Title: Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance A metaanalysis
1Efficacy and Safety of Ephedra and Ephedrine for
Weight Loss and Athletic PerformanceA
meta-analysis
- Department of Family Community Medicine
- Journal Club Presentation
- August 20, 2003
- Brian Swan, M.D.
2Why is this an important topic?
- In the United States, dietary supplements are
used by millions of people every day. - Dietary supplements are not required to have FDA
approval or to be registered with the FDA before
they are produced and marketed to consumers. - Currently, there are no FDA regulations to ensure
the identity, purity, quality, composition or
strength of dietary supplements. - These products are widely promoted by the
producers, often with unsubstantiated claims of
benefit and rarely any mention of potential
hazards. - Ephedra and ephedrine are among the most
controversial dietary supplements available, with
reports of toxicity linked to the use of these
compounds accumulating at an alarming rate.
3Objective of the Present Study?
- To assess the efficacy and safety of ephedra and
ephedrine, when it is used for weight loss and/or
enhancing athletic performance
4How was this objective approached?
- Reviewers searched 9 electronic databases for
published controlled trials and case reports - They also searched for unpublished or gray
literature - Posted announcements in the Journals,
Phytomedicine and Herbalgram - Wrote to several regulatory officials and herbal
experts in other countries seeking unpublished
evidence
5 Then what did they do?
- 2 independent reviewers conducted a meta-analysis
of the literature - Eligible studies were controlled trials studying
the efficacy and safety of ephedra and ephedrine
on weight loss or athletic performance - Eligible case reports involved adverse events
associated with the use of ephedra or ephedrine
6What variables were assessed in the studies?
- Variables assessed in controlled trials
- Efficacy in weight loss
- Adverse events / Safety
- Athletic performance
- Variables assessed in case reports
- Adverse events
7Methods How was the data synthesized for the
controlled trials?Weight loss trials
- First, they statistically pooled the outcomes by
- Clinically similar trials
- Monthly rates of weight loss (based on 2, 3, 4
month data separately) - Monthly weight loss effect sizes using a
random-effects model - Percentage weight loss from baseline (for
comparison with other weight loss products)
8Methods How was the data synthesized for the
controlled trials?Adverse effects / Safety trials
- They estimated the pooled-odds ratios (OR) for
clinically-related groups of symptoms
9Methods How was the data synthesized for the
controlled trials?Athletic performance trials
- Trials assessing athletic performance were too
heterogeneous to support statistical pooling. - They were reviewed individually.
10Methods How was the next piece of data
synthesized in the controlled trials?Weight loss
trials
- Next, they tested the outcomes for a dose effect
using a meta-regression model, defining the doses
as - Ephedrine low dose 10-20 mg/d
- Ephedrine medium dose 40-90 mg/d
- Ephedrine high dose 100-150 mg/d
11Methods How was the next piece of data
synthesized for the controlled trials?Adverse
events / safety trials
- For this variable, the outcomes for dose response
were then assessed by stratified analysis - with the dose strata defined as for the efficacy
analysis
12What other methods were employed to assess the
controlled trials?All trials
- Conducted sensitivity analyses
- Dropped trials by attrition rate 20
- Dropped trials that presented in abstract forms
- Dropped trials scoring 2 or less on the Jadad
scale of quality - Dropped trials that included other medications
with ephedrine (like ASA, synephrine)
13Methods Case reports
- Adverse events needed to be categorized
- Documented report that an adverse event occurred
- Documented report that the subject had consumed
ephedra or ephedrine within 24 hours prior to the
adverse event or a tox screen (blood or urine)
was found positive for either product - An adequate investigation by an expert clinician
excluded other potential causes
14Methods Case reports
- Adverse events were then labeled
- Sentinel event cases that met all 3 criteria
- Possible sentinel event cases that met the
first 2 criteria, but had other possible causes
in which to attribute the event
15ResultsEfficacy Weight Loss
- The comparisons of 20 controlled trials were
classified into 6 categories - Ephedrine vs. Placebo
- Ephedrine Caffeine vs. Placebo
- Ephedrine Caffeine vs. Ephedrine
- Ephedrine vs. Other weight loss product
- Ephedra vs. Placebo
- Ephedra with herbs (containing caffeine) vs.
Placebo
16ResultsEfficacy Weight LossEphedrine vs.
Placebo
- 5 randomized, placebo controlled trials, with
results reported at 3-4 months duration of
treatment assessed - Rate of weight loss above placebo was 0.6 kg/mth
(95 CI 0.2-1.0) - Average percentage weight loss in the treatment
groups (compared to pre-treatment weight) was 11
at 4 months - In dose analysis, only high doses of ephedrine
produced a weight loss statistically
significantly.
