Journal of Ethnopharmacology 75 (2001) 141– 164 www.elsevier.com/locate/jethpharm Should we be concerned about herbal remedies Memory Elvin-Lewis Department 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 in part to the recognition of the value of traditional medical systems, particularly of Asian origin, and the identification of medicinal plants from indigenous pharmacopeias that have been shown to have significant healing power, either in their natural state or as the source of new pharmaceuticals. Generally these formulations are considered moderate in efficacy and thus less toxic than most pharmaceutical 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, often guised as food, or food supplements, known as nutriceuticals, these formulations are readily available for those that wish to self-medicate. Within this system, in particular, are plants that lack ethnomedical verification of efficacy or safety. Unfortunately there is no universal regulatory system in place that insures that any of these plant remedies are what they say they are, do what is claimed, or most importantly are safe. Data will be presented in this context, outlining how adulteration, inappropriate formulation, or lack of understanding of plant and drug interactions have led to adverse reactions that are sometimes life-threatening or lethal. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Herbal remedies; Evolving pharmacopeias; Surveillance and research databases; Adverse effects; Regulatory challenges 1. Introduction During the latter part of the 20th century herbalism has become mainstream worldwide. This is due in part to the recognition of the value of traditional and indigenous pharmacopeias, the incorporation of some derived from these sources into pharmaceuticals (DeSmet et al., 1992a; DeSmet, 1997; Winslow and Kroll, 1998), the need to make health care affordable for all, and the perception that natural remedies are somehow safer and more efficacious than remedies that are pharmaceutically derived (Bateman et al., 1998; Murphy, 1999). For a variety of reasons more individuals are nowadays preferring to take personal control over their health, not only in the prevention of diseases but also to treat them. This is particularly true for a wide variety of chronic or incurable diseases (cancer, diabetes, arthritis) or acute illnesses readily treated at home (common cold etc.) (Kincheloe, 1997). In this respect many individuals have become disenchanted with the E-mail address: [email protected] (M. Elvin-Lewis). worth of allopathic treatments, and the adverse effects that can be anticipated. They are seemingly unaware of the potential problems associated with herbal use or the fact that their limited diagnostic skills, or of those prescribing treatment for them, may prevent the detection 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 considered herbal treatments to be innocuous or alternately, potentially problematical. Three decades ago only a few had any appreciation of the number of remedies that had their origins in herbal medicine and most had a vague impression of what herbalism, or other forms of alternate medicinal practices implied (Lipp, 1996). There was still a great deal of carry-over from the beginning of the 20th century when the introduction of wire services allowed for the dissemination of adverse effects of ‘snake-root’ concoctions and the like. As early as 1906, misbranding and adulteration were disallowed in the US Herbal remedies, not a part of ‘The Dispensatory of the United States of America’, 0378-8741/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 8 7 4 1 ( 0 0 ) 0 0 3 9 4 - 9 142 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 were shunned as if the danger associated with one remedy was common to all much like the notion that if ‘one mushroom is poisonous, all must be’ and by 1938, safety testing was mandated under the Federal Food, Drug and Cosmetic Act. By mid-century, pharmacognosy (study of plants affecting health) was a dying science. Dicta of the day, as outlined in a 1962 law (Kefauver –Harris Drug Amendments) required proof of safety and efficacy. This policy determined that only chemically defined and clinically evaluated medicines had value, and if pharmaceutically derived, must be prescribed by allopathic physicians. (Murphy, 1999). Licensure to practice in the US was confined to allopathic clinicians and others in naturopathy and homeopathy whose traditional use of herbs was well defined. Some leeway was also given to practicing traditional healers within Asian and indigenous communities. On the whole, other types of herbalists were not recognized (O’Hara et al., 1998). Such was the case for decades, until the ‘age of Aquarius’ arrived, and the ‘return to nature’ was the driving force of every ‘flower child’. In this wake, self-medication became the rule as old European herbals and indigenous remedies were revisited, and were used with impunity, without concern for adverse effects. In addition, hallucinogens, particularly from American indigenous cultures, became popular as many trying to escape the reality of a war-torn and ‘hidebound’ world, experimented with ‘altered states’. Soon ‘health food stores’ appeared, specializing in unrefined food, organic-grown vegetables, herbs and herbal preparations. With the opening up of Asian markets, other types of medicines were introduced, and were permitted since they were considered already ‘culturally acceptable’. A synthesis of all these types of herbal medicinal practices evolved into what can be called, ‘Neo-Western’ herbalism. Formulae found in this system are based upon both ethnomedical worth or are simply serendipitous inventions of the formulator. A belief of benefit over single-ingredient drugs is the corner stone of this form of herbalism that subscribes to the notion that ‘primary active ingredients in herbs are synergized by secondary compounds, and secondary compounds mitigate the side effects caused by primary active ingredients’ (McPartland and Pruitt, 1999). Since it is possible for single taxa to contain a family of related bioreactive compounds varying in potency, it is logical to presume that one or more of these will contribute to the totality of the effects observed (Lewis and Elvin-Lewis 1994; Elvin-Lewis and Lewis, 1995). It would follow that when mixtures of several crude extracts are used in formulations, enhancement of beneficial effects (or greater toxicity) is expected through either synergistic amplification or diminishment of possible adverse side effects. It is also presumed that their combination could prevent the gradual decline in effi- cacy that is frequently observed when single drugs are given over long periods of time (Borchers et al., 1997). Nowadays such remedies can be still found in ethnic and health food stores, but are also available in pharmacies and grocery stores. Unfortunately there is no universal regulatory system that ensures that these remedies are what they say they are, do what is claimed, or most importantly, are safe (Angell and Kassirer, 1998; DeSmet, 1993; DeSmet et al., 1997). 2. Evolving pharmacopeias 2.1. Major types of herbal medicine Four general types of Herbal Medicine exist which are Asian, European, Indigenous and Neo-Western. Many like the Asian and European systems go back thousands of years, appear in pharmacopeia, and with such a tradition of use are better understood than those of indigenous origins that are often only orally or secondarily recorded (DeSmet et al., 1992a; DeSmet, 1992b). 2.2. Indigenous herbalism Indigenous medicinal systems are the most diverse and are still practiced where such cultures are intact, but are continuously evolving as contact with other cultures continues. The knowledge may reside exclusively with traditional healers, or be generally known. Information regarding parameters of efficacy and toxicity can vary since claims are primarily anecdotal. Usually regional variations to formulae exist, and plants selected can be quite specific, generic, or inadvertently adulterated. It usually follows that when a remedy is widespread in acceptance its efficacy and safety has a sound 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 of Asian origin, particularly from India (Aryuvedic, Unani, Siddha), China (Wu-Hsing) and Japan (Kampo), and today they still follow the ideas of diagnosis and treatment known for millennia (Kanba et al., 1998; Wong et al., 1998; Vogel, 1991). Most of the remedies are mixtures of plants, sometimes also containing animal parts and minerals and are formulated to achieve expected therapeutic goals. They are often referred to as ‘drugs’. In these remedies it is not unusual to find more than one plant whose components have complementary effects that seemingly work together to enhance the therapeutic value or other properties of the mixture. This is also true for Indian dental M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 preparations that follow traditional formulations (Elvin-Lewis, 1987, 1989). Under ideal conditions, care is taken by traditionally trained practitioners to carefully identify the ingredients, to harvest the plants at very specific times to insure appropriate levels of bioreactivity, to prepare the remedies under strict rules, and to prescribe them to achieve an appropriate clinical response. In spite of the fact that parameters of use may be known to the practitioner, including side effects that can be expected, packaging inserts accompanying commercial products rarely cite these nor do they always accurately represent the contents. Also, there is a general acceptance in Asian countries, particularly India, for patients to seek concurrent treatment through more than one Indian Medicinal System as well as allopathy, or in Chinese herbalism to fraudulently incorporate pharmaceuticals in some remedies. This only compounds issues related to recognizing the source of potential side effects, and it is uncommon for them to be reported at all. Moreover, without