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Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic PerformanceA Meta-analysis

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Context Ephedra and ephedrine sometimes are used for weight loss or enhanced athletic performance, but the efficacy and safety of these compounds are uncertain.Objective To assess the efficacy and safety of ephedra and ephedrine used for weight loss and enhanced athletic performance.Data Sources We searched 9 databases using the terms ephedra, ephedrine, adverse effect, side effect, efficacy, effective, and toxic. We included unpublished trials and non–English-language documents. Adverse events reported to the US Food and Drug Administration MedWatch program were assessed.Study Selection Eligible studies were controlled trials of ephedra or ephedrine used for weight loss or athletic performance and case reports of adverse events associated with such use. Eligible studies for weight loss were human studies with at least 8 weeks of follow-up; and for athletic performance, those having no minimum follow-up. Eligible case reports documented that ephedra or ephedrine was consumed within 24 hours prior to an adverse event or that ephedrine or an associated product was found in blood or urine, and that other potential causes had been excluded. Of the 530 articles screened, 52 controlled trials and 65 case reports were included in the adverse events analysis. Of more than 18 000 other case reports screened, 284 underwent detailed review.Data Extraction Two reviewers independently identified trials of efficacy and safety of ephedra and ephedrine on weight loss or athletic performance; disagreements were resolved by consensus. Case reports were reviewed with explicit and implicit methods.Data Synthesis No weight loss trials assessed duration of treatment greater than 6 months. Pooled results for trials comparing placebo with ephedrine (n = 5), ephedrine and caffeine (n = 12), ephedra (n = 1), and ephedra and herbs containing caffeine (n = 4) yielded estimates of weight loss (more than placebo) of 0.6 (95% confidence interval, 0.2-1.0), 1.0 (0.7-1.3), 0.8 (0.4-1.2), and 1.0 (0.6-1.3) kg/mo, respectively. Sensitivity analyses did not substantially alter the latter 3 results. No trials of ephedra and athletic performance were found; 7 trials of ephedrine were too heterogeneous to synthesize. Safety data from 50 trials yielded estimates of 2.2- to 3.6-fold increases in odds of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations. Data are insufficient to draw conclusions about adverse events occurring at a rate less than 1.0 per thousand. The majority of case reports are insufficiently documented to allow meaningful assessment.Conclusions Ephedrine and ephedra promote modest short-term weight loss (≈0.9 kg/mo more than placebo) in clinical trials. There are no data regarding long-term weight loss, and evidence to support use of ephedra for athletic performance is insufficient. Use of ephedra or ephedrine and caffeine is associated with increased risk of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations. Figures in this Article Use of ephedrine alkaloid–containing products to promote weight loss or to enhance athletic performance has garnered a great deal of recent attention, due in part to a number of well-publicized adverse events reportedly associated with the use of ephedra- or ephedrine alkaloid–containing products.1- 3 These reports have led several groups to ask the US Food and Drug Administration (FDA) to ban the production and sale of ephedra products.4 Advocates counter that ephedra is safe and effective.5 The US Department of Health and Human Services requested this synthesis of available evidence regarding efficacy and safety of ephedra use to clarify the existing state of the science on ephedrine alkaloids. The National Institutes of Health will use this information to guide an expanded research effort to better understand the safety of ephedrine alkaloids.6
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REVIEW
Efficacy and Safety of Ephedra
and Ephedrine for Weight Loss
and Athletic Performance
A Meta-analysis
Paul G. Shekelle, MD, PhD
Mary L. Hardy, MD
Sally C. Morton, PhD
Margaret Maglione, MPP
Walter A. Mojica, MD, MPH
Marika J. Suttorp, MS
Shannon L. Rhodes, MFA
Lara Jungvig, BA
James Gagné, MD
USE OF EPHEDRINE ALKALOID
containing products to pro-
mote weight loss or to en-
hance athletic performance
has garnered a great deal of recent at-
tention, due in part to a number of well-
publicized adverse events reportedly as-
sociated with the use of ephedra- or
ephedrine alkaloid–containing prod-
ucts.1-3 These reports have led several
groups to ask the US Food and Drug Ad-
ministration (FDA) to ban the produc-
tion and sale of ephedra products.4Ad-
vocates counter that ephedra is safe and
effective.5The US Department of Health
and Human Services requested this syn-
thesis of available evidence regarding ef-
ficacy and safety of ephedra use to clarify
the existing state of the science on
ephedrine alkaloids. The National In-
stitutes of Health will use this informa-
tion to guide an expanded research ef-
fort to better understand the safety of
ephedrine alkaloids.6
Author Affiliations are listed at the end of this article.
