugshave been recorded and include effects on coagulationby feverfew (Murphy, 1999), garlic ginger, and ginkgoand antagonistic effects of ephedra. Noteworthy is theimmunosuppression that can be induced by long-termEchinacea used for immune stimulation. Photosensitiv-ity that is associated with St. Johns wort (Hypericumperforatum) and Psoralea corylifolia (an ingredient inseveral Chinese herbal formulations) (Maurice andCream, 1989) is considered rare (Blumenthal et al.,1998). However, according to one herbalist that hasobserved this reaction in a number of St Johns wortusers (Cathy Crandall, personal communication) thisphenomenon may be under-reported. Also, St Johnswort interacts with some anesthetic agents and resultsin eliciting mild monamine oxidase inhibition (MAOI),or selectively inhibits serotonin uptake (SSRI) (Mur-phy, 1999). Ginseng, while considered GRAS, has alsobeen reported to elicit a wide range of adverse condi-tions, and should be avoided with other stimulants andparticularly it should not be used by patients withcardiovascular disease due to its effect on blood pres-sure and heartbeat (chronotrophic effect), and its abil-ity to potentiate digoxin levels. Licorice hashypertensive effects and can potentiate the activity of

Table 4Cardiovascular herbal treatments, adverse reactions

Binomial Adverse effectCommon name References

Aesculus Hepatic toxicity, allergy, anaphylaxisHorse chestnut Jaspersen-Schib et al., 1996; Takegoshi et al.,hippocastanum 1986

Headache, nausea, hiccups, diminished efficacy of Singh et al., 1994; Dalvi et al., 1994CommiphoraGugulipidmukul other cardiovascular drugs including diltiazem

and propranolol

Crataegus ESCOP, 1997, 1999; Upton, 1999; Tyler, 1994;Potentiates digitalis activity, increases coronaryHawthornmonogyna dilatation effects of theophylline, caffeine, Mawrey, 1993

papaverine, sodium nitrate, adenosine andepinephrine, increase barbituate induced sleepingtimes

Rau6olfiaReserpine Sedation, inability to complete tasks, mental Webster and Koch, 1996; Brunton, 1996;serpentina depression, nasal congeston, increased gastric Mashour et al., 1998

secretion and mild diarrhea

Dan-shen Sal6ia Chan et al., 1995; Izzat et al., 1998; Yu et al.,Potentiates warfarin activity1997; Cheng, 2000militorrhiza

CNS and cardiotoxic, GI bleedingViscum album Stein and Berg, 1999Europeanmistletoe

Hypotension in cancer patients in treatment Anonymous, 1992Larrea tridentataChaparral

M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 153T

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an,

1997

;B

lum

enth

alC

aric

apa

paya

Pap

ain

incr

ease

dIN

R,

Ant

icoa

gula

ntP

apay

aex

trac

tda

mag

esm

ucou

sm

embr

anes

etal

.,19

98;

Wor

ldH

ealt

hof

GI

trac

tO

rgan

izat

ion,

1999

May

bead

diti

ve;

purp

ura;

addi

tive

effe

cts

Blu

men

thal

etal

.,19

98,

Har

pago

-phy

tum

Dev

ilscl

awA

ddit

ive

effe

cts

Wor

ldH

ealt

hO

rgan

izat

ion,

1999

Pro

cum

bens

Pos

sibl

yad

diti

veB

lum

enth

alet

al.,

1998

Cin

chon

aba

rkC

inch

ona

Pub

esce

nsSu

nter

,19

91;

Wor

ldH

ealt

hG

arlic

Alli

umS

ati6

umA

ddit

ive

effe

cts

Org

aniz

atio

n,19

99W

orld

Hea

lth

Org

aniz

atio

n,G

inge

rA

ddit

ive

effe

ct;

caus

esir

isZ

ingi

ber

Offi

cina

le19

99;

Blu

men

thal

,20

00bl

eedi

ngR

etar

dsab

sorp

tion

Mur

phy

etal

.,19

98F

ever

few

Tan

acet

umpa

rthe

nium

Ros

enbl

att

and

Min

del,

1997

Gin

kgo

Asp

irin

Gin

kgo

bilo

baP

lant

ago

spp.

