-
Journal of Ethnopharmacology 75 (2001) 141164
Should we be concerned about herbal remedies
Memory Elvin-LewisDepartment of Biology, Washington Uni6ersity,
Box 1137, St. Louis, MO 63130-4899, USA
Received 24 November 2000; received in revised form 5 December
2000; accepted 5 December 2000
Abstract
During the latter part of this century the practice of herbalism
has become mainstream throughout the world. This is due inpart to
the recognition of the value of traditional medical systems,
particularly of Asian origin, and the identification of
medicinalplants from indigenous pharmacopeias that have been shown
to have significant healing power, either in their natural state or
asthe source of new pharmaceuticals. Generally these formulations
are considered moderate in efficacy and thus less toxic than
mostpharmaceutical agents. In the Western world, in particular, the
developing concept that natural is better than chemical orsynthetic
has led to the evolution of Neo-Western herbalism that is the basis
of an ever expanding industry. In the US, oftenguised as food, or
food supplements, known as nutriceuticals, these formulations are
readily available for those that wish toself-medicate. Within this
system, in particular, are plants that lack ethnomedical
verification of efficacy or safety. Unfortunatelythere is no
universal regulatory system in place that insures that any of these
plant remedies are what they say they are, do whatis claimed, or
most importantly are safe. Data will be presented in this context,
outlining how adulteration, inappropriateformulation, or lack of
understanding of plant and drug interactions have led to adverse
reactions that are sometimeslife-threatening or lethal. 2001
Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Herbal remedies; Evolving pharmacopeias; Surveillance
and research databases; Adverse effects; Regulatory challenges
www.elsevier.com/locate/jethpharm
1. Introduction
During the latter part of the 20th century herbalismhas become
mainstream worldwide. This is due in partto the recognition of the
value of traditional and indige-nous pharmacopeias, the
incorporation of some derivedfrom these sources into
pharmaceuticals (DeSmet et al.,1992a; DeSmet, 1997; Winslow and
Kroll, 1998), theneed to make health care affordable for all, and
theperception that natural remedies are somehow saferand more
efficacious than remedies that are pharma-ceutically derived
(Bateman et al., 1998; Murphy,1999). For a variety of reasons more
individuals arenowadays preferring to take personal control over
theirhealth, not only in the prevention of diseases but alsoto
treat them. This is particularly true for a wide varietyof chronic
or incurable diseases (cancer, diabetes,arthritis) or acute
illnesses readily treated at home(common cold etc.) (Kincheloe,
1997). In this respectmany individuals have become disenchanted
with the
worth of allopathic treatments, and the adverse effectsthat can
be anticipated. They are seemingly unaware ofthe potential problems
associated with herbal use or thefact that their limited diagnostic
skills, or of thoseprescribing treatment for them, may prevent the
detec-tion of serious underlying conditions like malignancies(Saxe,
1987; Youngkin and Israel, 1996; Donaldson,1998; Winslow and Kroll,
1998; Shaw et al., 1999;Stewart et al., 1999).
Most allopathic practitioners have traditionally con-sidered
herbal treatments to be innocuous or alter-nately, potentially
problematical. Three decades agoonly a few had any appreciation of
the number ofremedies that had their origins in herbal medicine
andmost had a vague impression of what herbalism, orother forms of
alternate medicinal practices implied(Lipp, 1996). There was still
a great deal of carry-overfrom the beginning of the 20th century
when the intro-duction of wire services allowed for the
disseminationof adverse effects of snake-root concoctions and
thelike. As early as 1906, misbranding and adulterationwere
disallowed in the US Herbal remedies, not a partof The Dispensatory
of the United States of America,E-mail address:
[email protected] (M. Elvin-Lewis).
0378-8741/01/$ - see front matter 2001 Elsevier Science Ireland
Ltd. All rights reserved.PII: S 0 3 7 8 -8741 (00 )00394 -9
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164142
were shunned as if the danger associated with oneremedy was
common to all much like the notion that ifone mushroom is
poisonous, all must be and by 1938,safety testing was mandated
under the Federal Food,Drug and Cosmetic Act. By mid-century,
pharmacog-nosy (study of plants affecting health) was a
dyingscience. Dicta of the day, as outlined in a 1962
law(KefauverHarris Drug Amendments) required proofof safety and
efficacy. This policy determined that onlychemically defined and
clinically evaluated medicineshad value, and if pharmaceutically
derived, must beprescribed by allopathic physicians. (Murphy,
1999).Licensure to practice in the US was confined to allo-pathic
clinicians and others in naturopathy and home-opathy whose
traditional use of herbs was well defined.Some leeway was also
given to practicing traditionalhealers within Asian and indigenous
communities. Onthe whole, other types of herbalists were not
recognized(OHara et al., 1998).
Such was the case for decades, until the age ofAquarius arrived,
and the return to nature was thedriving force of every flower
child. In this wake,self-medication became the rule as old
Europeanherbals and indigenous remedies were revisited, andwere
used with impunity, without concern for adverseeffects. In
addition, hallucinogens, particularly fromAmerican indigenous
cultures, became popular as manytrying to escape the reality of a
war-torn and hide-bound world, experimented with altered states.
Soonhealth food stores appeared, specializing in unrefinedfood,
organic-grown vegetables, herbs and herbalpreparations. With the
opening up of Asian markets,other types of medicines were
introduced, and werepermitted since they were considered already
culturallyacceptable. A synthesis of all these types of
herbalmedicinal practices evolved into what can be
called,Neo-Western herbalism. Formulae found in this sys-tem are
based upon both ethnomedical worth or aresimply serendipitous
inventions of the formulator. Abelief of benefit over
single-ingredient drugs is thecorner stone of this form of
herbalism that subscribesto the notion that primary active
ingredients in herbsare synergized by secondary compounds, and
secondarycompounds mitigate the side effects caused by
primaryactive ingredients (McPartland and Pruitt, 1999). Sinceit is
possible for single taxa to contain a family ofrelated bioreactive
compounds varying in potency, it islogical to presume that one or
more of these willcontribute to the totality of the effects
observed (Lewisand Elvin-Lewis 1994; Elvin-Lewis and Lewis, 1995).
Itwould follow that when mixtures of several crude ex-tracts are
used in formulations, enhancement of benefi-cial effects (or
greater toxicity) is expected througheither synergistic
amplification or diminishment of pos-sible adverse side effects. It
is also presumed that theircombination could prevent the gradual
decline in effi-
cacy that is frequently observed when single drugs aregiven over
long periods of time (Borchers et al., 1997).Nowadays such remedies
can be still found in ethnicand health food stores, but are also
available in phar-macies and grocery stores. Unfortunately there is
nouniversal regulatory system that ensures that theseremedies are
what they say they are, do what isclaimed, or most importantly, are
safe (Angell andKassirer, 1998; DeSmet, 1993; DeSmet et al.,
1997).
2. Evolving pharmacopeias
2.1. Major types of herbal medicine
Four general types of Herbal Medicine exist whichare Asian,
European, Indigenous and Neo-Western.Many like the Asian and
European systems go backthousands of years, appear in pharmacopeia,
and withsuch a tradition of use are better understood than thoseof
indigenous origins that are often only orally orsecondarily
recorded (DeSmet et al., 1992a; DeSmet,1992b).
2.2. Indigenous herbalism
Indigenous medicinal systems are the most diverseand are still
practiced where such cultures are intact,but are continuously
evolving as contact with othercultures continues. The knowledge may
reside exclu-sively with traditional healers, or be generally
known.Information regarding parameters of efficacy and toxic-ity
can vary since claims are primarily anecdotal. Usu-ally regional
variations to formulae exist, and plantsselected can be quite
specific, generic, or inadvertentlyadulterated. It usually follows
that when a remedy iswidespread in acceptance its efficacy and
safety has asound therapeutic basis. It is these plants, in
particular,that can be found in Neo-Western herbalism.
2.3. Asian medicinal systems
The most established types of herbalism are those ofAsian
origin, particularly from India (Aryuvedic,Unani, Siddha), China
(Wu-Hsing) and Japan(Kampo), and today they still follow the ideas
ofdiagnosis and treatment known for millennia (Kanba etal., 1998;
Wong et al., 1998; Vogel, 1991). Most ofthe remedies are mixtures
of plants, sometimes alsocontaining animal parts and minerals and
are formu-lated to achieve expected therapeutic goals. They
areoften referred to as drugs. In these remedies it is notunusual
to find more than one plant whose componentshave complementary
effects that seemingly work to-gether to enhance the therapeutic
value or other prop-erties of the mixture. This is also true for
Indian dental
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
143
preparations that follow traditional formulations(Elvin-Lewis,
1987, 1989). Under ideal conditions,care is taken by traditionally
trained practitioners tocarefully identify the ingredients, to
harvest the plantsat very specific times to insure appropriate
levels ofbioreactivity, to prepare the remedies under strictrules,
and to prescribe them to achieve an appropriateclinical response.
In spite of the fact that parametersof use may be known to the
practitioner, includingside effects that can be expected, packaging
insertsaccompanying commercial products rarely cite thesenor do
they always accurately represent the contents.Also, there is a
general acceptance in Asian countries,particularly India, for
patients to seek concurrenttreatment through more than one Indian
MedicinalSystem as well as allopathy, or in Chinese herbalismto
fraudulently incorporate pharmaceuticals in someremedies. This only
compounds issues related torecognizing the source of potential side
effects, and itis uncommon for them to be reported at all.
More-over, without enforceable regulatory systems to gov-ern the
activities of practitioners and formulators,unexpected adverse
reactions are always likely. In thisrespect, formulations may be
inappropriately made,prescribed, or taken. Formulation diversity,
due toadvertent substitutions, can also exist in preparationswith
the same name. These changes are not alwaysobvious. Examples can be
found in Aryuvedic prepa-rations formulated in southern India,
where tradi-tional Himalayan plants are unavailable.
