1. health and fitness
2. alternative medicine
3. homeopathy

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: elvin@biology.wustl.edu (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. Table 8
illustrates guidelines for rational herb use and follows
many of those recommendations of Murphy (1999),
Drew and Myers (1997).
References
Akerele, O., 1993. Summary of WHO guidelines for the assessment of
herbal medicines. Herbalgram 26, 13 – 20.
Almeida, J.C., Grimsley, E.W., 1996. Coma from the health food
store, interaction between kava and alprazolam. Annals of Internal Medicine 125, 940– 941.
Anderson, I.B., Mullen, W.H., Meeker, J.E., Khojasteh-Bakht, C.,
Oishi, S., Nelson, S.D., Blanc, P., 1996. Pennyroyal toxicity,
measurement of toxic metabolite levels in two cases and review of
the literature. Annals of Internal Medicine 124, 726– 734.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164
Anderson, I.B., Mullen, W.H., Meeker, J.E., Khojasteh-Bakht, S.C.,
Oishi, S., Nelson, S.D., Angell, M., Kassirer, J.P., 1998. Alternative medicine — the risks of untested and unregulated remedies.
The New England Journal of Medicine 339, 839–841.
Angell, M., Kassirer, J.P., 1998. Alternative medicine — the risks of
untested and unregulated remedies. The New England Journal of
Medicine 339, 839– 841 Editorial.
Anonymous, 1989. Epidemiologic notes and reports cadmium and
lead exposure associated with pharmaceutical imported from Asia
— Texas. Morbidity and Mortality Weekly Reports 38, 612– 614.
Anonymous, 1992. Chaparral-induced toxic hepatitis — California
and Texas. Morbidity and Mortality Weekly Reports 41, 812–
814.
Anonymous, 1993a. Jin Bu Huan toxicity in Adults — Los Angelos
Morbidity and Mortality Weekly Reports 42, 920–922.
Anonymous, 1993b. Epidemiologic notes and reports Jin Bu Huan
toxicity in children — Colorado. Morbidity and Mortality
Weekly Reports 42, 633–636.
Anonymous, 1995a. Self-treatment with herbal and other plantderived remedies — rural Mississippi, 1993. Morbidity and Mortality Weekly Reports 44, 204–207.
Anonymous, 1995b. Anticholinergic poisoning associated with an
herbal tea — New York City, 1994. Morbidity and Mortality
Weekly Reports 44, 193–195.
Anonymous, 1996. Adverse events associated with ephedrine-containing products — Texas, December 1993–September 1995. Morbidity and Mortality Weekly Reports 45, 689–692.
Armstrong, N.C., Ernst, E., 1999. The treatment of eczema with
Chinese herbs, a systematic review of randomized clinical trials.
British Journal of Clinical Pharmacology 48, 262–264.
Aslam, M., Stockley, I.H., 1979. Interaction between curry ingredient
(karela) and drug (chlorpropamide). Lancet 1, 607 Letter.
Atal, C.K., Dubey, R.K., Singh, J., 1985. Biochemical basis of
enhanced drug bioavailability by piperine, evidence that piperine
is a potent inhibitor of drug metabolism. Journal Pharmacology
and Experimental Therapeutics 232, 258–262.
Awasthy, K.S., Chaurasia, O.P., Sinha, S.P., 1999. Prolonged murine
genotoxic effects of crude extracted from neem. Phytotherapy
Research 13, 81 – 83.
Bach, N., Thung, S.N., Schaffner, F., 89. Comfrey herb tea-induced
hepatic veno-occlusive disease. American Journal of Medicine
1989 1989, 97 – 99.
Backon, J., 1986. Ginger, inhibition of thromboxane synthetase and
stimulation of prostacyclin, relevance for medicine and psychiatry.
Medical Hypothesis 20, 271–278.
Bano, G., Raina, R.K., Zutshi, U., Bedi, K.L., Johri, R.K., Sarma,
S.C., 1991. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers.
European Journal of Clinical Pharmacology 41, 615–617.
Barrett, B., Kiefer, D., Rabago, D., 1999. Assessing the risks and
benefits of herbal medicine, an overview of scientific evidence.
Alternative Therapies in Health and Medicine 5, 40–49.
Baskaran, K., Kizar Ahamath, B., Radha Shanmugasundaram, K.,
Shanmugasundaram, E.R., 1990. Antidiabetic effect of a leaf
extract from Gymnema sylvestre in non-insulin-dependant diabetes mellitus patients. Journal Ethnopharmacology 30, 295– 305.
Batchelor, W.B., Heathcote, J., Wanless, I.R., 1995. Chaparral-induced hepatic injury. American Journal of Gastroenterology 90,
831– 833.
Bateman, J., Chapman, R.D., Simpson, D., 1998. Possible toxicity of
herbal remedies. Scottish Medical Journal 43, 7–15.
Beaugerie, L., Luboinski, J., Brusse, N., 1994. Drug induced
lymphocytic colitis. Gut 35, 426–428.
Benninger, J., Schneider, H.T., Schuppan, D., Kirchner, T., Hahn,
E.G., 1999. Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology 117, 1234–1237.
159
Bensousan A., Meyers, S.P., 1996. Towards a safer choice. The
practice of traditional Chinese medicine in Australia, Department
of Human Services, Australia.
Benzi, G., Ceci, A., 1997. Herbal medicines in European regulation.
Pharmaceutical Research 33, 355– 362.
Blumenthal, M., Busse, W.R., Goldberg, A., Gruenwald, J., Hall, T.,
Riggins, C.W., Rister, R.S., (eds.) Klein, S., Rister, R.S., (trans),
1998. The Complete German Commission E Monographs, Therapeutic Guide to Herbal Medicines. Klein S., Rister R.S., translators, Integrative Medicine Communications, Austin (TX),
American Botanical Council, Boston (MA).
Blumenthal, M., 1999. Monograph update, WHO publishes herbal
monographs; ABC, AHP, ESCOP and USP continue monograph
publication. Herbalgram 47, 40 – 45.
