U.S. Food and Drug Administration
HHS Acts to Reduce Potential Risks of Dietary Supplements Containing Ephedra
The Department of Health and Human Services (HHS) today announced a series
of actions designed to protect Americans from potentially serious risks of
dietary supplement products containing ephedra.
The results of a 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. The
Rand report also finds only limited evidence of health benefits resulting
from ephedra use.
On the basis of new evidence in the medical literature and in adverse event
reports, there are reasons for heightened concern that dietary supplements
containing ephedra may present a significant and unreasonable risk of
illness and injury.
To protect Americans from the potentially serious risks of these dietary
supplements, HHS and FDA are going to:
* Seek rapid public comment on the new evidence on health risks
associated with ephedra to establish an up-to-date record as quickly as
possible to support new restrictions on ephedra-containing products.
* Seek rapid public comment on whether the currently available evidence
and medical literature present a 'significant or unreasonabl risk of
illness or injury' from dietary supplements containing ephedra.
* Seek rapid comment on a strong new warning label on any ephedra products
that continue to be marketed.
* Immediately execute a series of actions against ephedra products making
unsubstantiated claims about sports performance enhancement.
* In addition, the nation's top public health officials issued strong
statements cautioning about the use of ephedra-containing products,
especially under conditions of strenuous exercise and in combination
with other stimulants, including caffeine.
'We want to caution all Americans - particularly athletes and those who
engage in strenuous activities - about using dietary supplements that
contain ephedra,' said Secretary of Health and Human Services Tommy G.
Thompson. 'There continue to be serious questions about the risks
surrounding this particular dietary supplement.'
'FDA will do all we can to protect Americans from potentially dangerous
dietary supplements,' said Commissioner of Food and Drugs Mark B.
McClellan, M.D., Ph.D. '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. The
standard for regulating the safety of dietary supplements is largely
untested, but we are committed to finding the right public health solution.'
Ephedra is a naturally occurring substance derived from the Chinese herbal
Ma Huang. Its principal active ingredient is ephedrine, which when
chemically synthesized is regulated as a drug. While products containing
natural ephedrine alkaloids have long been used to treat certain
respiratory symptoms in traditional Chinese medicine, in recent years they
been extensively promoted and used with the goals of aiding weight loss,
enhancing sports performance, and increasing energy.
Many of today's proposed actions involve a Federal Register notice, which
went on display today, reopening for 30 days the comment period on a draft
regulation FDA first proposed in 1997 and modified in 2000.
FDA's concerns about dietary supplements containing ephedra arise in part
from ephedra's mechanism of action in the body. Ephedra is an adrenaline
-like stimulant that can have potentially dangerous effects on
the nervous system and heart.
In addition, evidence is accumulating about potentially serious safety
problems following the use of ephedra-containing products. 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.
Moreover, its review of some 16,000 adverse event reports 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. 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. The study also identified other such events potentially associated
with ephedra, in which other factors may have contributed to the adverse
events or in which records were inadequate.
Two recent studies of ephedra's safety were published too late to be
included in the RAND Corporation's review, and each raises further
concerns about ephedra. One, published this month in the Annals of
Internal Medicine, found that although ephedra-products make up less than
one percent of all dietary supplement sales, these products account for 64
percent of adverse events associated with dietary supplements.
Another 'case-control' 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
Additional relevant evidence on whether the current system of regulating
ephedra's safety is adequate comes from results under FDA's more extensive
regulation of synthetic ephedrine, which is identical to the main
active ingredient in ephedra. Ephedrine has long been available in some
FDA-approved over-the-counter and prescription drugs. It appears that the
more controlled availability of synthetic ephedrine products, which are
available primarily for approved uses for respiratory symptoms and carry
mandatory warning labels, has not been associated with the same kind of
severe adverse events as have occurred with dietary supplements containing
ephedra. This long experience with synthetic ephedrine (in
over-the-counter drug products, not in dietary supplements) suggests that
significant restrictions on labeling, marketing, and/or access to
ephedrine might effectively address unreasonable risks associated with
certain forms of ephedra today.
'Although the overall evidence suggests that serious adverse events from
ephedra appear to be infrequent,' said Dr. McClellan, 'we know that such
events can be very serious and possibly fatal. 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. To give us the strongest
possible basis for further regulatory action, we are asking for quick
comments on whether these dietary supplements present an unreasonable risk
of harm, and whether it makes sense for FDA to seek new authority in this
Under the Dietary Supplement Health and Education Act of 1994, FDA does
not review dietary supplements for safety and effectiveness before the are
marketed. Rather, the law allows FDA to prohibit sale of a dietary
supplement if it 'presents a significant or unreasonable risk of injury.'
This legal standard of 'significant or unreasonable risk' implies a
risk-benefit calculation based on the best available scientific evidence.
It strongly suggests that the agency must determine if a product's known
or supposed risks outweigh any known or suspected benefits, based on the
available scientific evidence, in light of the claims the product makes
and in light of the product's being sold directly to consumers without
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
In a broad action against potentially dangerous products, FDA today sent
more than two dozen warning letters to firms marketing dietary supplements
that contain ephedrine alkaloids. The letters, targeted particularly
at products making claims for athletic performance, explain that any claims
their products make about effects on the structure and function of the
human body must be truthful and not misleading. They outline FDA's view in
light of the RAND report that the claims being made are not adequately
substantiated by scientific data, and they direct the companies to submit
any data supporting the claims within 15 days.
The letters also warn firms that they must not make claims about their
products' ability to treat or cure a disease or condition such as obesity.
Under the Federal Food, Drug and Cosmetic Act, unapproved products making
these 'disease claims' are unapproved new drugs and therefore subject to
other prompt regulatory actions, including injunctions against firms and
seizures of their products.
FDA will also continue to work closely with the Federal Trade Commission
to ensure that dietary supplement products containing ephedra do not make
false and misleading claims. ' If an ad says a product is 'safe,' the
advertisers must have competent and reliable evidence to prove the claim,'
said Timothy J. Muris, Chairman of the Federal Trade Commission.
'Consumers depend on advertising for information. Deceptive ad claims can
put a consumer's health at risk. That's why we will pursue
aggressively marketers making deceptive claims about the safety or
effectiveness of products.'
In addition, FDA today proposed a warning label for all ephedra-containing
dietary supplements. The proposed label 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 steps being announced today demonstrate FDA's commitment to taking
the most effective actions possible under current law, given the state of
the scientific evidence,' said Dr. McClellan. 'It may be possible to use
ephedra safely, in small doses, for some purposes. But in the face of
continued serious adverse events following the use of ephedra, there is a
problem. It is a problem we are determined to fix.'Once the 30-day comment
period has ended, FDA will analyze the comments and publish its
conclusions about the most appropriate approach to reducing the risk of
using dietary supplement products containing ephedrine alkaloids.
The National Advisory Council for the National Center for Complementary and
Alternative Medicine, part of NIH, is meeting March 17th to assess the
evidence on ephedra's safety and effectiveness in order to develop a
research agenda on ephedra. FDA will give that committee an opportunity to
comment on today's notice, should the committee find it appropriate to do
so. All interested parties may send written comments on these issues
involving ephedra until April 7, 2003, electronically to www.fda.gov/dockets/ecomments
or by regular mail to Dockets Management
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room
1061, Rockville, MD 20852.
Additional materials about the risks of products containing ephedrine
alkaloids, including a more technical FDA 'white paper,' may be found on