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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’ or‘synthetic’ 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.
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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: elvin@biology.wustl.edu (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).
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164144
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
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 145
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
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164146
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
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 147
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
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164148
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
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 149
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
able
2A
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M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 151
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-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164152
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
able
5D
rug
and
herb
alin
tera
ctio
ns
Adv
erse
effe
cts
Ref
eren
ces
Bio
reac
tivi
tyD
rug
Her
bT
axa
Bro
mel
ian
Pin
eapp
leen
zym
eA
nana
sco
mos
usD
iarr
hea,
incr
ease
dte
nden
cyA
ctiv
ity
enha
ncer
ofso
me
Neu
raue
r,19
61;
Tau
ssig
and
anti
biot
ics
and
Bat
kin,
1988
;B
lum
enth
alet
for
blee
ding
ifus
edsi
mul
tane
ousl
yw
ith
al.,
1998
;B
lum
enth
al,
2000
chem
o-th
erap
euti
cag
ents
;an
ti-i
nflam
mat
ory
agen
tan
tico
agul
ants
and
inhi
bito
rsof
thro
mbo
cyti
cag
greg
atio
ndu
eto
mod
ulat
ion
ofth
ear
achi
dona
teca
scad
e
War
fari
nSh
ulm
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
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 155
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.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164156
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
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164 157
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
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