Blumenthal, M., 2000. Interactions between herbs and conventional
drugs, introductory considerations. Herbalgram 49, 52 –63.
Blushan, M., Beck, M.H., 1997. Allergic contact dermatitis from tea
tree oil in a wart paint. Contact Dermatitis 36, 117– 118.
Boehnert, K.J., 1997. The use of Vitex agnus– castus for hyperprolactinemia. In: Brown, D.J. (Ed.), Quarterly Review Natural
Medicine. Seattle (WA) Natural Product Research Consultants,
Spring 1997, pp. 19 – 21.
Borchers, A.T., Hackman, R.M., Keen, C.L., Stern, J.S., Gershwin,
M.E., 1997. Complementary medicine, a review of immunomodulatory effects of Chinese herbal medicines. American Journal of
Clinical Nutrition 66, 1302– 1312.
Borins, M., 1998. The dangers of using herbs. Postgraduate Medicine
104, 91 – 95, 99 – 100.
Bossuyt, L., Dooms-Goossens, A., 1994. Contact sensitivity to nettles
and camomile in ‘alternative’ remedies. Contact Dermatitis 31,
131– 132.
Bras, G., Jelliffe, D.B., Stuart, K.L., 1954. Veno-occlusive disease of
liver with nonportal type of cirrhosis, occurring in Jamaica.
Archives of Pathology 57, 285– 300.
Brevoort, P., 1998. The booming US botanical market, a new
overview. Herbalgram 44, 33 – 446.
Brinker, F. 1997. Herb Contraindications and Drug Interactions.
Eclectic Institute.
Brunton, L.L., 1996. Agents affecting gastrointestinal water flux,
emesis and antiemetics, bile acids and pancreatic enzymes. In:
Hardman, J.G., Limbird, L.E., Monlnoff, P.B., et al. (Eds.),
Goodman and Gilman’s The Pharmaceutical Basis of Therapeutics, 9th. McGraw-Hill Book Company, New York, NY, pp.
917– 936.
Bruynzeel, D.P., 1999. Contact dermatitis due to tea tree oil. Tropical
Medicine and International Health 4, 630.
Buchness, M.R., 1998. Alternative medicine and dermatology. Seminars in Cutaneous Medical Surgery 17, 284– 290.
Burkey, J.L., Sauer, J., McQueen, C.A., Glenn Sipes, I., 2000.
Cytotoxicity and genotoxicity of methyleugenol and related congeners — a mechanism of activation for methyleugenol. Mutatation Resarch 453, 25 – 33.
Cahill, D.J., Fox, R., Wardle, P.G., Harlow, C.R., 1994. Multiple
follicular development associated with herbal medicine. Human
Reproduction 9, 1469– 1470.
Caldwell, S.H., Feeley, J.W., Wieboldt, T.F., Featherston, P.L.,
Dickson, P.C., 1994. Acute hepatitis with use of over-the-counter
herbal remedies. Virginia Medical Quarterly 121, 21 – 33.
CAM (Complementary and Alternative Medicine at NIH), 2000.
Databases offer information. 7, 7.
Catania, P.N., 1998. Problems with herbal remedies in anticoagulated
home care patients. Home Care Provider 3, 253– 255.
Chan, Y.K., 1997. Monitoring the safety of herbal medicines. Drug
Safety 17, 209– 215.
Chan, Y.K., Chan, J.C.N., Tomlinson, B., Critchley, J.A.J.H., 1993.
Chinese herbal medicines revisited, a Hong Kong perspective.
Lancet 342, 1532– 1534.
160
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164
Chan, K., Lo, A.C., Yeung, J.H., Woo, K.S., 1995. The effects of
Dansen (Sal6ia, miltiorrhiza) on warfarin enantiomers in rats.
Journal of Pharmacy and Pharmacology 47, 402–406.
Chakraborty, T., Podder, G., 1984. Herbal drugs in diabetes – Part
1: Hypoglycemic activity of indigenous plants in Streptozotocin
(STZ) induced diabetic rats. Journal of the Institute of Chemists
(India) 56, 20 – 22.
Chauvin, P., Dillon, J.C., Moren, A., 1994. An outbreak of Heliotrope food poisoning, Tadjikistan, November 1992– March
1993]. Sante 4, 263– 268.
Cheng, T.O., 2000. Interaction of herbal medicine with Coumadin.
Journal of Emergency Medicine 18, 122.
Commission E Monographs — Therapeutic Guide to Herbal
Medicines. Austin, TX. American Botanical Council, Boston,
MA, Integrative Medicine Communications.
Consumer Reports, 1995. Herbal roulette. November, 698–705.
Cosyns, J.P., Jadoul, M., Squifflet, J.P., Wese, F.X., van Ypersele de
Strihou, C., 1999. Urothelial lesions in Chinese-herb nephropathy.
American Journal of Kidney Diseases 33, 1011–1017.
Cugini, P., Gentile, R., Zard, A., Rocchi, G., 1983. Hypertension in
licorice abuse. A case report. Giornale Italiano di Cardiologia 13,
126– 128.
Culvenor, C.C.J., 1983a. Estimated intakes of pyrrolizidine alkaloids
by humans. A comparison with dose rates causing tumors in rats.
Journal of Toxicology and Environmental Health 11, 625– 635.
Culvenor, C.C.J., 1983b. Estimated intakes of pyrrolizidine alkaloids
by humans. A comparison with dose rates causing tumors in rats.
Journal of Toxicology and Environmental Health 11, 625– 635.
Cupp, M.J., 1999. Herbal remedies, adverse effects and drug interactions. American Family Physician 59, 1239–1245.
D’Arcy, P.F., 1991. Adverse reactions and interactions with herbal
medicines, I, adverse reactions. Adverse Drug Reaction and Toxicological Reviews 10, 189–208.
D’Arcy, P.F., 1993. Adverse reactions and interactions with herbal
medicines. Part 2 — drug interactions adverse drug reactions and
toxicological reviews 12, 147–162.
Dalen, J.E., 1998. ‘Conventional’ and ‘Unconventional’ Medicine.
Archives of Internal Medicine 158, 2179–2218.