Cou

mar

inse

riva

tive

sB

lum

enth

alet

al.,

1998

;P

sylli

umse

edW

orld

Hea

lth

Org

aniz

atio

n,19

99

Insu

linor

oral

Her

bal

anti

diab

etic

Ant

idia

beti

chy

po-g

lyca

emic

sA

ddit

ive

effe

cts

Yon

gcha

iyud

aet

al.,

1996

;A

loe

gel

and

juic

eA

loe6e

raA

slam

and

Stoc

kley

,19

79M

omar

dica

Cha

rant

iaB

itte

rm

elon

Add

itiv

eef

fect

sB

aska

ran

etal

.,19

90;

ESC

OP

,19

97;

Blu

men

thal

etal

.,19

98E

SCO

P,

1999

Gym

nem

asy

l6es

tre

Add

itiv

eef

fect

sG

urm

arle

aves

Fla

xsee

doi

lL

inum

Usi

tati

ssim

umE

SCO

P,

1997

;B

lum

enth

alet

Del

ays

abso

rpti

onof

drug

sal

.,19

98,

ESC

OP

,19

99ta

ken

sim

ulta

neou

sly;

indi

abet

ics

dela

ysgl

ucos

eab

sorp

tion

Pan

axG

inse

ngH

eada

ches

,tr

emul

osne

ss,

Phe

neiz

ine,

tria

zola

m,

Ant

idep

resa

ntan

tago

nist

sG

onza

lez-

Seijo

etal

.,19

95G

inse

nglo

raze

pam

inso

mni

a,ir

rita

bilit

y,vi

sual

halu

cina

tion

s

Cha

steb

erry

frui

tM

etoc

lopr

am-i

deV

itex

agnu

s-ca

stus

Pos

sibl

ein

tera

ctio

nsA

ntie

met

icB

lum

enth

alet

al.,

1998

;B

lum

enth

al,

2000

Enh

ance

ssy

mpa

thom

imet

icE

phed

raE

SCO

P,

1997

;B

lum

enth

alet

Ant

ihyp

erte

nsiv

eE

phed

rasi

nica

Gua

neth

idin

eef

fect

ofep

hedr

aal

.,19

98;

ESC

OP

,19

99;

Blu

men

thal

,20

00

Ana

lges

ics

Salic

ylis

m;

hype

rsen

siti

vity

Mal

iket

al.,

1994

;E

rnst

,A

spir

inS

alix

spp.

;G

ault

hria

Salic

inco

ntai

ning

herb

als

and

1998

oils

proc

umbe

ns,

Euc

alyp

tus

glob

ulus

M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164154T

able

5(C

onti

nued

)

Adv

erse

effe

cts

Ref

eren

ces

Dru

gB

iore

acti

vity

Her

bT

axa

Incr

ease

sth

eoph

yllin

es

Ata

let

al.,

1985

;B

ano

etal

.,P

iper

Nig

rum

;P

iper

long

umP

iper

ine

from

blac

kpe

pper

Ast

hmat

icpr

epar

atio

nsT

heop

hylli

neab

sorp

tion

,de

crea

ses

its

1991

met

abol

ism

Pot

enti

ates

acti

vity

and

Car

diac

Her

bals

cont

aini

ngca

rdia

cB

lum

enth

alet

al.,

1998

;E

rnst

,D

igit

alis

1998

;B

lum

enth

al,

2000

incr

ease

sto

xici

ty;

addi

tive

glyc

osid

esef

fect

sA

ddit

ive

ESC

OP

,19

97,

1999

;W

orld

Hea

lth

Org

aniz

atio

n,19

99A

rryt

hmia

,pa

lpit

atio

ns,

naus

ea,B

lum

enth

alet

al.,

1998

;E

rnst

,L

icor

ice

root

Gly

cyrr

hiza

glab

ra19

98ab

dom

inal

pain

Aco

nitu

ma

Add

itiv

eef

fect

s,in

duce

slo

ssK

,A

coni

tum

spp.

wit

hth

iazi

dedi

uret

ics

Incr

ease

sab

sorp

tion

Blu

men

thal

etal

.,19

98R

etar

dsab

sorp

tion

Wor

ldH

ealt

hO

rgan

izat

ion,

Tyr

amin

ein

duce

dhy

per-

tens

ive

Rhe

umof

ficin

ale

Rhu

barb

root

1999

cris

esB

lum

enth

alet

al.,

1998

Sm

ilax

spp.

Sars

apar

illa

Roo

tP

sylli

umP

lant

ago

spp.

