RHealth | Research Highlights
Ephedra—Is It Worth the Risk?
Key findings:
P
roducts that contain the herb ephedra have been promoted and used in the United
States since the 1980s to increase weight loss and enhance athletic performance. Yet
• Ephedra and ephedrine despite manufacturers’ claims, little research has been done to assess whether the prod-
promote modest short- ucts are safe, and the research studies that have been done have been too small to allow any
term weight loss; their firm conclusions to be drawn.
long-term effect is The questionable effectiveness of these products might not have raised public concern,
unknown. had the U.S. Food and Drug Administration (FDA) and major manufacturers of ephedra-
containing products not become the targets of growing numbers of consumer complaints in
• Ephedrine plus caffeine the late 1990s. Reports of adverse events, including serious side effects and even deaths, many
boosts immediate in apparently healthy young people, began increasing during this time. Prominent among the
physical performance victims have been several college and professional athletes. Thus, in recent years, several major
for fit young men; consumer health groups have called on the FDA to ban sales of ephedra-containing products.
there is no evidence The FDA classifies products containing herbal ephedra as dietary supplements, which are
that ephedra or regulated by the Dietary Supplement Health and Education Act of 1994 (DSHEA). Under
ephedrine improves DSHEA, dietary supplements are generally “presumed safe”; thus, manufacturers are required
long-term physical per- only to notify the FDA of their intent to market new products but are not required to estab-
formance of athletes lish the safety or effectiveness of their products. Once a dietary supplement is on the market,
or would work for the the FDA can restrict its use or ban sales of the product only if it can demonstrate convincingly
general public. that the product is unsafe.
As complaints continued to mount, the U.S. Department of Health and Human Services
• Ephedra and ephedrine called for a review of all the evidence, turning to the Southern California Evidence-Based
increase the risk of Practice Center (SCEPC), based at RAND. The SCEPC is one of 13 federally sponsored
nausea, vomiting, evidence-based practice centers nationwide that specializes in seeking answers to important
jitteriness, and palpi- health care questions through assessing and synthesizing the evidence from large numbers
tations. of research studies. Statistically combining the findings of many similar studies increases
researchers’ confidence that small apparent differences in the effects of two treatments are in
• These products may be fact real. We were asked to review all studies of ephedra-containing dietary supplements
linked to catastrophic conducted to date, to assess whether the substance actually lives up to manufacturers’ claims
events such as sudden and whether the supplements are safe for the general population, or whether they are in fact
death, heart attack, or responsible for the adverse effects that have been attributed to them.
stroke.
This Highlight summarizes RAND research reported in the following publications:
Shekelle P, Morton SC, Maglione M, Hardy M, Suttorp M, Roth E, Jungvig L, Mojica W, Gagné J, Rhodes S,
McKinnon E, and Newberry S. Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement:
Clinical Efficacy and Side Effects. Prepared for the Agency for Healthcare Research and Quality, 2003. Full
text available at www.ahrq.gov/clinic/ephedinv.htm.
Shekelle P, Hardy M, Morton SC, Maglione M, Mojica W, Suttorp M, Rhodes S, Jungvig L, and Gagné J.
Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A Meta-
Analysis. JAMA. March 26, 2003. Vol. 289, No. 12, pp. 1537–45.
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What is ephedra and why do people use it?
The herb ephedra, also known as ma huang, is a small, twiggy shrub native to Asia, where it has a long history of medicinal use,
as documented in ancient medical treatises from India and China. Traditional Chinese and Indian medicine uses the branches
of the herb to treat colds and wheezing and as a diuretic. Modern European practitioners of herbal medicine use ephedra only
to treat symptoms of respiratory diseases (such as bronchial asthma).
In the United States, the active components of ephedra, known as the ephedrine alkaloids (ephedrine; pseudoephedrine;
norephedrine, also known as phenylpropanolamine; and norpseudoephedrine) are commonly found in over-the-counter cold and
allergy medications. The ephedrine alkaloids are stimulants (similar to, but much weaker than, amphetamines) that can increase
heart rate and blood pressure and relax bronchial tissue, easing shortness of breath. At low doses, they are reputed to decrease
appetite, increase alertness and productivity, improve mood, and decrease fatigue; at higher doses, they may promote anxiety,
restlessness, and insomnia.