enforceable regulatory systems to govern the activities of practitioners and formulators, unexpected adverse reactions are always likely. In this respect, formulations may be inappropriately made, prescribed, or taken. Formulation diversity, due to advertent substitutions, can also exist in preparations with the same name. These changes are not always obvious. Examples can be found in Aryuvedic preparations formulated in southern India, where traditional Himalayan plants are unavailable. Without appropriate prescription labeling, adulterations are a particular problem in Asian medicines, and formulations have been found to contain substitutions of plant ingredients, dangerous levels of toxic plant components, unapproved ingredients like pharmaceuticals and heavy metals in addition to other toxic and allergenic substances (Anonymous, 1989; Chan et al., 1993; Chan, 1997; Drew and Myers, 1997; Ernst, 1997; Ko, 1998). For example, although strictly not herbal remedies, lead has been found in a Laotian preparation known as Pay-loo-ah, a Korean remedy, hai ge fen, containing clam shell powder (Borins, 1998) and in Indian traditional cosmetics used as eyeliners (surma) (Shaw et al., 1997). Chinese herbal medicines are typically unpalatable and can induce nausea and vomiting. Most reported adverse effects on the heart have been associated with Aconitum poisonings and certain topical skin preparations that can also cause liver damage (Chan, 1997; Drew and Myers, 1997; Ko, 1998; Armstrong and Ernst, 1999). In addition, pain or asthma remedies containing Datura metel are recognized to cause anticholinergic effects leading to reduced visceral activity. Liquorice, by affecting the sodium/potassium balance, can cause water retention. More serious are conditions like jaundice and brain damage due to neonatal 143 remedies containing berberine, additive or toxic effects due to undeclared pharmaceuticals like mefenamic acid and diazepam (Gertner et al., 1995), heavy metal adulterations (Schaumburg and Berger, 1992; Kew et al., 1993; Sheerin et al., 1994), or when inadvertent adulterations with Podophyllum emodi instead of londancao (Gentiana spp.) have elicited severe lifethreatening events (Chan, 1997; Drew and Myers, 1997). Highly concentrated alkaloid preparations like tetrahydropalmatine, a potent neuroreactive, can be found in Jin Bu Huan. This Chinese patent medicine used as a painkiller, has been associated with serious adverse reactions episodes in children and adults. Symptoms occurring in long-term users range from acute toxicity, lethargy, muscle weakness, respiratory compromise, bradycardia and coma, to ‘extreme fatigue’, fever, jaundice and hepatitis. These events were reported in the Communicable Disease Center’s Morbidity and Mortality Weekly Reports (Anonymous, 1993a,b), and by Horowitz et al. (1996). Ginseng preparations imported from China must always be suspect since not only can the content of the ginsenosides vary (Consumer Reports, 1995), but commercial formulations can be adulterated with potent and dangerous plants like mandrake (Mandrogora officinarum) containing scopolamine and Rauwolfia serpentina containing reserpine and stimulants like caffeine from Cola spp. (Drew and Myers, 1997). Certain Chinese remedies may be named the same but are formulated differently depending upon the unique condition of the patient; such is the case with Chinese herbal preparations called ‘Eternal Life’. Without appropriate labeling of its ingredients it is almost impossible to identify the source of any adverse effects associated with its use (Sanders et al., 1995). 2.4. European herbalism European Traditional Medicine has its roots mostly in antiquated Mediterranean civilizations and has over the centuries evolved in its utilization of both European and plants from abroad. In the Middle Ages the color or shape of a plant denoted a cosmic clue to its medical usefulness, and hence the Doctrine of Signatures was a criterion by which many plants were selected, e.g. heart-shaped leaf as a heart remedy, yellow plant parts for treating hepatitis, etc. By the 19th century, some of these medicinal plants had become part of the pharmacopeias of allopathy, naturopathy and homeopathy, and their therapeutic basis investigated by medicinal chemists and pharmacognosists. Usually when compounds are isolated, and sometimes totally synthesized, their pharmaceutical uses are more carefully regulated; aspirin, of course, being an early exception (DeSmet, 1993; DeSmet et al., 1997). 144 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 2.5. Neo-Western herbalism 3. Regulatory challenges In its totality European Traditional Medicine has matured along with American herbal introductions into Neo-Western herbalism. In this system single plant preparations that have been either selected from formulations found in ancient pharmacopeias or derived from medicinal plants valued in other cultures, including those of indigenous origin, are sold alone or as mixtures in an assortment of combinations. For example, one of the most popular plants in use in Europe today is Echinacea with its origins in North American (Midwestern) indigenous medicine (Lewis and Elvin-Lewis, 1977). Also, novel formulations can be devised without ethnomedical data to support their merit, or represent a mixture of plants known to a variety of medicinal systems (DeSmet, 1995a). To promote the sale of a particular product, examples exist where supporting ethnomedical data are purposely vague, obtuse, or contrived. While such mixtures may potentiate a remedy’s medicinal value, it is also possible that these combinations could promote adverse effects not known when individual plant components are used. Without traditional parameters to guide the consumer, the benefits or risks to these newly contrived formulations are currently unknown. While most British, European and Asian herbalists are formally trained within the context of known pharmacopeias or curricula, American herbalists can vary in their instruction, some being self-taught, while others undertake training in various types of apprenticeship programs. However, like allopathic clinicians, both naturopathic and homeopathic clinicians undergo classical training and in the US and Canada some schools of naturopathy also teach homeopathy as a sub-specialty. Both of these disciplines utilize specifically formulated medications that are understood for parameters of use. However, philosophies of diagnosis and treatment differ. Naturopathy, based on hydrotherapy and dietary treatment, currently prescribes formulations containing plant extracts or phytochemicals at pharmacognostically determined levels of efficacy. The philosophy of treatment is two-fold and includes both curative and maintenance (normalization) aspects. Homeopathic formulations (that contain plant extracts and other substances) are compounded under the philosophy that substances that cause specific toxic effects can, at extremely dilute concentrations, reduce similar effects elicited by disease states. While homeopathic remedies are often considered to only elicit placebo-like actions, practitioners recognize their worth, and understand that these remedies are not only bioreactive but may also elicit minor adverse effects like rashes, nausea, vomiting, agitation, shaking and allergic reactions (Shaw et al., 1997; Glisson et al., 1999). 3.1. Asia Overall, the incidence of serious adverse reactions is significantly lower with most of these therapeutic remedies when compared to pharmaceutically derived drugs. However, the need still exists to more closely monitor practitioners and formulators of any traditional medicine, including those of Asian origin, so that medicinal irregularities and unethical practices are reduced. Also, Chinese herbal prescriptions are individualized and when dispensed are not usually labeled, and should adverse effects arise, identification of their contents is difficult unless the patient has been provided a written copy of the formulation. Presuming that the formulation contains the plants described, verification may be impossible after processing has occurred. Should traditional remedies be prepared in an Asian country, and imported, the task of insuring safety is even more difficult since the notion of incorporating potentially toxic herbs or heavy metals may not be considered ‘harmful’ in the country of origin (Natori, 1980; Anonymous, 1989; Shaw et al., 1997). 3.2. Europe Unfortunately, regulatory standards vary from country to country, and thus claims of content, efficacy, and safety of any herbal remedy cannot always be assured. Germany is the leader in evolving rational regulatory policies (Benzi and Ceci, 1997). There, plant remedies are carefully delineated and registered in Commission E Monographs with known risk/benefit/drug interactions cited, and consistency of bioreactive compounds chemically defined as phytopharmaceuticals (Blumenthal et al., 1998). More detail is provided in the 50 monographs published by the European Scientific Cooperative on Phytotherapy and 10 additional monographs are underway (Blumenthal, 1999). While self-medication is the norm, prescriptions for some medications are also mandated. Most European countries are evolving similar policies (Benzi and Ceci, 1997), although in the United Kingdom only some herbal preparations fall under such strict regulatory guidelines (Mills, 1995). 