Dalvi, S.S., Nayak, V.K., Pohujani, S.M., Desai, N.K., Kshirsagar,
N.A., Gupta, K.C., 1994. Effect of gugulipid on bioavailability of
diltazem and propranolol. Journal of the Association of Physicians of India 42, 454–455.
Damm, D.D., Curran, A., White, D.K., Drummond, J.F., 1999.
Leukoplakia of the maxillary vestibule — an association with
Viadent? Oral Surgery, Oral Medicine, Oral Pathology, Oral
Radiology, Endodontics 87, 61–66.
Dandekar, U.P., Chandra, R.S., Dalvi, S.S., Joshi, M.V., Gokhale,
P.C., Sharma, A.V., Shah, P.U., Kshirsagar, N.A., 1992. Analysis
of a clinically important interaction between phenytoin and
Shankhapushpi, an ayurvedic preparation. Journal of Ethnopharmacologyacology 35, 285–288.
Datta, D.V., Khuroo, M.S., Mattocks, A.R., Aikat, B.K., Chhuttani,
P.N., 1978. Herbal medicines and veno-occlusive disease in India.
Postgraduate Medical Journal 54, 511–515.
DeSmet, P.A.G.M., 1992b. Drugs used in non-orthodox medicine. In:
Dukes, M.N.G. (Ed.), Side Effects of Drugs, 12th. Elsevier,
Amsterdam, pp. 1209–1232.
DeSmet, P.A.G.M., 1993. An introduction to herbal pharmacoepidemiology. Journal of Ethnopharmacology 38, 197–208.
DeSmet, P.A.G.M., 1995a. Health risks of herbal remedies. 1995
Drug Safety 13, 81 – 93.
DeSmet, P.A.G.M., 1995b. An introduction to herbal pharacoepidemiology. Journal of Ethnopharmacology 38, 197–208.
DeSmet, P.A.G.M., 1997. The role of plant-derived drugs and herbal
medicines in healthcare. Drugs 54, 801–840.
DeSmet, P.A.G.M., Brouwers, J.R.B.J., 1997. Pharmacokinetic evaluation of herbal remedies. Clinical Pharacokinetics 32, 427– 436.
DeSmet, P.A.G.M., D’Arcy, P.F., 1996. Drug interactions with
herbal and other non-orthodox remedies. In: D’Arcy, P., McElnay, J.C., Welling, P.G. (Eds.), Mechanisms of Drug Interactions.
Springer-Verlag, New York, pp. 327– 352.
DeSmet, P.A.G.M., Stricker, B.H.C., Wilderink, F., Wiersinga,
W.M., 1990. Hyperthyreoı¨dı¨e tijdens her gebruik van kelptabletten. Nederlands Tijdschrift voor Geneeskunde 134, 1058–
1059.
DeSmet, P.A.G.M., Keller, K., Hansel, R., Chandler, R.F., 1992a.
Adverse Effects of Herbal Drugs I and II. Springer-Verlag.
DeSmet, P.A., Keller, K., Hansel, R., Chandler, R.F., 1996. In:
Pharmaceutical of the World Health Organization, R (eds.), Adverse Effects of Herbal Drugs, Volume 3, Springer-Verlag, New
York.
DeSmet, P.A.G.M., Van den Eertwegh, A.J., Lesterhui, W., Stricker,
B.H., 1997. Hepatotoxicity associated with herbal tablets. British
Medical Journal 313, 92.
Donaldson, K., 1998. Introduction to the healing herbs. ORL Head
and Neck Nursing 16, 9 – 16.
Doyle, H., Kargin, M., 1996. Herbal stimulant containing ephedrine
has also caused psychosis. British Medical Journal 313, 756.
Letter.
Drew, A.K., Myers, S.P., 1997. Safety issues in herbal medicine,
implication for the health professions. Medical Journal of Australia 166, 538– 541.
Eisenberg, D.M., 1997. Advising patients who seek alternative medical therapies. Annals of Internal Medicine 127, 61 – 69.
Eisenberg, D.M., Davis, R.B., Ettner, S.L., Wilkey, S., Van Rompay,
M., Kessler, R.C., 1998. Trends in alternative medicine use in the
United States, 1990– 1997, results of a follow-up national survey.
Journal of the American Medical Association 280, 1569–1575.
El-Said, M., Fadulu, S.O., Juye, J.O., Sofowara, E.-A., 1971. Native
cures in Nigeria. II The antimicrobial properties of buffered
extracts of chewing sticks. Lloydia 34, 172– 174.
Elvin-Lewis, M., I n Press. Neem, From ethnodentistry to dental
products, A review of its antiodontopathic potential. Proceedings
of Neem Conference, UBC (1999).
Elvin-Lewis, M., 1987. Medicinal plants in dentistry, keynote address.
In: Saxena, R.C., Gupta, T.K. (Eds.), Proceedings of the Internationational Seminar on Clinical Pharmacology in Developing
Countries, vol. 2, pp. 1 – 9.
Elvin-Lewis, M., 1989. Development of phytochemicals for dental
use. in Proceedings 1st Congress of the Asian Federation of
Clinical Pharmacognisists (1988). Asian Federation Clinical Pharmacologists, Process and Production, Lucknow, pp. 66 –70.
Elvin-Lewis, M., Lewis, W.H., 1995. New concepts and medical and
dental ethnobotany. In: Schultes, R, Von Reis, S. (Eds.), Ethnobotany, evolution of a discipline. Dioscordes Press, Portland, pp.
303– 310.
Elvin-Lewis, M., Hamiolos, D., El-Najdawi, E., Wedner, H.J., 1985.
Essential oil hypersensitivity in apththous stomatitis patients.
Journal Dental Research 64, 33.
Ernst, E., 1998. Harmless herbs? A review of the recent literature.
The American Journal of Medicine 104, 170– 178.
Ernst, E., 1999. Herbal medications for common ailments in the
elderly. Drugs Aging 15, 423– 428.
ESCOP, European Scientific Cooperative on Phytotherapy. ESCOP
monographs on the medicinal uses of plant drugs. Exeter, UK,
ESCOP, 1997.
