CHAPTER 6. T
HE
S
AFETY OF
H
ERBAL
P
RODUCTS
Essentials of Complementary and Alternative Medicine
CHAPTER 6. T
HE
S
AFETY OF
H
ERBAL
P
RODUCTS
Peter A.G.M. De Smet
Introduction
Nontraditional Hazards
Excipients
Consumer-Related Determinants of Adverse Effects
Situational Risks
Adverse Effects
Individual Herbs
Recreational Herbs
Traditional Chinese Medicines
Individual Herbs
Traditional Indian and Pakistani Medicines
Chapter References
INTRODUCTION
A consumer of an officially licensed herbal medicine may not have to be concerned about the correct
identity of the ingredients, but an individual who goes into the
field to collect his or her own herbs should. Austrian physicians described a case of a young boy who developed venoocclusive disease of the liver after long-term
consumption of a tea prepared from
Adenostyles alliariae. The boy's parents had erroneously gathered this plant instead of coltsfoot (
Tussi-lago farfara), and
A.
alliariae contains a much higher level of hepatotoxic pyrrolizidine alkaloids than does coltsfoot (
1
,
2
). Botanical identity can also be problematic within the context of
commercially available materials. For example, German researchers exposed that Sarothamni scoparii flos does not always originate from
Sarothamnus scoparius
(Besenginster) but may also come from
Spartium junceum (Spanischer Ginster) (
3
). This adulteration could be clinically relevant because the flowers of
S. junceum
are rich in cytisine-type quinolizidine alkaloids (
4
,
5
).
The botanical quality of prepackaged herbal products may also cause problems, especially in countries (such as the United States) that do not categorize these
products as medicines (
6
). As a result, these products remain exempt from governmental approval processes, and their quality may remain essentially uncontrolled (
7
,
8
). An example in the United States concerned a South American product labeled as “Paraguay Tea.” This product was associated with an outbreak of anticholinergic
poisoning. On chemical analysis, the product yielded belladonna alkaloids instead of the xanthine derivatives that were expected in a preparation from
Ilex
paraguarariensis (
8
).
Herbal products should be free not only from toxic botanical adulterants, but also from other contaminants (
Table 6.1
) (
9
), such as substantial residues of pesticides
(
Table 6.2
) (
10
). The need to prevent contamination with pathogenic microorganisms was illustrated by the case of a bone marrow transplant recipient, who probably
acquired hepatic mycosis from the ingestion of a naturopathic
medicine contaminated with a Mucor fungus (
11
). There is also evidence that medicinal plant materials
from India and Sri Lanka can be contaminated with toxigenic fungi (
Aspergillus,
Fusarium). Because aflatoxin B has sometimes been recovered from these materials
in potentially unsafe amounts, it is prudent to improve their storage conditions (
9
,
12
,
13
).
Table 6.1. Potential Contaminants to Account for in Quality Control of Herbal Medicines
Table 6.2. Pesticide Residue Limits in Herbal Medicines*
Another practical concern is the presence of toxic metals (e.g., lead, arsenic) or conventional pharmaceuticals (e.g., corticosteroids, nonsteroidal antiinflammatory
drugs, benzodiazepines) in certain herbal medicines of Asian origin. These hazards have been denounced for more than two decades, but they continue to pose an
occasional threat to public health (
9
). Although most of the recent reports on the undeclared presence of Western pharmaceuticals involve Chinese herbal medicines,
the contamination of herbal medicines with pharmaceuticals is not necessarily limited to products of Oriental origin. We analyzed Dutch herbal drops for weight
reduction that were declared to contain
Ephedra and 14 other ingredients because a Dutch professional cyclist had tested positive for norpseudoephedrine at a
doping control urinalysis. The level of norpseudoephedrine in the investigated product was substantially higher than that of ephedrine, which is normally not the case
in Chinese
Ephedra plants. The manufacturer later admitted that his product had been spiked (
14
).
Although the safety of herbal medicines can be compromised by deficient product quality, some herbal products become more dangerous when they have excellent
quality. Yohimbe products rich in yohimbine will be less safe for over-the-counter use than products containing no or negligible amounts of this alkaloid (
15
,
16
).
