Hearsay Medicine Is Not Evidence-Based Medicine

“All truths are easy to understand once they are discovered; the point is to discover them.”

Galileo Galilei

Understanding the clinical and biological effects of drugs and dietary supplements through carefully conducted research is imperative to improve consumer health and safety. Unfortunately, in contrast to approved drugs, the understanding of clinical and biological effects of dietary supplements is severely limited because of the lack of such research. This discrepancy in research is likely a consequence of divergent regulatory requirements. Drugs are rigorously regulated by the U.S. Food and Drug Administration; the Food and Drug Administration must approve drugs for safety and effectiveness, based on rigorous research, before they reach the consumer. In contrast, dietary supplements, under the Dietary Supplement Health and Education Act of 1994, can be sold without approval of safety or efficacy. Although marketing efforts of dietary supplements must not make claims related to prevention and treatment of disease, in advertising or labeling, as would be done with a new drug product, nevertheless, the use of dietary supplements as medicaments is occurring frequently. Fortunately, efforts by the Food and Drug Administration to modify these severe limitations are ongoing but may not be enough to abrogate the problem. Reflecting on what we do know about the safety of, efficacy of, and difficulties inherent in research of dietary supplements may point the way to a more helpful future approach.

With respect to safety, multiple studies have shown the potential danger of dietary supplements, despite the common misconception that natural products must be safe. After extensive use of ephedra-containing herbal supplements, often used to boost energy and for weight loss, clinical reports and studies showed an association with severe cardiovascular toxicity, including deaths (1). This led to a ban on ephedra-containing products. After use of an herbal combination product, PC-SPES, thought to help men with prostate cancer, a study showed that it had a strong estrogenic effect in men, which clarified the mechanism for any activity (estrogens are known to affect prostate cancer) and warned of potentially life-threatening toxicity, as it was well known that estrogens can cause severe life-threatening cardiovascular toxicity in men (2). This knowledge of the product's mechanism of clinical effect and toxicity then led researchers to further studies, which resulted in identification of estrogens and other prescription contaminants in variable amounts in some preparations that led to removal of the product from the market (3). By reflecting on these two examples alone, it became clear that the clinical effects of these products in patients were caused by chemical targeting of a known pathway in the body (a drug effect), which was amphetamine-like in the case of ephedra and estrogen action in the case of PC-SPES. Once we know the class of compounds in the product, we know the likely clinical effects. Therefore, we hypothesize that any dietary supplement that induces a pharmacologic/toxicological activity contains compounds (natural and/or synthetic), and that these compounds are likely to be within known drug classes.

With this hypothesis in mind, we now turn to the study by Shariat and colleagues (4) in this issue of Clinical Cancer Research. Shariat and colleagues observed two cases of patients that developed aggressive prostate cancer associated with consumption of an androgenic product used for building muscle mass and/or sexual performance. They also conducted some laboratory studies that suggested that this product may stimulate growth of tumor cells in culture but were not enough to be definitive. Although we feel that such an uncontrolled case report is, at best, an association, it does support the possibility that this product was responsible for the adverse outcome of the patients described and warrants concern in the use of products that are sold with the intention of an androgenic effect. Currently, although unproven associations have been reported, there is no definitive evidence that controlled pharmaceutical testosterone replacement therapy in elderly men increases the risk of prostate cancer, and controlled prescription use has been associated with potential benefits (5, 6). Further studies are needed to fully understand the risks and benefits of supplemental testosterone and the effect of supraphysiologic levels of testosterone on the prostate at various stages of human development. Despite this lack of knowledge regarding supplementation and prostate cancer, severe toxicities of anabolic steroid use, or abuse, and other hormonally active chemicals that may be present in the product have clearly been shown. Taken together, it is only logical, therefore, to assume that if a dietary supplement has the potential to induce androgenic effects, it must have similar potential risks to any drug that targets the hormonal axis in the body. As a simple argument, in line with our overall hypothesis, if a product has androgenic effects, such as muscle building, it likely has chemicals (either natural or synthetic) that can induce androgen-like toxicities in other target tissues.

Given such uncertainty in the safety and efficacy in dietary supplements, it is imperative that efforts be made to protect consumers, who are bombarded with advertisements for dietary supplements as therapeutic replacements. The Food and Drug Administration is making efforts to address these concerns, including a regulatory rule requiring good manufacturing practices for dietary supplements.⁴

We believe that the only way to guard and promote the health of the consumer is to require sufficient research on the safety and efficacy of dietary supplements. From a research perspective, if there is clinical activity, then isolating the active components should be a priority. From a regulatory perspective, an approval process based on data supporting safety and efficacy for supplements is in order. This would encourage research for approvals that are based on data supporting clinical effect and safety. The use of unproven products based on hearsay evidence, which lack rigorous data showing safety and efficacy, as is required for drug approval, is risky. As physicians and researchers, we must continue to strive to understand the clinical and biological effects of dietary supplements, as well as prescription drugs, before any recommendations can be made regarding use in consumers and usefulness to science.