Report on dietary supplements containing ephedra makes urgent call for research to develop dose guid

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.”

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.