Withoutappropriate prescription labeling, adulterations are
aparticular problem in Asian medicines, and formula-tions have been
found to contain substitutions ofplant ingredients, dangerous
levels of toxic plant com-ponents, unapproved ingredients like
pharmaceuticalsand heavy metals in addition to other toxic and
aller-genic substances (Anonymous, 1989; Chan et al.,1993; Chan,
1997; Drew and Myers, 1997; Ernst,1997; Ko, 1998). For example,
although strictly notherbal remedies, lead has been found in a
Laotianpreparation known as Pay-loo-ah, a Korean remedy,hai ge fen,
containing clam shell powder (Borins,1998) and in Indian
traditional cosmetics used as eye-liners (surma) (Shaw et al.,
1997).
Chinese herbal medicines are typically unpalatableand can induce
nausea and vomiting. Most reportedadverse effects on the heart have
been associated withAconitum poisonings and certain topical skin
prepara-tions that can also cause liver damage (Chan, 1997;Drew and
Myers, 1997; Ko, 1998; Armstrong andErnst, 1999). In addition, pain
or asthma remediescontaining Datura metel are recognized to cause
anti-cholinergic effects leading to reduced visceral
activity.Liquorice, by affecting the sodium/potassium balance,can
cause water retention. More serious are condi-tions like jaundice
and brain damage due to neonatal
remedies containing berberine, additive or toxic effectsdue to
undeclared pharmaceuticals like mefenamicacid and diazepam (Gertner
et al., 1995), heavy metaladulterations (Schaumburg and Berger,
1992; Kew etal., 1993; Sheerin et al., 1994), or when
inadvertentadulterations with Podophyllum emodi instead oflondancao
(Gentiana spp.) have elicited severe life-threatening events (Chan,
1997; Drew and Myers,1997). Highly concentrated alkaloid
preparations liketetrahydropalmatine, a potent neuroreactive, can
befound in Jin Bu Huan. This Chinese patent medicineused as a
painkiller, has been associated with seriousadverse reactions
episodes in children and adults.Symptoms occurring in long-term
users range fromacute toxicity, lethargy, muscle weakness,
respiratorycompromise, bradycardia and coma, to extreme fa-tigue,
fever, jaundice and hepatitis. These events werereported in the
Communicable Disease Centers Mor-bidity and Mortality Weekly
Reports (Anonymous,1993a,b), and by Horowitz et al. (1996).
Ginseng preparations imported from China must al-ways be suspect
since not only can the content of theginsenosides vary (Consumer
Reports, 1995), butcommercial formulations can be adulterated with
po-tent and dangerous plants like mandrake (Mandrogoraofficinarum)
containing scopolamine and Rauwolfiaserpentina containing reserpine
and stimulants likecaffeine from Cola spp. (Drew and Myers, 1997).
Cer-tain Chinese remedies may be named the same butare formulated
differently depending upon the uniquecondition of the patient; such
is the case with Chineseherbal preparations called Eternal Life.
Without ap-propriate labeling of its ingredients it is almost
impos-sible to identify the source of any adverse effectsassociated
with its use (Sanders et al., 1995).
2.4. European herbalism
European Traditional Medicine has its roots mostlyin antiquated
Mediterranean civilizations and has overthe centuries evolved in
its utilization of both Eu-ropean and plants from abroad. In the
Middle Agesthe color or shape of a plant denoted a cosmic clueto
its medical usefulness, and hence the Doctrine ofSignatures was a
criterion by which many plants wereselected, e.g. heart-shaped leaf
as a heart remedy, yel-low plant parts for treating hepatitis, etc.
By the 19thcentury, some of these medicinal plants hadbecome part
of the pharmacopeias of allopathy,naturopathy and homeopathy, and
their therapeuticbasis investigated by medicinal chemists and
pharma-cognosists. Usually when compounds are isolated,
andsometimes totally synthesized, their pharmaceuticaluses are more
carefully regulated; aspirin, of course,being an early exception
(DeSmet, 1993; DeSmet etal., 1997).
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164144
2.5. Neo-Western herbalism
In its totality European Traditional Medicine hasmatured along
with American herbal introductions intoNeo-Western herbalism. In
this system single plantpreparations that have been either selected
from formu-lations found in ancient pharmacopeias or derived
frommedicinal plants valued in other cultures, includingthose of
indigenous origin, are sold alone or as mix-tures in an assortment
of combinations. For example,one of the most popular plants in use
in Europe todayis Echinacea with its origins in North American
(Mid-western) indigenous medicine (Lewis and Elvin-Lewis,1977).
Also, novel formulations can be devised withoutethnomedical data to
support their merit, or represent amixture of plants known to a
variety of medicinalsystems (DeSmet, 1995a). To promote the sale of
aparticular product, examples exist where supportingethnomedical
data are purposely vague, obtuse, or con-trived. While such
mixtures may potentiate a remedysmedicinal value, it is also
possible that these combina-tions could promote adverse effects not
known whenindividual plant components are used. Without
tradi-tional parameters to guide the consumer, the benefits orrisks
to these newly contrived formulations are cur-rently unknown.
While most British, European and Asian herbalistsare formally
trained within the context of known phar-macopeias or curricula,
American herbalists can vary intheir instruction, some being
self-taught, while othersundertake training in various types of
apprenticeshipprograms. However, like allopathic clinicians,
bothnaturopathic and homeopathic clinicians undergo clas-sical
training and in the US and Canada some schoolsof naturopathy also
teach homeopathy as a sub-spe-cialty. Both of these disciplines
utilize specifically for-mulated medications that are understood
forparameters of use. However, philosophies of diagnosisand
treatment differ. Naturopathy, based on hydrother-apy and dietary
treatment, currently prescribes formu-lations containing plant
extracts or phytochemicals atpharmacognostically determined levels
of efficacy. Thephilosophy of treatment is two-fold and includes
bothcurative and maintenance (normalization) aspects.Homeopathic
formulations (that contain plant extractsand other substances) are
compounded under the phi-losophy that substances that cause
specific toxic effectscan, at extremely dilute concentrations,
reduce similareffects elicited by disease states. While
homeopathicremedies are often considered to only elicit
placebo-likeactions, practitioners recognize their worth, and
under-stand that these remedies are not only bioreactive butmay
also elicit minor adverse effects like rashes, nausea,vomiting,
agitation, shaking and allergic reactions(Shaw et al., 1997;
Glisson et al., 1999).
3. Regulatory challenges
3.1. Asia
Overall, the incidence of serious adverse reactions
issignificantly lower with most of these therapeutic reme-dies when
compared to pharmaceutically derived drugs.However, the need still
exists to more closely monitorpractitioners and formulators of any
traditionalmedicine, including those of Asian origin, so
thatmedicinal irregularities and unethical practices are re-duced.
Also, Chinese herbal prescriptions are individu-alized and when
dispensed are not usually labeled, andshould adverse effects arise,
identification of their con-tents is difficult unless the patient
has been provided awritten copy of the formulation. Presuming that
theformulation contains the plants described, verificationmay be
impossible after processing has occurred.Should traditional
remedies be prepared in an Asiancountry, and imported, the task of
insuring safety iseven more difficult since the notion of
incorporatingpotentially toxic herbs or heavy metals may not
beconsidered harmful in the country of origin (Natori,1980;
Anonymous, 1989; Shaw et al., 1997).
3.2. Europe
Unfortunately, regulatory standards vary from coun-try to
country, and thus claims of content, efficacy, andsafety of any
herbal remedy cannot always be assured.Germany is the leader in
evolving rational regulatorypolicies (Benzi and Ceci, 1997). There,
plant remediesare carefully delineated and registered in Commission
EMonographs with known risk/benefit/drug interactionscited, and
consistency of bioreactive compounds chemi-cally defined as
phytopharmaceuticals (Blumenthal etal., 1998). More detail is
provided in the 50 mono-graphs published by the European Scientific
Coopera-tive on Phytotherapy and 10 additional monographsare
underway (Blumenthal, 1999). While self-medica-tion is the norm,
prescriptions for some medications arealso mandated. Most European
countries are evolvingsimilar policies (Benzi and Ceci, 1997),
although in theUnited Kingdom only some herbal preparations
fallunder such strict regulatory guidelines (Mills, 1995).
3.3. US
In the US regulatory mechanisms regarding herbal-ism were
non-existent until only a few years ago, andeven then and now they
still lack true enforcementcapability. FDA Commissioner Kessler
voiced concernsregarding safety in 1993 and proposed removal
ofherbal products without proven safety and efficacy. Asa reaction
to this proposal the Dietary SupplementHealth and Education Act
(DSHEA) was inaugurated
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
145
in 1994. Under this act many botanical medicinesdefined as a
vitamin, a mineral, an herb or otherbotanical (or) amino acid are
now sold under the guiseof food or dietary supplement (Brevoort,
1998; Mur-phy, 1999). As long as no medical claims are present
onthe label they are exempt from strict pharmaceuticalregulations.
Any display literature must further claimthat the product has not
been reviewed by the FDA oris not intended for medication. Also in
1997, a FederalCommission on Dietary Supplements was
establishedthat recommended that manufacturers provide science-base
evidence to consumers. To some physicians likeAngell and Kassirer
(1998), these guidelines, and vagueor oblique claims related to the
maintenance of goodhealth, still begs the issue regarding proven
safety orefficacy. They emphasize that since these herbal reme-dies
are not classified as medications they are not underFDA scrutiny.
Without being appropriately evaluatedfor content, safety or
efficacy it is difficult to determineparameters of use. However,
should adverse reactionsbecome apparent, the FDA could investigate
and inter-vene to remove the product (Murphy, 1999). Moreover,the
FTC (Federal Trade Commission) is active in defin-ing the
regulatory framework for advertising claims fordietary supplements.
The legal and regulatory aspectsof these US government agencies in
overseeing the herband dietary supplement industry from the
perspectiveof the Consumer Healthcare Products Association hasbeen
recently reviewed and is a useful reference to thoserequiring
details of such aspects (Soller, 2000).
