PRO & CON.
Dr. Donald D. Hensrud is director of the Executive Health Program at the Mayo Clinic, Rochester, Minn.
The Food and Drug Administration received 140 reports of adverse events associated with the use of dietary supplements containing ephedrine alkaloids during the period June 1997 through the end of March 1998. These reports were reviewed by two clinical pharmacologists at the University of California, San Francisco. Last December, they reported that 48 of the events, which occurred in 43 people, were definitely or probably related to the use of supplements containing ephedrine alkaloids (N. Engl. J. Med. 343:1833-38, 2000).
Many clinically significant, life-threatening adverse events were included among these 43 cases: 5 people who had a cardiac arrest or sudden death; 2 with myocardial infarctions; 3 with arrhythmias; 4 with strokes; 1 with seizures; and 8 people with palpitations, tachycardia, or both. Three of these cases resulted in deaths, seven led to permanent impairments, and four people require ongoing medical treatment. The remaining 29 cases had full recovery.
Many of those with serious adverse events were young and otherwise healthy.
The authors of this analysis also noted that, based on statistics gathered by manufacturers of ephedrine-containing dietary supplements, about 12 million Americans are estimated to have used such supplements during 1999. Although the number of reported adverse events was small relative to the estimated number of users, the FDA must weigh the risks for the entire population.
Several contraindications preclude the use of ephedrine-containing supplements, yet people may not be aware of them, may not follow them, or may inadvertently take other medications or dietary supplements that could interact with ephedrine and cause adverse events. Even if the risk of an adverse event is low, the risk of a serious adverse event is high enough to warrant the FDA's withdrawing or restricting these agents.
There is little evidence documenting the efficacy of ephedrine alkaloids for weight loss. The only data that support these agents as effective for weight loss are in a randomized, controlled study with a total of 167 participants that has, to date, been reported only as an abstract at an obesity-treatment meeting last year.
The abstract, by C.N. Boozer and associates, described a study in which participants were treated with an herbal supplement that contained ma huang (90 mg/day ephedrine) and koala nut (192 mg/day caffeine). Among those who completed the 6-month phase of the study, the 42 in the active treatment group had an average 15.2-pound weight loss, compared with an average 6.8-pound loss among the 38 on placebo.
This study, done at St. Luke's-Roosevelt Hospital Center in New York, is also cited as the best documentation of the safety of ephedrine and caffeine. But it is not reasonable to extrapolate safety from a study in which a total of 83 people received the active agents. Unless an adverse event is common, it may not be detected in a study of this size.
Drug therapy is part of managing the epidemic of obesity. But until there is better evidence that ephedrine alkaloids are effective for promoting weight loss, we cannot be sure that the benefits of these agents outweigh their risks.
John N. Hathcock, Ph.D., is vice president for nutritional and regulatory science at the Council for Responsible Nutrition, Washington.
A comprehensive risk analysis of ephedrine alkaloids was finished last December by Cantox Health Sciences International, an independent scientific consulting company. The analysis was sponsored by the Council for Responsible Nutrition, which represents 105 companies in the dietary supplement industry. The findings apply to ephedrine alkaloids that occur in the dietary supplement ephedra.
The analysis found that a safe upper dosage limit for ephedrine alkaloids was 90 mg/day, with no more than 30 mg per dose. The findings also included these additional qualifications: ephedrine alkaloids should not be used by people younger than 18; they should not be used for more than 6 months at a time; a person should consult with his or her health care provider before using supplements containing ephedrine alkaloids. Furthermore, such supplements should not be used by people with these contraindications: hypertension, heart disease, thyroid disease, pancreatic cancer, or by those concurrently taking certain medications.
The risk analysis was based on a review of all available information, including the adverse-event reports collected by the FDA, the results from a variety of animal studies, and results from clinical trials, especially the 19 that are directly relevant to the safe upper limit. The most noteworthy of these trials is the Boozer study
In that study, a total of 84 people received placebo, and 83 received a daily herbal supplement that contained 90 mg of ephedrine alkaloids and 192 mg of caffeine. During the 4-week, acute phase of the study, subjects were monitored for their physiologic responses using ambulatory blood pressure and ECG monitors. The active treatment produced a significant increase in average blood pressure and heart rate, but these were judged not hazardous by the investigators. There was no excess of ventricular events or tachycardias in the actively treated group, compared with those who received placebo.
In the 6-month, chronic-treatment phase, 46 people received the active drugs and 38 were treated with placebo. At the end of this phase, those on active treatment had an average weight loss of 15.2 pounds, compared with an average of 6.8 pounds in the placebo group. The active treatment was associated with significantly more self-reports of dry mouth, heartburn, and insomnia. But there was no difference between the placebo- and ephedra-treated groups in the incidence of chest pain, palpitations, irritability, nausea, or constipation.
Most of the adverse event reports that the FDA gathered during 1997 and 1998 are not conclusive. Many reports contain little information of reliable quality, while others lack critical information needed to assign causality. Most of the reports lack reliable information on the dose of ephedra or ephedrine alkaloids that was used. A few that might be causally related involved intakes that far exceeded label recommendations. Some cases are confounded by preexisting conditions, and others are confounded by the concurrent intake of other substances that may have caused or contributed to the event.
The data that formed the basis for the study's conclusions are a much more reliable basis for judging safety than are adverse event reports.