Herbal medicines today and the roots of modern pharmacology.

The desire to take medicines is one feature which distinguishes man, the animal, from his fellow creatures (1). Thus did William Osler express skepticism about remedies available in the early 20th century and an avuncular indulgence toward patients who wanted them. His comment expresses the attitude of many physicians today toward consumers of herbal medicines, and indeed may be timeless: Medicinal herbs were found in the personal effects of an ice man, whose body was frozen in the Swiss Alps for more than 5000 years (2). Since these herbs appear to have treated the parasites found in his intestine (2), the desire to take medicines may signify a timeless quest for cures that flowers today in the form of widely acclaimed new drugs. The effectiveness of a modern drug is ultimately judged by the results of clinical trials. Ordinarily, such trials are designed to test the assumption that a drug's pharmacologic activity will favorably affect a disease process, which in turn is viewed in terms of a physiologic model. Clinical trials yield convincing results, however, only if they are conducted in accordance with principles that, for example, ensure elimination of bias and reduce the possibility that results occurred merely by chance. Trials must also use drug preparations with consistent pharmacologic properties. These principles apply to all drugs, whether they originate as traditional remedies or in precepts of molecular biology. Indeed, such principles have successfully guided digitalis from medicinal plant to modern drug; we might ask, therefore, how these principles apply to the evaluation of today's herbal medicines. Digitalis: From Folk Remedy to Modern Drug Withering, who introduced foxglove to the medical profession in 1785 (3), took the first steps in transforming digitalis from a folk remedy to a modern drug when he simplified a family receipt for dropsy that contained more than 20 substances (3) by assuming that foxglove was the active ingredient. Careful clinical observations then enabled him to recognize the plant's slim margin of safety and thus the importance of dose: just enough foxglove to cause diuresis, but not enough to cause vomiting or very slow pulse. Bioassays and Chemical Standardization By the early 20th century, it was understood that activities of medicines derived from foxglove were influenced by such factors as the time when the leaves are gathered, and climatic and soil conditions [as well as] the manner in which the drug is prepared for the market (4). Clearly, plants have ingredients with therapeutic activity, but their preparations must be standardized to yield consistent products, which therefore can be given in doses that are maximally safe and effective. In 1906, the pharmacopeia contained a daunting number of digitalis preparationsfor example, Digitin, Extractum Digitalis, and Infusum Digitalis (5)whose potency had never been investigated. When these preparations were investigated by using a new bioassay based on the fact that digitalis causes asystole in the frog, the results were surprising: The potencies of 16 commercial digital preparations varied over a fourfold range (4). Fortunately, the bioassay also provided a way to control this problem, and the frog bioassay was soon officially adopted by the United States Pharmacopeia to standardize digitalis preparations. This bioassay, which indicated the importance of laboratory studies for the emerging science of pharmacology, provided the means to standardize the potency of a chemically complex herbal medicine, even when its active ingredients were uncertain. Soon the quest for even better methods of standardizing digitalis yielded several dozen bioassays in more than six different animal species (6). Thus, the cat heart assay replaced the frog heart assay, which in turn was replaced by the pigeon assay. The ultimate bioassay, however, was done in humans; it was based on the digitalis-induced changes in a patient's electrocardiogram (7). Although digoxin, now the preferred form of digitalis, can be standardized chemically, a bioassay of sorts is still required to establish its bioavailability (8) and, hence, the pharmaceutical standardization needed to carry out the clinical trials that shape our current perspective on the drug (9). Herbal Remedies in the United States Today Challenges in Standardizing Herbal Medicines Unfortunately, standardization methods such as those described for digitalis are not suitable for many herbs. Bioassays must be based on biological models, which are not available for the health claims made for many popular herbs, and chemical analysis has limited value when the ingredients responsible for a plant's activity have not been identified. In addition, if the active ingredient of an herb were known, it would remain unclear whether the crude herb would be preferable to its purified active principle. In the absence of definitive information in this regard, such traditional