Car

diac

arrh

ythm

ia,

tach

ycar

dia;

ESC

OP

,19

97;

Blu

men

thal

etC

ytis

ussc

opar

ius

Scot

chbr

oom

Incr

ease

ssy

mpa

thom

imet

ical

.,19

98;

ESC

OP

,19

99;

acti

onof

ephe

dra;

coul

dca

use

fata

lhy

per-

tens

ion

Wor

ldH

ealt

hO

rgan

izat

ion,

1999

;B

lum

enth

al,

2000

ESC

OP

,19

97;

Blu

men

thal

etE

phed

raE

phed

rasi

nica

al.,

1998

;E

SCO

P,

1999

;W

orld

Hea

lth

Org

aniz

atio

n,19

99;

Blu

men

thal

,20

00C

ontr

aind

icat

ive

wit

hca

rdia

cB

lum

enth

alet

al.,

1998

;W

orld

glyc

o-si

des,

spir

ono

lact

one,

Hea

lth

Org

aniz

atio

n,19

99am

ilori

dein

crea

sed

sens

itiv

ity

todi

gita

lisB

lum

enth

alet

al.,

1998

;W

orld

Add

itiv

eef

fect

s;ir

isbl

eedi

ngM

AO

Hea

lth

Org

aniz

atio

n,19

99w

ith

aspi

rin

Inhi

bito

rsA

ntag

onis

tic

due

tohi

ghV

itam

inK

cont

ent

Blu

men

thal

etal

.,19

98;

Wor

ldL

icor

ice

root

aG

lycy

rrhi

zagl

abra

Seca

leal

kalo

idde

riva

tive

sH

ealt

hO

rgan

izat

ion,

1999

Blu

men

thal

etal

.,19

98;

Wor

ldP

ossi

ble

addi

tive

effe

cts

Thi

azid

edi

uret

ics

Hea

lth

Org

aniz

atio

n,19

99A

ddit

ive

effe

cts

Add

itiv

eef

fect

sD

Arc

y,19

93G

inkg

oG

inkg

obi

loba

Bra

ssic

acea

eet

c.B

rass

ica

spp.

(bro

ccal

i)

and

War

fari

nce

rtai

not

her

gree

nve

geta

bles

Bac

kon,

1986

;W

orld

Hea

lth

Zin

gibe

rof

ficin

ale

Gin

ger

Org

aniz

atio

n,19

99


Tab

le5

(Con

tinu

ed)

Dru

gR

efer

ence

sH

erb

Tax

aB

iore

acti

vity

Adv

erse

effe

cts

Alli

umsa

ti6u

mG

arlic

Sunt

er,

1991

DA

rcy,

1993

Hor

sech

estn

utA

ecul

ushi

ppoc

asta

num

Con

trai

ndic

ativ

e;re

cipr

ocal

Ora

lco

ntra

cept

ives

;ho

rmon

eO

ral

cont

race

ptiv

es(e

.g.

Blu

men

thal

etal

.,19

98;

Vit

exag

nus

cast

usC

hast

eber

ryfr

uit

Blu

men

thal

,20

00ha

lope

rido

l)w

eaki

ngef

fect

ofdo

pam

ine

ther

apy

rece

ptor

anta

goni

sts

Pot

enti

ates

psyc

hoac

tive

acti

vity

DA

rcy,

1993

;E

rnst

,19

98H

allu

cino

gens

Her

bal

Tet

racy

clin

e,pr

opra

nolo

l,al

coho

lH

allu

cin-

ogen

sC

inna

mon

Cin

nam

omum

zela

nicu

mM

agic

mus

hroo

m

Psi

locy

bese

mila

ncea

ta

Seda

tive

Her

bal

seda

tive

sA

lcoh

ol,

anti

hist

amin

esD

row

sine

ss,

obtu

nds

abili

tyto

Val

eria

naof

ficin

alis

DA

rcy,

1993

;D

eSm

etet

al.,

Val

eria

n19

96us

em

achi

nery

;po

tent

iate

sef

fect

sof

anti

depr

essa

nts,

anti

hist

amin

ics,

anti

spas

mod

ics

Pas

sion

flow

erP

assi

flora

inca

rnat

aD

Arc

y,19

93A

trop

abe

llado

nna,

Dat

ura

Ant

icho

lin-e

rgic

sola

nace

aest

rom

oniu

m,

Hyo

cyam

usni

ger,

Man

drag

ora

offic

inar

um

Cen

tella

asia

tica

,C

on6o

l6ul

usSe

izur

eco

ntro

lP

heny

toin

Red

uces

plas

ma

leve

ls;

seiz

ure

Shan

kha-

phus

piSw

inya

rdan

dW

oodh

ead,

1982

;D

ande

kar

etal

.,19

92pl

uric

aulis

,N

ardo

stac

hys

cont

rol

lost

jaat

aman

si,

Nep

teta

ellip

tica

,N

epet

ahi

ndos

tana

and

Ons

osm

abr

acte

atum

Eve

ning

prim

rose

Oen

othe

rasp

p.P

heno

thia

zine

s

Cya

mop

sis

tetr

a-g

onol

oba

Gua

rgu

mO

pper

etal

.,19

90;