ESCOP, European Scientific Cooperative on Phytotherapy. ESCOP
monographs on the medicinal uses of plant drugs. Exeter, UK,
ESCOP, 1999.
Faber, P., Strenge-Hess, A., 1988. Relevance of rhein excretion into
breast milk. Pharmacology 1 (36), 212– 220 Supplement.
FDA/CFSAN AEMS Search Results, US Food and Drug Administration, Center for Food Safety and Applied Nutrition, Office of
Special Nutritionals, October, 2000.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164
Foti, C., Nettis, E., Panebianco, R., Cassano, N., Diaferio, A., Pia,
D.P., 2000. Contact urticaria from Matricaria chamomilla. 2000
Contact Dermatitis 42, 360–361.
Fox, D.W., Hart, M.C., Bergeson, P.S., Jarret, P.B., Stillman, A.E.,
Huxtable, R.J., 1978. Pyrrolizidine (Senecio) intoxication mimicking Reye syndrome. Journal of Pediatrics 90, 980–982.
Galloway, J.H., Farmer, K., Weeks, G.R., Marsh, I.D., Forrest,
A.R., 1992. Potentially hazardous compound in a herbal slimming
remedy. [Letter]. Lancet 340, 179.
Gandolfo, G.M., Girrelli, G., Conti, L., 1992. Hemolytic anemia and
thrombocytopenia induced by cyanidanol. Acta Haematologica
88, 96 – 99.
Georgiou, M., Sianidou, L., Hatzis, T., Papadatos, J., Koutselinis,
A., 1988. Hepatotoxicity due to Atractylis gummifera-L. Journal
of Toxicology and Clinical Toxicology 26, 487–493.
Gertner, E., Marshall, P.S., Filandrinos, D., Potek, A.S., Smith,
T.M., 1995. Complications resulting from the use of Chinese
herbal medications containing undeclared prescription drugs.
Arthritis and Rheumitism 38, 614–617.
Ghani, A., Eriksson, M., Kristiannsson, B., Qirbi, A., 1987. The
influence of khat-chewing on birth-weight in full-term infants.
Social Science and Medicine 24, 625–627.
Giordano-Labadie, F., Schwarze, H.P., Bazex, J., 2000. Allergic
contact dermatitis from amomile used in phytotherapy. Contact
Dermatitis 42, 247.
Glisson, J., Crawford, R., Street, S., 1999. Review, critique, and
guidelines for the use of herbs and homeopathy. Nurse Practitioner 24, 44 – 46, 53, 60 passim, quiz 68–69.
Goodwin, J.S., Tangum, M.R., 1998. Battling quakery, attitudes
about micronutrient supplements in American academic medicine.
Archives of Internal Medicine 158, 2187–2191.
Gonzalez-Seijo, J.C., Ramos, Y.M., Lastra, I., 1995. Manic episode
and ginseng, a report of a possible case. Journal of Clinical
Psychopharmacology 15, 447–448.
Gordon, L.A., 1999. Compositae dermatitis. Australian Journal of
Dermatology 40, 123–128.
Greig, J.E., Thoo, S.L., Carson, C.F., Riley, T.V., 1999. Allergic
contact dermatitis following use of a tea tree oil hand-wash not
due to tea tree oil. Contact Dermatitis 41, 354–355.
Hamouda, C., Amamou, M., Thabet, H., Yacoub, M., Hedhili, A.,
Bescharnia, F., Ben Salah, N., Zhioua, M., Abdelmoumen, S., El
Mekki Ben Brahim, N., 2000. Plant poisonings from herbal
medication admitted to a Tunisian toxicologic unit, 1983– 1998.
Veterinary and Human Toxicology 53, 885–892.
Hausen, B.M., 1981. Occupational contact allergy to feverfew
Tanacetum parthenium (L.) Schult Asteraceae. Derm Beruf
Umwelt 29, 18 – 21.
Hausen, B.M., 1984. Toothpaste allergy. Deutsche Medizinische
Wochenschrift 109, 300–302.
Hausen, B.M., 1996. A 6-year experience with compositae mix.
American Journal of Contact Dermatitis 7, 94–99.
Hill, K.R., Rohdes, K., Stafford, J.L., Aub, R., 1951. Liver disease in
Jamaican children (serous hepatosis). West Indian Medical Journal 1, 49 – 63.
Horowitz, R.S., Feldhaus, K., Dart, R.C., Stermitz, F.R., Beck, J.J.,
1996. The clinical spectrum of Jin Bu Huan Toxicity. Archives
Internal Medicine 156, 899–903.
Hughes, W.T., 1995. Postulates for the evaluation of adverse reactions to drugs. Clinical Infectious Disease 20, 179–182.
Izzat, M.B., Yim, A.P., El-Zufari, M.H., 1998. A taste of Chinese
medicine. Annuals of Thoracic Surgery 66, 941–942.
Jamieson, D.D., Duffield, P.H., 1990. Positive interaction of ethanol
and kava resin in mice. Clinical Experimental Pharmacology and
Physiology 17, 509– 514.
Jankel, C.A., Speedie, S.M., 1990. Detecting drug interactions, a
review of the literature. DICP, The Annals of Pharmacotherapy
24, 982– 988.
161
Jaspersen-Schib, R., Theus, L., Guirguis-Oeschger, M., Gossweiler,
B., Meie Abt, P.J., 1996. Schweizerische medizinische wochenschrift. Journal Suisse de Medecine 126, 1085– 1098.
Jensen-Jarolim, E., Reider, N., Fritsch, R., Breiteneder, H., 1998.
Fatal outcome of anaphylaxis to camomile-containing enema
during labor: a case study. Journal of Allergy Clinical Immunology 102, 1041– 1042.
Jones, T.K., Lawson, B.M., 1998. Profound neonatal congestive heart
failure caused by maternal consumption of blue cohosh herbal
medication. Journal of Pediatrics 132, 550– 552.
Kanba, S., Yamada, K., Mizushima, H., Asai, M., 1998. Use of
herbal medicine for treating psychiatric disorders in Japan. Psychiatry and Clinical Neurosciences 52, S331– S333 Suppl.
