Safety Issues with Herbal Medicine

Joseph I. Boullata, PharmD, and Angela M. Nace, PharmD, Department of Pharmacy Practice, Temple University School of Pharmacy, and the Drug Information Center, Temple University Hospital, Philadelphia, Pennsylvania.

Pharmacotherapy. 2000;20(3) 

In This Article

Approaches to Adverse Effects

All medicinal agents have potentially unexpected effects including toxicity, and herbals are no different. As with other drugs, the risk of unexpected effects may be influenced by a user's age, gender, genetics, nutrition status, and concurrent disease states and treatments. Unexpected effects of herbal medicines may be classified as intrinsic or extrinsic to the compound.[31]

Intrinsic effects are due to inherent phyto-chemicals in the given product, such as predictable dose-related toxicity and interactions, as well as idiosyncratic reactions.[31] Predictable, dose-dependent adverse effects are easier to identify than idiosyncratic reactions but are poorly documented.

In clinical practice recognizing adverse effects of herbal medicine is not routine and their reporting is even less frequent. In fact, such reporting is not mandatory for manufacturers or distributors. This is in contrast to systems in place for traditional drugs and makes it difficult to determine adverse event rates for specific herbals. Pharmacists, physicians, nurses, and others are encouraged to report adverse effects and product quality issues through the FDA Special Nutritionals Adverse Event Monitoring system or the MedWatch system, or to the USP Practitioner's Reporting Network. Postmarketing surveillance can identify adverse effects and products of poor quality. This in turn improves information and recommendations to consumers. Of the limited number of dietary supplement adverse event reports to the FDA in 1998, 7% involved St. John's wort, 8% ginkgo biloba, and at least 17% ephedra-containing products.[32] Of the larger number of reports to the Center for Food Safety and Applied Nutrition Adverse Events Monitoring System, the proportions are somewhat less.[33]

Even less is known about interactions than about adverse effects. Interactions of traditional herbal medicine with prescription drugs are only beginning to be considered and may be most significant for certain classes such as anti-coagulants.[34,35,36] These interactions may vary with the frequency or consistency of herbal self-medication. It is estimated that 15 million adults in the United States are at risk for such interactions, including altered bioavailability and efficacy of prescription drugs.[7] No mechanism is in place to determine this risk adequately. Relying on personal experience with patients who take herbal medicines cannot serve as the basis for excluding uncommon reactions; postmarketing surveillance plays a critical role. A brief list of interactions is shown in Table 1 .[3,4,37,38,39,40] Little information exists on interactions between herbals and nutrients. Interactions between herbal medicines are even less well documented.

With growing consumer interest has come a proliferation of dietary supplements with more than one ingredient. Adverse effects from such products may relate to an herbal or to another constituent. For example, adverse effects including rhabdomyolysis and renal failure were attributed to chromium picolinate, a dietary component often combined with herbal constituents.[41,42,43]

Extrinsic effects result from misidentification of the plant; lack of standardization; impurities through contamination, substitution, or adulteration; incorrect preparation or dosage; and inappropriate labeling.[31] A consumer's greatest concern should be with raw herb products collected in an uncontrolled fashion, compared with those approved as medicines. Unfortunately, most people who take herbal medicine do not consume products that fall in the latter group and therefore are susceptible to possible health risks.[44]

Plant misidentification may be due to similarities in appearance during bulk purchase or when harvested. In addition, confusing nomenclature or several terms with common, transliterated, Latin, and scientific names lead to misidentification. Inadvertent substitution of raw materials may cause adverse effects.[45,46] Batch-to-batch reproducibility continues to be of concern in standardization of herbal medicines.

