Ephedra's Safety Called into Question Again

BOSTON--Researchers from the New England Medical Center reviewed adverse events involving ephedra (ma huang) use, and concluded that the herb is temporally related to stroke, myocardial infarction and sudden death. The review, published by David Samenuk, M.D., et al in the January issue of the Mayo Clinic Proceedings (77,1: 12-16, 2002) (www.mayo.edu/proceedings), was conducted through a comprehensive search of the Food and Drug Administration's (FDA) Adverse Reaction Monitoring System.

A search of the FDA database between the years 1995 and 1997 garnered 926 cases of possible ma huang toxicity. Inclusion criteria for the study included adverse cardiovascular events (sudden death, myocardial infarction or stroke) in association with ma huang use. After excluding cases of suspected ma huang toxicity, use of illicit substances and cases where a reasonable alternative explanation was possible for cardiovascular events, the researchers reviewed a total of 37 cases. Of these, 36 patients reported using dosages within the manufacturers' guidelines; however, researchers found that ma huang was temporally related to 16 cases of stroke, 10 cases of myocardial infarction and 11 cases of sudden death. Prior cardiovascular disease was reported in only one of the 37 cases. A point the researchers cited as being cause for concern was that ma huang was associated with sudden death even in the absence of structural heart disease, and most of the patients were young and demonstrated no risk factors for cardiovascular disease, such as diabetes, hypertension, smoking or family history of cardiovascular disease.

"Ma huang may precipitate life-threatening cardiovascular events," the authors wrote. "These observations raise questions regarding the adequacy of self-regulation for product quality, consistency, potency and purity within the nutraceutical industry." The authors also questioned regulatory structure established by the Dietary Supplement Health and Education Act (DSHEA) of 1994, which dictates herbal remedies must be shown to be "unsafe" before FDA can request they be withdrawn from the market.

"The findings are very similar in this publication to what was reported on a later set of AERs by Haller and Benowitz (NEJM, 343: 1833-38, 2000)," said John Hathcock, Ph.D., vice president of nutritional and regulatory science for the Council for Responsible Nutrition (CRN). "[Samenuk et al] do a much better job than Haller and Benowitz in recognizing the limitations that must be associated with their attempt to reach conclusions." Hathcock explained, saying the authors state that an "observational study" is limited in its structure, without being able to go back and talk to the subjects or verify serum levels of the herb.

"This is a set of AERs, and adverse event reports, even when they're well done, are just half of a case-controlled study: they're the cases without the controls," Hathcock said. "So nobody is going to get close to establishing causality based on these."

A further point Hathcock raised was the fact that it is generally unknown whether the 37 subjects in the trial were taking any additional products or had any preexisting conditions that could have contributed to the adverse reactions. "One has to be skeptical because of the historical inaccuracy of individual subject reporting," Hathcock said. "The history of nutrition research of self-reported intakes is notoriously inaccurate." For clinical credibility, Hathcock continued, researchers should verify the delivery dose. As an example, he cited a study conducted by Carol Boozer, Patricia Daly and colleagues that is currently under peer review but available in abstract form on the CRN Web site (www.crnusa.org). Boozer et al conducted a randomized, double blind, placebo-controlled clinical trial on the weight loss effects of ephedra. Their results demonstrated that ephedra, used according to dose restrictions of three 30 mg doses per day, is safe and effective for weight loss.

"We stand by our CRN policy and we stand by the Cantox report," Hathcock stated. "Ephedra is safe and effective when used as directed according to the label and by those for whom the product is intended--and that has to be limited by the label instructions about contraindicated substances and preexisting health conditions that would preclude [ephedra use]."

In a related editorial piece also published in the January issue of the Mayo Clinic Proceedings (77,1: 7-9, 2002), Bruce Lindsay, M.D., of the Washington University School of Medicine in St. Louis questioned whether it is DSHEA that is to blame for adverse events associated with supplement use. Lindsay stated that manufacturers are not working to ensure product safety. "Unfortunately, despite the paucity of data on the safety of these products, there appears to be no serious effort by the manufacturers to support studies that would provide this information," he said. Lindsay went on, saying DSHEA has allowed the industry to position itself so that "well-designed scientific trials are not required to market dietary supplements." In addition, he added that DSHEA should be changed to allow FDA a more active role in approving dietary supplements for market.

Hathcock countered this view, stating, "In many ways, under DSHEA, new dietary ingredients are more rigorously regulated than GRAS ingredients for conventional foods. For dietary supplements at least, FDA must be notified regarding new ingredients, whereas with ordinary food ingredients, a company can assert self-declaration of GRAS [generally recognized as safe] without notifying FDA. . These authors are clearly arguing for a drug model. They argue that there is no scientifically established benefit from ephedra. I urge them to read the Boozer and Daly results with regard to weight loss and to recognize the rate of morbidity and mortality that go with obesity and how common obesity is."

"There's a misunderstanding, I think, among health professionals regarding what DSHEA does or doesn't do," added Mark Blumenthal, founder and executive director of the American Botanical Council (ABC). "I'm not sure about Lindsay, but it's certainly true that many health professionals do not know that DSHEA gives FDA added authority to remove unsafe dietary supplements from the market. ... In addition, dietary supplements that are currently found to be mislabeled are illegal based on prior law, and FDA has not exercised its authority to remove some of these mislabeled products from the marketplace."