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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).
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
2. Evolving pharmacopeias
143
144
3. Regulatory challenges
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
145
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
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).
147
(OHara 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
contact irritation have been reported; and it is especially to be avoided in ocular preparations (OHara 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 (OHara 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
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
149
Piper methysticum
Hypericum perforatum
Milk thistle
Saw palmetto
Valerian
Kava
Hepatoprotective
Laxatives
Benign prostatic
hypertrophy
reduction
Sedatives
Stimulants
Goldenseal
Catha edulis
Areca catechu
Ephedra sinica
Paullinia cupana
Khat
Betel nut
Ephedra
Guarana
Serenoa repens
Silybum marianum
Hydrastis canadensis
References
Photosensitization
Ernst, 1998
Ernst, 1998
Anti-infective
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) 141164
151
Table 3
Hepatotoxicity related to herbal remedies
Type of
compound
Herb or taxa
References
Pyrrolizidine
alkaloids
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
Anthren
Atractylate
Atraclylis gummifera
Safrole
Sassafras albidum
Unknown
152
Table 4
Cardiovascular herbal treatments, adverse reactions
Common name
Binomial
Adverse effect
References
Horse chestnut
Aesculus
hippocastanum
Gugulipid
Commiphora
mukul
Hawthorn
Crataegus
monogyna
Reserpine
Rau6olfia
serpentina
Dan-shen
Sal6ia
militorrhiza
European
mistletoe
Viscum album
Chaparral
Larrea tridentata
Anonymous, 1992
Bromelian
Warfarin
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
Ephedra
Chasteberry fruit
Panax Ginseng
Momardica Charantia
Bitter melon
Ginseng
Aloe 6era
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
Adverse effects
Carica papaya
Ananas comosus
Taxa
Papaya extract
Pineapple enzyme
Herb
References
Theophylline
Digitalis
Asthmatic preparations
Cardiac
Warfarin
Thiazide diuretics
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
References
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, spironolactone,
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
DArcy, 1993
Taxa
Licorice root
Herb
154
M. El6in-Lewis / Journal of Ethnopharmacology 75 (2001) 141164
Evening primrose
Alcohol, antihistamines
Phenytoin
Phenothiazines
Sedative
Seizure control
Psyllium seed
Kelp
Lithium, carba-mazepine,
cardiac glycosides, coumarin
derivatives
Thyroid supplement or alone
Guar gum
Passion flower
Anticholin-ergic solanaceae
Herbal sedatives
Valerian
Hallucin-ogens
Cinnamon
Magic mushroom
Herbal
Phenoxymethi-penicillin
Slimming agents
Shankha-phuspi
Tetracycline, propranolol,
alcohol
Hallucinogens
Chasteberry fruit
Sunter, 1991
DArcy, 1993
References
DArcy, 1993
Contraindicative; reciprocal
weaking effect of dopamine
receptor antagonists
Adverse effects
Laminaria, Macrocystis,
Nereocystis spp.
Plantago spp.
Cyamopsis tetra-gonoloba
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 agnuscastus
Allium sati6um
Aeculus hippocastanum
Garlic
Horse chestnut
Taxa
Herb
Drug
Bioreactivity
Table 5 (Continued)
156
157
Table 6
Adulterations in herbal remedies
Type of remedy Ingredient
Adulterant
Clinical presentation
References
Senecio longilobus
Tussilago farfara
Grain use
Heliotropium and
Crotalaria
Comfrey Teas
Symphytum officinale
Atropa belladona
Digitalis purpurea
Poisoning
Poisoning
Digitalis purpurea
Poisoning
Mistletoe
extract
Phoradendron, Viscum
Skull cap
(Scutellaria
laterflora)
Hepatitis
Mate or
paraguay tea
Ilex paraguarensis
Possibly Senecio
longilobus
Belladonna
alkaloids
VOD
Anticholergenic poisoning
Anonymous, 1995b
Peppermint,
coltsfoot tea
Seniciphylline
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-
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
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 physicians 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
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