The “hype” about ephedra
Dietary supplements that contain ephedra have been used widely to promote weight loss and increase energy. Ephedra refers to a genus of herbs that contains one or more sympathomimetic alkaloids, including ephedrine. It has been used for thousands of years in traditional Chinese medicine to treat asthma and other respiratory diseases. The herb extract is known as ma huang and contains several ephedra alkaloids—ephedrine, pseudephedrine, phenylpropanolamine and others.
The ephedra-linked death of major league baseball pitcher Steve Bechler this past spring (among other adverse events) has called to question the safety of this supplement. As orthopaedic surgeons often caring for an active population, it is imperative to be aware of the dangers being implicated with ephedra and its derivatives. Their sympathomimetic effects include vasoconstriction, bronchodilation and increased blood pressure, heart rate and cardiac contractile forces.
Ephedra usage in the United States became popular in the 1920s as a nasal decongestant, central nervous system stimulant and asthma treatment, but its use declined substantially as safer alternatives became available. Over the past 50 years, ephedra has been used to assist with weight loss. However, the research to support the use of ephedra for short-term weight loss is minimal. Ephedra has also become popular in athletics and competition because of its theoretical ability to increase energy and give athletes “an edge.” However, there has been no research to support this theory, and in fact, all research to date has shown no improvement in athletic training or performance with the use of ephedra or its derivatives.
In spite of its unsubstantiated claims, manufacturers of dietary supplements that contain ephedra alkaloids reported that 3 billion servings were sold in 1999. If taken as directed, this would equate to 12 million users of these supplements in 1999. Nutritional supplement sales during 1999 were $14.7 billion dollars with a large portion of this attributed to supplements containing ephedra. It is estimated that one percent of the population has used an ephedra product.
The U.S. Food and Drug Administration (FDA) regulates dietary supplements, although under very different regulations than those governing prescription medications and over-the-counter drugs. The Dietary Supplement Health and Education Act (DSHEA) of 1994 established that substances classified as dietary supplements are not “drugs” and are not held to the same strict pre- and post-marketing regulations. Under the provisions of the DSHEA, manufacturers of dietary supplements are not required to provide evidence of efficacy or safety prior to marketing the product.
In March 2003, the FDA published a proposed rule requiring manufacturers of dietary supplements and ingredients to follow stringent good manufacturing practices to ensure such products enter the marketplace free from adulteration and meeting standards for purity, consistency and labeling. Once a dietary supplement has been marketed, the FDA must demonstrate that the product is “unsafe” before it can consider removing the product from the market.
In 1995, in response to a growing number of adverse event reports, the FDA attempted to place warning labels on products containing ephedra. In 1997, it proposed dose limits of ephedrine alkaloid, with a maximum of seven consecutive days usage. Due to pressure from consumers, supplement manufacturers and others, the FDA-proposed warnings were withdrawn in 2000.
Adverse events hard to quantify
The adverse events attributed to ephedra are difficult to quantify. Ephedra is classified as a nutritional supplement and not a drug. Manufacturers are encouraged but not required to report suspected adverse events to the FDA. Adverse events are mainly reported through MedWatch, a program that relies on voluntary reporting by health care providers and consumers. It is estimated that less than 15 percent of all adverse events are voluntarily reported.
Over a two-year period (1997 to 1999), 140 reports of adverse events related to the use of ephedra were submitted to MedWatch. A critical review of these cases revealed that 62 percent were definitely, probably or possibly related to the use of supplements containing ephedra alkaloids. The most common reported effect was hypertension, followed by tachycardia, stroke and seizures. Ten events resulted in death, and 13 produced permanent disability.1 The majority of these catastrophic events were in patients under the age of 40.
The National Institutes of Health, recognizing the potential for serious adverse reactions with ephedra and ephedrine, commissioned the RAND study in 2002.2 Reported in February 2003, the RAND study assessed the safety of herbal ephedra and ephedrine and evaluated its efficacy for weight loss and athletic performance enhancement. A meta-analysis of 20 trials did support a statistically significant short-term weight loss (compared to placebo) for up to six months. No studies assessed the long-term effects of ephedra-containing supplements on weight loss or adverse effects. Seven studies were identified that assessed the effect of ephedrine on athletic performance. No study showed any improvement in performance.
More research needed
Adverse events were assessed from reports to the FDA of over 1,000 events related to herbal ephedra and 125 events related to ephedrine. A total of 18,502 case reports were also obtained from a single manufacturer of ephedra products. Death, heart attack, stroke, seizure and psychiatric episodes were associated with products containing ephedra. The RAND study concluded that significant research is needed to fill numerous gaps in our knowledge of the efficacy and safety of ephedra.
The safety of ephedra was questioned in another recent study published in the Annals of Internal Medicine. Using reports to a national poison control center, it was estimated that products containing ephedra account for 64 percent of all adverse reactions to herbs in the United States, yet these products represent only 0.82 percent of herbal product sales. The risk of adverse events from ephedra was 100 times the risk associated with all other herbs.3
The concerns about ephedra have prompted the American Academy of Orthopaedic Surgeons to issue a formal comment to the Food and Drug Administration supporting the removal of dietary supplements containing ephedra alkaloids from the U.S. marketplace. According to FDA Commissioner Mark McClellan, MD, PhD, the FDA is indeed considering such a ban and will review all comments and current evidence before issuing any final rule. Prompted by the ephedra-linked deaths of both an Illinois high school football player and a collegiate football player, the state of Illinois has already banned the sale of supplements containing ephedra alkaloids, as have numerous counties and municipalities throughout the United States.
The Complementary and Alternative Medicine Committee encourages you to routinely ask and counsel your patients about their use of ephedra and other herbal and dietary supplements.
1. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. New England Journal Medicine 2000 Dec 21; 343(25): 1833-8.
2. Shekelle P, Morton S, Maglione M, et al. Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Evidence Report/Technology Assessment No. 76 (Prepared by Southern California Evidence-based Practice Center, RAND, under Contract No. 290-97-0001, Task Order No. 9) AHRQ Publication No. 03-E022. Agency for Healthcare Research and Quality. February 2003.
3. Bent S, Tiedt TN, Odden MC, Shlipak MG. The relative safety of ephedra compared with other herbal products. Annals of Internal Medicine 2003 Mar 18; 138(6): 468-71.
Julie Dodds, MD, is a member of the AAOS Complementary and Alternative Medicine Committee. She also serves as associate professor at Michigan State University in East Lansing, Mich.