Attempts are being made to bring some sense out ofthis current
regulatory chaos since it is in the bestinterest of everyone to do
so. In this regard, pharma-cognosists and natural products chemists
have onceagain become active in trying to understand the
thera-peutic basis of herbal remedies and toxicologists
areaddressing issues of the origins of potential adverseeffects as
incidences of associated use or abuse becomeevident. As a
complement to these efforts a number oforganizations are preparing
monographs to delineatedetails of herbs that are popularly used as
phy-tomedicines and medicinal plant preparations so thattheir
recognition as official medicines may result(McGuffin et al.,
1997). The most ambitious is that ofthe American Herbal
Pharmacopeia and TherapeuticCompendium with plans to publish at
least 2000 mono-graphs of this nature. Also, the herb trade in
recogniz-ing its responsibility to provide appropriate
guidelines,has recently published through the American
ProductsHerbal Association (AHPA) The Botanical SafetyHandbook, 2nd
edition (1998). The FDA accepts thisorganizations Herbs of Commerce
as the authoritativetext for label nomenclature related to
available herbalproducts. To aid pharmacists in understanding
risksand benefits of herbal products, the United States
Phar-macopeia (USP) is also compiling standard mono-
graphs for herbal dietary supplements and
dispensatoryinformation (DI). They have already published
11monographs and an additional 12 are under prepara-tion. In order
to set standards to document the qualityof herbal products, and
outline the therapeutic parame-ters for safe and effective use,
publication of the WHOMonographs on Selected Medicinal Plants is
on-going(Akerele, 1993). Volume 1 (1999) contains 28 mono-graphs on
31 plant species and Volume 2 to be pub-lished in 2000, an
additional 29 monographs(Blumenthal, 1999).
Furthermore, the FDA is considering reviewing cer-tain
botanicals via the IND/NDA (Investigational NewDrug/New Drug
Application) process. Presently thereare at least 50 botanicals or
botanical formulas holdingactive IND applications. Priority will be
given to thosewith a long-history of safety, particularly for
short-termuse since information is unlikely to be adequate
tosupport claims of safety for long-term use. In somecases issues
related to accompanying chemistry andtoxicological data remain to
be resolved (Murphy,1999). Recently, a Federal Commission on
DietarySupplements has been established (1997) recommendsthat
manufacturers provide science-based evidence toconsumers. Also to
support evaluation of herbalmedicines and other non-traditional
remedies the Na-tional Institutes of Health (Bethesda, MD) formed
theOffice of Alternative Medicine in 1992 that has recentlybeen
up-graded to the National Center for Complemen-tary and Alternative
Medicine (Murphy, 1999). Eventu-ally, these initiatives and others
evolving elsewhere, areexpected to provide needed information to
validate thistype of therapy. To aid in this endeavor two
searchabledatabases generated by the US National Institutes
ofHealth on dietary supplements exist. The
InternationalBibliographic Information on Dietary
Supplements(IBIDS) can be accessed at the ODS website
http://odp.od.nih.gov/ods. Currently, IBIDS contains 400
000citations and abstracts of published international, scien-tific
literature on dietary supplements, including vita-mins, minerals,
and botanicals and is updatedquarterly. Scheduled to go online in
2001, CARDS(Computer Access to Research on Dietary Supple-ments)
will identify ongoing, federally funded researchon dietary
supplements and individual nutrients (CAM,2000). Within this
context clinical evaluation protocolsshould include those outlined
in Table 1.
3.4. Canada
In Canada similar regulatory mechanisms are beinginstituted and
in March of 1999, an Office of NaturalHealth Products was created
to assure that Canadianconsumers have access to a full range of
safe healthproducts. The Office will undertake or coordinate allthe
regulatory functions within the life-cycle of natural
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164146
health products from pre-market assessment forproduct licensing
through licensing of establishments,post-approval monitoring and
the compliance and en-forcement tools appropriate with ensuring
health pro-tection. This will include the development ofappropriate
training standards of manufacturing anddistribution establishments.
Within this context, crite-ria to determine the applicability of
efficacy as reflectedin labeling claims will be established and
informationdisseminated to allow the Canadian consumer to
makeinformed self-care decisions. Accommodations will bemade for
aboriginal healers. Currently, Health Canadapolicy allows an
individual to import a 3 month supplyof a drug product for their
own personal use that is notsubject to these evolving regulatory
policies (Koryrskyj,1977).
4. Surveillance of adverse effects through databases
Regardless of the type of herbalism being practicedsome adverse
reactions are more easily recognizablethan others. Postulates have
been proposed by Hughes(1995) to define if adverse effects are
linked to a druguse. According to Stewart (1990), DeSmet
(1995b),events that are pharmacologically predictable are
oftendose-dependant and thus preventable by dose reduc-tion, or if
allergenic, by elimination. However, in spiteof the mode of
application, individual differences inphysiology may elicit a
variety of idiosyncratic local orsystemic reactions, including
those that are life threat-ening. Age may also be a factor and
those remediesmost frequently used by the elderly may elicit
varyingresponses (Ernst, 1999). Similarly, long-term use canproduce
predictable reactions or consist of delayedeffects such as
carcinogenicity and teratogenicity. Tobetter understand the scope
of these problems andbring them forward to the public DeSmet
(1995b)
proposed that forms of herbal post marketing surveil-lances be
conducted to detect serious adverse reactions,quantify their
incidence and identify contributive andmodifying factors.
Obviously, the success of such en-deavors depends on those willing
to voluntarily andspontaneously report such events to appropriate
healthcare officials, pharmocologists
(http,//www.faseb.org/aspet/H&MIG3.htmc top), regulatory bodies
(FDAMEDWATCH (http,//www.vmcfscan.fda.gov/dms/aems.html)), and
responsible parties in the herb tradeindustry itself, like the
American Botanical Council(http,//www.herbs.org), who are collating
these data forpublic dissemination (Winslow and Kroll, 1998).
With the number of mixed plant formulations nowmarketed in the
US alone, it is particularly importantto refer to web sites that
can provide on an on-goingbasis useful information on current
adverse reactions.Overall, the US is still a long way from the
develop-ment of standardized herbal drugs, called
phytophar-maceuticals, which have been formulated (in a fashion)to
ensure a reproducible effect by undergoing suitablemeans of
identification and clinical evaluations toachieve international
approval. Obviously these areneeded steps if allopathic acceptance
is to follow (An-gell and Kassirer, 1998). In the interim,
information isaccumulating that is providing appropriate ways
tounderstand herbal therapies and can be elicited frominternet
sources like the National Center for Comple-mentary and Alternative
Medicine (http,//nc-cam.nih.gov), American Botanical
Council(www.herbalgram.org), US Food and Drug Adminis-tration
(www.fda.gov), and the US Pharmacopeia(www.U.S.p.org) (Murphy,
1999).
5. Bridging the gap between herbalism and allopathy
Most importantly, it is now recognized that allo-pathic
clinicians have little training in understandinghow various forms
of herbalism and self-medicationsare impacting on the health of
their patients, who areoften, also under prescriptive medication.
However, asawareness of potential interactions with
allopathictreatments and herbal remedies increases, many
clini-cians and hospitals are eliciting this information
onadmission questionnaires (Murphy, 1999). To ensurethat patients
will be forthcoming with the information,it is recommended that
such solicitations be carefullyworded so as not to be judgmental.
This is essentialsince a patients response to treatment,
particularly in aclinical trial, could be distorted when concurrent
useswith herbal remedies are not revealed (Kassler et al.,1991;
Buchness, 1998; Donaldson, 1998).
To increase the sensitivity of future practitioners, anumber of
US medical schools are developing coursesin Complementary and
Alternative Medicine, including
Table 1Proposed clinical evaluation protocol for the development
of anherbal drug
Confirm ethnomedical value in country of originNote all
parameters of use particularly among children, the aged
or others with underlying disease statesReview traditional
formulations to understand rationale of useKnow variations to
standard formulations and reasons for
additions or substitutionsConduct controlled clinical trial with
formulation considered to
be the bestIdentify bioreactive components to insure
standardization of
contentConduct toxicological studies to understand safe
parameters of
useConduct placebo-based clinical trials following
appropriate
guidelines for patient entry, evaluations of efficacy etc.
tocomply with regulations where product is to be sold
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
147
some exposure to herbal medicinal practices. At thispoint these
curricula vary and are by no means univer-sal. As a complement to
this effort, the need to offercontinuing education courses for
physicians, nurses,pharmacists, nutritionists and the like should
be pro-moted (Dalen, 1998).
6. Pharmacokinetic behavior of plant-derived drugs
Studies on plant-derived drugs primarily with quinineand
sparteine have provided a better understanding offactors affecting
the pharmacokinetic behavior of drugswithin human populations. It
has been recognized, forinstance, that age effects storage and
clearance ratesjust as the ability to metabolically oxidize certain
com-pounds can be genetically determined and racially fo-cused.
Diseases affecting the kidney and liver can alterthe clearance
rates of certain compounds or exacerbateunderlying conditions.
Infections like malaria can actu-ally raise the plasma levels of
the medication (quinine)just as low protein diets can alter urine
pH, which whenalkaline, can slow its renal clearance. Smoking or
cer-tain drug interactions can also effect oral or
metabolicclearance rates. Normal ovarian function can be alteredby
use of Vitex agnus castus (Cahill et al., 1994). Allthese
activities can impact either beneficial or adverseeffect of drugs
and/or herbal therapies (DeSmet andBrouwers, 1997).
7. Herbal drug transmission in utero or throughmothers milk
It is well known that transmission of particular drugsin utero
to the fetus or through breast milk to an infantcan take place.
Evidence is accumulating that this isalso true should mothers use
certain herbal remediesduring pregnancy or while nursing their
babies. Effectsmay be transient, grave, or fatal. The fetus is in
partic-ular jeopardy should herbs with teratogenic, carcino-genic,
toxic or abortifacient properties be employed.For example,
constituents like salicylates are potentiallyteratogenic and
embryocidal, even if applied externallyin Oil of Wintergreen.