17ResultsEfficacy Weight lossEphedrine
Caffeine vs. Placebo
- 7 randomized, double-blind, placebo controlled
trials, with results reported at 2 and 4 months
duration of treatment assessed - Rate of weight loss was 1.0 kg/mth (95 CI
0.7-1.3) above placebo - Average percentage of weight loss in the
ephedrine caffeine treated patients (compared
to pre-treatment weight) was 11 at 4 months - In dose analysis, no statistically significant
differences found
18ResultsEfficacy Weight lossEphedrine
Caffeine vs. Ephedrine
- 3 controlled trials assessed
- Rate of weight loss was 0.4 kg/mth (95 CI
0.02-0.7) above Ephedrine alone - No dose analysis performed
19ResultsEfficacy Weight lossEphedrine
Caffeine vs. Other weight loss product
- 2 controlled trials assessed
- No statistically significant differences in
weight loss when compared to Dexfenfluramine or
Diethylpropion (Tenuate)
20ResultsEfficacy Weight lossEphedra with herbs
(containing caffeine) vs. Placebo
- 4 randomized, placebo controlled trials assessed
- Rate of weight loss was 1.0 kg/mth (95 CI
0.6-1.3) above placebo alone - Average percentage weight loss in the ephedra
treated patients (compared to pre-treatment
weight) was 5.2 at 4 months - Only medium doses assessed, no dose analysis
performed
21ResultsEfficacy Athletic Performance
- 7 controlled trials assessed (individually)
- Combination of Ephedrine (1 mg/kg) Caffeine (5
mg/kg) consistently demonstrated a 20-30
increase in performance compared to placebo - Neither Ephedrine (up to doses of 1 mg/kg) nor
Caffeine (up to doses of 5 mg/kg) alone had
significant effects on exercise performance - Combination of Ephedrine Caffeine ( at above
doses) resulted in increased incidences of
side-effects, such as nausea / vomiting (compared
to lower doses)
22ResultsAdverse Events Controlled Trials
- 50 randomized, placebo controlled trials assessed
- Participants in active treatment had between 2.2
and 3.6 increased odds for adverse events
including psychiatric sx, autonomic
hyperactivity, upper GI sx, and heart
palpitations - In dose analysis, there was a trend toward higher
risk of adverse events with higher doses of
ephedrine, but this trend was not statistically
significant - 1 trial of herbal ephedra (herbal caffeine free)
reported a statistically significant 2-fold
increase in gastrointestinal symptoms
23ResultsAdverse Events Controlled Trials
24ResultsAdverse Events Case Reports
- 70 published case reports reviewed
- 1,820 FDA Med-Watch Files screened
- 15,951 cases reported to one manufacturer of
ephedra-containing dietary supplements screened
25ResultsAdverse Events Case Reports
- Sentinel events (following consumption of
ephedra-containing products) - 2 deaths
- 3 myocardial infarctions
- 9 cerebrovascular accidents
- 3 seizures
- 5 psychiatric events
26ResultsAdverse Events Case Reports
- Sentinel events (following consumption of
ephedrine-containing products) - 3 deaths
- 2 myocardial infarctions
- 2 cerebrovascular accidents
- 1 seizure
- 5 psychiatric events
27ResultsAdverse Events Case Reports
28Conclusions
- Analysis of the available literature provided
sufficient evidence that short-term use of
ephedrine at high doses promotes weight loss in
selected patient populations. - Short-term use of ephedrine caffeine, or
ephedra, or ephedra herbs containing caffeine
promoted weight loss in these populations.
29Other conclusions.
- The overall effect of ephedra or ephedrine on
athletic performance is still unknown. - The investigators were unable to identify any
controlled trials of ephedra. - The few identified trials of ephedrine did not
study it as it is used by the general population
(that is, with repeated use)
30Also.
- Sufficient evidence was found to conclude that
ephedra and ephedrine are associated with 2 to 3
times the risk of psychiatric events/symptoms,
autonomic symptoms, upper GI symptoms, and heart
palpitations.
31Study limitations
- There were a few.
- Some trials had method problems, but the
sensitivity analyses conducted were able to
support their main analysis with respect to
ephedrine caffeine, and with respect to ephedra - Significant heterogeneity among the athletic
performance trials prevented the completion of a
formal meta-analysis on the variable
32Further limitations
- The generalizability of the results to the use of
ephedra or ephedrine in a general population may
not be valid. - The weight loss trials frequently involved
medical screening to detect preexisting
conditions that may predispose subjects to an
increased risk of adverse events. Such patients
were then excluded from the trials.
33And
- The weight loss trials as a group had limited
duration of treatment times. - Therefore, complete conclusions about the
association between ephedra and weight loss over
longer and more clinically relevant intervals
could not be made.
34To Conclude
- If you, or your patients are looking for the best
way to lose a minimal amount of weight, while
experiencing the enjoyment of psychotic episodes,
anginal chest pain and severe acid reflux, you
need look no further than your local supermarket
or nutritional supplement store. - The End
35Reference
- Shekelle PG, Hardy ML, Morton SC, Maglione M,
Mojica WA, Suttorp MJ, Rhodes CL, Jungviv L,
Gagne J. Efficacy and Safety of Ephedra and
Ephedrine for Weight Loss and Athletic
Performance. JAMA 20032891537-45.