3.3. US In the US regulatory mechanisms regarding herbalism were non-existent until only a few years ago, and even then and now they still lack true enforcement capability. FDA Commissioner Kessler voiced concerns regarding safety in 1993 and proposed removal of herbal products without proven safety and efficacy. As a reaction to this proposal the Dietary Supplement Health and Education Act (DSHEA) was inaugurated M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 in 1994. Under this act many botanical medicines defined as ‘a vitamin, a mineral, an herb or other botanical (or) amino acid are now sold under the guise of food or dietary supplement (Brevoort, 1998; Murphy, 1999). As long as no medical claims are present on the label they are exempt from strict pharmaceutical regulations. Any display literature must further claim that the product has not been reviewed by the FDA or is not intended for medication. Also in 1997, a Federal Commission on Dietary Supplements was established that recommended that manufacturers provide sciencebase evidence to consumers. To some physicians like Angell and Kassirer (1998), these guidelines, and vague or oblique claims related to the maintenance of good health, still begs the issue regarding proven safety or efficacy. They emphasize that since these herbal remedies are not classified as medications they are not under FDA scrutiny. Without being appropriately evaluated for content, safety or efficacy it is difficult to determine parameters of use. However, should adverse reactions become apparent, the FDA could investigate and intervene to remove the product (Murphy, 1999). Moreover, the FTC (Federal Trade Commission) is active in defining the regulatory framework for advertising claims for dietary supplements. The legal and regulatory aspects of these US government agencies in overseeing the herb and dietary supplement industry from the perspective of the Consumer Healthcare Products Association has been recently reviewed and is a useful reference to those requiring details of such aspects (Soller, 2000). Attempts are being made to bring some sense out of this current regulatory chaos since it is in the best interest of everyone to do so. In this regard, pharmacognosists and natural products chemists have once again become active in trying to understand the therapeutic basis of herbal remedies and toxicologists are addressing issues of the origins of potential adverse effects as incidences of associated use or abuse become evident. As a complement to these efforts a number of organizations are preparing monographs to delineate details of herbs that are popularly used as phytomedicines and medicinal plant preparations so that their recognition as official medicines may result (McGuffin et al., 1997). The most ambitious is that of the American Herbal Pharmacopeia and Therapeutic Compendium with plans to publish at least 2000 monographs of this nature. Also, the herb trade in recognizing its responsibility to provide appropriate guidelines, has recently published through the American Products Herbal Association (AHPA) The Botanical Safety Handbook, 2nd edition (1998). The FDA accepts this organization’s Herbs of Commerce as the authoritative text for label nomenclature related to available herbal products. To aid pharmacists in understanding risks and benefits of herbal products, the United States Pharmacopeia (USP) is also compiling standard mono- 145 graphs for herbal dietary supplements and dispensatory information (DI). They have already published 11 monographs and an additional 12 are under preparation. In order to set standards to document the quality of herbal products, and outline the therapeutic parameters for safe and effective use, publication of the WHO Monographs on Selected Medicinal Plants is on-going (Akerele, 1993). Volume 1 (1999) contains 28 monographs on 31 plant species and Volume 2 to be published in 2000, an additional 29 monographs (Blumenthal, 1999). Furthermore, the FDA is considering reviewing certain botanicals via the IND/NDA (Investigational New Drug/New Drug Application) process. Presently there are at least 50 botanicals or botanical formulas holding active IND applications. Priority will be given to those with a long-history of safety, particularly for short-term use since information is unlikely to be adequate to support claims of safety for long-term use. In some cases issues related to accompanying chemistry and toxicological data remain to be resolved (Murphy, 1999). Recently, a Federal Commission on Dietary Supplements has been established (1997) recommends that manufacturers provide science-based evidence to consumers. Also to support evaluation of herbal medicines and other non-traditional remedies the National Institutes of Health (Bethesda, MD) formed the Office of Alternative Medicine in 1992 that has recently been up-graded to the National Center for Complementary and Alternative Medicine (Murphy, 1999). Eventually, these initiatives and others evolving elsewhere, are expected to provide needed information to validate this type of therapy. To aid in this endeavor two searchable databases generated by the US National Institutes of Health on dietary supplements exist. The International Bibliographic Information on Dietary Supplements (IBIDS) can be accessed at the ODS website http:// odp.od.nih.gov/ods. Currently, IBIDS contains 400 000 citations and abstracts of published international, scientific literature on dietary supplements, including vitamins, minerals, and botanicals and is updated quarterly. Scheduled to go online in 2001, CARDS (Computer Access to Research on Dietary Supplements) will identify ongoing, federally funded research on dietary supplements and individual nutrients (CAM, 2000). Within this context clinical evaluation protocols should include those outlined in Table 1. 3.4. Canada In Canada similar regulatory mechanisms are being instituted and in March of 1999, an Office of Natural Health Products was created to assure that Canadian consumers have access to a full range of safe health products. ‘‘The Office will undertake or coordinate all the regulatory functions within the life-cycle of natural 146 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 health products from pre-market assessment for product licensing through licensing of establishments, post-approval monitoring and the compliance and enforcement tools appropriate with ensuring health protection. This will include the development of appropriate training standards of manufacturing and distribution establishments.’’ Within this context, criteria to determine the applicability of efficacy as reflected in labeling claims will be established and information disseminated to allow the Canadian consumer to make informed self-care decisions. Accommodations will be made for aboriginal healers. Currently, Health Canada policy allows an individual to import a 3 month supply of a drug product for their own personal use that is not subject to these evolving regulatory policies (Koryrskyj, 1977). 4. Surveillance of adverse effects through databases Regardless of the type of herbalism being practiced some adverse reactions are more easily recognizable than others. Postulates have been proposed by Hughes (1995) to define if adverse effects are linked to a drug use. According to Stewart (1990), DeSmet (1995b), events that are pharmacologically predictable are often dose-dependant and thus preventable by dose reduction, or if allergenic, by elimination. However, in spite of the mode of application, individual differences in physiology may elicit a variety of idiosyncratic local or systemic reactions, including those that are life threatening. Age may also be a factor and those remedies most frequently used by the elderly may elicit varying responses (Ernst, 1999). Similarly, long-term use can produce predictable reactions or consist of delayed effects such as carcinogenicity and teratogenicity. To better understand the scope of these problems and bring them forward to the public DeSmet (1995b) Table 1 Proposed clinical evaluation protocol for the development of an herbal drug Confirm ethnomedical value in country of origin Note all parameters of use particularly among children, the aged or others with underlying disease states Review traditional formulations to understand rationale of use Know variations to standard formulations and reasons for additions or substitutions Conduct controlled clinical trial with formulation considered to be the best Identify bioreactive components to insure standardization of content Conduct toxicological studies to understand safe parameters of use Conduct placebo-based clinical trials following appropriate guidelines for patient entry, evaluations of efficacy etc. to comply with regulations where product is to be sold proposed that forms of herbal post marketing surveillances be conducted to ‘detect serious adverse reactions, quantify their incidence and identify contributive and modifying factors’. Obviously, the success of such endeavors depends on those willing to voluntarily and spontaneously report such events to appropriate health care officials, pharmocologists (http,//www.faseb.org/ aspet/H&MIG3.htm c top), regulatory bodies (FDA ‘MEDWATCH’ (http,//www.vmcfscan.fda.gov/ dms/ aems.html)), and responsible parties in the herb trade industry itself, like the American Botanical Council (http,//www.herbs.org), who are collating these data for public dissemination (Winslow and Kroll, 1998). With the number of mixed plant formulations now marketed in the US alone, it is particularly important to refer to web sites that can provide on an on-going basis useful information on current adverse reactions. Overall, the US is still a long way from the development of standardized herbal drugs, called phytopharmaceuticals, which have been formulated (in a fashion) to ensure a reproducible effect by undergoing suitable means of identification and clinical evaluations to achieve international approval. Obviously these are needed steps if allopathic acceptance is to follow (Angell and Kassirer, 1998). In the interim, information is accumulating that is providing appropriate ways to understand herbal therapies and can be elicited from internet sources like the National Center for Complementary and Alternative Medicine (http,//nccam.nih.gov), American Botanical Council (www.herbalgram.org), US Food and Drug Administration (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 allopathic clinicians have little training in understanding how various forms of herbalism and self-medications are impacting on the health of their patients, who are often, also under prescriptive medication. However, as awareness of potential interactions with allopathic treatments and herbal remedies increases, many clinicians and hospitals are eliciting this information on admission questionnaires (Murphy, 1999). To ensure that patients will be forthcoming with the information, it is recommended that such solicitations be carefully worded so as not to be judgmental. This is essential since a patient’s response to treatment, particularly in a clinical trial, could be distorted when concurrent uses with herbal remedies are not revealed (Kassler et al., 1991; Buchness, 1998; Donaldson, 1998). To increase the sensitivity of future practitioners, a number of US medical schools are developing courses in Complementary and Alternative Medicine, including M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 some exposure to herbal medicinal practices. At this point these curricula vary and are by no means universal. As a complement to this effort, the need to offer continuing education courses for physicians, nurses, pharmacists, nutritionists and the like should be promoted (Dalen, 1998). 