Ingestion of sassafras (Sassafrasalbidum), tea popular in the US
for its flavor and use asa diuretic (DArcy, 1993), might also pose
problems tothe fetus. This is suggested by studies in mice
wheretransplacental carcinogenesis has been found to occurfollowing
treatment with sassafras and is possiblycaused by its major
carcinogenic component, safrole(DeSmet, 1992b). Neonatal jaundice
has been traced tothe use of goldenseal and barberry and its
hydrastinecontent. Also, since feverfew (Tanacetum parthenium) isa
traditional inducer of menses, its use to treatheadaches during
pregnancy should be avoided
(OHara et al., 1998). Infant deaths due to veno-occlu-sive
disease have been associated with the consumptionof pyrrolizidine
alkaloid containing teas or cough reme-dies during pregnancy
(Roulet et al., 1988; Winship,1991). Since there is a risk of
bleeding disorders beingtransmitted to the fetus or breast feeding
infant hep-arin-containing herbs should also be avoided
duringpregnancy or lactation (Ernst, 1997). Due to its
do-paminergic actions, the same is true for use of chaste-berry
fruit (Vitex agnus-castus Boehnert, 1997). Birthweights are also
lower in women chewing the stimulant,khat (Catha edulis) during
pregnancy (Ghani et al.,1987). At parturition, blue cohosh
(Caulophyllum thal-ictroides), used to promote uterine contractions
shouldbe avoided since a neonate developed acute
myocardialinfarction, associated with profound congestive
heartfailure and shock. The infant remained critically ill
forseveral weeks but survived. This event was believed dueto
vasoactive glycosides, a toxic alkaloid, and sparteinefound in the
plant (Jones and Lawson, 1998).
Also consumption by a mother of senna laxative,with rhein, was
reported as having elicited catharsis inher nursing infant (Faber
and Strenge-Hess, 1988).Comfrey tea, now banned, contains a
potentially harm-ful pyrrolizidine alkaloid, echimidine known to
havehepatotoxic, genotoxic and carcinogenic properties isalso
excreted in breast milk (Winship, 1991). In oneinstance a
veno-occlusive hepatic illness resemblingBuddChiari syndrome was
linked to the consumptionof a tea containing flowers of Tussilago
farfara androots of Petasites officinalis (Radix petasitidis)
(Rouletet al., 1988; Spang, 1989), and in another, senecionine,a
pyrrolizidine alkaloid present in an herbal coughremedy was
responsible for this fatal illness (Fox et al.,1978).
8. Allergic reactions
Allergic reactions that can occur with herbal use aremanifested
in a variety of forms (Rieder, 1994). BothType I immediate
hypersensitivity reactions leading torhinitis, headache, dermatitis
(hives), and/or anaphylac-tic shock are commonly induced by
cross-reactionsamong Asteraceous (daisy family) plants taken
inter-nally, whereas delayed Type IV, contact dermatitis ismore
prevalent when topical applications are used(Gordon, 1999). Within
this family, wide cross-reac-tions are known and a major
sensitizing plant in the USis ragweed (Ambrosia spp.), it follows
that patients withknown sensitivity to ragweed should avoid
Asteraceousherbal teas like chamomile (Chamaemelum nobile)(Lewis,
1992b) or other remedies containing flowerheads and pollen, and
particularly in concentratedforms such as bee pollen (propolis)
preparations. Whenused as a vulnerary agent, rare allergic
reactions and
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164148
contact irritation have been reported; and it is espe-cially to
be avoided in ocular preparations (OHara etal., 1998). Also royal
jelly, a thick mixture of honey andpollen naturally contaminated
with pollen allergens hasbeen repeatedly linked to cases of severe
bronchospasm(Perharic et al., 1993). In Europe, where ragweed
isunknown or uncommon, chamomile was once consid-ered safe for use
as a tea or in a variety of medications,unless of course one is
allergic to the wormwoods(Artemisia) of Spain and elsewhere (Subiza
et al., 1989)or other Asteraceae (Hausen, 1981, 1996). Recently
anumber of reports from throughout Europe suggestthat sensitization
can take place and allergic reactionsmay be manifest systemically
(Rodriguez-Serna et al.,1998) as dermatitis (Subiza et al., 1989;
Paulsen et al.,1993; Bossuyt and Dooms-Goossens, 1994; Pereira
etal., 1997; Foti et al., 2000; Giordano-Labadie et al.,2000), or
when used in an enema during labor, as fatalanaphylaxis
(Jensen-Jarolim et al., 1998). Recently tworeports from Australia
regarding Echinacea-inducedanaphylaxis (Mullins, 1998; Myer and
Wohlmuth 1998)elicit further concerns regarding the use of
asteraceousplants in complementary medicine. In this
context,contact with feverfew (Tanacetum parthenium) mayelicit
contact dermatitis (Hausen, 1981) and in herbalpreparations can be
contraindicative to those allergic toother members of the
Asteraceae. For example, should,a sensitized patient use a feverfew
preparation to treatheadache their condition could be amplified
rather thanreduced (OHara et al., 1998). Also yohimbine has
beenreported as causing a lupus-like syndrome (Sandler andAronson,
1993). Recently a number of adverse reportshave been associated
with flavonoids used in Europeanherbal preparations (Ernst, 1998),
e.g. cyanidanol elicit-ing hemolytic anemia (Gandolfo et al.,
1992), cirkancausing chronic diarrhea (Maechel, 1992),
sciadopitysincausing severe nephropathy (Lin and Ho, 1994)
andcolitis from a phlebotonic French drug, cyclo-3 fortcontaining
Ruscus aculeatus, hersperidin methyl chal-cone, ascorbic acid
(Beaugerie et al., 1994).
Essential oil delayed-hypersensitivity can be relatedto episodes
of aphthous stomatitis (canker sores), whenother predisposing
factors like atopy and stress are inplace. In a preliminary study
of eight patients withaphthous stomatitis, of 34 essential oils or
their compo-nents tested, 30 of these substances proved to
elicitsome reactivity in one or more patients, whereas fourcontrol
patients were unreactive. Using lymphoblastictransformation to test
hypersensitivity, a major excitingagent was found to be eugenol
found in spices (oil ofcloves), herbs, foods (artichokes),
flavorings, cosmetics,fragnances and medicinals. Walnut, anise,
dill, pepper-mint, caraway, and lavender were also significant
elici-tors (Elvin-Lewis et al., 1985) in addition to cashew nutand
its urushiol (Lewis and Elvin-Lewis, 1977). L-car-vone in many mint
and peppermint oils has also been
implicated in contact allergies (Paulsen et al., 1993)
andcheilitis induced by use of toothpaste (Hausen, 1984).In another
study when patch testing (Standard Eu-ropean Series) was used to
test 20 patients with apht-hous stomatitis, a positive reaction to
a number of foodsubstances were also considered clinically relevant
andavoidance of the offending allergens recommend(Nolan et al.,
1991).
It is also possible that inhalation of some of theessential oils
including lavender, jasmine and rosewoodused in perfumes or as an
ingredient in aromatherapycan elicit similar allergic reactions in
the nasal passagesand respiratory tract, (Schaller and Korting,
1995; Sel-vaag et al., 1995a; Sugiura et al., 2000).
Aromathera-pists may also be at risk of developing dermatitis
fromcontinued contact with these oils (Selvaag et al.,
1995b).Dermatological conditions associated with contact
ofallergenic plants and their products have been recentlyreviewed
by Sassevile (1999).
9. Dental products
Adverse effects of dental products containing plantcomponents
are rare, but are worthwhile considering(Ocasio et al., 1999).
These formulations often includenatural sources of calcium
carbonate that can vary inabrasivity, and when derived from
seashells may con-tain high amounts of mercury. It is not unusual
forAsian herbal dentifrices to be packaged in lead tubingand it is
unclear how many are still being sold in thisway.
Aside from hypersensitivity reactions to flavoringagents that
are primarily essential oils, or myrrh that isoften used as a
breathe freshener, long-term exposureto other components may elicit
more serious effects(Elvin-Lewis, 1987, 1989; Elvin-Lewis and
Lewis, 1995).For example, American and Canadian dental
productscontaining blood-root (Sanguinaria canadensis)
extract,frequently promoted by dentists, have recently beenshown to
induce a sanguinaria-associated leukoplakiasyndrome
(hyperorthokeratosis, epithelial atrophy, andepithelial atypia/mild
dysplasia) that in one instancewas also contiguous to a squamous
cell sarcoma(Damm et al., 1999). Although these observations
havebeen vigorously defended as being spurious (Munro etal., 1999)
the fact remains that sanguinaria extract hasrecently been removed
from the Viadent formulation!The flat structure of the alkaloids
(sanguinarine andcherylethrine) and their ability to intercalate
with DNAwere known at the time of formulation 15 years agoand were
predictive of potential carcinogenicity (Cul-venor, 1983a,b). The
concern of pyrrolizidine alkaloidmutagenicity (Yamanaka et al.,
1979; Takanashi et al.,1980) was provided to the company but since
results ofAmes and other mutagenicity tests were reported as
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
149
equivocal, the sale of the formulation was allowed. Thecompany
and its Expert Panel of advisors (as relatedto me) considered the
tingling or irritating sensationreported by some users to be
associated with the flavor-ing agent. They did not consider, as
relevant, the factthat users of an African chewing stick, Fagara
xan-thoxyloides containing related alkaloids, also reportedsimilar
effects (El-Said et al., 1971). (How this type ofchronic irritation
predisposed to the precancerous le-sions is unknown.) While many
pharmacognosists, andmyself, continued to be concerned about
accumulativecarcinogenic effects, a few considered the amount of
thecompounds in the formulations to be of little conse-quence. To
date, almost 100 cases of leukoplakia havebeen reported in
long-term users. This has resulted in arecent reformulation of the
product and the removal ofthe offending alkaloids. Little is known
about the con-sequences of use elsewhere in the body, but these
arehighly bioreactive alkaloids. It is recognized that
dentalproducts are swallowed during oral hygiene and that, atleast
with fluoride; they can be absorbed beneficiallyinto the bones and
teeth. It is important to also empha-size that there was no
ethnodental validation to supportthe development of the product in
the first place, inspite of claims to the contrary, unless of
course onewere to rely on anecdotal information from one
horsetrainer that used blood-root to remove plaque fromhorses
teeth!