Corresponding Author and Reprints: Paul G. Shekelle,
MD, PhD, Southern California Evidence-based
Practice Center–RAND, 1700 Main St, PO Box 2138,
Santa Monica, CA 90407-2138 (e-mail: shekelle
@rand.org).
Context Ephedra and ephedrine sometimes are used for weight loss or enhanced
athletic performance, but the efficacy and safety of these compounds are uncertain.
Objective To assess the efficacy and safety of ephedra and ephedrine used for weight
loss and enhanced athletic performance.
Data Sources We searched 9 databases using the terms ephedra,ephedrine,ad-
verse effect,side effect,efficacy,effective, and toxic. We included unpublished trials
and non–English-language documents. Adverse events reported to the US Food and
Drug Administration MedWatch program were assessed.
Study Selection Eligible studies were controlled trials of ephedra or ephedrine used
for weight loss or athletic performance and case reports of adverse events associated with
such use. Eligible studies for weight loss were human studies with at least 8 weeks of
follow-up; and for athletic performance, those having no minimum follow-up. Eligible
case reports documented that ephedra or ephedrine was consumed within 24 hours prior
to an adverse event or that ephedrine or an associated product was found in blood or
urine, and that other potential causes had been excluded. Of the 530 articles screened,
52 controlled trials and 65 case reports were included in the adverse events analysis. Of
more than 18000 other case reports screened, 284 underwent detailed review.
Data Extraction Two reviewers independently identified trials of efficacy and safety
of ephedra and ephedrine on weight loss or athletic performance; disagreements were
resolved by consensus. Case reports were reviewed with explicit and implicit methods.
Data Synthesis No weight loss trials assessed duration of treatment greater than 6
months. Pooled results for trials comparing placebo with ephedrine (n=5), ephedrine
and caffeine (n=12), ephedra (n= 1), and ephedra and herbs containing caffeine (n= 4)
yielded estimates of weight loss (more than placebo) of 0.6 (95% confidence interval,
0.2-1.0), 1.0 (0.7-1.3), 0.8 (0.4-1.2), and 1.0 (0.6-1.3) kg/mo, respectively. Sensitiv-
ity analyses did not substantially alter the latter 3 results. No trials of ephedra and ath-
letic performance were found; 7 trials of ephedrine were too heterogeneous to syn-
thesize. Safety data from 50 trials yielded estimates of 2.2- to 3.6-fold increases in
odds of psychiatric, autonomic, or gastrointestinal symptoms, and heart palpitations.
Data are insufficient to draw conclusions about adverse events occurring at a rate less
than 1.0 per thousand. The majority of case reports are insufficiently documented to
allow meaningful assessment.
Conclusions Ephedrine and ephedra promote modest short-term weight loss (0.9
kg/mo more than placebo) in clinical trials. There are no data regarding long-term weight
loss, and evidence to support use of ephedra for athletic performance is insufficient.
Use of ephedra or ephedrine and caffeine is associated with increased risk of psychi-
atric, autonomic, or gastrointestinal symptoms, and heart palpitations.
JAMA. 2003;289:1537-1545 www.jama.com
See also p 1568 and Patient Page.
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, March 26, 2003—Vol 289, No. 12 1537
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METHODS
Identification and Synthesis
of Controlled Trials
Since ephedrine is believed to be the al-
kaloid most responsible for the effects
of herbal ephedra, we searched for con-
trolled trials of ephedrine or ephedra
that assessed either weight loss or ath-
letic performance in humans.