6. Pharmacokinetic behavior of plant-derived drugs Studies on plant-derived drugs primarily with quinine and sparteine have provided a better understanding of factors affecting the pharmacokinetic behavior of drugs within human populations. It has been recognized, for instance, that age effects storage and clearance rates just as the ability to metabolically oxidize certain compounds can be genetically determined and racially focused. Diseases affecting the kidney and liver can alter the clearance rates of certain compounds or exacerbate underlying conditions. Infections like malaria can actually raise the plasma levels of the medication (quinine) just as low protein diets can alter urine pH, which when alkaline, can slow its renal clearance. Smoking or certain drug interactions can also effect oral or metabolic clearance rates. Normal ovarian function can be altered by use of Vitex agnus castus (Cahill et al., 1994). All these activities can impact either beneficial or adverse effect of drugs and/or herbal therapies (DeSmet and Brouwers, 1997). 7. Herbal drug transmission in utero or through mother’s milk It is well known that transmission of particular drugs in utero to the fetus or through breast milk to an infant can take place. Evidence is accumulating that this is also true should mothers use certain herbal remedies during pregnancy or while nursing their babies. Effects may be transient, grave, or fatal. The fetus is in particular jeopardy should herbs with teratogenic, carcinogenic, toxic or abortifacient properties be employed. For example, constituents like salicylates are potentially teratogenic and embryocidal, even if applied externally in Oil of Wintergreen. Ingestion of sassafras (Sassafras albidum), tea popular in the US for its flavor and use as a diuretic (D’Arcy, 1993), might also pose problems to the fetus. This is suggested by studies in mice where transplacental carcinogenesis has been found to occur following treatment with sassafras and is possibly caused by its major carcinogenic component, safrole (DeSmet, 1992b). Neonatal jaundice has been traced to the use of goldenseal and barberry and its hydrastine content. Also, since feverfew (Tanacetum parthenium) is a traditional inducer of menses, its use to treat headaches during pregnancy should be avoided 147 (O’Hara et al., 1998). Infant deaths due to veno-occlusive disease have been associated with the consumption of pyrrolizidine alkaloid containing teas or cough remedies during pregnancy (Roulet et al., 1988; Winship, 1991). Since there is a risk of bleeding disorders being transmitted to the fetus or breast feeding infant heparin-containing herbs should also be avoided during pregnancy or lactation (Ernst, 1997). Due to its dopaminergic actions, the same is true for use of chasteberry fruit (Vitex agnus-castus Boehnert, 1997). Birth weights are also lower in women chewing the stimulant, khat (Catha edulis) during pregnancy (Ghani et al., 1987). At parturition, blue cohosh (Caulophyllum thalictroides), used to promote uterine contractions should be avoided since a neonate developed acute myocardial infarction, associated with profound congestive heart failure and shock. The infant remained critically ill for several weeks but survived. This event was believed due to vasoactive glycosides, a toxic alkaloid, and sparteine found in the plant (Jones and Lawson, 1998). Also consumption by a mother of senna laxative, with rhein, was reported as having elicited catharsis in her nursing infant (Faber and Strenge-Hess, 1988). Comfrey tea, now banned, contains a potentially harmful pyrrolizidine alkaloid, echimidine known to have hepatotoxic, genotoxic and carcinogenic properties is also excreted in breast milk (Winship, 1991). In one instance a veno-occlusive hepatic illness resembling Budd –Chiari syndrome was linked to the consumption of a tea containing flowers of Tussilago farfara and roots of Petasites officinalis (Radix petasitidis) (Roulet et al., 1988; Spang, 1989), and in another, senecionine, a pyrrolizidine alkaloid present in an herbal cough remedy was responsible for this fatal illness (Fox et al., 1978). 8. Allergic reactions Allergic reactions that can occur with herbal use are manifested in a variety of forms (Rieder, 1994). Both Type I immediate hypersensitivity reactions leading to rhinitis, headache, dermatitis (hives), and/or anaphylactic shock are commonly induced by cross-reactions among Asteraceous (daisy family) plants taken internally, whereas delayed Type IV, contact dermatitis is more prevalent when topical applications are used (Gordon, 1999). Within this family, wide cross-reactions are known and a major sensitizing plant in the US is ragweed (Ambrosia spp.), it follows that patients with known sensitivity to ragweed should avoid Asteraceous herbal teas like chamomile (Chamaemelum nobile) (Lewis, 1992b) or other remedies containing flower heads and pollen, and particularly in concentrated forms such as bee pollen (propolis) preparations. When used as a vulnerary agent, rare allergic reactions and 148 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 contact irritation have been reported; and it is especially to be avoided in ocular preparations (O’Hara et al., 1998). Also royal jelly, a thick mixture of honey and pollen naturally contaminated with pollen allergens has been repeatedly linked to cases of severe bronchospasm (Perharic et al., 1993). In Europe, where ragweed is unknown or uncommon, chamomile was once considered 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 a number of reports from throughout Europe suggest that sensitization can take place and allergic reactions may be manifest systemically (Rodriguez-Serna et al., 1998) as dermatitis (Subiza et al., 1989; Paulsen et al., 1993; Bossuyt and Dooms-Goossens, 1994; Pereira et al., 1997; Foti et al., 2000; Giordano-Labadie et al., 2000), or when used in an enema during labor, as fatal anaphylaxis (Jensen-Jarolim et al., 1998). Recently two reports from Australia regarding Echinacea-induced anaphylaxis (Mullins, 1998; Myer and Wohlmuth 1998) elicit further concerns regarding the use of asteraceous plants in complementary medicine. In this context, contact with feverfew (Tanacetum parthenium) may elicit contact dermatitis (Hausen, 1981) and in herbal preparations can be contraindicative to those allergic to other members of the Asteraceae. For example, should, a sensitized patient use a feverfew preparation to treat headache their condition could be amplified rather than reduced (O’Hara et al., 1998). Also yohimbine has been reported as causing a lupus-like syndrome (Sandler and Aronson, 1993). Recently a number of adverse reports have been associated with flavonoids used in European herbal preparations (Ernst, 1998), e.g. cyanidanol eliciting hemolytic anemia (Gandolfo et al., 1992), cirkan causing chronic diarrhea (Maechel, 1992), sciadopitysin causing severe nephropathy (Lin and Ho, 1994) and colitis from a phlebotonic French drug, cyclo-3 fort containing Ruscus aculeatus, hersperidin methyl chalcone, ascorbic acid (Beaugerie et al., 1994). Essential oil delayed-hypersensitivity can be related to episodes of aphthous stomatitis (canker sores), when other predisposing factors like atopy and stress are in place. In a preliminary study of eight patients with aphthous stomatitis, of 34 essential oils or their components tested, 30 of these substances proved to elicit some reactivity in one or more patients, whereas four control patients were unreactive. Using lymphoblastic transformation to test hypersensitivity, a major exciting agent was found to be eugenol found in spices (oil of cloves), herbs, foods (artichokes), flavorings, cosmetics, fragnances and medicinals. Walnut, anise, dill, peppermint, caraway, and lavender were also significant elicitors (Elvin-Lewis et al., 1985) in addition to cashew nut and its urushiol (Lewis and Elvin-Lewis, 1977). L-carvone in many mint and peppermint oils has also been implicated in contact allergies (Paulsen et al., 1993) and cheilitis induced by use of toothpaste (Hausen, 1984). In another study when patch testing (Standard European Series) was used to test 20 patients with aphthous stomatitis, a positive reaction to a number of food substances were also considered clinically relevant and avoidance of the offending allergens recommend (Nolan et al., 1991). It is also possible that inhalation of some of the essential oils including lavender, jasmine and rosewood used in perfumes or as an ingredient in aromatherapy can elicit similar allergic reactions in the nasal passages and respiratory tract, (Schaller and Korting, 1995; Selvaag et al., 1995a; Sugiura et al., 2000). Aromatherapists may also be at risk of developing dermatitis from continued contact with these oils (Selvaag et al., 1995b). Dermatological conditions associated with contact of allergenic plants and their products have been recently reviewed by Sassevile (1999). 