Adverse effects of other popular herbal dental prod-ucts are
unknown. It is prudent to read the labels andbe aware of the plant
products that they contain sincemany, especially if claimed to be
of Ayurvedic origin,are mixtures of numerous substances with
quantities ofeach ingredient unrevealed. However, such
productsshould be avoided if information regarding their abilityto
be locally irritating (a possible predisposing factorfor cancer),
evoke contact dermatitis, or systemicallybioreactive is brought
forward. This is a concern withTea Tree Oil, (Melaleuca
alternifolia) found in herbaldental products. It is antiseptic but
the oil can belocally irritating and elicits contact dermatitis
(Knightand Hausen, 1994; Blushan and Beck, 1997; Greig etal.,
1999), vulvovaginitis (Varma et al., 2000), and ifingested is toxic
to the central nervous system (Rubel etal., 1998; Bruynzeel, 1999).
Neem (Azadirachta indica)used a chewing-stick or as an oil-extract
in dentalproducts might also potentially elicit problems. Neem
isvalued for its antimicrobial and anti-inflammatory ef-fects and
for its ability to ameliorate gingivitis (Elvin-Lewis, in press).
However, little is known regarding theexact nature of the neem
components it contains suchas the highly regarded insecticide and
anti-feedent,azadirachtin. Although early Ames tests have
beenreported as negative, its structure suggests it may
bepotentially carcinogenic. It is known to elicit disruptivechanges
in metaphase chromosomes in both insects and
mice (Rosenkranz and Klopman, 1995; Awasthy et al.,1999). Neem
oil, bark and leaf extracts are particularlybioreactive and are
currently being evaluated for a widerange of medicinal uses (Van
der Nat et al., 1991),including hypoglycemic action (Chakraborty
and Pod-der, 1984), and because of immunomodulatory effects,also
for contraceptive and abortifacient activities(Mukherhee et al.,
1996; Talwar et al., 1997a,b). Leafextracts have also been shown to
adversely affect thy-roid function in mice, (Panda and Kar, 2000).
If theideal neem dentifrice is to be formulated then com-pounds
that promote dental health should be retainedand others that could
potentially elicit adverse effectseliminated (Elvin-Lewis, in
press).
10. Problems associated with long-term use
Today, many herbal remedies are being used prophy-lactically to
maintain or enhance good health or pre-vent certain conditions from
occurring. Since many ofthese herbal medications are popular and
promoted asboth safe and efficacious, it is not always possible
forthe long-term user to understand why this practicecould be
harmful. Symptoms can vary from trivial tosevere and are
particularly disconcerting when theyeffect the heart, blood
pressure, liver, gastrointestinaltract and nervous or endocrine
systems (Table 2). Note-worthy are effects associated with ginseng,
golden seal,milk thistle, cassia, saw-palmetto, valerian, and a
vari-ety of stimulants (DArcy, 1993; Anonymous, 1995a;Ernst, 1998;
OHara et al., 1998) including those thatcontain caffeine, like
guarana (Paullinia cupana) ormate (Ilex paraguariensis). The latter
beverage has alsobeen implicated in inducing oral cancers (Victora
et al.,1990), but clear correlative evidence has yet to
beforthcoming. Another herbal stimulant, Ma Huang,containing
ephedrine, has been reported to cause hallu-cinations and paranoia
(Anonymous, 1996; Doyle andKargin, 1996). Also anthranoid laxatives
such as aloe,cascara, rhubarb, and senna, commonly considered
assafe, may be a risk factor for colorectal cancer if usedon a
long-term basis (Siegers et al., 1992). Similarly,abuse of these
laxatives can increase the loss of serumK, thereby potentiating the
effects of cardiac glycosidesand antiarrhythmic agents (Blumenthal,
2000). The useof astragulus root (Astragulus membranaceus), a
majorimmunostimulating herb of Chinese medicine, may
becontraindicative when patients are undergoing im-munosuppressive
therapy (DeSmet and DArcy, 1996).Also, black cohosh (Cimicifuga
racemosa) used forgynecologic disorders (Liske, 1998) and to
treatrheumatism, can when taken in large doses or forprolonged
periods cause nausea, vomiting and gas-troenteritis (Saxe, 1987).
Similar conditions have alsobeen reported for blue cohosh
(Caulophyllum thalic-
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164150T
able
2A
dver
seef
fect
sof
long
-ter
mhe
rbal
use
Com
mon
nam
eB
inom
ial
Adv
erse
effe
cts
Ref
eren
ces
Bio
reac
tivi
ty
Gin
seng
Hyp
erte
nsiv
ean
dch
rono
trop
icSi
egal
,19
79;
Saxe
,19
87;
DA
rcy,
1991
;E
leut
hero
cocc
usse
ntic
osus
Ada
ptog
enK
assl
eret
al.,
1991
;W
ilkie
and
Cor
dess
acti
viti
es;
may
incr
ease
digo
xin
leve
ls19
94;
Gon
zale
z-Se
ijoet
al.,
1995
;E
rnst
,19
97;
OH
ara
etal
.,19
98;
FD
A/C
FSA
NA
EM
SSe
arch
Res
ults
,20
00P
rom
otes
mas
talg
ia;
rare
lyca
uses
Pan
axgi
nsen
g;
P.
quin
quef
oliu
spo
stm
enop
ausa
lbl
eedi
ng;\
3g
per
day
caus
esg
inse
ngab
use
synd
rom
eco
nsis
ting
ofm
orni
ngdi
arrh
ea,
nerv
ousn
ess,
inso
mni
a,ra
sh,
depr
essi
onan
dam
enor
rhea
;in
ciga
rett
esex
acer
bate
ssy
mpt
oms
insc
hizo
pren
icpa
tien
ts;
indu
ces
man
icst
ate
inde
pres
sive
pati
ents
;pa
lpit
atio
ns,
naus
ea,
vom
itin
g,bl
urre
dvi
sion
,ho
arse
ness
,ab
norm
alut
erin
ebl
eedi
ng
OH
ara
etal
.,19
98;
FD
A/C
FSA
NA
nti-
infe
ctiv
eG
olde
nsea
lH
ydra
stis
cana
dens
isU
tero
toni
c,av
oid
inpr
egna
ncy
AE
MS
Sear
chR
esul
ts,
2000
Indu
ces
neon
atal
jaun
dice
May
oppo
sean
tico
agul
ants
Inla
rge
dose
sca
uses
GI
upse
t,hy
pert
ensi
on,
seiz
ures
,re
spir
ator
yfa
ilure
,an
dca
rdia
csp
asm
sA
nore
xia,
derm
atom
yosi
tis,
elev
ated
seru
mir
on,
psyc
hosi
s,sw
olle
nliv
er,
dam
aged
stom
ach
linin
g,de
ath
Sily
bum
mar
ianu
mM
ildla
xati
ve,
alle
rgy
Hep
atop
rote
ctiv
eB
lum
enth
alet
al.,
1998
;O
Har
aet
al.,
Milk
this
tle
1998
;W
alti
etal
.,19
86
Blu
men
thal
etal
.,19
98A
bdom
inal
pain
,di
arrh
ea,
pote
ntia
llyL
axat
ives
Senn
a,an
thro
idla
xati
ves;
Alo
eve
raS
enna
alex
andr
ina
(Cas
sia
senn
a);
carc
inog
enic
;w
ith
othe
rsca
npo
tent
iate
juic
e;B
uckt
horn
bark
and
berr
y;A
loe6e
ra;
Rha
mnu
sfr
angu
la;
Rha
mnu
spu
rshi
ana
card
iac
gyco
side
san
dan
tiar
rhyt
hmic
Cas
cara
sagr
ada
bark
agen
tsdu
eto
incr
ease
dK
Saw
palm
etto
Ben
ign
pros
tati
cR
are
and
mild
gast
roin
test
inal
(GI)
Tas
caet
al.,
1985
;O
Har
aet
al.,
1998
;S
eren
oare
pens
FD
A/C
FSA
NA
EM
SSe
arch
Res
ults
,hy
pert
roph
yup
set,
head
ache
s,di
arrh
ea,
redu
ctio
ngy
neco
mas
tia,
paro
xysm
alat
rial
2000
fibri
llati
on,
vent
ricu
lar
rupt
ure
and
deat
hin
one
pati
ent
Cau
ses
drow
sine
ss,
GI
upse
t,liv
erV
aler
ian
offic
inal
is;
Pas
siflo
raSe
dati
ves
OH
ara
etal
.,19
98;
Cal
dwel
let
al.,
Val
eria
n19
94;
Wor
ldH
ealt
hO
rgan
izat
ion,
1999
func
tion
abno
rmal
itie
s,he
adac
he,
inca
rnat
a;
Bup
leur
umfla
catu
mpa
lpit
atio
ns,
inso
mni
aJa
mie
son
and
Duf
field
,19
90;
Alm
eida
Pip
erm
ethy
stic
umP
oten
tiat
esC
NS
seda
tive
sK
ava
and
Gri
msl
ey,
1996
Hyp
eric
umpe
rfor
atum
OH
ara
etal
.,19
98St
.Jo
hns
wor
tP
hoto
sens
itiz
atio
n
Kha
tC
atha
edul
isC
hron
icliv
erdy
sfun
ctio
nSt
imul
ants
Shaw
etal
.,19
97E
rnst
,19
98A
reca
cate
chu
Bet
elnu
tD
eter
iora
tion
ofps
ycho
sis
inpa
tien
tsw
ith
pree
xist
ing
psyc
hiat
ric
diso
rder
sE
rnst
,19
98E
phed
rasi
nica
Eph
edra
Agi
tati
onan
dpa
lpit
atio
nsP
aulli
nia
cupa
naG
uara
naE
rnst
,19
98A
gita
tion
and
inso
mni
a
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
151
Table 3Hepatotoxicity related to herbal remedies
Herb or taxa ReferencesType ofcompound
Pyrrolizidine Senecio, Crotalaria, Symphytum, Winship, 1991;
Hill et al., 1951; Bras et al., 1954; Fox et al., 1978; Lyford et
al.,Heliotropium 1976alkaloids
Mentha puleguim, Hedeoma pulegoidesMonoterpene Sullivan et al.,
1979; Anderson et al., 1996(pennyroyal)(puleguim)
Teucrium poliumm (gemander)Diterpenoid Larrey et al., 1992;
World Health Organization, 1992; DArcy, 1993
DeSmet et al., 1996Anthren Cassia angustifolia (senna)
Jin Bu Huan concentrated alkaloidLevotetrahydrop- Anonymous,
1993a,b; Horowitz et al., 1996almitine
Atractylate Georgiou et al., 1988; Stickel et al., 2000; Hamouda
et al., 2000Atraclylis gummifera
Safrole Sassafras albidum Segelman et al., 1976; Liu et al.,
1999; Burkey et al., 2000
Larrea tridentata (chaparral)Nordihydroguair- Anonymous, 1992;
Sheikh et al., 1997; Batchelor et al., 1995etic acid
Strahl et al., 1998; Ruze, 1990Piper methysticum
(kava)UnknownBenninger et al., 1999Chelidonium majus
troides) (Saxe, 1987), in addition to adverse effects tothe
newborn when used to promote labor (Jones andLawson, 1998).