We searched the following elec-
tronic databases in March and April
2001: MEDLINE (1965-2001), EMBASE
(1974-2001), BIOSIS (1969-2001), Al-
lied and Complementary Medicine Da-
tabase (AMED) (1984-2001), MANTIS
(1880-2000), the Cochrane Con-
trolled Clinical Trials Register Data-
base, and International Pharmaceuti-
cal Abstracts (1970-2001), PASCAL
(1973-2001), and SCISEARCH (1974-
1989, 1990-2001). Search terms in-
cluded ephedra,ephedrine,adverse effect,
side effect,efficacy,effective, and toxic. The
specific search strategies are displayed
in an Appendix of detailed methods
available at http://www.rand.org/health
/epc. We then searched the reference lists
of each retrieved article. There was no
language restriction. We also searched
for unpublished or “gray” literature by
posting announcements in the jour-
nals Phytomedicine and Herbalgram and
by writing to numerous regulatory of-
ficials and herbal experts in other coun-
tries seeking unpublished evidence.
Two trained reviewers indepen-
dently reviewed titles, abstracts, and ar-
ticles to identify controlled trials in hu-
mans assessing weight loss or athletic
performance. Disagreements were re-
solved by consensus. Articles meeting
these inclusion criteria were then re-
viewed in duplicate to abstract data re-
garding study design and execution, par-
ticipants, therapies, and outcomes
(abstracted variables are available at
http://www.rand.org/health/epc). To as-
sess efficacy in weight loss, we included
only trials with at least 8 weeks’ dura-
tion of treatment, because shorter dura-
tions of treatment are thought to be less
informative. To assess adverse events, we
included all identified controlled trials
for either indication. Articles were not
masked for author or journal.
Trials assessing athletic perfor-
mance were too heterogeneous to sup-
port statistical pooling. For the weight
loss and adverse events analyses, we
abstracted the relevant outcome data
(weight loss, occurrence of an adverse
event). Weight loss outcomes were
pooled in clinically similar groups of
trials. We first verified that weight loss
was linear over the range of time for
which data were available by compar-
ing pooled monthly rates of weight loss
based on 2- month, 3- month, and
4-month data separately. We then pooled
monthly weight loss effect sizes using a
random-effects model.7We also pooled
percentage weight loss from baseline in
the treatment groups for comparison
with other weight loss products.
We tested for a dose effect using a
meta-regression model,8defining an
ephedrine low dose as 10 to 20 mg/d;
medium dose as 40 to 90 mg/d; and
high dose as 100 to 150 mg/d.
We conducted sensitivity analyses to
determine the robustness of our conclu-
sions. One sensitivity analysis divided the
trials into those with less than 20% at-
trition compared with all others. A sec-
ond analysis dropped an included trial
by Moheb et al9that presented data in
abstract form and required sample-size
assumptions. A third analysis assessed
only those trials scoring 3 or greater on
the Jadad scale of quality,10,11 which gives
points based on randomization, blind-
ing, and description of withdrawals, and
ranges from 0 (poor) to 5 (good). In
other settings a threshold of 3 has been
shown to be related to bias.11 We also per-
formed sensitivity analyses where rel-
evant by dropping trials that included
other medications (aspirin, syneph-
rine) with ephedrine. The sensitivity
analysis based on study quality was speci-
fied a priori; all others were post hoc af-
ter examining the relevant studies.
For the safety analysis, we esti-
mated the pooled odds ratio (OR) for
clinically related groups of symptoms
using exact conditional inference meth-
ods because of the rarity of events. To
assess dose response, we conducted a
stratified analysis with the dose strata
defined as for the efficacy analysis.
We assessed the possibility of pub-
lication bias by evaluating a funnel plot
of effect sizes for asymmetry, which re-
sults from the nonpublication of small,
negative trials. Because graphical evalu-
ation can be subjective, we also con-
ducted an adjusted rank correlation
test12 and a regression asymmetry test.13
We conducted all analyses using
Stata14 except for the exact analyses,
which were conducted using StatXact,15
with P.05 considered significant. A
more detailed explanation of these meth-
ods is available at http://www.rand.org
/health/epc.
Because the randomized trials had,
even in aggregate, low statistical power
to assess the possibility of rare adverse
events, we searched for and reviewed
case reports of adverse events associ-
ated with use of ephedrine or ephedra.