9. Dental products Adverse effects of dental products containing plant components are rare, but are worthwhile considering (Ocasio et al., 1999). These formulations often include natural sources of calcium carbonate that can vary in abrasivity, and when derived from seashells may contain high amounts of mercury. It is not unusual for Asian herbal dentifrices to be packaged in lead tubing and it is unclear how many are still being sold in this way. Aside from hypersensitivity reactions to flavoring agents that are primarily essential oils, or myrrh that is often used as a breathe freshener, long-term exposure to other components may elicit more serious effects (Elvin-Lewis, 1987, 1989; Elvin-Lewis and Lewis, 1995). For example, American and Canadian dental products containing blood-root (Sanguinaria canadensis) extract, frequently promoted by dentists, have recently been shown to induce a sanguinaria-associated leukoplakia syndrome (hyperorthokeratosis, epithelial atrophy, and epithelial atypia/mild dysplasia) that in one instance was also contiguous to a squamous cell sarcoma (Damm et al., 1999). Although these observations have been vigorously defended as being spurious (Munro et al., 1999) the fact remains that sanguinaria extract has recently been removed from the Viadent formulation! The flat structure of the alkaloids (sanguinarine and cherylethrine) and their ability to intercalate with DNA were known at the time of formulation 15 years ago and were predictive of potential carcinogenicity (Culvenor, 1983a,b). The concern of pyrrolizidine alkaloid mutagenicity (Yamanaka et al., 1979; Takanashi et al., 1980) was provided to the company but since results of Ames and other mutagenicity tests were reported as M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 equivocal, the sale of the formulation was allowed. The company and its ‘Expert Panel’ of advisors (as related to me) considered the tingling or irritating sensation reported by some users to be associated with the flavoring agent. They did not consider, as relevant, the fact that users of an African chewing stick, Fagara xanthoxyloides containing related alkaloids, also reported similar effects (El-Said et al., 1971). (How this type of chronic irritation predisposed to the precancerous lesions is unknown.) While many pharmacognosists, and myself, continued to be concerned about accumulative carcinogenic effects, a few considered the amount of the compounds in the formulations to be of little consequence. To date, almost 100 cases of leukoplakia have been reported in long-term users. This has resulted in a recent reformulation of the product and the removal of the offending alkaloids. Little is known about the consequences of use elsewhere in the body, but these are highly bioreactive alkaloids. It is recognized that dental products are swallowed during oral hygiene and that, at least with fluoride; they can be absorbed beneficially into the bones and teeth. It is important to also emphasize that there was no ethnodental validation to support the development of the product in the first place, in spite of claims to the contrary, unless of course one were to rely on anecdotal information from one horse trainer that used blood-root to remove plaque from horses teeth! Adverse effects of other popular herbal dental products are unknown. It is prudent to read the labels and be aware of the plant products that they contain since many, especially if claimed to be of Ayurvedic origin, are mixtures of numerous substances with quantities of each ingredient unrevealed. However, such products should be avoided if information regarding their ability to be locally irritating (a possible predisposing factor for cancer), evoke contact dermatitis, or systemically bioreactive is brought forward. This is a concern with Tea Tree Oil, (Melaleuca alternifolia) found in herbal dental products. It is antiseptic but the oil can be locally irritating and elicits contact dermatitis (Knight and Hausen, 1994; Blushan and Beck, 1997; Greig et al., 1999), vulvovaginitis (Varma et al., 2000), and if ingested is toxic to the central nervous system (Rubel et al., 1998; Bruynzeel, 1999). Neem (Azadirachta indica) used a chewing-stick or as an oil-extract in dental products might also potentially elicit problems. Neem is valued for its antimicrobial and anti-inflammatory effects and for its ability to ameliorate gingivitis (ElvinLewis, in press). However, little is known regarding the exact nature of the neem components it contains such as the highly regarded insecticide and anti-feedent, azadirachtin. Although early Ames tests have been reported as negative, its structure suggests it may be potentially carcinogenic. It is known to elicit disruptive changes in metaphase chromosomes in both insects and 149 mice (Rosenkranz and Klopman, 1995; Awasthy et al., 1999). Neem oil, bark and leaf extracts are particularly bioreactive and are currently being evaluated for a wide range of medicinal uses (Van der Nat et al., 1991), including hypoglycemic action (Chakraborty and Podder, 1984), and because of immunomodulatory effects, also for contraceptive and abortifacient activities (Mukherhee et al., 1996; Talwar et al., 1997a,b). Leaf extracts have also been shown to adversely affect thyroid function in mice, (Panda and Kar, 2000). If the ideal neem dentifrice is to be formulated then compounds that promote dental health should be retained and others that could potentially elicit adverse effects eliminated (Elvin-Lewis, in press). 10. Problems associated with long-term use Today, many herbal remedies are being used prophylactically to maintain or enhance good health or prevent certain conditions from occurring. Since many of these herbal medications are popular and promoted as both safe and efficacious, it is not always possible for the long-term user to understand why this practice could be harmful. Symptoms can vary from trivial to severe and are particularly disconcerting when they effect the heart, blood pressure, liver, gastrointestinal tract and nervous or endocrine systems (Table 2). Noteworthy are effects associated with ginseng, golden seal, milk thistle, cassia, saw-palmetto, valerian, and a variety of stimulants (D’Arcy, 1993; Anonymous, 1995a; Ernst, 1998; O’Hara et al., 1998) including those that contain caffeine, like guarana (Paullinia cupana) or mate (Ilex paraguariensis). The latter beverage has also been implicated in inducing oral cancers (Victora et al., 1990), but clear correlative evidence has yet to be forthcoming. Another herbal stimulant, Ma Huang, containing ephedrine, has been reported to cause hallucinations and paranoia (Anonymous, 1996; Doyle and Kargin, 1996). Also anthranoid laxatives such as aloe, cascara, rhubarb, and senna, commonly considered as safe, may be a risk factor for colorectal cancer if used on a long-term basis (Siegers et al., 1992). Similarly, abuse of these laxatives can increase the loss of serum K, thereby potentiating the effects of cardiac glycosides and antiarrhythmic agents (Blumenthal, 2000). The use of astragulus root (Astragulus membranaceus), a major immunostimulating herb of Chinese medicine, may be contraindicative when patients are undergoing immunosuppressive therapy (DeSmet and D’Arcy, 1996). Also, black cohosh (Cimicifuga racemosa) used for gynecologic disorders (Liske, 1998) and to treat rheumatism, can when taken in large doses or for prolonged periods cause nausea, vomiting and gastroenteritis (Saxe, 1987). Similar conditions have also been reported for blue cohosh (Caulophyllum thalic- Piper methysticum Hypericum perforatum Milk thistle Senna, anthroid laxatives; Aloe vera juice; Buckthorn bark and berry; Cascara sagrada bark Saw palmetto Valerian Kava St. John’s wort Hepatoprotective Laxatives Benign prostatic hypertrophy reduction Sedatives Stimulants Valerian officinalis; Passiflora incarnata; Bupleurum flacatum Goldenseal Catha edulis Areca catechu Ephedra sinica Paullinia cupana Khat Betel nut Ephedra Guarana Serenoa repens Senna alexandrina (Cassia senna); Aloe 6era; Rhamnus frangula; Rhamnus purshiana Silybum marianum Hydrastis canadensis Blumenthal et al., 1998; O’Hara et al., 1998; Walti et al., 1986 O’Hara et al., 1998; FDA/CFSAN AEMS Search Results, 2000 Siegal, 1979; Saxe, 1987; D’Arcy, 1991; Kassler et al., 1991; Wilkie and Cordess 1994; Gonzalez-Seijo et al., 1995; Ernst, 1997; O’Hara et al., 1998; FDA/CFSAN AEMS Search Results, 2000 References Chronic liver dysfunction Deterioration of psychosis in patients with preexisting psychiatric disorders Agitation and palpitations Agitation and insomnia Photosensitization Causes drowsiness, GI upset, liver function abnormalities, headache, palpitations, insomnia Potentiates CNS sedatives Rare and mild gastrointestinal (GI) upset, headaches, diarrhea, gynecomastia, paroxysmal atrial fibrillation, ventricular rupture and death in one patient Ernst, 1998 Ernst, 1998 Shaw et al., 1997 Ernst, 1998 Jamieson and Duffield, 1990; Almeida and Grimsley, 1996 O’Hara et al., 1998 O’Hara et al., 1998; Caldwell et al., 1994; World Health Organization, 1999 Tasca et al., 1985; O’Hara et al., 1998; FDA/CFSAN AEMS Search Results, 2000 Abdominal pain, diarrhea, potentially Blumenthal et al., 1998 carcinogenic; with others can potentiate cardiac gycosides and antiarrhythmic agents due to increased K Mild laxative, allergy Induces neonatal jaundice May oppose anticoagulants In large doses causes GI upset, hypertension, seizures, respiratory failure, and cardiac spasms Anorexia, dermatomyositis, elevated serum iron, psychosis, swollen liver, damaged stomach lining, death Uterotonic, avoid in pregnancy Promotes mastalgia; rarely causes postmenopausal bleeding; \3 g per day causes ‘ginseng abuse syndrome’ consisting of morning diarrhea, nervousness, insomnia, rash, depression and amenorrhea; in cigarettes exacerbates symptoms in schizoprenic