11. Effects on internal organs
Detoxification and clearance of poisonous substancesfrom the
body are primarily a function of the liver andkidneys and they are
often the first to be affected bytoxic herbs (Larrey, 1994; DeSmet
et al., 1996; Kaplow-itz, 1997; Nortier et al., 1999; Stickel et
al., 2000).Sometimes the causes are more obtuse, as when kavauser
developed a necrotizing hepatitis (Strahl et al.,1998), but not the
usual kava dermatology of yellowand scaling skin associated with
long-term use (Ruze,1990). Equally perplexing are the number of
cases ofacute hepatitis following the use of greater
celadine(Chelidonium majus) for treating biliary and
gastricdisorders (Benninger et al., 1999), or the one case
ofnecrotizing hepatitis possibly associated with use oflesser or
common celidine (Strahl et al., 1998). Simi-larly, May apple
(Podophyllum peltatum) used as a livertonic has been found to cause
nausea, vomiting, inflam-mation and edema of the bowel, diarrhea,
elevated liverenzymes and hematologic abnormalities (Saxe,
1987).Table 3 lists some of these or other herbs most
prob-lematical to the liver.
Over 100 hepatotoxic pyrrolizidine alkaloids arefound within
species of the Asteraceae, Borginaceae,and Fabaceae. Such plants
are consumed as food, formedicinal purposes, or as contaminants of
other agri-cultural crops (FDA/CFSAN AEMS Search Results,2000).
Pyrrolizidine alkaloids and others, equally
heinous are particularly harmful to the liver and lungs,causing
veno-occlusive disease (Winship, 1991). Whilethe disease is
relatively rare in the US and is usuallyrelated to the consumption
of herbal remedies (Sprang,1989) mass human poisonings have
occurred elsewherefrom ingestion of seeds with these alkaloids
contami-nating cereal crops (Chauvin et al., 1994; Drew andMyers,
1997). Abdominal pain, vomiting, and the de-velopment of ascites
characterize this condition. Pa-tients may recover if the alkaloid
intake is discontinuedand the liver damage not too severe,
otherwise deathcan follow. In Jamaica, for example, endemic
veno-oc-clusive disease, has been linked to the consumption
ofSenecio or Crotalaria spp. as bush teas (Hill et al.,1951; Bras
et al., 1954). Comfrey teas have now beenbanned in the US due to
this serious side effect (Ridker,1989). Some, like chaparral tea
for example, should beavoided during cancer treatments or when
underlyingdiseases of the liver are known. A retrospective studyon
adverse effects of herbal medicines by the NationalPoisons Unit
(London) led the authors (Perharic et al.,1994) to recommend that
routine liver function tests bedone on individuals using Chinese
herbal remedies.This is important since so many cases of liver
damageleading to acute liver failure have been associated withthe
use of Chinese herbal remedies for the treatment ofskin disorders
(Shaw et al., 1997; Armstrong and Ernst,1999).
Care should also be taken when using herbal medica-tions to
treat cardiovascular problems (Mashour et al.,1998). While some may
be worthwhile, many containnatural cardiac glycosides, blood
thinners, or affectblood pressure and are not only bioreactive on
theirown but can work with prescribed medications to po-
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164152
tentiate or diminish their action (Catania, 1998). Forexample,
ginger contains a potent inhibitor of throm-boxan synthetase
(Backon, 1986) that prolongs bleedingtime. According to Miller
(1998) its use could result inadverse implications for pregnant
patients or those onconcomitant warfarin therapy. It is
noteworthynonetheless, that ginger is still a favored remedy
totreat nausea from morning or motion sickness. Fever-few
(Tanacetum parthenium) has the potential of poten-tiating platelet
inhibitors and its use as a headacheremedy should be avoided during
therapy with blood-thinning agents (OHara et al., 1998). It is also
recom-mended that heparin-like herbs not be taken duringpregnancy
or lactation, since cranial bleeding or otherassociated effects
could be induced in the fetus ornursing infant, respectively
(Pansatiankul andRatanasir, 1992; Pansatinkul and McKnanee, 1993).
Anumber of cases of allergy and anaphylactic shock(Jaspersen-Schib
et al., 1996) and one case of hepaticinjury (Takegoshi et al.,
1986) have been associatedwith the use of horse chestnut species to
treat chronicvenous insufficiency (Ernst, 1999) (Table 4).
12. Effects under predisposing conditions
Patients taking herbs for various purposes may alsopredispose
themselves to unwanted conditions prior tosurgery, when pregnant,
if atopic, or under treatmentfor other conditions, including those
that require psy-choactive medications. Deaths due to medication
ofgenerally recognized as safe herbs are extremely rare.
These events are more likely due to adulterants in
theformulations, to unknown interactions in complex mix-tures, as a
result of undisclosed pharmaceutical interac-tions, to
inappropriate dosage or use, or to underlyingfactors associated
with the specific patient (OHara etal., 1998; FDA/CFSAN AEMS Search
Results, 2000).A variety of serious reactions due to use alone,
withother herbal medications, or with pharmaceutical drugshave been
recorded and include effects on coagulationby feverfew (Murphy,
1999), garlic ginger, and ginkgoand antagonistic effects of
ephedra. Noteworthy is theimmunosuppression that can be induced by
long-termEchinacea used for immune stimulation. Photosensitiv-ity
that is associated with St. Johns wort (Hypericumperforatum) and
Psoralea corylifolia (an ingredient inseveral Chinese herbal
formulations) (Maurice andCream, 1989) is considered rare
(Blumenthal et al.,1998). However, according to one herbalist that
hasobserved this reaction in a number of St Johns wortusers (Cathy
Crandall, personal communication) thisphenomenon may be
under-reported. Also, St Johnswort interacts with some anesthetic
agents and resultsin eliciting mild monamine oxidase inhibition
(MAOI),or selectively inhibits serotonin uptake (SSRI) (Mur-phy,
1999). Ginseng, while considered GRAS, has alsobeen reported to
elicit a wide range of adverse condi-tions, and should be avoided
with other stimulants andparticularly it should not be used by
patients withcardiovascular disease due to its effect on blood
pres-sure and heartbeat (chronotrophic effect), and its abil-ity to
potentiate digoxin levels. Licorice hashypertensive effects and can
potentiate the activity of
Table 4Cardiovascular herbal treatments, adverse reactions
Binomial Adverse effectCommon name References
Aesculus Hepatic toxicity, allergy, anaphylaxisHorse chestnut
Jaspersen-Schib et al., 1996; Takegoshi et al.,hippocastanum
1986
Headache, nausea, hiccups, diminished efficacy of Singh et al.,
1994; Dalvi et al., 1994CommiphoraGugulipidmukul other
cardiovascular drugs including diltiazem
and propranolol
Crataegus ESCOP, 1997, 1999; Upton, 1999; Tyler,
1994;Potentiates digitalis activity, increases
coronaryHawthornmonogyna dilatation effects of theophylline,
caffeine, Mawrey, 1993
papaverine, sodium nitrate, adenosine andepinephrine, increase
barbituate induced sleepingtimes
Rau6olfiaReserpine Sedation, inability to complete tasks, mental
Webster and Koch, 1996; Brunton, 1996;serpentina depression, nasal
congeston, increased gastric Mashour et al., 1998
secretion and mild diarrhea
Dan-shen Sal6ia Chan et al., 1995; Izzat et al., 1998; Yu et
al.,Potentiates warfarin activity1997; Cheng, 2000militorrhiza
CNS and cardiotoxic, GI bleedingViscum album Stein and Berg,
1999Europeanmistletoe
Hypotension in cancer patients in treatment Anonymous,
1992Larrea tridentataChaparral
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
153T
able
5D
rug
and
herb
alin
tera
ctio
ns
Adv
erse
effe
cts
Ref
eren
ces
Bio
reac
tivi
tyD
rug
Her
bT
axa
Bro
mel
ian
Pin
eapp
leen
zym
eA
nana
sco
mos
usD
iarr
hea,
incr
ease
dte
nden
cyA
ctiv
ity
enha
ncer
ofso
me
Neu
raue
r,19
61;
Tau
ssig
and
anti
biot
ics
and
Bat
kin,
1988
;B
lum
enth
alet
for
blee
ding
ifus
edsi
mul
tane
ousl
yw
ith
al.,
1998
;B
lum
enth
al,
2000
chem
o-th
erap
euti
cag
ents
;an
ti-i
nflam
mat
ory
agen
tan
tico
agul
ants
and
inhi
bito
rsof
thro
mbo
cyti
cag
greg
atio
ndu
eto
mod
ulat
ion
ofth
ear
achi
dona
teca
scad
e
War
fari
nSh
ulm
an,
1997
;B
lum
enth
alC
aric
apa
paya
Pap
ain
incr
ease
dIN
R,
Ant
icoa
gula
ntP
apay
aex
trac
tda
mag
esm
ucou
sm
embr
anes
etal
.,19
98;
Wor
ldH
ealt
hof
GI
trac
tO
rgan
izat
ion,
1999
May
bead
diti
ve;
purp
ura;
addi
tive
effe
cts
Blu
men
thal
etal
.,19
98,
Har
pago
-phy
tum
Dev
ilscl
awA
ddit
ive
effe
cts
Wor
ldH
ealt
hO
rgan
izat
ion,
1999
Pro
cum
bens
Pos
sibl
yad
diti
veB
lum
enth
alet
al.,
1998
Cin
chon
aba
rkC
inch
ona
Pub
esce
nsSu
nter
,19
91;
Wor
ldH
ealt
hG
arlic
Alli
umS
ati6
umA
ddit
ive
effe
cts
Org
aniz
atio
n,19
99W
orld
Hea
lth
Org
aniz
atio
n,G
inge
rA
ddit
ive
effe
ct;
caus
esir
isZ
ingi
ber
Offi
cina
le19
99;
Blu
men
thal
,20
00bl
eedi
ngR
etar
dsab
sorp
tion
Mur
phy
etal
.,19
98F
ever
few
Tan
acet
umpa
rthe
nium
Ros
enbl
att
and
Min
del,
1997
Gin
kgo
Asp
irin
Gin
kgo
bilo
baP
lant
ago
spp.