Case reports cannot be considered, ex-
cept in extraordinary circumstances, to
be conclusive evidence of a cause-and-
effect relationship. Case reports can,
however, be useful to establish the po-
tential for a causal relationship. We as-
sessed all reports for ephedrine and
ephedra in the FDA MedWatch files as
of September 30, 2001, all case reports
we identified in published literature, and
a very large file of symptoms reported
to a manufacturer of ephedra-contain-
ing dietary supplements. All case re-
ports were screened and we reviewed in
detail all reports of death, myocardial in-
farction/acute coronary syndromes/
other cardiac symptoms, cerebrovascu-
lar accident/transient ischemic attack/
other neurologic symptoms, seizure, and
serious psychiatric symptoms.
We searched for documentation that
(1) an adverse event had occurred; (2)
the subject had consumed ephedra or
ephedrine within 24 hours prior to the
adverse event or that a toxicological ex-
amination had revealed ephedrine or
one of its associated products in the
blood or urine; and (3) an adequate in-
vestigation had evaluated for and ex-
cluded other potential causes. Cases
meeting all these criteria were labeled
“sentinel events.” Cases meeting the
first 2 criteria that had other possible
causes of the event were labeled “pos-
EPHEDRA AND EPHEDRINE FOR WEIGHT LOSS AND ATHLETIC PERFORMANCE
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sible sentinel events.” We used the clini-
cal judgment of expert clinicians to as-
sess whether other causes had been
adequately evaluated and excluded.
RESULTS
FIGURE 1illustrates the flow of litera-
ture reviewed. We identified 550 ar-
ticles. These included 3 clinical trials that
were unpublished at the time our re-
view was undertaken; one has since been
published. We were unable to obtain 20
articles; from their titles and keywords
none appeared to be clinical trials of
ephedrine or ephedra.
Efficacy: Weight Loss
We identified 44 controlled trials (51
articles) that assessed ephedra, ephed-
rine, or ephedrine and other com-
pounds used for weight loss. Of these,
18 trials were excluded from pooled
analysis because they had a duration of
treatment shorter than 8 weeks; an-
other 6 trials were excluded for other
reasons (eg, insufficient data for meta-
analysis; crossover design without pro-
vider outcomes at the crossover point).
For the remaining 20 trials, we clas-
sified the comparisons made into 6 cat-
egories: ephedrine vs placebo, ephed-
rine and caffeine vs placebo, ephedrine
and caffeine vs ephedrine alone, ephed-
rine vs another active weight loss phar-
maceutical, ephedra vs placebo, ephe-
dra with herbs containing caffeine vs
placebo. We found no trials of ephe-
dra vs another active weight loss
therapy. Details of the 19 placebo-
controlled studies are presented in
TABLE 1.
Ephedrine vs Placebo. We identi-
fied 5 trials containing 6 comparisons
that assessed the effect of ephedrine vs
placebo.9,22,25,28,29 All 5 were described
as randomized, placebo-controlled trials
with results reported at 3 or 4 months’
duration of treatment. The random-
effects pooled estimate of the rate of
weight loss was 0.6 kg per month above
weight lost with placebo (95% confi-
dence interval [CI], 0.2-1.0) (FIGURE 2).
The pooled average percentage weight
loss in the ephedrine-treated patients,
compared with pretreatment weight,
was 11% at 4 months. A sensitivity
analysis of only those trials scoring 3
or greater on the Jadad scale yielded a
pooled estimate of effect substantially
lower than that yielded by the main
analysis (weight loss rate, 0.2 kg per
month); this difference (compared with
the main analysis) was statistically sig-
nificant (P=.049). All of these trials had
an attrition rate of greater than 20% and
therefore no sensitivity analysis on at-
trition could be performed. A final sen-
sitivity analysis dropping the trial by
Moheb et al9did not materially change
these results. In our dose analysis, only
high doses of ephedrine produced a
weight loss that was statistically sig-
nificantly greater than zero, and the
difference in weight loss between me-
dium-dose trials and high-dose trials ap-
proached statistical significance
(P=.05). Neither graphical assess-
ment nor statistical tests yielded evi-
dence of publication bias (P=.45 for
rank test; P=.82 for regression test).