Nontraditional Hazards
Safety claims cannot always be based on long-standing traditional herbal experience: not all herbal medicines have firm roots in traditional practices, and this seems
an underestimated issue. When traditional source plants are extracted in a nontraditional way (e.g., by resorting to a nonpolar solvent, such as hexane),
the question
can be raised whether this nontraditional extract is just as safe as the traditional one. Until recently, the ostrich fern (
Matteuccia struthiopteris) was generally
considered a nontoxic, edible plant with a history of use as a spring vegetable that went back to the 1700s. However, recent observations of serious gastrointestinal
toxicity following the consumption of lightly sauteed or blanched ostrich fern shoots suggest that this vegetable is safe only when thoroughly cooked before use (
17
).
A similar example is the recent outbreak of bronchiolitis obliterans in Taiwan, which was associated with the ingestion of
Sauropus androgynus. This herb normally is
cooked before being eaten as a vegetable, but in this case the numerous victims had all consumed uncooked leaf juice as an unproven method of weight control (
18
).
It is also possible that an herbal ingredient may have no medicinal tradition at all, and its route of administration or dose level may be quite different from that used in
a traditional setting. The question could be raised, for instance, to which extent the excellent oral safety record of certain traditional herbs is applicable to the herbal
cigarettes, which are nowadays available in Western health food stores. After all, there is evidence to suggest that certain respiratory risks attributed to tobacco
smoking may extend to the smoking of nontobacco herbal products, particularly marijuana (
19
,
20
,
21
,
22
,
23
and
24
).
Excipients
An inconspicuous source of adverse reactions to herbal medicines are the excipients (
25
). This has been illustrated by the careful evaluation of a case of contact
dermatitis caused by a commercial ointment containing a
Centella asiatica extract. Instead of automatically assuming that this
ingredient was responsible, the
investigators decided to seek confirmation by patch testing with the individual components. It was thus discovered that the reactions were caused mainly by the
presence of propylene glycol. A true allergic response to the botanical components remained unproven (
26
). Lanolin is among the notorious contact allergens that can
be present as excipient in topical applications (
27
). In an evaluation of the contact sensitization potential of five commercial herbal ointments in 1032 consecutive or
randomly selected visitors to patch test clinics, 2 of the 11 patients with a positive response had been sensitized by lanolin (
28
). There have also been reports about
the presence of pesticide residues in lanolin (
29
,
30
).
Another noteworthy excipient is alcohol. Psychological and physical dependence on herbal medicines with a high alcohol content seem rare, but they have been
reported (
31
). There is also an association between a case of suspected fetal alcohol syndrome with a history of maternal ingestion of a herbal tonic (containing 14%
alcohol) daily for the first two months (
32
). The U.S. Food and Drug Administration has ruled that the alcohol concentration in over-the-counter drug products intended
for oral ingestion should not exceed 10% for adults and children over 12 year of age, 5% for children between 6 and 12 years of age, and 0.5% for children under 6
years of age (
33
).
CONSUMER-RELATED DETERMINANTS OF ADVERSE EFFECTS
The chance of an adverse reaction to an herbal medicine depends not only on the product's actual composition and manner of use, but also on consumer-bound
parameters, such as age, genetics, and concomitant diseases. For instance, the risk that the alkaloid berberine in Chinese
Coptis spp. elicits jaundice seems to be
most substantial in infants who are deficient in glucose-6-phosphate dehydrogenase (
34
,
35
and
36
). Another example is that slow metabolizers of the quinolizidine
alkaloid sparteine will be more prone to the oxytocic potential and other toxic effects of
Cytisus scoparius than rapid metabolizers (
35
,
36
and
37
). This latter example
illustrates the general principle that pharmacokinetic information can help to predict certain types of consumer-dependent adverse effects.
However complex the
composition of an herbal medicine may be, its constituents are chemical entities which, besides having pharmacodynamic properties, must obey the same
pharmacokinetic rules that apply to conventional drug molecules. In other words, insight into the ways in which the pharmacokinetics of complementary medicines are
modified by factors such as hepatic or renal insufficiency provides a rational tool for predicting and avoiding dose-related adverse effects (
38
).
Another intriguing finding is that Chinese subjects are more sensitive to the effect of atropine on heart rate than are Caucasian subjects, who in their turn seem to be
more sensitive than Black individuals (
39
). A theoretical implication of such interracial differences is that local experience with a traditional herbal remedy cannot
always be extrapolated indiscriminately to societies with another ethnic make-up.