Cou
mar
inse
riva
tive
sB
lum
enth
alet
al.,
1998
;P
sylli
umse
edW
orld
Hea
lth
Org
aniz
atio
n,19
99
Insu
linor
oral
Her
bal
anti
diab
etic
Ant
idia
beti
chy
po-g
lyca
emic
sA
ddit
ive
effe
cts
Yon
gcha
iyud
aet
al.,
1996
;A
loe
gel
and
juic
eA
loe6e
raA
slam
and
Stoc
kley
,19
79M
omar
dica
Cha
rant
iaB
itte
rm
elon
Add
itiv
eef
fect
sB
aska
ran
etal
.,19
90;
ESC
OP
,19
97;
Blu
men
thal
etal
.,19
98E
SCO
P,
1999
Gym
nem
asy
l6es
tre
Add
itiv
eef
fect
sG
urm
arle
aves
Fla
xsee
doi
lL
inum
Usi
tati
ssim
umE
SCO
P,
1997
;B
lum
enth
alet
Del
ays
abso
rpti
onof
drug
sal
.,19
98,
ESC
OP
,19
99ta
ken
sim
ulta
neou
sly;
indi
abet
ics
dela
ysgl
ucos
eab
sorp
tion
Pan
axG
inse
ngH
eada
ches
,tr
emul
osne
ss,
Phe
neiz
ine,
tria
zola
m,
Ant
idep
resa
ntan
tago
nist
sG
onza
lez-
Seijo
etal
.,19
95G
inse
nglo
raze
pam
inso
mni
a,ir
rita
bilit
y,vi
sual
halu
cina
tion
s
Cha
steb
erry
frui
tM
etoc
lopr
am-i
deV
itex
agnu
s-ca
stus
Pos
sibl
ein
tera
ctio
nsA
ntie
met
icB
lum
enth
alet
al.,
1998
;B
lum
enth
al,
2000
Enh
ance
ssy
mpa
thom
imet
icE
phed
raE
SCO
P,
1997
;B
lum
enth
alet
Ant
ihyp
erte
nsiv
eE
phed
rasi
nica
Gua
neth
idin
eef
fect
ofep
hedr
aal
.,19
98;
ESC
OP
,19
99;
Blu
men
thal
,20
00
Ana
lges
ics
Salic
ylis
m;
hype
rsen
siti
vity
Mal
iket
al.,
1994
;E
rnst
,A
spir
inS
alix
spp.
;G
ault
hria
Salic
inco
ntai
ning
herb
als
and
1998
oils
proc
umbe
ns,
Euc
alyp
tus
glob
ulus
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164154T
able
5(C
onti
nued
)
Adv
erse
effe
cts
Ref
eren
ces
Dru
gB
iore
acti
vity
Her
bT
axa
Incr
ease
sth
eoph
yllin
es
Ata
let
al.,
1985
;B
ano
etal
.,P
iper
Nig
rum
;P
iper
long
umP
iper
ine
from
blac
kpe
pper
Ast
hmat
icpr
epar
atio
nsT
heop
hylli
neab
sorp
tion
,de
crea
ses
its
1991
met
abol
ism
Pot
enti
ates
acti
vity
and
Car
diac
Her
bals
cont
aini
ngca
rdia
cB
lum
enth
alet
al.,
1998
;E
rnst
,D
igit
alis
1998
;B
lum
enth
al,
2000
incr
ease
sto
xici
ty;
addi
tive
glyc
osid
esef
fect
sA
ddit
ive
ESC
OP
,19
97,
1999
;W
orld
Hea
lth
Org
aniz
atio
n,19
99A
rryt
hmia
,pa
lpit
atio
ns,
naus
ea,B
lum
enth
alet
al.,
1998
;E
rnst
,L
icor
ice
root
Gly
cyrr
hiza
glab
ra19
98ab
dom
inal
pain
Aco
nitu
ma
Add
itiv
eef
fect
s,in
duce
slo
ssK
,A
coni
tum
spp.
wit
hth
iazi
dedi
uret
ics
Incr
ease
sab
sorp
tion
Blu
men
thal
etal
.,19
98R
etar
dsab
sorp
tion
Wor
ldH
ealt
hO
rgan
izat
ion,
Tyr
amin
ein
duce
dhy
per-
tens
ive
Rhe
umof
ficin
ale
Rhu
barb
root
1999
cris
esB
lum
enth
alet
al.,
1998
Sm
ilax
spp.
Sars
apar
illa
Roo
tP
sylli
umP
lant
ago
spp.
Car
diac
arrh
ythm
ia,
tach
ycar
dia;
ESC
OP
,19
97;
Blu
men
thal
etC
ytis
ussc
opar
ius
Scot
chbr
oom
Incr
ease
ssy
mpa
thom
imet
ical
.,19
98;
ESC
OP
,19
99;
acti
onof
ephe
dra;
coul
dca
use
fata
lhy
per-
tens
ion
Wor
ldH
ealt
hO
rgan
izat
ion,
1999
;B
lum
enth
al,
2000
ESC
OP
,19
97;
Blu
men
thal
etE
phed
raE
phed
rasi
nica
al.,
1998
;E
SCO
P,
1999
;W
orld
Hea
lth
Org
aniz
atio
n,19
99;
Blu
men
thal
,20
00C
ontr
aind
icat
ive
wit
hca
rdia
cB
lum
enth
alet
al.,
1998
;W
orld
glyc
o-si
des,
spir
ono
lact
one,
Hea
lth
Org
aniz
atio
n,19
99am
ilori
dein
crea
sed
sens
itiv
ity
todi
gita
lisB
lum
enth
alet
al.,
1998
;W
orld
Add
itiv
eef
fect
s;ir
isbl
eedi
ngM
AO
Hea
lth
Org
aniz
atio
n,19
99w
ith
aspi
rin
Inhi
bito
rsA
ntag
onis
tic
due
tohi
ghV
itam
inK
cont
ent
Blu
men
thal
etal
.,19
98;
Wor
ldL
icor
ice
root
aG
lycy
rrhi
zagl
abra
Seca
leal
kalo
idde
riva
tive
sH
ealt
hO
rgan
izat
ion,
1999
Blu
men
thal
etal
.,19
98;
Wor
ldP
ossi
ble
addi
tive
effe
cts
Thi
azid
edi
uret
ics
Hea
lth
Org
aniz
atio
n,19
99A
ddit
ive
effe
cts
Add
itiv
eef
fect
sD
Arc
y,19
93G
inkg
oG
inkg
obi
loba
Bra
ssic
acea
eet
c.B
rass
ica
spp.
(bro
ccal
i)
and
War
fari
nce
rtai
not
her
gree
nve
geta
bles
Bac
kon,
1986
;W
orld
Hea
lth
Zin
gibe
rof
ficin
ale
Gin
ger
Org
aniz
atio
n,19
99
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
155
Tab
le5
(Con
tinu
ed)
Dru
gR
efer
ence
sH
erb
Tax
aB
iore
acti
vity
Adv
erse
effe
cts
Alli
umsa
ti6u
mG
arlic
Sunt
er,
1991
DA
rcy,
1993
Hor
sech
estn
utA
ecul
ushi
ppoc
asta
num
Con
trai
ndic
ativ
e;re
cipr
ocal
Ora
lco
ntra
cept
ives
;ho
rmon
eO
ral
cont
race
ptiv
es(e
.g.
