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FDA Report: Ephedra and Ephedrine for Weight Loss and Athletic
Performance Enhancement:
Clinical Efficacy and Side Effects (Summary)
Copied and converted to html from: http://www.fda.gov/OHRMS/DOCKETS/98fr/95N-0304-bkg0003-ref07-09-Summary.pdf
Summary
Overview
At the direction of the funding agencies (National Institute of Health
Office of Dietary
Supplements (ODS), the National Center for Complementary and Alternative
Medicine
(NCCAM), and the Agency for Healthcare Research and Quality (AHRQ)), and
in consultation
with our Technical Expert Panel, we addressed research questions
regarding the efficacy of
herbal ephedra and ephedrine for weight loss and athletic performance
through a comprehensive
literature review and synthesis of evidence. We assessed the safety of
these products through
review of clinical trials. Meta-analysis was performed where
appropriate. In addition, we
reviewed herbal ephedra– and ephedrine-related adverse events reports
on file with the U.S.
Food and Drug Administration (FDA), published case reports, and reports
to a manufacturer of
ephedra-containing products. It is expected that the results of this
review will be used to direct
further research.
Reporting the Evidence
The following questions were provided to us by the funding agencies and
guided this
evidence report.
Weight Loss
1. What is the evidence for efficacy of ephedra-containing dietary
supplement products in
weight loss, over a sustained period of time?
2. Can efficacy for weight loss be attributed to ephedra alone, or
ephedra in combination
with other ingredients (e.g., caffeine)?
3. Does ephedra have additive effects with other agents?
4. What dosage levels of ephedra are necessary to achieve weight
loss?
Athletic Performance
1. What is the evidence for efficacy of ephedra-containing dietary
supplement products in
terms of energy enhancement and enhancement of athletic performance,
over a sustained
period of time?
2. Can efficacy for energy enhancement and enhancement of athletic
performance be
attributed to ephedra alone, or ephedra in combination with other
ingredients (e.g.,
caffeine) that produce energy enhancement and/or enhancement of
athletic performance?
3. Does ephedra have additive effects with other agents?
4. What dosage levels of ephedra are necessary to achieve energy
enhancement and
enhancement of athletic performance?
Safety Assessment
1. Does use of ephedra-containing dietary supplement products over a
sustained period of
time increase the risk of cardiovascular disease (CVD) or other
serious and life-
threatening events in specific populations?
2. What populations are at risk of CVD and other life-threatening
events through use of
ephedra over a sustained period of time?
xiii
3. Can the risk for adverse events in these populations be attributed
to ephedra alone, or in
combination with other ingredients (e.g., caffeine)?
4. Does ephedra have additive effects with other agents?
5. What dosage levels of ephedra produce risk of CVD or other
life-threatening events?
6. Do ephedra-containing dietary supplement products alter
physiologic markers of
cardiovascular function?
7. What are the metabolic actions of ephedra, so as to explain its
beneficial and adverse
effects?
In addition to answering these 15 questions about ephedra-containing
dietary supplement products, we were also asked to synthesize the available information on
the same questions for the purified alkaloid, ephedrine.
After searching published reports, journal articles, conference
presentations, and various
sources of unpublished studies, we identified 52 controlled clinical
trials of ephedrine or herbal
ephedra for weight loss or athletic performance in humans. The Food and
Drug Administration
provided us with copies of over 1,000 adverse event reports (AERs)
related to herbal ephedra
and 125 AERs related to ephedrine. These reports often included
interviews with patients and/ or
family members, extensive medical records, and copies of product labels.
We identified 65 case
reports in the literature and received a disk of 15,951 reports
containing 18,502 cases from
Metabolife, a manufacturer of ephedra products.
Methodology
Efficacy. Data for the efficacy analysis were abstracted from
reports of controlled trials onto
a specially designed form containing questions about the study design,
the number of patients
and comorbidities, dosage, adverse events, the types of outcome
measures, and the time from
intervention until outcome measurement. We selected the variables for
abstraction with input
from the project’s technical experts. Two physicians, working
independently, each extracted data
from the same reports and resolved disagreements by consensus.