patients; induces manic state in depressive patients; palpitations, nausea, vomiting, blurred vision, hoarseness, abnormal uterine bleeding Panax ginseng; P. quinquefolius Anti-infective Hypertensive and chronotropic activities; may increase digoxin levels Adverse effects Eleutherococcus senticosus Ginseng Adaptogen Binomial Common name Bioreactivity Table 2 Adverse effects of long-term herbal use 150 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 151 Table 3 Hepatotoxicity related to herbal remedies Type of compound Herb or taxa References Pyrrolizidine alkaloids Senecio, Crotalaria, Symphytum, Heliotropium Winship, 1991; Hill et al., 1951; Bras et al., 1954; Fox et al., 1978; Lyford et al., 1976 Monoterpene (puleguim) Mentha puleguim, Hedeoma pulegoides Sullivan et al., 1979; Anderson et al., 1996 (pennyroyal) Diterpenoid Teucrium poliumm (gemander) Larrey et al., 1992; World Health Organization, 1992; D’Arcy, 1993 Anthren Cassia angustifolia (senna) DeSmet et al., 1996 Levotetrahydrop- Jin Bu Huan concentrated alkaloid almitine Anonymous, 1993a,b; Horowitz et al., 1996 Atractylate Atraclylis gummifera Georgiou et al., 1988; Stickel et al., 2000; Hamouda et al., 2000 Safrole Sassafras albidum Segelman et al., 1976; Liu et al., 1999; Burkey et al., 2000 Nordihydroguair- Larrea tridentata (chaparral) etic acid Anonymous, 1992; Sheikh et al., 1997; Batchelor et al., 1995 Unknown Strahl et al., 1998; Ruze, 1990 Benninger et al., 1999 Piper methysticum (kava) Chelidonium majus troides) (Saxe, 1987), in addition to adverse effects to the newborn when used to promote labor (Jones and Lawson, 1998). 11. Effects on internal organs Detoxification and clearance of poisonous substances from the body are primarily a function of the liver and kidneys and they are often the first to be affected by toxic herbs (Larrey, 1994; DeSmet et al., 1996; Kaplowitz, 1997; Nortier et al., 1999; Stickel et al., 2000). Sometimes the causes are more obtuse, as when kava user developed a necrotizing hepatitis (Strahl et al., 1998), but not the usual ‘kava dermatology’ of yellow and scaling skin associated with long-term use (Ruze, 1990). Equally perplexing are the number of cases of acute hepatitis following the use of greater celadine (Chelidonium majus) for treating biliary and gastric disorders (Benninger et al., 1999), or the one case of necrotizing hepatitis possibly associated with use of ‘lesser or common celidine’ (Strahl et al., 1998). Similarly, May apple (Podophyllum peltatum) used as a liver tonic has been found to cause nausea, vomiting, inflammation and edema of the bowel, diarrhea, elevated liver enzymes and hematologic abnormalities (Saxe, 1987). Table 3 lists some of these or other herbs most problematical to the liver. Over 100 hepatotoxic pyrrolizidine alkaloids are found within species of the Asteraceae, Borginaceae, and Fabaceae. Such plants are consumed as food, for medicinal purposes, or as contaminants of other agricultural 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). While the disease is relatively rare in the US and is usually related to the consumption of herbal remedies (Sprang, 1989) mass human poisonings have occurred elsewhere from ingestion of seeds with these alkaloids contaminating cereal crops (Chauvin et al., 1994; Drew and Myers, 1997). Abdominal pain, vomiting, and the development of ascites characterize this condition. Patients may recover if the alkaloid intake is discontinued and the liver damage not too severe, otherwise death can follow. In Jamaica, for example, endemic veno-occlusive disease, has been linked to the consumption of Senecio or Crotalaria spp. as ‘ bush teas’ (Hill et al., 1951; Bras et al., 1954). Comfrey teas have now been banned in the US due to this serious side effect (Ridker, 1989). Some, like chaparral tea for example, should be avoided during cancer treatments or when underlying diseases of the liver are known. A retrospective study on adverse effects of herbal medicines by the National Poisons Unit (London) led the authors (Perharic et al., 1994) to recommend that routine liver function tests be done on individuals using Chinese herbal remedies. This is important since so many cases of liver damage leading to acute liver failure have been associated with the use of Chinese herbal remedies for the treatment of skin disorders (Shaw et al., 1997; Armstrong and Ernst, 1999). Care should also be taken when using herbal medications to treat cardiovascular problems (Mashour et al., 1998). While some may be worthwhile, many contain natural cardiac glycosides, blood thinners, or affect blood pressure and are not only bioreactive on their own but can work with prescribed medications to po- M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 152 tentiate or diminish their action (Catania, 1998). For example, ginger contains a potent inhibitor of thromboxan synthetase (Backon, 1986) that prolongs bleeding time. According to Miller (1998) its use could result in adverse implications for pregnant patients or those on concomitant warfarin therapy. It is noteworthy nonetheless, that ginger is still a favored remedy to treat nausea from morning or motion sickness. Feverfew (Tanacetum parthenium) has the potential of potentiating platelet inhibitors and its use as a headache remedy should be avoided during therapy with bloodthinning agents (O’Hara et al., 1998). It is also recommended that heparin-like herbs not be taken during pregnancy or lactation, since cranial bleeding or other associated effects could be induced in the fetus or nursing infant, respectively (Pansatiankul and Ratanasir, 1992; Pansatinkul and McKnanee, 1993). A number of cases of allergy and anaphylactic shock (Jaspersen-Schib et al., 1996) and one case of hepatic injury (Takegoshi et al., 1986) have been associated with the use of horse chestnut species to treat chronic venous insufficiency (Ernst, 1999) (Table 4). 12. Effects under predisposing conditions Patients taking herbs for various purposes may also predispose themselves to unwanted conditions prior to surgery, when pregnant, if atopic, or under treatment for other conditions, including those that require psychoactive medications. Deaths due to medication of generally recognized ‘as safe’ herbs are extremely rare. These events are more likely due to adulterants in the formulations, to unknown interactions in complex mixtures, as a result of undisclosed pharmaceutical interactions, to inappropriate dosage or use, or to underlying factors associated with the specific patient (O’Hara et al., 1998; FDA/CFSAN AEMS Search Results, 2000). A variety of serious reactions due to use alone, with other herbal medications, or with pharmaceutical drugs have been recorded and include effects on coagulation by feverfew (Murphy, 1999), garlic ginger, and ginkgo and antagonistic effects of ephedra. Noteworthy is the immunosuppression that can be induced by long-term Echinacea used for immune stimulation. Photosensitivity that is associated with St. John’s wort (Hypericum perforatum) and Psoralea corylifolia (an ingredient in several Chinese herbal formulations) (Maurice and Cream, 1989) is considered rare (Blumenthal et al., 1998). However, according to one herbalist that has observed this reaction in a number of St John’s wort users (Cathy Crandall, personal communication) this phenomenon may be under-reported. Also, St John’s wort interacts with some anesthetic agents and results in eliciting mild monamine oxidase inhibition (MAOI), or selectively inhibits serotonin uptake (SSRI) (Murphy, 1999). Ginseng, while considered GRAS, has also been reported to elicit a wide range of adverse conditions, and should be avoided with other stimulants and particularly it should not be used by patients with cardiovascular disease due to its effect on blood pressure and heartbeat (chronotrophic effect), and its ability to potentiate digoxin levels. Licorice has hypertensive effects and can potentiate the activity of Table 4 Cardiovascular herbal treatments, adverse reactions Common name Binomial Adverse effect References Horse chestnut Aesculus hippocastanum Hepatic toxicity, allergy, anaphylaxis Jaspersen-Schib et al., 1996; Takegoshi et al., 1986 Gugulipid Commiphora mukul Headache, nausea, hiccups, diminished efficacy of other cardiovascular drugs including diltiazem and propranolol Singh et al., 1994; Dalvi et al., 1994 Hawthorn Crataegus monogyna Potentiates digitalis activity, increases coronary dilatation effects of theophylline, caffeine, papaverine, sodium nitrate, adenosine and epinephrine, increase barbituate induced sleeping times ESCOP, 1997, 1999; Upton, 1999; Tyler, 1994; Mawrey, 1993 Reserpine Rau6olfia serpentina Sedation, inability to complete tasks, mental depression, nasal congeston, increased gastric secretion and mild diarrhea Webster and Koch, 1996; Brunton, 1996; Mashour et al., 1998 Dan-shen Sal6ia militorrhiza Potentiates warfarin activity Chan et al., 1995; Izzat et al., 1998; Yu et al., 1997; Cheng, 2000 European mistletoe Viscum album CNS and cardiotoxic, GI bleeding Stein and Berg, 1999 Chaparral Larrea tridentata Hypotension in cancer patients in treatment Anonymous, 1992 Bromelian Warfarin Activity enhancer of some antibiotics and chemo-therapeutic agents; anti-inflammatory agent Anticoagulant Insulin or oral hypo-glycaemics Pheneizine, triazolam, lorazepam Metoclopram-ide Guanethidine Aspirin Antidiabetic Antidepresant antagonists Antiemetic Antihypertensive Analgesics Aspirin Coumarin serivatives Drug Bioreactivity Table 5 Drug and herbal interactions Procumbens Cinchona Pubescens Allium Sati6um Zingiber Officinale Tanacetum parthenium Ginkgo biloba Plantago spp. Cinchona bark Garlic Ginger Feverfew Ginkgo Psyllium seed Gymnema syl6estre Linum Usitatissimum Gurmar leaves Flaxseed oil Ephedra sinica Vitex agnus-castus Salicin containing herbals and Salix spp.; Gaulthria oils procumbens, Eucalyptus globulus Ephedra Chasteberry fruit Panax Ginseng Momardica Charantia Bitter melon Ginseng Aloe 6era Aloe gel and