Seid

ner

etP

heno

xym

ethi

-pen

icill

inIn

hibi

tsab

sorp

tion

;ca

nin

duce

Slim

min

gag

ents

obst

ruct

ions

inth

ebo

wel

orin

al.,

1990

;L

ewis

,19

92a

pati

ents

wit

hes

opha

geal

stri

ctur

esIn

hibi

tsab

sorp

tion

Evo

kes

hype

ror

Psy

llium

seed

Wor

ldH

ealt

hO

rgan

izat

ion,

Lit

hium

,ca

rba-

maz

epin

e,P

lant

ago

spp.

card

iac

glyc

osid

es,

coum

arin

hypo

thyr

oidi

sm,

skin

1999

hype

rsen

siti

vity

deri

vati

ves

Aut

oim

mun

eth

rom

bocy

tope

nia

Kim

and

Kim

,20

00Sh

iloan

dH

irsc

h,19

86L

amin

aria

,M

acro

cyst

is,

Kel

pT

hyro

idsu

pple

men

tor

alon

eN

ereo

cyst

issp

p.K

elp

wit

har

seni

cP

yeet

al.,

1992

aF

requ

entl

yin

Chi

nese

herb

alfo

rmul

atio

ns.


digitalis and thiazide diuretics (Cugini et al., 1983;Blumenthal, 2000; Olukoga and Donaldson, 2000; Shi-bata, 2000). Influences on thyroid function can vary;for example, kelp used for weight loss can inducehyperthyroidism (DeSmet et al., 1990) whereas, use ofhorseradish remedies can result in hypothyroidism(DArcy, 1993). Valerian (Valeriana officinalis) isknown to potentiate the sedation or excitation effects ofcertain sedatives or anxiolytics, respectively (Miller,1998; Murphy, 1999). While considered GRAS, vale-rian has also been reported in rare cases to elicitheadache, palpitations, insomnia (OHara et al., 1998),pruritis, anorexia, hepatitis and intoxication (FDA/CF-SAN AEMS Search Results, 2000). Use of Devils Claw(Harpagophytum procumbens) for anorexia, dyspepsiaand degenerative disorders of the locomotor system arecontraindicated in individuals with gastric and duode-nal ulcers or with individuals with gallstones (Blumen-thal et al., 1998). Arsenic has been found to anadulterant in a variety of herbal formulations (FDA/CFSAN AEMS Search Results, 2000) and in kelp hasbeen reported to cause autoimmune thrombocytopenia(Pye et al., 1992).

13. Effects of slimming agents

Natural slimming agents can also be problematical ashas been found for guar gum that has elicited severeadverse obstructions of the bowel and esophagus, par-ticularly among those with esophageal abnormalities(Opper et al., 1990; Seidner et al., 1990) that in oneinstance was fatal (Lewis, 1992a). The presence ofsparteine in a variety of herbal remedies used for slim-ming and diabetes has been reported to cause circula-tory collapse, respiratory arrest (Galloway et al., 1992)and classic anticholinergic effects (Tsiodras et al.,1999). Also, because of its oxytoxic effects sparteine-containing herbals would be contraindicative for use inpregnancy (Bensousan and Meyers, 1996). Blossoms ofgermander (Teucrium chamaedrys) in herbal teas orcapsules to treat obesity have been shown to causeacute hepatitis (Larrey et al., 1992). A patient takingwarfarin and using papaya extract (containing papain)for slimming was shown to have an increased interna-tional normalized ratio (INR), the patientsprothrombin time was only restored to normal follow-ing withdrawal of both substances (Shaw et al., 1997).Aristolochia species have been responsible for disordersreferred to as Chinese herb nephropathy (CHN) (Van-haelen et al., 1994) or Fanconi syndrome in Japan, andTanaka et al. (2000) suggests that differences in clinicalpresentation may be due to the amount or type ofaristolochic acids ingested. For example, in Belgium, avariety of Chinese herbal remedies use for slimmingpurposes were linked to a rapidly progressive interstitial

renal fibrotic syndrome (Vanherweghem et al., 1993). Insome cases Aristolochia fangchi was incriminated. Thesame type of renal failure was associated with 12 Chi-nese in Taiwan using a variety of traditional Chineseherbal preparations (Yang et al., 2000) and two othersin the UK (Lord et al., 1999). In two cases in Japan,Fanconi syndrome involved the use of the Chinesemedicine, Kanmokutsu containing A. manshuriensis(Tanaka et al., 2000). This syndrome may also beassociated with the development of overt transitionalcell carcinoma (TCC) (Cosyns et al., 1999). In Taiwan,bronciolitis obliterans (rapidly progressive respiratorydistress) was related to the consumption of uncookedvegetable juice of Sauropus androgynus in guava orpineapple juice (Lai et al., 1996). Used in a weightcontrol formulation for 10 weeks, 23 individuals wereaffected.