Concurrent use of other drugs must also be considered. For instance, consumers of caffeine-containing herbs (
Cola,
Ilex, and
Paullinia) may have an increased risk of
adverse effects, such as tremors or tachycardia, when they concurrently ingest pipemidic acid, ciprofloxacin, or enoxacin, because these antibacterial quinolones
inhibit the hepatic metabolism of caffeine (
40
,
41
,
42
and
43
). Likewise, the oxidative metabolism of sparteine, a quinolizidine alkaloid in Scotch broom (
Cytisus
scoparius), can be inhibited by the simultaneous intake of haloperidol (
44
), moclobemide (
45
), or quinidine (
46
). This latter example shows that the interfering drug
does not have to be a synthetic compound but can also come from nature. According to a comment on the numerous adverse events associated with Ma Huang
(
Ephedra) consumption
in the United States, the adverse effects of combined ephedrine and caffeine may be greater than those from the consumption of either
compound alone (
47
). Besides the possibility that the toxicity of an herbal compound is increased by a conventional drug, there is also the possibility that the effects
of a conventional medicine are enhanced by an herbal medicine. For example, the Indian herbal drug karela (
Momordica charantia) has hypoglycemic properties (
48
)
and can thereby interfere with conventional antidiabetic treatment (
49
).
For an extensive overview of adverse drug interactions between conventional medicines and herbal products, the reader is referred to a publication elsewhere (
50
).
SITUATIONAL RISKS
Herbal medicines that are generally safe under normal conditions can be hazardous in specific circumstances. For example, psoralen-rich herbal preparations may
produce phototoxic burns in visitors to tanning salons or in patients undergoing PUVA therapy (
51
,
52
). Therefore, it is important to provide the consumer of herbal
medicines with adequate product information, in which such situational hazards are clearly indicated.
Among the safety issues that need attention in this respect is the risk that herbal products make their consumers less fit for driving. This hazard should be taken into
consideration for any plant-derived drug with central depressant activity, such as
Rauvolfia (
53
) and tetrahydropalmatine (
54
).
An even more inconspicuous risk is that top athletes may unwittingly take a doping agent in the form of a herbal product because the list of doping substances, which
is issued by the International Olympic Committee, comprises several substances that occur naturally in herbs (
55
). Among these doping agents are ephedrines and
caffeine, which are regularly present in Western health food preparations (
56
,
57
and
58
).
ADVERSE EFFECTS
Individual Herbs
The following provides an overview of adverse effects of herbal preparations that have been reported in the literature. Unless otherwise specified, the presented data
have been derived from previous reviews (
59
,
60
and
61
). For additional information about this subject, the reader is referred to a rapidly
growing list of detailed
textbooks on herbal medicines (
62
,
63
,
64
,
65
,
66
,
67
,
68
,
69
,
70
,
71
,
72
,
73
,
74
and
75
). Herbs, which are primarily used for recreational purposes, are reviewed
separately, as are herbs primarily employed within the context of traditional Chinese and Indian medicine.
Sometimes, this review does not focus on the crude herb but on one or more components. This approach is acceptable because, in principle, the toxic potential of an
herbal product does not depend on its natural origin but on the pharmacological characteristics and dose levels of its bioactive constituents. Although it is conceivable
that the toxicity of an individual herbal constituent can be modified by one or more of the other constituents, this is by no means some iron-clad rule: a complex
composition does not always protect the consumer against the toxicity of a single constituent, and it might also result in a more toxic remedy.
A potential hazard of most medicinal herbs is allergic contact dermatitis, but this risk is much more substantial for certain herbs (e.g., those containing sensitizing
sesquiterpene lactones) than for others (
27
,
76
). Another common adverse effect ascribed to various herbs is gastrointestinal disturbances (e.g., caused by the
presence of tannins or irritating saponins). More serious problems can be elicited by herbs containing well-known botanical substances with toxic potential (e.g.,
cardiac glycosides, podophyllotoxin, reserpine). It should be noted that such classical drug substances may reside in a less familiar botanical source. For example,
cardiac glycosides occur not only in such well-known source plants as foxglove (
Digitalis) and oleander (
Nerium oleander), but are also found in pleurisy root
(
Asclepias tuberosa) (
77
). Serious health risks are also possible with certain obsolete herbs, which were formerly employed in medicine but have now been
superseded by other, less dangerous alternatives (e.g.,
chenopodium oil, male fern). In addition to such classical toxic agents, several herbs and herbal constituents
have been repeatedly associated in recent years with new adverse effects of such a serious nature that their unrestricted internal use as phytotherapeutic agents no