Blu
men
thal
etal
.,19
98;
Vit
exag
nus
cast
usC
hast
eber
ryfr
uit
Blu
men
thal
,20
00ha
lope
rido
l)w
eaki
ngef
fect
ofdo
pam
ine
ther
apy
rece
ptor
anta
goni
sts
Pot
enti
ates
psyc
hoac
tive
acti
vity
DA
rcy,
1993
;E
rnst
,19
98H
allu
cino
gens
Her
bal
Tet
racy
clin
e,pr
opra
nolo
l,al
coho
lH
allu
cin-
ogen
sC
inna
mon
Cin
nam
omum
zela
nicu
mM
agic
mus
hroo
m
Psi
locy
bese
mila
ncea
ta
Seda
tive
Her
bal
seda
tive
sA
lcoh
ol,
anti
hist
amin
esD
row
sine
ss,
obtu
nds
abili
tyto
Val
eria
naof
ficin
alis
DA
rcy,
1993
;D
eSm
etet
al.,
Val
eria
n19
96us
em
achi
nery
;po
tent
iate
sef
fect
sof
anti
depr
essa
nts,
anti
hist
amin
ics,
anti
spas
mod
ics
Pas
sion
flow
erP
assi
flora
inca
rnat
aD
Arc
y,19
93A
trop
abe
llado
nna,
Dat
ura
Ant
icho
lin-e
rgic
sola
nace
aest
rom
oniu
m,
Hyo
cyam
usni
ger,
Man
drag
ora
offic
inar
um
Cen
tella
asia
tica
,C
on6o
l6ul
usSe
izur
eco
ntro
lP
heny
toin
Red
uces
plas
ma
leve
ls;
seiz
ure
Shan
kha-
phus
piSw
inya
rdan
dW
oodh
ead,
1982
;D
ande
kar
etal
.,19
92pl
uric
aulis
,N
ardo
stac
hys
cont
rol
lost
jaat
aman
si,
Nep
teta
ellip
tica
,N
epet
ahi
ndos
tana
and
Ons
osm
abr
acte
atum
Eve
ning
prim
rose
Oen
othe
rasp
p.P
heno
thia
zine
s
Cya
mop
sis
tetr
a-g
onol
oba
Gua
rgu
mO
pper
etal
.,19
90;
Seid
ner
etP
heno
xym
ethi
-pen
icill
inIn
hibi
tsab
sorp
tion
;ca
nin
duce
Slim
min
gag
ents
obst
ruct
ions
inth
ebo
wel
orin
al.,
1990
;L
ewis
,19
92a
pati
ents
wit
hes
opha
geal
stri
ctur
esIn
hibi
tsab
sorp
tion
Evo
kes
hype
ror
Psy
llium
seed
Wor
ldH
ealt
hO
rgan
izat
ion,
Lit
hium
,ca
rba-
maz
epin
e,P
lant
ago
spp.
card
iac
glyc
osid
es,
coum
arin
hypo
thyr
oidi
sm,
skin
1999
hype
rsen
siti
vity
deri
vati
ves
Aut
oim
mun
eth
rom
bocy
tope
nia
Kim
and
Kim
,20
00Sh
iloan
dH
irsc
h,19
86L
amin
aria
,M
acro
cyst
is,
Kel
pT
hyro
idsu
pple
men
tor
alon
eN
ereo
cyst
issp
p.K
elp
wit
har
seni
cP
yeet
al.,
1992
aF
requ
entl
yin
Chi
nese
herb
alfo
rmul
atio
ns.
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001)
141164156
digitalis and thiazide diuretics (Cugini et al.,
1983;Blumenthal, 2000; Olukoga and Donaldson, 2000; Shi-bata,
2000). Influences on thyroid function can vary;for example, kelp
used for weight loss can inducehyperthyroidism (DeSmet et al.,
1990) whereas, use ofhorseradish remedies can result in
hypothyroidism(DArcy, 1993). Valerian (Valeriana officinalis)
isknown to potentiate the sedation or excitation effects ofcertain
sedatives or anxiolytics, respectively (Miller,1998; Murphy, 1999).
While considered GRAS, vale-rian has also been reported in rare
cases to elicitheadache, palpitations, insomnia (OHara et al.,
1998),pruritis, anorexia, hepatitis and intoxication (FDA/CF-SAN
AEMS Search Results, 2000). Use of Devils Claw(Harpagophytum
procumbens) for anorexia, dyspepsiaand degenerative disorders of
the locomotor system arecontraindicated in individuals with gastric
and duode-nal ulcers or with individuals with gallstones
(Blumen-thal et al., 1998). Arsenic has been found to anadulterant
in a variety of herbal formulations (FDA/CFSAN AEMS Search Results,
2000) and in kelp hasbeen reported to cause autoimmune
thrombocytopenia(Pye et al., 1992).
13. Effects of slimming agents
Natural slimming agents can also be problematical ashas been
found for guar gum that has elicited severeadverse obstructions of
the bowel and esophagus, par-ticularly among those with esophageal
abnormalities(Opper et al., 1990; Seidner et al., 1990) that in
oneinstance was fatal (Lewis, 1992a). The presence ofsparteine in a
variety of herbal remedies used for slim-ming and diabetes has been
reported to cause circula-tory collapse, respiratory arrest
(Galloway et al., 1992)and classic anticholinergic effects
(Tsiodras et al.,1999). Also, because of its oxytoxic effects
sparteine-containing herbals would be contraindicative for use
inpregnancy (Bensousan and Meyers, 1996). Blossoms ofgermander
(Teucrium chamaedrys) in herbal teas orcapsules to treat obesity
have been shown to causeacute hepatitis (Larrey et al., 1992). A
patient takingwarfarin and using papaya extract (containing
papain)for slimming was shown to have an increased interna-tional
normalized ratio (INR), the patientsprothrombin time was only
restored to normal follow-ing withdrawal of both substances (Shaw
et al., 1997).Aristolochia species have been responsible for
disordersreferred to as Chinese herb nephropathy (CHN) (Van-haelen
et al., 1994) or Fanconi syndrome in Japan, andTanaka et al. (2000)
suggests that differences in clinicalpresentation may be due to the
amount or type ofaristolochic acids ingested. For example, in
Belgium, avariety of Chinese herbal remedies use for
slimmingpurposes were linked to a rapidly progressive
interstitial
renal fibrotic syndrome (Vanherweghem et al., 1993). Insome
cases Aristolochia fangchi was incriminated. Thesame type of renal
failure was associated with 12 Chi-nese in Taiwan using a variety
of traditional Chineseherbal preparations (Yang et al., 2000) and
two othersin the UK (Lord et al., 1999). In two cases in
Japan,Fanconi syndrome involved the use of the Chinesemedicine,
Kanmokutsu containing A. manshuriensis(Tanaka et al., 2000). This
syndrome may also beassociated with the development of overt
transitionalcell carcinoma (TCC) (Cosyns et al., 1999). In
Taiwan,bronciolitis obliterans (rapidly progressive
respiratorydistress) was related to the consumption of
uncookedvegetable juice of Sauropus androgynus in guava orpineapple
juice (Lai et al., 1996). Used in a weightcontrol formulation for
10 weeks, 23 individuals wereaffected.
14. Drug and herbal interactions
Numerous examples exist of drug and herbal interac-tions. These
effects may potentiate or antagonize drugabsorption or metabolism,
the patients metabolism, orcause unwanted side-reactions such as
hypersensitivity(Brinker, 1997; Cupp, 1999; Blumenthal, 2000).
Sucheffects may also impinge on pharmaceutical productinteractions
occurring concurrently with those elicitedby herbal use (Aslam and
Stockley, 1979; Jankel andSpeedie, 1990). Care should be taken to
understandeffects of foods (Williams et al., 1993; Kane and
Lip-sky, 2000) or herbal remedies during anti-coagulanttherapy, in
the treatment of diabetes, depression, pain,asthma, the heart,
blood pressure, and for slimming. Byway of illustration, the high
content of vitamin K in avariety of green vegetables, particularly
broccoli andother Brassicaceae, can in large amounts, be
antagonistto the effects of anti-coagulant therapy (DArcy, 1993).In
addition, grapefruit juice, can lead to the elevationof serum
concentrations of a variety of medications likecyclosporine, some
1,4-dihydropyridine calcium antago-nists, and some
3-hydroxy-3-methyglutaryl coenzyme Areductase inhibitors (Kane and
Lipsky, 2000). Also,unwanted side-effects like gynaecomastia can
occurwith ginseng and rauwolfia with a variety of medica-tions,
hallucinations with cinnamon and tetracycline,sedative effects with
valerian or passion flower andanti-histamines, elevated blood
pressure with thizidinediuretic and Ginkgo biloba and seizures may
even beincreased if evening primrose is taken in addition
tophenothiazines (Newall et al., 1996; Shaw et al.,
1997).Similarly, the Ayurvedic remedy Sankhapushpi con-taining
Centella asisatica, Con6ol6ulus pluricaum, Nar-dostachys jatamansi,
Nepeta ellipica, Nepeta hindostanaand Onosma bracteatum reduced
plasma levels ofphenytoin, given concurrently, and resulted in the
loss
-
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
157
Table 6Adulterations in herbal remedies
Adulterant Clinical presentationType of remedy
ReferencesIngredient
Cough medicine Stillman et al., 1977; Fox et al., 1978Gordolobo
Senecio longilobus Veno-occlusive disease (VOD)and infant deathused
by
mother
UnknownHerbal tea used Tussilago farfara Fatal VOD in infant
Roulet et al., 1988; Sprang, 1989by mother
Grain use Heliotropium andGrains, poaceae etc. VOD,
hepatosplenomegaly and Datta et al., 1978; Chauvin et al.,1994;
McDermott and Ridker, 1990ascites in AsiaCrotalaria
Comfrey Teas Unsafe, cumulative effectsSymphytum officinale Bach
et al., 1989; Ridker andleading to VOD McDermott, 1989; McDermott
and
Ridker, 1990Atropa belladona PoisoningDigitalis purpurea
Poisoning
Plantago majorPlantain extract Digitalis purpurea Poisoning
Phoradendron, Viscum Skull capMistletoe Hepatitis Moum et al.,
1992(Scutellariaextractlaterflora)
Ilex paraguarensis Possibly Senecio VOD McGee et al., 1976Mate
orparaguay tea longilobus
Belladonna Anticholergenic poisoning Anonymous,
1995balkaloids
Peppermint, Mentha X piperita and Sperl et al.,
1995Seniciphylline Reversible VOD in an infantTussilago
farfaracoltsfoot tea
of seizure control (Dandekar et al., 1992) (Table 5).
Inaddition, when St Johns wort (Hypericum perforatum)is used
simultaneously with a wide variety of drugs thatuse CYPEA4 as a
substrate, activity is lowered sincethis herb is considered to
increase the activity of theisoenzyme CYPEA4 (Blumenthal, 2000).
Salicin-con-taining oils and herbal medications have been known
toelicit adverse conditions. For example, accidental inges-tion by
an infant of oils of wintergreen, camphor andeucalyptus cause