Ephedrine and Caffeine vs Pla-
cebo. We identified 12 trials that as-
sessed the effect of ephedrine and caf-
feine vs placebo for weight loss,*with
results reported at between 2 and 4
months’ duration of treatment. Seven
were described as randomized, double-
blind, placebo-controlled trials. The
random-effects pooled estimate of the
rate of weight loss was 1.0 kg per month
above weight lost with placebo (95% CI,
0.7-1.3) (Figure 2). The pooled aver-
age percentage weight loss in the ephed-
*References 16, 19, 21-24, 26, 27, 29-31.
Figure 1. Flow of Reviewed Literature
52 Randomized Controlled Trials or Controlled
Clinical Trials (59 Articles)
71 Case Reports or
Case Series
550 Articles Requested
452 Identified by Library Search
64 Identified by Outreach to Expert
34 Identified in Reference Lists
530 Articles Screened
20 Not Found
52 Included in Adverse
Events Analysis
20 Included in Weight
Loss Meta-analysis
400 Excluded
149 Topic
101 Subject
68 Population
36 Study Design: Descriptive
30 Study Design: Review/Meta-analysis
9 Study Design: Not RCT, CCT, Case
Series, or Case Report
4 Not an Article
3 Duplicate of Article Already Included
8 Athletic Performance
Trials
44 Weight Loss Trials6 Duplicate Reports
Excluded
65 Included in Adverse
Events Analysis
52 Trials Evaluated
for Adverse Events
Analysis
24 Excluded From Weight
Loss Meta-analysis
18 Follow-up <
8 wk
6 Other
RCT indicates randomized cointrolled trial; CCT, controlled clinical trial.
*Various reasons (see “Methods” section).
†2 studies had no placebo group and therefore did not contribute to the odds ratio meta-analysis.
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rine- and caffeine-treated patients, com-
pared with pretreatment weight, was
11% at 4 months. A sensitivity analy-
sis of only those trials that scored 3 or
greater on the Jadad scale yielded a re-
sult similar to that yielded by the main
analysis. Another sensitivity analysis of
only those trials that had less than 20%
attrition also yielded a similar result. A
third sensitivity analysis dropping the
trial by Moheb et al9did not change the
primary analysis. Neither did sensitiv-
ity analyses that dropped trials that in-
cluded synephrine or aspirin. In our
dose analysis, there was a trend to-
ward increased weight loss with higher
doses (weight loss greater than that lost
with placebo of 0.9, 0.9, and 1.4 kg/mo
for low, medium, and high doses, re-
spectively) but these differences were
not statistically significant. Neither
graphical assessment nor statistical tests
revealed publication bias (P=.30 for
rank test; P=.12 for regression test).
Ephedrine and Caffeine vs Ephed-
rine. We identified 3 trials that in-
cluded comparisons that assessed a
combination of ephedrine and caf-
feine vs ephedrine alone.9,22,29 All 3 had
attrition rates of greater than 20%. The
random-effects pooled estimate of
weight loss was 0.4 kg per month above
weight lost with ephedrine alone (95%
CI, 0.02-0.7) (data not shown). There
were too few trials to perform any sen-
sitivity analysis.
Ephedrine vs Another Active Weight
Loss Pharmaceutical. We identified 2
trials that compared ephedrine vs an-
other active weight loss therapy.26,32 Both
took place in Denmark and did not have
sufficient statistical power to detect even
a 30% difference between groups. One
trial compared dexfenfluramine with a
combination of ephedrine and caf-
feine.32 At 15 weeks of treatment there
was no statistically significant differ-
ence in weight loss between groups.
The second trial compared the Elsinore
pill (a prescription containing ephed-
rine and caffeine) with diethylpropion
Table 1. Placebo-Controlled Trials Used in Meta-analysis
Source
Jadad
Scale Score Intervention (Dose, mg)
Trial
Duration
Sample Size, No.