Kane, G.C., Lipsky, J.J., 2000. Drug-grapefruit juice interactions.
Mayo Clinic Proceedings 75, 933– 942 Review.
Kaplowitz, N., 1997. Hepatotoxicity of herbal remedies, insights into
the intricacies of plant– animal warfare and cell death. Gastroenterology 113, 1408– 1412.
Kassler, W.J., Blanc, P., Greenblatt, R., 1991. The use of medicinal
herbs by human immunodeficiency virus-infected patients.
Archives of Internal Medicine 151, 2281– 2288.
Kew, J., Morris, C., Aihie, A., Fysh, R., Jones, S., Brooks, D., 1993.
Arsenic and mercury intoxication due to Indian ethnic remedies.
British Medical Journal 306, 506– 507.
Kim, J.Y., Kim, K.R., 2000. Dietary iodine intake and urinary iodine
excretion in patients with thyroid diseases. Yonsei Medical Journal 41, 22 – 28.
Kincheloe, L., 1997. Herbal medicines can reduce costs in HMO.
Herbalgram 41, 49.
Knight, T.E., Hausen, B.M., 1994. Melaleuca oil (tea tree oil) dermatitis. Journal American Academy of Dermatology 30, 423–427.
Ko, R.J., 1998. Adulterants in Asian patent medicines. New England
Journal of Medicine 339, 847.
Koryrskyj, A., 1977. Herbal products in Canada. How safe are they?
1977 Canadian Family Physician 43, 697– 702.
Lai, R.S., Chaing, A.A., Wu, M.T., Wang, J.S., Lai, N.S., Lu, J.Y.,
Ger, L.P., Roggli, V., 1996. Outbreak of bronchiolitis obilterans
associated with consumption of Sauropus androgynus in Taiwan.
Lancet 348, 83 – 85.
Larrey, D., 1994. Liver involvement in the course of phytotherapy.
Presse Medicale 23, 691– 693.
Larrey, D., Vial, T., Pauwels, A., Castot, A., Biour, M., David, M.,
Michel, H., 1992. Hepatitis after germander (Teucrium
chamaedrys) administration, another instance of herbal medicine
hepatotoxicity. Annals of Internal Medicine 117, 129– 132.
Lewis, J.H., 1992a. Esophageal and small bowel obstruction from
guar-containing diet pills, analysis of 26 cases reported to the
FDA. American Journal of Gastroenterology 87, 1424–1428.
Lewis, W.H., 1992b. Allergenic potential of commercial chamomile,
Chamaemelum nobile (Asteraceae). Economic Botany 46, 426–
430.
Lewis, W.H., Elvin-Lewis, M., 1994. Basic quantitative and experimental research phases of future ethnobotany with reference to
the medicinal plants of South America. In: Chadwick, J., Marsh,
J. (Eds.), Ethnobotany and the Search for New Drugs. John
Wiley and Sons, New York, pp. 60 – 76.
Lewis, W.H., Elvin-Lewis, M., 1977. Medical Botany, Plants Affecting Mans Health. John Wiley Interscience, NY.
Lin, J.L., Ho, Y.S., 1994. Flavonoid-induced acute nephropathy.
American Journal of Kidney Disease 23, 433– 440.
Lipp, F.J., 1996. The efficacy, history and politics of medicinal plants.
Alternative Therapy and Health Medicine 2, 36 – 41.
Liske, E., 1998. Therapeutic efficacy and safety of Cimicifuga
racemosa for gynecologic disorders. Advances in Therapy 15,
45 – 53 Review.
Liu, T.Y., Chen, C.C., Chen, C.L., Chi, C.W., 1999. Safrole-induced
oxidative damage in the liver of Sprague– Dawley rats. Food and
Chemical Toxicology 37, 697– 702.
162
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164
Lord, G.M., Tagore, R., Cook, T., Gower, P., Pusey, C.D., 1999.
Nepthropathy caused by Chinese herbs in the UK. Lancet 354,
481– 482.
Lyford, C.L., Vergara, G.G., Moeller, D.D., 1976. Hepatic veno-occlusive disease originating in Ecuador. Gastroenterology 70, 105–
108.
Maechel, H., 1992. Diarrh( chronique secondaire au Cirkan, [Letter].
Gastroenterologie Clinique et Biologique 16, 373.
Malik, A.S., Zabidi, M.H., Noor, A.R., 1994. Acute salicylism due to
accidental ingestions of a traditional medicine. Singapore Medical
Journal 35, 215– 216.
Mashour, N.H., Lin, G.I., Frishman, W.H., 1998. Herbal medicine
for the treatment of cardiovascular disease, clinical considerations. Archives of Internal Medicine 158, 2225–2234.
Maurice, P.D.L., Cream, J.J., 1989. The dangers of herbalism. British
Medical Journal 299, 1204.
Mawrey, D.B., 1993. Herbal Tonic Therapies. Keats Publishing Inc.,
New Canaan, Conn.
McDermott, V.W., Ridker, P.M., 1990. The Budd–Chiari syndrome
and hepatic veno-occlusive disease. Recognition and treatment.
Archives of Surgery 125, 525–527.
McGuffin, M., Hobbs, C., Upton, R., Goldber, A., 1997. Introduction, American Herbal Products Association’s Botanical Safety
Handbook. CRC Press.
McPartland, J.M., Pruitt, P.L., 1999. Side effects of pharmaceuticals
not elicited by comparable herbal medicines, the case of tetrahydrocannabinol and marijuana. Alternative Therapy Health and
Medicine 5, 57 – 62.
Miller, L.G., 1998. Herbal medicinals. Selected clinical considerations
focusing on known or potential drug–herb interactions. Archives
of Internal Medicine 158, 2200–2211.
Mills, S.Y., 1995. European pilot studies are under way. British
Medical Journal 311, 1570.
Moum, B., Aukrust, P., Schrumpf, E., Mørk, T., Mathisen, Ø., Elgjo,
K., 1992. Naturmidler kan fora˚rsaje geksesjader. Tidsskrift for
den Norske Laegeforening 112, 1308–1311.