In selecting studies for the meta-analysis of weight loss efficacy, we
considered only those
trials of at least eight weeks treatment duration. Our technical expert
panel judged that shorter
treatment durations were insufficient to assess weight loss. In
selecting studies on athletic
performance, we found that these studies varied widely with respect to
intervention. Because of
this heterogeneity, we compared and contrasted these studies in a
narrative review, rather than
performing a statistical synthesis.
The effects of ephedra/ephedrine on weight loss were examined in six
different types of
comparisons: (1) ephedrine versus placebo; (2) ephedrine plus caffeine
versus placebo;
(3) ephedrine plus caffeine versus ephedrine; (4) ephedrine versus other
active treatment;
(5) ephedra versus placebo; and (6) ephedra plus herbs containing
caffeine versus placebo. The
last comparison subgroup contained only a single trial; thus, effect
sizes were estimated only for
the first five. The effect size was calculated by dividing the outcome
of a study (e.g., difference
in weight loss per month between the two groups) by its standard
deviation, which produces a
unitless measure that is useful when comparing studies that assess
outcomes (such as weight)
xiv
that are similar but are measured differently (e.g., weight loss in
pounds versus change in body
mass index). Effect sizes were pooled separately for each of the five
comparison subgroups. In
addition, we used meta-regression to conduct a cross-subgroup synthesis
on the effect sizes of
the subgroups with a placebo comparison: ephedrine versus placebo;
ephedrine plus caffeine
versus placebo; and ephedra plus herbs containing caffeine versus
placebo.
Safety. We reviewed each report of a controlled trial (regardless
of treatment duration) for
data on adverse events. Adverse events were recorded onto a spreadsheet
that identified each
study arm, the description of the adverse event as listed in the
original article, and the numbers of
subjects and adverse events in each arm. We then compared event rates in
the ephedra or
ephedrine groups to those in the placebo groups. We conducted a
meta-analysis on those adverse
event symptoms for which appreciable numbers of events were noted in the
controlled trials.
Adverse event reports compiled by the Food and Drug Administration (FDA)
concerning
ephedra or ephedrine were also reviewed by our physician reviewers.
Within the time and
resource constraints of this report, we reviewed all available reports
of death, myocardial
infarction (heart attack), cerebral vascular accident (stroke), seizure,
and serious psychiatric
illness filed prior to September 30, 2001. We also reviewed published
case reports as well as
event reports filed with Metabolife, a manufacturer of
ephedra-containing products. After
screening, all case reports were subjected to a review.
Based on input from our technical expert panel and the literature on
methods to assess
adverse event reports, we identified three important criteria for
inclusion of such reports:
1. Documentation of an adverse event that met our selection criteria.
2. Documentation that the person having the adverse event took an
ephedra-containing
supplement or ephedrine within 24 hours prior to the event (for cases of
death,
myocardial infarction, stroke, or seizure).
3. Documentation that alternative explanations for the adverse event
were investigated and
were excluded with reasonable certainty.
We classified cases that met all three of these criteria as “sentinel
events.” Cases in which the
event might have had other possible causes but the pharmacology of
ephedrine could have
contributed were classified as “possible sentinel events.” Cases of
death, myocardial infarction,
cerebral vascular accident, and seizure were reviewed by internists,
with additional review (as
indicated) by a cardiologist, neurologist, or rheumatologist.
Psychiatric cases were reviewed by a
psychiatrist specializing in addictions and a psychologist with
expertise in substance abuse. The
criterion for use within 24 hours was not required for psychiatric
cases.
Findings
Efficacy for Weight Loss. We identified 44 controlled trials that
assessed use of ephedra or
ephedrine used for weight loss. Of these, 18 were excluded from pooled
analysis because they
had a treatment duration of less than eight weeks. Six additional trials
were excluded for a
variety of other reasons. Of the remaining 20 trials included in the
meta-analysis, only five tested
xv
herbal ephedra-containing products. Together, these 20 trials assessed
678 persons who
consumed either ephedra or ephedrine. The majority of studies of both
ephedra and ephedrine are
plagued by methodological problems (particularly, high attrition rates)
that might contribute to
bias. These methodological limitations must be considered when
interpreting any conclusions
regarding the efficacy of these products. Nevertheless, the evidence we
identified and assessed
supports an association between short-term use of ephedrine, ephedrine
plus caffeine, or dietary
supplements that contain ephedra with or without herbs containing
caffeine and a statistically
significant increase in short-term weight loss (compared to placebo).