Average Weight Loss,
(SD), kg
Placebo Intervention Placebo Intervention
Astrup et al,16 1992 2 Ephedrine (60) and caffeine (600) 8 wk 8 8 8.4 (2.9) 10.1 (1.0)
Boozer et al,17 2002 5 Ephedrine from ma huang (86.4)
and caffeine from kola nut (196)
24 wk 84 83 2.6 (3.2) 5.3 (5.0)
Boozer et al,18 2001 5 Ephedrine from ma huang (77.4)
and caffeine from guarana (300)
8 wk 32 35 0.8 (2.4) 4.0 (3.4)
Buemann et al,19
1994
3 Ephedrine (60) and caffeine (600) 8 wk 16 16 7.1 (2.4) 8.4 (2.4)
Colker et al,20 2001 2 Ephedrine from ma huang
(unknown dose) and Coleus
forksohlli (unknown dose)
8 wk 12 14 0.49 (2.35) 2.56 (2.35)
Daly et al,21 1993 2 Ephedrine (150), caffeine (150), and
aspirin (330)
8 wk 15 14 0.7 (2.2) 2.2 (2.3)
Donikyan
(unpublished data,
2002)
4 Ephedrine from ma huang (72) and
chromium picolinate
(450 µg)
12 wk 94 92 1.4 (2.7) 3.4 (3.1)
Greenway et al
(unpublished data)
2 Ephedrine from ma huang (72) and
caffeine from unspecified
herb (210)
12 wk 20 20 0.8 (2.6) 3.9 (4.0)
Jensen et al,22 1980 1 Ephedrine (100) 16 wk 17 24 0.5 (4.7) 7.9 (4.7)
Ephedrine (100) and caffeine (275) 23 9.4 (4.7)
Kalman et al,23 2000 3 Ephedrine (40), caffeine (400),
synephrine (10), and aspirin (30)
8 wk 14 16 2.1 (2.4) 3.1 (2.4)
Kettle et al,24 1998 0 Ephedrine (20) and caffeine (200) 6 mo 45 45 12.8 (6.7) 15.6 (7.1)
Lumholtz et al,25 1980 2 Ephedrine (120) 18 wk 63 63 4.0 (5.3) 9.5 (5.3)
Malchow-Moller
et al,26 1981
3 Ephedrine (60) and caffeine (150) 12 wk 33 49 4.1 (3.5) 8.1 (3.5)
Moheb et al,91998 2 Ephedrine (150) 12 wk 32 64 6.2 (3.5) 8.8 (3.5)
Ephedrine (150) and caffeine (150) 64 8.9 (3.5)
Molnar et al,27 2000 4 Ephedrine (30-60) and caffeine
(100 for 1 wk)
20 wk 16 16 0.5 (4.3) 7.9 (6.0)
Pasquali et al,28 1985 3 Ephedrine (75) 3 mo 21 19 8.7 (3.5) 8.7 (2.4)
Ephedrine (150) 22 10.2 (3.5)
Quaade et al,29 1992 3 Ephedrine (60) 24 wk 45 45 13.2 (6.6) 14.3 (5.9)
Ephedrine (60) and caffeine (600) 45 16.6 (6.8)
Roed et al,30 1980 3 Ephedrine (120) and caffeine (300) 12 wk 69 69 5.2 (3.5) 10.0 (3.5)
Van Mil and Molnar,31
2000
1 Ephedrine (60) and caffeine (600) 20 wk 16 16 1.5 (8.1) 8.7 (5.7)
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(Tenuate).26 At 12 weeks of treatment,
there was no statistically significant dif-
ference in weight loss between groups.
Ephedra vs Placebo. We identified
a single trial that assessed ephedra vs
placebo (L.A. Donikyan, unpublished
data, 2002). This trial was a random-
ized, double-blind, parallel-group as-
sessment of Metab-O-LITE (Rexall Sun-
down, Boca Raton, Fla), which contains
ephedra and other compounds but caf-
feine or herbs that contain caffeine. The
duration of the trial was 3 months. This
trial reported a rate of weight loss of 0.8
kg per month greater than weight lost
with placebo for the group receiving
ephedra (95% CI, 0.4-1.2) (Figure 2).
This trial had 17% attrition.
Ephedra with Herbs Containing Caf-
feine vs Placebo. We identified 4 trials
(3 published17,18,20 and 1 unpublished
[F. Greenway et al, unpublished data])
that assessed the effect of ephedra with
herbs containing caffeine, with results
reported at between 2 and 4 months’
duration of treatment. All 4 were de-
scribed as randomized placebo-
controlled trials. The pooled random-
effects estimate of the rate of weight loss
was 1.0 kg per month above weight lost
with placebo (95% CI, 0.6-1.3) (Fig-
ure 2). The pooled average percent
weight loss in the ephedra-treated pa-
tients, compared with pretreatment
weight, was 5.2% at 4 months. A sen-
sitivity analysis with only those trials
scoring 3 or more on the Jadad scale
yielded a result similar to the main
analysis. All these studies assessed me-
dium doses of ephedra and therefore no
analysis stratified by dose was pos-
sible. Neither graphical assessment or
statistical tests revealed any evidence of
publication bias (P=.73 for rank test;
P=.23 for regression test).