herbal preparations as digitalis leaf and opium have been replaced by such drugs as digoxin and codeine, respectively. How can an herb be standardized if its active ingredients are not known and there is no suitable bioassay? EGb 761, a patented extract of Ginkgo biloba, is a commendable attempt to solve this problem and to achieve a consistent formulation of ginkgo. Thus, EGb 761 sets feasible standards for how and where ginkgo is grown and harvested, how the leaves are extracted, and the target values for several chemical constituents of the medicinal product (10). EGb 761, which aims for chemical consistency and, presumably, therapeutic consistency, was used in three of four studies that, on the basis of a meta-analysis, concluded that ginkgo conferred a small but significant benefit in patients with Alzheimer disease (11). In the absence of evidence to the contrary, those who hope to replicate these trial results would justifiably select this ginkgo product in preference to others with less well-specified standards of botanical and chemical consistency. Recent studies with St. John's wort, however, remind us of the potential pitfalls of standardizing a medicinal herb to constituents that may not be responsible for therapeutic activity. For years, St. John's wort, which meta-analysis finds superior to placebo for treatment of mild to moderate depression (12), has been standardized by its content of hypericin. Hypericin, however, has never been confirmed as the herb's active ingredient and may be no more than a characteristic ingredient of the plant, useful for botanical verification but not necessarily for therapeutic standardization. Another constituent of St. John's wort, hyperforin, now appears to be a more potent antidepressant than hypericin. Thus, the potency of various St. John's wort extracts for inhibiting the neuronal uptake of serotonin, a characteristic of conventional antidepressants such as fluoxetine, increases with increasing hyperforin content. Studies in animal models of depression (13) and patients with mild to moderate depression (14) suggest that antidepressant activity is related to content of hyperforin, not hypericin. For example, a three-arm clinical trial of 147 patients that compared two St. John's wort extracts of equal hypericin content with placebo found antidepressant activity to be higher for the extract that had a 10-fold higher hyperforin content (14). Although this trial was relatively small and therefore of limited statistical significance, its results suggest that antidepressant activity demonstrated in a meta-analysis of past studies (12) may have resulted from the fortuitous inclusion of hyperforin in many of the St. John's wort formulations included. If the active ingredient of St. John's wort products used in these studies was not optimized, the studies as a group would undoubtedly underestimate the potential antidepressant activity of St. John's wort. Additional evidence suggests that the consumer is not receiving the full possible benefit of St. John's wort. On a recent visit to a local food store, I found St. John's wort preparations that were reminiscent of digitalis formulations at the beginning of the 20th century. Some were said to contain 0.3% (300 mg) hypericin, another was a liquid formulation containing 180 mg of hypericins, and a third contained 0.3% (450 mg) hypericin. The highest content of 0.3% hypericin was 530 mg. Yet another product carried the label St. John's wort, but its contents were not quantified. Hyperforin content was listed only for some products, whereas other products indicated that St. John's wort had been combined with such ingredients as kava, Echinacea, licorice root, or coconut. The parts of the plant used in the preparations were described as leaf, flowers and stem, aerial parts, or simply fl ers and leaf. Although labels on some St. John's wort products indicated an awareness of recent studies on hyperforin, other labels confirmed that there is no barrier to selling herbal preparations of doubtful scientific rationale and uncertain potency. Clinical Trials of Herbs Randomized clinical trials have become the gold standard for evaluating the efficacy of a drug and have assumed a similar status for evaluating an herbal remedy. Although the methodology of herbal trials is improving, some studies cited in herbal compendia have shortcomings. One problem is that results of herbal trials often do not reach statistical significance because they enroll fewer participants than trials of a conventional drug, and the role of chance may be overlooked in interpreting such trials. For example, the results of clinical studies were recently examined to determine whether parthenolide, a characteristic component of feverfew, was necessary for feverfew's apparent role in prevention of migraine. It was reasoned (15) that parthenolide could not be the sole active ingredient of feverfew because the parthenolide content of the feverfew preparation used in one negative trial (16)