The use of ephedra to promote weight loss and enhance athletic performance began to gain popularity in the United States
in the early 1990s. The increase in popularity of herbal products and over-the-counter medications that seem to promote weight
loss is probably attributable to a combination of factors, including the recent precipitous rise in overweight and obesity rates,
news stories suggesting that prescription diet drugs may be dangerous, the reluctance of many overweight people to talk with
their doctors about weight control, and the growing belief on the part of many people that natural substances such as herbs (and
those perceived as natural) are safer than mainstream medicines.
People have used dietary supplements to enhance athletic performance for many years. Use of dietary supplements and
over-the-counter medications containing stimulants like ephedrine to enhance athletic performance increased throughout the
latter part of the 20th century, perhaps in part because of the bans imposed on use of amphetamines and because of the acceler-
ating intensity of competitive sports.
What We Did (and Why) performed an exhaustive search and review of the medical
research “literature” using the well-accepted procedures
Our assessment of the evidence was guided by a distinguished of evidence-based medicine. The literature review was con-
panel of technical experts, both basic scientists and clinicians. ducted by our staff with the assistance of several clinical
This group included cardiologists, exercise physiologists, phar- experts.
macologists, and toxicologists, as well as specialists in obesity, Only controlled clinical trials and randomized con-
nutrition, and the science of pharmacognosy. The technical trolled trials of effectiveness—that is, studies that satisfied a
expert panel recommended that we also review studies of over- strict set of quality criteria—were included in our analysis.
the-counter medications that contain the chemical ephedrine, Randomized controlled trials (RCT) are clinical trials in
presumed to be the primary active ingredient of ephedra which participants are assigned randomly to one of two or
(ephedrine-containing products are regulated as pharmaceuti- more treatment groups. Controlled clinical trials are those
cals, not as dietary supplements). In addition, many ephedra- in which participants are assigned to a treatment group
containing supplements also include herbs that contain caffeine, using a semi-random procedure (such as a participant’s date
and products that contain ephedrine often include caffeine. of birth, a patient identification number, or the order of
Because caffeine is believed to have effects that are similar to enrollment). In all, we reviewed the results of 52 clinical
ephedrine, such combinations could potentially be more pow- trials that measured the effects of ephedra or ephedrine on
erful than either substance alone. Thus, we were also asked to weight loss and athletic performance. Most of these studies
review the evidence for the effectiveness and safety of supple- included one group of participants who were randomly cho-
ments that combine ephedra and caffeine as well as ephedrine sen to receive only a placebo (an inactive dummy pill). This
and caffeine-containing products. type of study maximizes the likelihood that any differences
To assess the evidence for the effectiveness of ephedra found between the groups taking the test supplement and
and ephedrine in weight loss and athletic performance, we those taking the placebo are real, not due to chance or bias.
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What We Found First, we reviewed the clinical trials included in our
analyses of weight loss and athletic performance, most of
Studies of Weight Loss. Studies of weight loss usually measure which reported adverse events for both treatment and placebo
the weight lost over the course of the study, the weight lost per groups. The trials contained no reports of very serious
month, or the proportion of an individual’s original weight that adverse events (such as death and cardiovascular events).
was lost. For each group of studies that made the same com- This is not surprising, considering that the occurrence of
parisons (for example, all studies that compared the effects of such events is likely to be quite rare (less than one in a
ephedra and herbal caffeine on weight loss with the effects of a thousand users) and the clinical trials included only a few
placebo), we combined the results of all studies in that group, thousand people. However, we found a two- to threefold
using a statistical technique called meta-analysis, and calculated increase in the occurrence of nausea, vomiting, anxiety, auto-
the average total weight lost as well as the average lost per month. nomic hyperactivity, and palpitations, and a trend toward
Over the short term (four to six months), ephedrine, an increase in headaches.
ephedrine plus caffeine, and supplements containing We also reviewed descriptions of medical cases pub-
ephedra or ephedra plus caffeine promoted modest increases lished in peer-reviewed journals. This review identified 70
in weight loss, about two pounds per month more than the reports of adverse events, including heart attacks, strokes,
weight loss of persons taking the placebo. Products contain- and serious psychiatric problems. We then obtained all
ing caffeine seemed to promote slightly more weight loss adverse-event reports submitted to the FDA prior to Sep-
than those containing only ephedrine. However, none of tember 2001 that were associated with the use of ephedra-
the studies lasted longer than six months, far less than the or ephedrine-containing products and for which records
twelve months researchers consider the minimum necessary existed: more than 1,500 adverse-event reports on ephedra
to establish the value of a weight loss product (studies that and 125 on products containing ephedrine. Finally, we ana-
lasted less than two months were excluded from our analysis lyzed more than 18,000 adverse-event reports received by
because two months is simply too short a time to assess a one of the largest U.S. manufacturers of ephedra-containing
meaningful change in weight). dietary supplements. These reports had been turned over to
Studies of Athletic Performance. We found no studies the FDA at the request of the U.S. Deptartment of Justice.