Mukherhee, S., Lohiya, N.K., Pal, R., Sharma, M.G., Talwar, G.P.,
1996. Purified neem (Azadirachta indica) seed extracts (Praneem)
abrogate pregnancy in primates. Contraception 53, 375–378.
Mullins, R.J., 1998. Echinacea-associated anaphylaxis. Medical Journal of Australia 168, 170–171.
Munro, I.C., Delzell, E.S., Nestmann, E.R., Lynch, B.S., 1999.
Viadent usage and oral leukopakia, a spurious association. Regulatory Toxicology and Pharmacology 30, 182–196.
Murphy, J.M., 1999. Preoperative considerations with herbal
medicines. American Organization of Registered Nurses Journal
69, 173– 183.
Myer, S.P., Wohlmuth, H., 1998. Echinacea-associated anaphylaxis.
Medical Journal of Australia 168, 583–584.
Natori, S., 1980. Application of herbal drugs to health care in Japan.
Journal of Ethnopharmacology 2, 65–70.
Neurauer, R.A., 1961. A plant protease for potentiation of and
possible replacement of antibiotics. Experiment Medical Surgery
19, 143– 160.
Newall, C.A., Anderson, L.A., Phillipson, J.D., 1996. Herbal
medicines a guide for health care professionals. The Pharmaceutical Press, London.
Nolan, A., Lamey, P.J., Milligan, K.A., Forsyth, A., 1991. Recurrent
aphthous ulceration and food sensitivity. Journal Oral Pathology
and Medicine 20, 473–475.
Nortier, J., Depierreux, M., Vanherwehem, J.L., 1999. Herbal remedies and nephrotoxicity. Revue Medicale de Bruxelles 20, 9 – 14.
Ocasio, N.A., Salomowitz, B.H., Sher, M.R., 1999. Natural remedies
recommended for the management of oral health. New York
State Dental Journal 65, 22–24.
O’Hara, M., Kiefer, D., Farrell, K., Kemper, K., 1998. A review of
12 commonly used medicinal herbs. Archives Family Medicine 7,
523– 536.
Olukoga, A., Donaldson, D., 2000. Liquorice and its health implications. Journal of the Royal Society of Health 120, 83 – 89 Review.
Opper, F.H., Isaacs, K.L., Warshauer, D.M., 1990. Esophageal obstruction with a dietary fiber product designed for weight reduction. Journal Clinical Gastroenterology 12, 667– 669.
Panda, S., Kar, A., 2000. How safe is neem extract with respect to
thyroid function in male mice? Pharmacological Research 41,
419– 422.
Pansatinkul, B.J., McKnanee, R., 1993. Dicoumarol content in alcoholic her elixirs. South Asian Journal Tropical Medicine and
Public Health 24 (1), 201– 203 Suppl.
Pansatiankul, B.J., Ratanasir, B., 1992. Acquired prothrombin complex deficiency syndrome. Bulletin Department Medical Service
17, 485– 492.
Paulsen, E., Andersen, K.E., Carlsen, L., Egsgaard, H., 1993. Carvone: an overlooked contact allergen cross-reacting with
sesquiterpene lactones? Contact Dermatitis 29, 138– 143.
Pereira, F., Santos, R., Pereira, A., 1997. Contact dermatitis from
camomile tea. Contact Dermatitis 36, 307.
Perharic, L., Shaw, D., Murray, V., 1993. Toxic effects of herbal
medicine and food supplements. Lancet 342, 180– 181.
Perharic, L., Shaw, D., Colbridge, M., House, I., Leon, C., Murray,
V., 1994. Toxicological problems resulting from exposure to traditional remedies and food supplements. Drug Safety 11, 284–294.
Pye, K.G., Kelsey, S.M., House, I.M., Newland, A.C., 1992. Severe
dyserthyropiesis and autoimmune thrombocytopenia associated
with ingestion of kelp supplement. [Letter]. Lancet 339, 1540.
Ridker, P.M., McDermott, V.W., 1989. Comfrey herb tea and hepatic
veno-occlusive disease. Lancet 1 (8639), 657– 658.
Rieder, M.J., 1994. Mechanisms of unpredictable adverse drug reactions. Drug Safety 11, 196– 212.
Rodriguez-Serna, M., Sanchez-Motilla, J.M., Ramon, R., Aliaga, A.,
1998. Allergic and systemic contact dermatitis from Matricaria
chamomilla tea. Contact Dermatitis 39, 192– 193.
Rosenblatt, M., Mindel, J., 1997. Spontaneous hyphema associated
with ingestion of Ginkgo biloba extract. [Letter]. New England
Journal of Medicine 336, 1108.
Rosenkranz, H.S., Klopman, G., 1995. An examination of the potential genotoxic carcinogenicity of a biopesticide derived from the
neem tree. Environmental and Molecular Mutagenesis 26, 255–
260.
Roulet, M., Ricardo, L., Rivier, L., Calame, A., 1988. Hepatic
veno-occlusive disease in newborn infant of a woman drinking
herbal tea. Journal of Pediatrics 112, 433– 439.
Rubel, D.M., Freeeman, S., Southwell, I.A., 1998. Tea tree oil
allergy, what is the offending agent? Report of three cases of tea
tree oil allergy and review of the literature. Australian Journal of
Dermatology 39, 244– 247.
Ruze, P., 1990. Kava-induced dermopathy, a niacin deficiency?
Lancet 335, 1442– 1445.
Sanders, D.M., Kennedy, N., McKendrick, M.W., 1995. Monitoring
the safety of herbal remedies. British Medical Journal 311, 1569.
Sandler, B., Aronson, P., 1993. Yohimbine-induced cutaneous drug
eruption, progressive renal failure, and lupus-like syndrome. Urology 41, 343– 345.
Sassevile, D., 1999. Phytodermatitis. Journal Cutaneous Medical
Surgery 3, 263– 279.
Saxe, T.G., 1987. Toxicity of medicinal herbal preparations. American Family Physician 35, 135– 142.