juice Herbal antidiabetic Possibly additive Additive effects Harpago-phytum Devils claw Salicylism; hypersensitivity Enhances sympathomimetic effect of ephedra Possible interactions Headaches, tremulosness, insomnia, irritability, visual halucinations Additive effects Delays absorption of drugs taken simultaneously; in diabetics delays glucose absorption Additive effects Additive effects Additive effect; causes iris bleeding Retards absorption Papain increased INR, damages mucous membranes of GI tract Maybe additive; purpura; additive effects Additive effects Diarrhea, increased tendency for bleeding if used simultaneously with anticoagulants and inhibitors of thrombocytic aggregation due to modulation of the arachidonate cascade Adverse effects Carica papaya Ananas comosus Taxa Papaya extract Pineapple enzyme Herb Malik et al., 1994; Ernst, 1998 ESCOP, 1997; Blumenthal et al., 1998; ESCOP, 1999; Blumenthal, 2000 Blumenthal et al., 1998; Blumenthal, 2000 Gonzalez-Seijo et al., 1995 ESCOP, 1997; Blumenthal et al., 1998, ESCOP, 1999 Yongchaiyuda et al., 1996; Aslam and Stockley, 1979 Baskaran et al., 1990; ESCOP, 1997; Blumenthal et al., 1998 ESCOP, 1999 Blumenthal et al., 1998 Sunter, 1991; World Health Organization, 1999 World Health Organization, 1999; Blumenthal, 2000 Murphy et al., 1998 Rosenblatt and Mindel, 1997 Blumenthal et al., 1998; World Health Organization, 1999 Blumenthal et al., 1998, World Health Organization, 1999 Shulman, 1997; Blumenthal et al., 1998; World Health Organization, 1999 Neurauer, 1961; Taussig and Batkin, 1988; Blumenthal et al., 1998; Blumenthal, 2000 References M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 153 Theophylline Digitalis Asthmatic preparations Cardiac Warfarin Thiazide diuretics Secale alkaloid derivatives Inhibitors MAO Drug Bioreactivity Table 5 (Continued) Aconitum spp. Rheum officinale Smilax spp. Plantago spp. Cytisus scoparius Ephedra sinica Aconituma Rhubarb root Sarsaparilla Root Psyllium Scotch broom Ephedra Ginkgo Brassica spp. (broccali ) and certain other green vegetables Ginger Zingiber officinale Ginkgo biloba Brassicaceae etc. Glycyrrhiza glabra Glycyrrhiza glabra Licorice roota Adverse effects Blumenthal et al., 1998; Ernst, 1998; Blumenthal, 2000 Atal et al., 1985; Bano et al., 1991 References Backon, 1986; World Health Organization, 1999 Cardiac arrhythmia, tachycardia; Increases sympathomimetic ESCOP, 1997; Blumenthal et action of ephedra; could cause al., 1998; ESCOP, 1999; fatal hyper-tension World Health Organization, 1999; Blumenthal, 2000 ESCOP, 1997; Blumenthal et al., 1998; ESCOP, 1999; World Health Organization, 1999; Blumenthal, 2000 Contraindicative with cardiac Blumenthal et al., 1998; World glyco-sides, spirono–lactone, Health Organization, 1999 amiloride increased sensitivity to digitalis Additive effects; iris bleeding Blumenthal et al., 1998; World with aspirin Health Organization, 1999 Antagonistic due to high Vitamin K content Blumenthal et al., 1998; World Health Organization, 1999 Possible additive effects Blumenthal et al., 1998; World Health Organization, 1999 Additive effects Additive effects D’Arcy, 1993 ESCOP, 1997, 1999; World Health Organization, 1999 Arrythmia, palpitations, nausea, Blumenthal et al., 1998; Ernst, abdominal pain 1998 Additive effects, induces loss K, with thiazide diuretics Increases absorption Retards absorption Blumenthal et al., 1998 Tyramine induced hyper-tensive World Health Organization, crises 1999 Blumenthal et al., 1998 Potentiates activity and increases toxicity; additive effects Additive Piper Nigrum; Piper longum Increases theophylline’s absorption, decreases its metabolism Taxa Licorice root Herbals containing cardiac glycosides Piperine from black pepper Herb 154 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 Evening primrose Alcohol, antihistamines Phenytoin Phenothiazines Sedative Seizure control a Psyllium seed Kelp Lithium, carba-mazepine, cardiac glycosides, coumarin derivatives Thyroid supplement or alone Kelp with arsenic Guar gum Passion flower Anticholin-ergic solanaceae Herbal sedatives Valerian Hallucin-ogens Cinnamon ‘Magic mushroom’ Herbal Phenoxymethi-penicillin Frequently in Chinese herbal formulations. Slimming agents Shankha-phuspi Tetracycline, propranolol, alcohol Hallucinogens Chasteberry fruit Oral contraceptives (e.g. haloperidol) Blumenthal et al., 1998; Blumenthal, 2000 Sunter, 1991 D’Arcy, 1993 References D’Arcy, 1993 Drowsiness, obtunds ability to D’Arcy, 1993; DeSmet et al., use machinery; potentiates 1996 effects of antidepressants, antihistaminics, antispasmodics Potentiates psychoactive activity D’Arcy, 1993; Ernst, 1998 Contraindicative; reciprocal weaking effect of dopamine receptor antagonists Adverse effects Laminaria, Macrocystis, Nereocystis spp. Plantago spp. Cyamopsis tetra-gonoloba Inhibits absorption; can induce obstructions in the bowel or in patients with esophageal strictures Inhibits absorption Evokes hyper or hypothyroidism, skin hypersensitivity Autoimmune thrombocytopenia Pye et al., 1992 Kim and Kim, 2000 Shilo and Hirsch, 1986 World Health Organization, 1999 Opper et al., 1990; Seidner et al., 1990; Lewis, 1992a Centella asiatica, Con6ol6ulus Reduces plasma levels; seizure Swinyard and Woodhead, pluricaulis, Nardostachys control lost 1982; Dandekar et al., 1992 jaatamansi, Nepteta elliptica, Nepeta hindostana and Onsosma bracteatum Oenothera spp. Passiflora incarnata Atropa belladonna, Datura stromonium, Hyocyamus niger, Mandragora officinarum Valeriana officinalis Cinnamomum zelanicum Psilocybe semilanceata Vitex agnus–castus Allium sati6um Aeculus hippocastanum Garlic Horse chestnut Oral contraceptives; hormone therapy Taxa Herb Drug Bioreactivity Table 5 (Continued) M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 155 156 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 digitalis and thiazide diuretics (Cugini et al., 1983; Blumenthal, 2000; Olukoga and Donaldson, 2000; Shibata, 2000). Influences on thyroid function can vary; for example, kelp used for weight loss can induce hyperthyroidism (DeSmet et al., 1990) whereas, use of horseradish remedies can result in hypothyroidism (D’Arcy, 1993). Valerian (Valeriana officinalis) is known to potentiate the sedation or excitation effects of certain sedatives or anxiolytics, respectively (Miller, 1998; Murphy, 1999). While considered GRAS, valerian has also been reported in rare cases to elicit headache, palpitations, insomnia (O’Hara et al., 1998), pruritis, anorexia, hepatitis and intoxication (FDA/CFSAN AEMS Search Results, 2000). Use of Devil’s Claw (Harpagophytum procumbens) for anorexia, dyspepsia and degenerative disorders of the locomotor system are contraindicated in individuals with gastric and duodenal ulcers or with individuals with gallstones (Blumenthal et al., 1998). Arsenic has been found to an adulterant in a variety of herbal formulations (FDA/ CFSAN AEMS Search Results, 2000) and in kelp has been reported to cause autoimmune thrombocytopenia (Pye et al., 1992). 13. Effects of slimming agents Natural slimming agents can also be problematical as has been found for guar gum that has elicited severe adverse obstructions of the bowel and esophagus, particularly among those with esophageal abnormalities (Opper et al., 1990; Seidner et al., 1990) that in one instance was fatal (Lewis, 1992a). The presence of sparteine in a variety of herbal remedies used for slimming and diabetes has been reported to cause circulatory collapse, respiratory arrest (Galloway et al., 1992) and classic anticholinergic effects (Tsiodras et al., 1999). Also, because of its oxytoxic effects sparteinecontaining herbals would be contraindicative for use in pregnancy (Bensousan and Meyers, 1996). Blossoms of germander (Teucrium chamaedrys) in herbal teas or capsules to treat obesity have been shown to cause acute hepatitis (Larrey et al., 1992). A patient taking warfarin and using papaya extract (containing papain) for slimming was shown to have an increased international normalized ratio (INR), the patient’s prothrombin time was only restored to normal following withdrawal of both substances (Shaw et al., 1997). Aristolochia species have been responsible for disorders referred to as Chinese herb nephropathy (CHN) (Vanhaelen et al., 1994) or Fanconi syndrome in Japan, and Tanaka et al. (2000) suggests that differences in clinical presentation may be due to the amount or type of aristolochic acids ingested. For example, in Belgium, a variety of Chinese herbal remedies use for slimming purposes were linked to a rapidly progressive interstitial renal fibrotic syndrome (Vanherweghem et al., 1993). In some cases Aristolochia fangchi was incriminated. The same type of renal failure was associated with 12 Chinese in Taiwan using a variety of traditional Chinese herbal preparations (Yang et al., 2000) and two others in the UK (Lord et al., 1999). In two cases in Japan, Fanconi syndrome involved the use of the Chinese medicine, Kanmokutsu containing A. manshuriensis (Tanaka et al., 2000). This syndrome may also be associated with the development of overt transitional cell carcinoma (TCC) (Cosyns et al., 1999). In Taiwan, bronciolitis obliterans (rapidly progressive respiratory distress) was related to the consumption of uncooked vegetable juice of Sauropus androgynus in guava or pineapple juice (Lai et al., 1996). Used in a weight control formulation for 10 weeks, 23 individuals were affected. 