Report on dietary supplements containing ephedra makes urgent call for research to develop dose guidelines, safety warnings

November 06, 2000

A study undertaken for the Food and Drug Administration to assess the safety of popular dietary supplements containing ephedra concludes that these products can pose severe health risks and even kill some people, prompting an urgent need to pinpoint those at greatest risk and establish safe daily doses for the supplements. Scientists at the University of California, San Francisco who conducted the study also say ephedra-containing products should be more uniformly and explicitly labeled.

The analysis will appear in the December 21 issue of The New England Journal of Medicine. It has been posted early on the journal's web site due to its health implications.

The paper draws on a study the UCSF team prepared for the FDA, assessing 140 reports the agency received on adverse effects from ephedrine-containing supplements. The full report was published in the Federal Register earlier this year.

Of the 140 reports the FDA received concerning adverse effects analyzed, the researchers found that just under a third (31 percent), or 43 of the people "definitely" or "probably" suffered an adverse effect from ephedrine in a dietary supplement. Of these 43, three died, seven suffered permanent injury and four more required on-going medical treatment, the report shows.

Serious effects among these people included five cardiac arrests - two fatal and three resulting in permanent brain damage and disability; four strokes and ten cases of hypertension.

When a second group was included in the analysis - those whose physical symptoms were "possibly" related to ephedrine products - the number of deaths rose to ten out of 87 people, and permanent disabilities rose to 13 out of the 87.

The researchers call for large-scale, controlled studies to quantify the dangers of ephedrine-containing products and to identify who is vulnerable to the serious side effects -- steps needed to determine a maximum daily safe dose.

The UCSF scientists also urge the FDA to move quickly to impose more uniform, mandatory labeling of contents and quantities. In addition, they say, the claimed benefits of these products are questionable and unproven compared with potentially severe risks.

"When I talk to people about taking products containing ephedra to lose a few pounds, I tell them that the products have caused strokes and other severe side effects, and ask them to consider if that is an acceptable risk," said Christine Haller, MD, lead author on the NEJM paper and a post-doctoral researcher in the lab of senior author Neal Benowitz, MD. Benowitz is a UCSF professor of medicine, psychiatry and biopharmaceutical sciences at the UCSF-affiliated San Francisco General Hospital Medical Center. "Although 140 serious ill effects may not seem like that many compared to the number of consumers of these products," says Haller, "adverse effects are widely believed to be underreported by ten-fold or more. So, we believe there are many more injuries than are represented by the FDA reports. And with ephedra, the potential risks are not accompanied by any clear benefits."

"We think, that as currently marketed, these supplements are unreasonably hazardous," said Benowitz. "When used as labeled, ephedrine- containing nutritional supplements present a significant and unreasonable risk of injury."

Ephedrine-containing supplements are a popular product in the U.S., used by about 12 million people, with some three billion "servings" sold last year, according to industry statistics. They are stimulants, used for short-term energy boosts to enhance athletic performance and endurance, to help people exercise longer, feel more alert, and to dampen appetite, Haller explained. Studies indicate that weight loss with the aid of such products is only temporary, she added. In addition, as people continue to take ephedrine-containing supplements, the body becomes tolerant, and they must take more to get the same effect.

Most of the stimulating supplements are derived from the herbal plant ma huang, and often also contain caffeine derived from guarana.

"Both ephedra and caffeine are stimulant drugs, and when consumed in combination, the stimulation is much more intense," Benowitz said. "When people drink coffee or other caffeine beverages while taking the supplements, the stimulating effect may become even more pronounced."

Dozens of ephedrine-containing products are sold, with a great variability in the accuracy, completeness and adequacy of labels citing ingredients and potential adverse health effects, Haller and Benowitz say. "There must be more FDA regulatory control," Haller said. First, uniform product labeling should be enforced, with all ingredients and stimulant quantities specified in a consistent way from product to product."

In addition, Haller and Benowitz say, the FDA must come up with a safe dosing recommendation: a maximum allowable dosage per 24 hours. This may require more research to pinpoint the risk factors, since the researchers suspect but do not know for sure who is at greatest risk.

"People should use these supplements with caution and consider the risks, but we need to be more clear about who specifically is at risk," Benowitz says.

"Since ephedrine-containing supplements are stimulants, we suspect that the people who should avoid them are those who have kidney disease, those with pre-existing heart disease, high blood pressure, over-active thyroid, or psychiatric disorders, and those with autonomic insufficiency -- abnormalities in the nerves controlling their cardiovascular system -- and those with histories of seizures and diabetes."

In 1999, the FDA asked Hall and Benowitz to analyze 140 reports the agency had received in the previous two years of adverse reactions to dietary supplements containing ephedrine. The scientists were asked to assess the causes of adverse reactions in order to determine how many could be clearly linked to ephedra - and to what degree of certainty. Most of the adverse reaction reports came from people who had experienced the side effects or from their doctors.

Haller and Benowitz examined the reports and supplemental medical records, and developed a standardized rating system for assessing the causes of the adverse reactions. Adverse events were considered definitely related to ephedra alkaloids in dietary supplements only if the symptoms recurred with the reintroduction of the product or when the onset of symptoms coincided with the expected peak blood plasma concentration of the drug and resolved within an interval consistent with expected duration of the effect of ephedrine.

About a third of the 140 cases, or 31 percent, were deemed "definitely" or "probably" related to ephedra, and another 31 percent were "possibly" related to the supplement. Within this group of 87 people, about 60 percent were female. Most people in this group were between 18 and 45 years of age, but about 7 percent were under 18.

It was within this group of 87 people that 10 deaths and 13 permanent disabilities were reported. The full report Haller and Benowitz prepared for the FDA is found in the Federal Register, Vol. 65, issue 64, April 3, 2000. It is Federal docket #00N-1200. The FDA report was titled "Review of Adverse Reaction Reports Involving Ephedrine-containing Herbal Products."
-end-
More information on the FDA report can be found at: www.accessdata.fda.gov/scripts/oc/ohrms/index.cfm.

The research was supported by funds from the Food and Drug Administration, the National Institute on Drug Abuse, National Institutes of Health.

Note to Reporters and Editors: Neal Benowitz, senior author of the article in The New England Journal of Medicine, can be reached during the weekend by leaving a message for him at his UCSF office: 415-206-8324.

University of California - San Francisco

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