Contamination is a repeated problem due to lack of quality control. Raw plant materials may be contaminated with pesticide residues and microorganisms including fungi.[31,47] Clinically important morbidity may occur from contami-nation with heavy metals such as arsenic, lead, cadmium, and mercury.[48,49,50,51,52,53,54,55] Constituents of Digitalis lanata in raw materials identified as "plantain" and used by numerous manufacturers of dietary supplements have been identified.[56]

Contamination of herbal products consumed by both adults and children with prescription and nonprescription drugs (e.g., belladonna alkaloids, cardiac glycosides, triamcinolone, mefenamic acid, indomethacin, chlordiazepoxide, diazepam, estazolam, opioids, dexamethasone, aspirin, caffeine, theophylline, diclofenac, chlorpheniramine, ephedrine, acetaminophen, thiazides, antimicrobials) may lead to adverse clinical outcome and even death.[38,56,57,58,59,60,61,62,63,64,65,66] A contaminated product is mislabeled, but more important, unlisted ingredients may be respon-sible for adverse effects attributed to an herb.

Over 40 drug adulterants not listed on labels were identified in Chinese herbal products.[67] About 24% of over 2600 traditional Chinese medicines sampled contained a therapeutic adulterant, with over half containing two or more adulterants including antiinflammatory, analgesic, and diuretic agents.[68] Even a sample of herbal creams used to manage eczema contained unlabeled dexamethasone at pharmacologic doses.[69]

Apart from extrinsic effects, adverse effects may be classified by organ system. Most common general reactions involve the skin, liver, and gastrointestinal tract. Herbal drugs can cause hypersensitivity reactions from dermatitis to anaphylaxis.[38]

Significant hepatotoxic effects, possibly idiosyncratic, were reported with germander, chaparral, borage, coltsfoot, life root, pennyroyal, and skullcap.[70,71,72,73,74] It is estimated that liver enzyme elevation occurs in 1% of patients consuming traditional Chinese herbs and may necessitate avoidance in patients with a history of liver dysfunction, or at least routine enzyme monitoring.[75] It is best to avoid combining a drug and an herbal that both are associated with potential hepatotoxic effects.

Nausea and possibly vomiting, although usually self-limited, can occur with several herbs, for example, echinacea and ephedra. Diarrhea is reported with a number of herbals, many of which are consumed as teas.[76,77] Of more concern with teas are morbid gastrointestinal, cardiac, and hematologic effects and anaphylaxis.[78] These products may contain cardiac glycosides, coumarins, anthraquinone cathartics, and adrenergic mediators.[77] Antagonism of warfarin by green tea was reported, likely due to the tea's vitamin K content.[36]

Neurologic, cardiovascular, pulmonary, endocrine, renal, and hematologic systems are also affected.[79] Even traditional Chinese herbal medicines, despite a long history, have safety profiles that require further investigation.[80] Hepatitis was associated with unregulated Chinese herbal remedies containing either several components or single ingredients[81,82]; although, it did not occur in a trial involving an encapsulated product derived from regulated raw herbs.[83] Besides hepatitis, accidental ingestion caused life-threatening neurologic and cardiovascular manifestations in children.[84]

Several herbal medicines, alone or in multi-ingredient products, for a variety of purported effects, were identified as being unsafe. For example, borage, calamus, chaparral, coltsfoot, comfrey, germander, life root, pennyroyal, and sassafras are considered hepatotoxic and/or carcinogenic.[70,85,86] Sauropus androgynus and Aristolochia sp are implicated in hepatitis, and bronchiolitis obliterans with renal failure and death.[87,88,89] A few of these, such as melatonin, are banned or restricted in some countries outside the United States.

Long-term effects, including those on fertility, have not been evaluated. Other aspects of long-term use that have not been well examined are the potential for carcinogenicity and teratogenicity given the latency periods involved. Long-term use of herbal drugs once considered safe, for example anthranoid laxatives, may be a risk factor for colorectal cancer.[90] A special note of caution is sounded concerning pregnant or lactating women and children. The risk of using poorly studied drug products in these groups may outweigh benefits unless documented otherwise. Few data are available on the effects of herbals during gestation, let alone on specific weeks or trimesters of pregnancy, as transfer across the placenta is poorly studied. Neonatal heart failure attributed to maternal use of blue cohosh was described recently.[91] As a general guideline, in the absence of safety data it is best to avoid herbal products during pregnancy and lactation, as well as in infancy or childhood.


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