14. Drug and herbal interactions Numerous examples exist of drug and herbal interactions. These effects may potentiate or antagonize drug absorption or metabolism, the patient’s metabolism, or cause unwanted side-reactions such as hypersensitivity (Brinker, 1997; Cupp, 1999; Blumenthal, 2000). Such effects may also impinge on pharmaceutical product interactions occurring concurrently with those elicited by herbal use (Aslam and Stockley, 1979; Jankel and Speedie, 1990). Care should be taken to understand effects of foods (Williams et al., 1993; Kane and Lipsky, 2000) or herbal remedies during anti-coagulant therapy, in the treatment of diabetes, depression, pain, asthma, the heart, blood pressure, and for slimming. By way of illustration, the high content of vitamin K in a variety of green vegetables, particularly broccoli and other Brassicaceae, can in large amounts, be antagonist to the effects of anti-coagulant therapy (D’Arcy, 1993). In addition, grapefruit juice, can lead to the elevation of serum concentrations of a variety of medications like cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors (Kane and Lipsky, 2000). Also, unwanted side-effects like gynaecomastia can occur with ginseng and rauwolfia with a variety of medications, hallucinations with cinnamon and tetracycline, sedative effects with valerian or passion flower and anti-histamines, elevated blood pressure with thizidine diuretic and Ginkgo biloba and seizures may even be increased if evening primrose is taken in addition to phenothiazines (Newall et al., 1996; Shaw et al., 1997). Similarly, the Ayurvedic remedy ‘Sankhapushpi’ containing Centella asisatica, Con6ol6ulus pluricaum, Nardostachys jatamansi, Nepeta ellipica, Nepeta hindostana and Onosma bracteatum reduced plasma levels of phenytoin, given concurrently, and resulted in the loss M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 157 Table 6 Adulterations in herbal remedies Type of remedy Ingredient Adulterant Clinical presentation References Cough medicine Gordolobo used by mother Senecio longilobus Veno-occlusive disease (VOD) and infant death Stillman et al., 1977; Fox et al., 1978 Herbal tea used Unknown by mother Tussilago farfara Fatal VOD in infant Roulet et al., 1988; Sprang, 1989 Grain use Grains, poaceae etc. Heliotropium and Crotalaria VOD, hepatosplenomegaly and ascites in Asia Datta et al., 1978; Chauvin et al., 1994; McDermott and Ridker, 1990 Comfrey Teas Symphytum officinale Unsafe, cumulative effects leading to VOD Bach et al., 1989; Ridker and McDermott, 1989; McDermott and Ridker, 1990 Atropa belladona Digitalis purpurea Poisoning Poisoning Plantain extract Plantago major Digitalis purpurea Poisoning Mistletoe extract Phoradendron, Viscum Skull cap (Scutellaria laterflora) Hepatitis Moum et al., 1992 Mate or paraguay tea Ilex paraguarensis Possibly Senecio longilobus Belladonna alkaloids VOD McGee et al., 1976 Anticholergenic poisoning Anonymous, 1995b Reversible VOD in an infant Sperl et al., 1995 Peppermint, coltsfoot tea Mentha X piperita and Tussilago farfara Seniciphylline of seizure control (Dandekar et al., 1992) (Table 5). In addition, when St John’s wort (Hypericum perforatum) is used simultaneously with a wide variety of drugs that use CYPEA4 as a substrate, activity is lowered since this herb is considered to increase the activity of the isoenzyme CYPEA4 (Blumenthal, 2000). Salicin-containing oils and herbal medications have been known to elicit adverse conditions. For example, accidental ingestion by an infant of oils of wintergreen, camphor and eucalyptus caused generalized seizures (Malik et al., 1994) and use of an herbal medication, massive hemolysis (Baker and Thomas, 1987). Theoretically salicin containing herbs and salicylates, like aspirin, could interact and potentiate their activity, although no report has yet to appear in the literature (Blumenthal, 2000). Also patients undertaking anti-coagulant therapy should be warned against eating large amounts of green vegetables like broccoli and others high in vitamin K content (D’Arcy, 1993). 15. Adulterations Adulterations in herbal remedies are particularly disconcerting since they occur so unexpectedly. Usually they remain undetected unless they can be linked to an outbreak or epidemic. In this respect veno-occlusive disease due to pyrrolizidine alkaloids, discussed else- where, can be life-threatening or fatal (Chauvin et al., 1994; Drew and Myers, 1997). While adulterations related to Asian medicines have already been reviewed, it is noteworthy that misidentification of plants has resulted in a number of other serious events primarily due to poisonings with digitalis (often mistaken for comfrey), belladonna and skullcap (Table 6). 16. Conclusion Overall, when compounded and prescribed appropriately the safety of traditional herbal medications is high. It is generally recognized that life-threatening events are rare, compared to the hundreds of thousands reported for pharmaceutical products each year. This is due, in part, to the moderate bioreactivity that is imparted by most herbal preparations and the knowledge that is known regarding parameters of use. Although linkage to some adverse effects may not be discovered, since problems are likely to be under reported, it is reasonable to assume that there is a wide margin of safety for many popular remedies. There are always risks when appropriate regulations do not mandate the appropriate formulation of the remedies, or when selfmedication fosters abuse. While it is assumed that most practitioners of herbalism conduct their activities in a conscientious and ethical manner, it is difficult to know 158 M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164 if their skills can match the challenge of dealing with the problem at hand. Moreover, it must be appreciated that most allopathic practitioners have little knowledge of the fundamental premises of herbalism or how its practice might impact on their diagnostic decisions and treatments. Clearly promoting appropriate education at medical schools and through continuing education courses can remedy this situation. Hopefully this will generate respect for aspects of healing utilizing certain plant remedies that are not generally apart of allopathic practice. However, to aid in the identification of potential adverse effects, allopathic clinicians should always question their patients about their alternative medicinal practices, including herbal use. This should be done in the context of understanding its meaning to the patient and the implications that it might have to his or her total well-being. Eisenberg (1997) has recommended that this strategy include ‘a formal discussion of patient’s preferences and expectations, the maintenance of symptom diaries, and follow-up visits to monitor for potentially harmful situations’. This is important since a national survey conducted by him and others (Eisenberg et al., 1998; Barrett et al., 1999) on trends in alternative medicine in the United States between 1990 and 1997 was particularly revealing. It showed that at least a third of patients used unconventional therapy, and the majority of these did so for chronic conditions. These same patients also sought treatment from allopathic practitioners, but were unlikely to inform their medical doctor of other treatments they were undertaking. In this context, the following guidelines related to temporal associations of herbal use may be useful when adverse effects are suspected (Table 7). It is essential that anyone considering taking herbal medications must be well informed and not rely on unfounded claims found in other than scientific literature. It should be emphasized that even within the context of medical journals, observations reported as ‘Letters to the Editor’ are likely to be perpetuated as fact until proven otherwise by subsequent clinical evaluations (Anderson et al., 1998; Goodwin and Tangum, 1998). Current US Table 7 Evaluation of adverse effects Practitioners may recognize acute symptoms of toxicity but are unlikely to link effects associated with hepatotoxicity, teratogenicity or carcinogenicity to use Temporal association between exposure and effect Disappearance of effect after product discontinued Reappearance of effect when product re-introduced Association of product use and interactions with medicines Occupational chemicals, and recreational drugs Association with underlying disease states considered Association of exposure and effects known in scientific literature Table 8 Rationale herb use guidelines Be informed, seek out unbiased, scientific sources Do not depend upon product claims alone Inform your allopathic physician of self-medication regimens Be aware that an allopathic physician’s knowledge of herbal remedies may be limited Know benefits and risks and potential side effects Read labels carefully, do not exceed recommended dose ranges Know potential drug interactions Never use if pregnant or nursing Take care when giving to children Take care when giving to the elderly Do not use for serious illnesses Do not use for prolonged periods Know your source, formulator or manufacturer Select standardized formulations Understand that batch-to-batch variations of the formula may occur To avoid misidentification, do not collect plants yourself Make sure packaging is appropriately labeled with contents Make sure that labeling includes scientific names Store appropriately to prevent loss of potency law is very restrictive regarding what can be put on a label and because of the description of the use that is implied, can often be misleading. Also, when authors of booklets, pamphlets or package-inserts, or personnel selling the products lack appropriate credentials one has to be wary of claims that are being made. In these instances it is always possible that fact and misinformation are being mixed together for other than altruistic reasons. Further, perspective herbal users must be conscious that these medicines are usually formulated from raw materials and as such contain a wide range of substances that can vary both in pharmacokinetic and pharmacognostic capabilities. It is important to emphasize that some well known foods can also potentiate or antagonize pharmaceutical treatments and thus their use should be restricted under certain conditions (Perharic et al., 1993, 1994). The notion that ‘natural is safe’ has little meaning in reality unless, of course, one puts into the same context the idea that ‘pharmaceutically derived’ is not always totally beneficial. 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