The Food and Drug Administration (FDA) is asking for public comment on the weight-loss herb ephedra as part of a series of actions following the release of an independent report which found the herb may be associated with important health risks.
The RAND Corporation study commissioned by the National Institutes of Health, as well as other recent studies, provide additional evidence that ephedra may be associated with important health risks, says the FDA. The Rand report also finds only limited evidence of health benefits resulting from ephedra use.
The FDA actions follow recent news linking the death of Orioles pitcher Steve Belcher to ephedrine supplements.
The FDA has released a Federal Register notice reopening for 30 days the comment period on a draft regulation on ephedra first proposed by the FDA in 1997 and modified in 2000.
The agency has also proposed a warning label for all ephedra-containing dietary supplements. It warns about the risks of serious adverse events, including heart attack, seizure, stroke, and death; cautions that the risk can increase with the dose, with strenuous exercise, and with other stimulants such as caffeine; specifies certain groups (such as women who are pregnant or breast feeding) who should never use these products; and lists other conditions, such as diseases and the use of certain medications, that rule out the use of ephedrine alkaloids.
The FDA has highlighted several conditions which appear to heighten the risk of the herb. Commissioner of Food and Drugs Mark B. McClellan, said: "We are particularly concerned about the risks of using products containing ephedra during heavy workouts, with caffeine and other stimulants, in a diet program that stresses the cardiovascular system, or by people under the age of 18. We are also concerned about potential stresses to the body caused by the long-term use of ephedra."
Ephedra, derived from the Chinese herbal Ma Huang, contains the active ingredient ephedrine, which when chemically synthesized is regulated as a drug. Ephedra has recently been extensively promoted to help weight loss and enhance sports performance, but it is an adrenaline-like stimulant that can have potentially dangerous effects on the nervous system and heart.
The RAND study has concluded that ephedra is associated with higher risks of mild to moderate side effects such as heart palpitations, psychiatric and upper gastrointestinal effects, and symptoms of autonomic hyperactivity such as tremor and insomnia, especially when it is taken with other stimulants.
The review involved around 16,000 adverse event reports which revealed two deaths, four heart attacks, nine strokes, one seizure, and five psychiatric cases involving ephedra in which the records appeared thorough and no other contributing factors were identified.
However RAND called such cases 'sentinel events', because they may indicate a safety problem but do not prove that ephedra caused the adverse event. The study recognized that such case studies are a weak form of scientific evidence - other unmeasured factors may have contributed, and such serious adverse events are likely to happen (albeit at very low rates) among the millions of users of ephedra anyway.
A recent study, published too late to be included in the RAND review, in last month's Annals of Internal Medicine, found that although ephedra-products make up less than 1 per cent of all dietary supplement sales, these products account for 64 per cent of adverse events associated with dietary supplements.
Another study, published in the journal Neurology, concluded that the rate of hemorrhagic (bleeding) strokes among ephedra users was statistically significantly higher than among non-users, for people who take doses above 32 milligrams a day. Many ephedra dietary supplement labels recommend that users take up to approximately 100 mg of ephedra daily.
The FDA also questioned current safety regulations for ephedra. Synthetic ephedrine, which is identical to the main active ingredient in ephedra, has long been available in some FDA-approved over-the-counter and prescription drugs. The FDA says these products have not been associated with the same kind of severe adverse events as with dietary supplements containing ephedra. This suggests that significant restrictions on labeling, marketing, and/or access to ephedrine may address the unreasonable risks associated with certain forms of ephedra today, according to the agency.
Dr McClellan said: "We believe that the current scientific evidence strongly suggests that at least some ephedra products present an unreasonable risk. We also believe that FDA's system for regulating synthetic versions of the chemicals in ephedra appears to have a much better track record of safety."
Under the Dietary Supplement Health and Education Act of 1994, FDA can prohibit sale of a dietary supplement if it 'presents a significant or unreasonable risk of injury'. The FDA has to determine however, if a product's known or supposed risks outweigh any known or suspected benefits.
In seeking comment on these issues, FDA is reopening a proposed rule entitled "Dietary Supplements Containing Ephedrine Alkaloids." That proposal would have required a warning statement for these products, as well as restrictions on their potency and composition. FDA later withdrew parts of this proposed rule because of concerns about the specific scientific evidence in the proposal, expressed by the General Accounting Office.
FDA has also sent out warning letters to firms marketing dietary supplements that contain ephedrine alkaloids, particularly products making claims for athletic performance, and said it will continue to work closely with the Federal Trade Commission to ensure that dietary supplement products containing ephedra do not make false and misleading claims.
McClellan described the steps as "the most effective actions possible under current law, given the state of the scientific evidence", although it remains to be seen how much protection future actions will give consumers.
Clearly pleased that the FDA has not yet limited sale of ephedra products, the Ephedra Education Council (EEC) said that the RAND review "confirms the need for an end to the speculation about adverse reactions to ephedra consumption, like the rush to judgment over the tragic death of Orioles pitcher Steve Bechler".
The EEC statement added: "The RAND review confirms what the EEC and scientific experts have said all along, that no serious events have occurred in any clinical setting, and that the risk of experiencing any adverse reaction to ephedra, if any, is small. The correct path for assessing the potential risk of ephedra is through scientific research, and not speculation."
The Natural Nutritional Foods Association (NNFA) also released a statement supporting the FDA actions. "NNFA supports the use of a fairly extensive label statement warning against use by various populations, including those under the age of 18. NNFA also supports quantitative limits of 24 milligrams of ephedrine alkaloids per serving, with a maximum of 100 milligrams per day."
It said it will be reviewing the new documents and determining whether any new evidence would alter its position.
Interested parties may send written comments on ephedra to the FDA until April 7, 2003.