Schaller, M., Korting, H.C., 1995. Clinical Experimental Dermatology 20, 143– 145.
Schaumburg, H.H., Berger, A., 1992. Alopecia and sensory polyneuropathy from thallium in a Chinese herbal medications. [letter].
Journal of the American Medical Association 268, 3430–3431.
Segelman, A.B., Segelman, F.P., Karlinger, J., Sofia, R.D., 1976.
Sassafras and herb tea. potential health hazards. Journal American Medical Association 236, 477.
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164
Seidner, D.L., Roberts, I.M., Smith, M.S., 1990. Esophageal obstruction after ingestion of a fiber-containing die pill. Gastroenterology
99, 1820– 1822.
Selvaag, E., Holm, J.O., Thune, P., 1995a. Contact allergy to essential oils. Tidsskr Nor Laegeforen 115, 3369–3370.
Selvaag, E., Holm, J.O., Thune, P., 1995b. Allergic contact dermatitis
in an aroma therapist with multiple sensitization to essential oils.
Contact Dermatitis 33, 354–355.
Shaw, D., Leon, C., Kolev, S., Murray, V., 1997. Traditional remedies and food supplements, a 5-year toxicological study. Drug
Safety 17, 342– 356.
Shaw, D., Murray, V., Volans, G., 1999. Adverse effects of herbal
remedies and OTC medicines. British Journal of Clinical Pharmacology 47 (227– 228), 229–230.
Sheerin, N.S., Monk, P.N., Aslam, M., Thurston, H., 1994. Simultaneous exposure to lead, arsenic and mercury from Indian ethnic
remedies. British Journal of Clinical Practice 48, 332–333.
Sheikh, N.M., Philen, R.M., Love, L.A., 1997. Chaparral-associated
hepatotoxicity. Archives Internal Medicine 157, 913–919.
Shibata, S., 2000. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi. Journal of
the Pharmaceutical Society of Japan 120, 849–862.
Shilo, S., Hirsch, J.H., 1986. Iodine-induced hyperthyroidism in a
patient with a normal thyroid gland. Post Graduate Medicine 62,
661– 662.
Shulman, A. 1997. Toxicological problems of traditional remedies
and food supplements. International Journal of Alternative and
Complementary Medicine 1997 Jan, 9–10.
Siegal, R.K., 1979. Ginseng abuse syndrome. Journal of the American Medical Association 241, 1614–1615.
Siegers, C.P., Von Hertzberg-Lottin, E., Ott, M., 1992. Anthranoid
laxative abuse, a risk for colorectal cancer? TIPS Gut 34, 229–
231.
Singh, R.B., Niaz, M.A., Ghosh, S., 1994. Hypolipidemic and antioxidant effects of Commiphora mukul an adjunct to dietary therapy
in paitents with hypercholesterolemia. Cardiovascular Drugs and
Therapy 8, 659– 664.
Soller, W., 2000. Regulation in the herb market: the myth of the
‘Unregulated Industry’. Herbalgram 49, 64–67.
Spang, R., 1989. Toxicity of tea containing pyrrolizidine alkaloids.
Journal of Pediatrics 115, 1025.
Sperl, W., Stuppner, H., Gassner, I., Judmaier, W., Dietze, O., Vogel,
W., 1995. Reversible hepatic veno-occlusive disease in an infant
after consumption of pyrrolizidine-containing herbal tea. Eureopean Journal of Pediatrics 154, 112–116.
Sprang, R., 1989. Toxicity of tea containing pyrrolizidine alkaloids.
Journal of Pediatrics 115, 1025.
Stein, G.M., Berg, P.A., 1999. Characterisation of immunological
reactivity of patients with adverse effects during therapy with an
aqueous mistletoe extract. European Journal of Medical Research
4, 169– 177.
Stewart, M.J., 1990. Toxic risks of inappropriate therapy. Clinical
Biochemistry 23, 73 –77.
Stewart, M.J., Moar, J.J., Steenkamp, P., Kokot, M., 1999. Findings
in fatal cases of poisoning attributed to traditional remedies in
South Africa. Forensic Science International 101, 177–183.
Stickel, F., Egerer, G., Seitz, H.K., 2000. Hepatotoxicity of botanicals. Public Health Nutrition 3, 113–1234.
Stillman, A.S., Huxtable, R., Consroe, P., Kohnen, P., Smith, S.,
1977. Hepatic veno-occlusive disease due to pyrrolizidine (Senecio) poisoning in Arizona. Gastroenterology 73, 349–352.
Strahl, S., Ehret, V., Dahm, H.H., Maier, K.P., 1998. Necrotizing
hepatitis after taking herbal remedies. Deutsche Medizinishe
Wochenschrift 123, 1410–1414.
Subiza, J., Subiza, J.L., Alonso, M., Hinojosa, M., Garcia, R., Jerez,
M., Subiza, E., 1989. Anaphylactic reaction after the ingestion of
chamomile tea, a study of cross-with other composite pollens.
Journal Allergy and Clinical Immunology 84, 353–358.
163
Sugiura, M., Hayakawa, R., Kato, Y., Sugiura, K., Hashimoto, R.,
2000. Results of patch testing with lavender oil in Japan. Contact
Dermatitis 43, 157– 160.
Sullivan, J.B., Jr., Rumack, B.H., Thomas, H., Jr., Peterson, R.G.,
Bryson, P., 1979. Pennyroyal oil poisoning and hepatotoxicity.
Journal American Medical Association 242, 2873– 2874.
Sunter, W.H., 1991. Warfarin and garlic. [Letter]. Pharmacology
Journal 246, 722.
Swinyard, E.A., Woodhead, J.H., 1982. Experimental detection quantificiation and evaluation of anticonvulsants. In: Woodbury,
D.M., Penry, J.K., Pippenger, C.E. (Eds.), Antiepileptic Drugs.
Raven Press, New York, NY, pp. 111– 126.
Takanashi, H., Umeda, M., Hirono, I., 1980. Mutation Research 78,
67 – 77.
Takegoshi, K., Tohyama, T., Okuda, K., Suzuki, K., Ohta, G., 1986.