Adding caffeine to
ephedrine modestly increases the amount of weight loss. There is no
evidence that the effect of
ephedra-containing dietary supplements with herbs containing caffeine
differs from that of
ephedrine plus caffeine: Both result in weight loss that is
approximately two pounds per month
greater than that with placebo, for up to four to six months. No studies
have assessed the long-
term effects of ephedra-containing dietary supplements or ephedrine on
weight loss; the longest
duration of treatment in a published study was six months.
Efficacy for Physical Performance Enhancement. The effect of
ephedrine on athletic
performance was assessed in seven studies. No studies have assessed the
effect of herbal
ephedra-containing dietary supplements on athletic performance. The few
studies that assessed
the effect of ephedrine on athletic performance have, in general,
included only small samples of
fit individuals (young male military recruits) and have assessed the
effects only on very short-
term immediate performance. Thus, these studies did not assess ephedrine
as it is used in the
general population. The data support a modest effect of ephedrine plus
caffeine on very short-
term athletic performance. No studies have assessed the sustained use of
ephedrine on
performance over time. The only study that assessed the additive effects
of these agents reported
that ephedrine must be supplemented with caffeine to affect athletic
performance.
Safety Issues. The data on adverse events were drawn from
clinical trials and case reports
published in the literature, submitted to the FDA, and reported to
Metabolife, a manufacturer of
ephedra-containing supplement products. The strongest evidence for
causality should come from
clinical trials; however, in most circumstances, such trials do not
enroll sufficient numbers of
patients to adequately assess the possibility of rare outcomes. Such was
the case with our review
of ephedrine and ephedra-containing dietary supplements. Even in
aggregate, the clinical trials
enrolled only enough patients to detect a serious adverse event rate of
at least 1.0 per 1,000. For
rare outcomes, we reviewed case reports, but a causal relationship
between ephedra or ephedrine
use and these events cannot be assumed or proven.
Evidence from controlled trials was sufficient to conclude that the use
of ephedrine and/or
the use of ephedra-containing dietary supplements or ephedrine plus
caffeine is associated with
two to three times the risk of nausea, vomiting, psychiatric symptoms
such as anxiety and change
in mood, autonomic hyperactivity, and palpitations.
The majority of case reports are insufficiently documented to make an
informed judgment
about a relationship between the use of ephedrine or ephedra-containing
dietary supplements and
the adverse event in question. For prior consumption of
ephedra-containing products, we
identified two deaths, three myocardial infarctions, nine
cerebrovascular accidents, three
seizures, and five psychiatric cases as sentinel events; for prior
consumption of ephedrine, we
xvi
identified three deaths, two myocardial infarctions, two cerebrovascular
accidents, one seizure,
and three psychiatric cases as sentinel events. We identified 43
additional cases as possible
sentinel events with prior ephedra consumption and seven additional
cases as possible sentinel
events for prior ephedrine consumption. About half the sentinel events
occurred in persons aged
30 years or younger. Classification as a sentinel event does not imply a
proven cause and effect
relationship.
We did not assess the plethora of additional symptoms that have been
reported in the
published literature and the FDA Medwatch file for ephedra-containing
dietary supplements and
ephedrine products.
Future Research
Our analysis of the evidence reveals numerous gaps in the literature
regarding the efficacy
and safety of ephedra-containing dietary supplements. First, long-term
assessments of the
effectiveness of herbal ephedra or ephedrine for promoting weight loss
are lacking. We identified
no study with a treatment duration longer than six months. To improve
health outcomes and
reduce the risk of morbidities associated with being overweight,
sufficient weight loss (5 to 10
percent of body weight) and long-term weight maintenance are necessary.
Therefore, the benefit
of ephedrine or herbal ephedra-containing dietary supplements for health
outcomes is unknown.
Evidence regarding the effect of herbal ephedra or ephedrine on physical
performance that
reflects its use in the general population (repeated or long-term use by
a representative sample) is
also needed.
In order to assess a causal relationship between ephedra or ephedrine
consumption and
serious adverse events, a hypothesis-testing study is needed. Continued
analysis of case reports
cannot substitute for a properly designed study to assess causality. A
case-control study would
probably be the study design of choice.
xvii
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