14. Drug and herbal interactions

Numerous examples exist of drug and herbal interac-tions. These effects may potentiate or antagonize drugabsorption or metabolism, the patients metabolism, orcause unwanted side-reactions such as hypersensitivity(Brinker, 1997; Cupp, 1999; Blumenthal, 2000). Sucheffects may also impinge on pharmaceutical productinteractions occurring concurrently with those elicitedby herbal use (Aslam and Stockley, 1979; Jankel andSpeedie, 1990). Care should be taken to understandeffects of foods (Williams et al., 1993; Kane and Lip-sky, 2000) or herbal remedies during anti-coagulanttherapy, in the treatment of diabetes, depression, pain,asthma, the heart, blood pressure, and for slimming. Byway of illustration, the high content of vitamin K in avariety of green vegetables, particularly broccoli andother Brassicaceae, can in large amounts, be antagonistto the effects of anti-coagulant therapy (DArcy, 1993).In addition, grapefruit juice, can lead to the elevationof serum concentrations of a variety of medications likecyclosporine, some 1,4-dihydropyridine calcium antago-nists, and some 3-hydroxy-3-methyglutaryl coenzyme Areductase inhibitors (Kane and Lipsky, 2000). Also,unwanted side-effects like gynaecomastia can occurwith ginseng and rauwolfia with a variety of medica-tions, hallucinations with cinnamon and tetracycline,sedative effects with valerian or passion flower andanti-histamines, elevated blood pressure with thizidinediuretic and Ginkgo biloba and seizures may even beincreased if evening primrose is taken in addition tophenothiazines (Newall et al., 1996; Shaw et al., 1997).Similarly, the Ayurvedic remedy Sankhapushpi con-taining Centella asisatica, Con6ol6ulus pluricaum, Nar-dostachys jatamansi, Nepeta ellipica, Nepeta hindostanaand Onosma bracteatum reduced plasma levels ofphenytoin, given concurrently, and resulted in the loss


Table 6Adulterations in herbal remedies

Adulterant Clinical presentationType of remedy ReferencesIngredient

Cough medicine Stillman et al., 1977; Fox et al., 1978Gordolobo Senecio longilobus Veno-occlusive disease (VOD)and infant deathused by

mother

UnknownHerbal tea used Tussilago farfara Fatal VOD in infant Roulet et al., 1988; Sprang, 1989by mother

Grain use Heliotropium andGrains, poaceae etc. VOD, hepatosplenomegaly and Datta et al., 1978; Chauvin et al.,1994; McDermott and Ridker, 1990ascites in AsiaCrotalaria

Comfrey Teas Unsafe, cumulative effectsSymphytum officinale Bach et al., 1989; Ridker andleading to VOD McDermott, 1989; McDermott and

Ridker, 1990Atropa belladona PoisoningDigitalis purpurea Poisoning

Plantago majorPlantain extract Digitalis purpurea Poisoning

Phoradendron, Viscum Skull capMistletoe Hepatitis Moum et al., 1992(Scutellariaextractlaterflora)

Ilex paraguarensis Possibly Senecio VOD McGee et al., 1976Mate orparaguay tea longilobus

Belladonna Anticholergenic poisoning Anonymous, 1995balkaloids

Peppermint, Mentha X piperita and Sperl et al., 1995Seniciphylline Reversible VOD in an infantTussilago farfaracoltsfoot tea

of seizure control (Dandekar et al., 1992) (Table 5). Inaddition, when St Johns wort (Hypericum perforatum)is used simultaneously with a wide variety of drugs thatuse CYPEA4 as a substrate, activity is lowered sincethis herb is considered to increase the activity of theisoenzyme CYPEA4 (Blumenthal, 2000). Salicin-con-taining oils and herbal medications have been known toelicit adverse conditions. For example, accidental inges-tion by an infant of oils of wintergreen, camphor andeucalyptus cause

should we be concerned about herbal remedies

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