A case of Venoplant-induced hepatic injury. Gastroenterology
Japan 21, 62 – 65.
Talwar, G.P., Shah, S., Mukherjee, S., Chabra, R., 1997a. Induced
termination of pregnancy by purified extracts of Azadirachta
indica (neem): mechanisms involved. American Journal of Reproductive Immunology 37, 485– 491.
Talwar, G.P., Raghuvanshi, P., Misra, R., Mukherjee, S., Shah, S.,
1997b. Plant immunomodulators for termination of unwanted
pregnancy and for contraception and reproductive health. Immunology and Cell Biology 75, 190– 192.
Tanaka, A., Nishida, R., Maeda, K., Sugawara, A., Kuwahara, T.,
2000. Chinese herb nephropathy in Japan presents adult-onset
Fanconi syndrome, could different components of aristolochic
acids cause a different type of Chinese herb nerphropathy? Clinical Nephrology 53, 301– 306.
Tasca, A., Barulli, M., Cavazzana, A., Zattoni, F., Artibani, W.,
Pagano, F., 1985. Treatment of obstructive symptomatology
caused by prostatic adenoma with an extract of Serenoa repens.
double-blind clinical study vs placebo. Minerva Urologica e Nefrologica 37, 87 – 91.
Taussig, S.J., Batkin, S., 1998. Bromelain, the enzyme complex of
pineapple (Ananus comosus) and its clinical application. An update. Journal of Ethnopharmacology 22, 191– 203.
Tsiodras, S., Shin, R.K., Christian, M., Shaw, L.M., Sass, D.A.,
1999. Anticholinergic toxicity associated with lupine seeds as a
home remedy for diabetes mellitus. Anuals of Emergency
Medicine 33, 715– 717.
Tyler, V.E., 1994. Herbs of Choice, The Therapeutic use of Phtyomedicines. Pharmaceutical Product Press, New York, NY.
Upton, R. (Ed.), 1999. Hawthorn leaf with flower (Crataegus spp.).
American Herbal Pharmacopoeia, Soquel (CA).
Van der Nat, J.M., van der Sluis, W.G., de Silva, K.T., Labadie,
R.P., 1991. Ethnopharmacognostical survey of Azadirachta indica
A. Juss (Meliaceae). Journal of Ethnopharmacology 199135, 1–
24.
Vanhaelen, M., Vanaelen-Fastre, R., But, P., Vanhenweghem, J-L.,
1994. Identification of aristolochic acid in Chinese herbs. Lancet
343, 174 Letter.
Vanherweghem, J.L., Depierreux, M., Tielemans, C., Abramowicz,
D., Dratwa, M., Jadoul, M., Richard, C., Vandervelde, D., Vanhaelen-Fastre, R., et al., 1993. Rapidly progressive interstitial
renal fibrosis in young women, association with slimming regimen
including Chinese herbs. Lancet 341, 387– 391.
Varma, S., Blackford, S., Statham, B.N., Blackwell, A., 2000.
Combinted contact allergy to tea tree oil and lavender oil complicating chronic vulvovaginitis. Contact Dermatitis 42, 309–310.
Victora, C.G., Munoz, N., Horta, B.L., Ramos, E.O., 1990. Patterns
of mate drinking in a Brazilian city. Cancer Research 50, 7112–
7115.
Vogel, H.G., 1991. Similarities between various systems of traditional
medicine. considerations for the future of ethnopharmacology.
Journal of Ethnopharmacology 35, 179– 190.
164
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141–164
Walti, M., Neftel, K.A., Jost, R., Jaeger, A., Berg, P., Heinzel, F.,
Weitzel, M., 1986. IE. and IgG antibodies against flavonoids
following therapy with flavonoid-containing drugs. Schweizerische
Medizinische Wochenschrift. Journal Suisse de Medecine 116,
98– 103.
Webster, J., Koch, H.F., 1996. Aspects of tolerability of centrally
acting antihypertensive drugs. Journal of Cardiovascular Pharmacology 27 (3), S49– S54 Supplement.
Wilkie, A., Cordess, C.H., 1994. Ginseng, a root just like a carrot?
Journal of Medicine 87, 594–596.
Williams, L., Davis, J.A., Lowenthal, D.T., 1993. Medical Clinics of
North America 77, 815–829.
Winship, K.A., 1991. Toxicity of comfrey. Adverse Drug Reactions
and Toxicology Reviews 10, 47–59.
Winslow, L.C., Kroll, D.J., 1998. Herbs as medicines. Archives of
Internal Medicine 158, 2192–2199.
Wong, A.H., Smith, M., Boon, H.S., 1998. Herbal remedies in
psychiatric practice. Archives of General Psychiatry 55, 1033–
1044.
.
World Health Organization, 1992. Herbal medicines containing germander withdrawn. PHA Information Exchange Service. Alert
no. 27, 19 May 1992, Geneva, WHO.
World Health Organization, 1999. WHO monographs on selected
medicinal plants. Vol. 1 Geneva, The Organization.
Yamanaka, M., Nagao, M., Sugimura, T., Furuya, T., Shirai, A.,
Matsushima, T., 1979. Mutagenicity of pyrrolizine alkaloids in
the salmonella/mammalian– microsome test. Mutation Research
68, 211– 216.
Yang, C.S., Lin, C.H., Chan, S.H., Hsu, H.C., 2000. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal
drugs. American Journal of Kidney Diseases 35, 313– 318.
Yongchaiyuda, S., Rungpitarangi, V., Bunyapraphatsara, N., et al.,
1996. Antidiabetic activity of Aloe 6era L. juice. clinical trial in
new cases of diabetes mellitus. Phytomedicine 3, 241– 243.
Youngkin, E.Q., Israel, D.S. 1996. A review and critique of common
herbal alternative therapies. 21, 39, 43 – 6, 49 – 52 passim.
Yu, C.M., Chan, J.C., Sanderson, J.E., 1997. Chinese herbs and
warfarin potentiation by ‘danshen’. Journal of Internal Medicine
241, 337– 339.