that assessed the effects of ephedra-containing dietary supple- Based on the available evidence, these reports were classified
ments on athletic performance. Thus we analyzed only studies as “sentinel events,” “possible sentinel events,” or lacking in
of products containing ephedrine or ephedrine plus caffeine— sufficient evidence (see Table 1).
seven studies in all. No two studies were judged similar enough
in design to combine their results: Measures of athletic perfor-
mance varied widely from one study to another. As a result,
Table 1. Criteria for Classifying Adverse Events
our conclusions regarding the effects of ephedrine on athletic
performance are based on a nonquantitative synthesis of the
Sentinel Event Possible Sentinel Event
research rather than on meta-analysis. In addition, no study
looked at long-term changes in performance. Documentation of the Documentation of the
Our analysis found that one-time use of ephedrine- adverse event adverse event
containing products seems to enhance immediate physical Documentation (by report Documentation (by report
performance, but only when taken in combination with or toxicology exam) that or toxicology exam) that
ephedra or ephedrine was ephedra or ephedrine was
caffeine. These results, too, must be interpreted with caution. consumed within the prior consumed within the prior
The studies assessed performance immediately after a single 24 hours* 24 hours*
dose; none of the studies examined the type of chronic,
Documentation that other Other potential causes exist
long-term use typical of consumers of these products. What’s possible causes of the or were not effectively
more, the study participants—all young, fit males—may not event were evaluated and excluded
excluded
be typical of the average consumer.
*The 24-hour requirement was not applied to reports of psychiatric
Studies of Safety. To assess the safety of ephedra- and events because these events are believed to result from prolonged use.
ephedrine-containing products, we reviewed four sources for
reports of adverse events.
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The majority of the adverse-event reports lacked suffi-
Table 2. Adverse Events Associated with
cient information to demonstrate a connection between the
Ephedra and Ephedrine
event and use of ephedra or ephedrine. Nevertheless, we did
identify a number of reports of sentinel and possible sentinel Number
Number of Possible
events, including death, stroke, myocardial infarction (heart Number of Sentinel Sentinel
attack), ventricular tachycardia/fibrillation, cardiac arrest, Event of Events Events Events
pulmonary arrest, transient ischemic attack, brain hemor- Death 84 5 12
rhage, seizure, psychiatric symptoms, and gastrointestinal
Myocardial
symptoms (see Table 2). Of particular concern is that half infarction (heart
the sentinel events occurred in apparently healthy people attack) 26 5 7
under the age of 30.
Other cardiac 30 0 3
Cerebrovascular
event (stroke) 56 11 12
What Should Be Done?
Seizure 40 4 7
The studies we reviewed suggest that ephedra- and ephedrine- Other
containing products may be modestly effective in promoting neurological 8 0 1
weight loss, but the evidence on enhancing athletic perfor-
Psychiatric event 91 8 8
mance is not definitive. However, the use of ephedra or
ephedrine does cause an increase in jitteriness, mood changes,
palpitations, nausea, and vomiting. Moreover, the adverse-event
reports raise serious concerns about the safety of ephedra and
ephedrine products.
In response to our report, the federal government Such a study would compare ephedra use by individuals
quickly moved to propose stricter labeling of ephedra prod- who suffered death or another illness with use by similar
ucts and solicited public comment on whether the safety individuals who have not suffered severe health problems. A
evidence thus far warrants further restrictions. By itself, study of this type could also be used to compare the safety
the existing evidence is insufficient to link these products of ephedra-containing supplements and products containing
conclusively with death and other serious health problems. ephedrine. Finally, a case-control study could help answer
However, our analysis of the existing studies and their safety questions quickly, thus avoiding the expense and time
shortcomings suggests that a more definitive answer to that would be needed to conduct a large-scale randomized
questions about ephedra’s safety could be obtained by doing controlled trial and potentially saving lives.
what is called a “case-control” study.
Abstracts of all RAND Health publications and full text of many research documents can be found on the RAND Health web site at www.rand.org/health. RAND
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