Efficacy: Athletic Performance
We found 8 published controlled
trials33-40 of the effects of synthetic
ephedrine on athletic performance;
most were crossover designs and all but
1 also included caffeine. One study as-
sessed the effect of ephedrine and ex-
ercise training on basal metabolic rate,
did not report athletic performance out-
comes, and is not described below.33
The remaining 7 trials were not appro-
priate for pooled analysis because they
involved different types of exercise
(power and endurance) and different
outcome measures, so they are dis-
cussed here individually. We found no
trials assessing the effects of herbal
ephedra on athletic performance.
Six trials by Bell and colleagues34-39 as-
sessed the exercise capacity of small
groups of healthy male participants (all
trials included 24 participants or fewer)
and are summarized in TABLE 2. These
trials reported that neither caffeine nor
ephedrine alone had significant effects on
parameters of exercise performance such
as oxygen consumption, time to exhaus-
tion, or carbon dioxide production, but
the combination of ephedrine and caf-
feine consistently demonstrated a 20%
to 30% increase in performance. The
single trial of strength training did show
an improvement in muscle endurance
but only on the first of 3 repetitions. In
the only trial to test the effects of ephed-
rine and caffeine on thermal regulation,
no increase in temperature was re-
ported. Nausea and vomiting were re-
ported in a third of the participants given
ephedrine at a dose of 1 mg/kg with 5
mg/kg of caffeine, but not in any of those
given a lower dose of 0.8 mg/kg of ephed-
rine and 4 mg/kg of caffeine.
Figure 2. Monthly Weight Loss in Placebo-Controlled Trials
Favors
Intervention
Favors
Placebo
Ephedra vs Placebo
Donikyan (Unpublished Data, 2002)
Ephedra With Herbs Containing Caffeine vs Placebo
Boozer et al,18 2001
Boozer et al,17 2002
Colker et al,20 2001
Greenway et al (Unpublished Data)
Combined
Ephedrine vs Placebo
Jensen et al,22 1980
Lumholtz et al,25 1980
Moheb et al,9 1998
Pasquali et al,28 1985
Pasquali et al,28 1985
Quaade et al,29 1992
Combined
Ephedrine and Caffeine vs Placebo
Astrup et al,16 1992
Buemann et al,19 1994
Daly et al,21 1993
Jensen et al,22 1980
Kalman et al,23 2000
Kettle et al,24 1998
Malchow-Moller et al,26 1981
Moheb et al,9 1998
Molnar et al,27 2000
Quaade et al,29 1992
Roed et al,30 1980
Van Mil and Molnar,31 2000
Combined
Weight Loss, kg
–4.0 –3.0 –2.0 –1.0 0 1.0
Sizes of boxes correspond to sample sizes. Error bars indicate 95% confidence intervals.
EPHEDRA AND EPHEDRINE FOR WEIGHT LOSS AND ATHLETIC PERFORMANCE
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One other trial was identified. It re-
ported no statistically significant im-
provement in a battery of tests of physi-
cal function including oxygen uptake,
measures of endurance and power, re-
action time, hand-eye coordination,
speed, and self-perceived exertion.40
Safety Assessment:
Randomized Trials
Two of 52 trials were excluded from the
OR analysis because they did not have
a placebo group.32,41 There were nu-
merous symptoms reported as ad-
verse events in the remaining 50 trials
of ephedra and ephedrine. We grouped
clinically similar symptoms into 7 cat-
egories: (1) psychiatric symptoms, ie,
those described in the original clinical
trials as “euphoria,” “neurotic behav-
ior,” “agitation,” “neuropsychiatric,”
“depressed mood,” “giddiness,” “irri-
tability,” and “anxiety;” (2) auto-
nomic hyperactivity symptoms, ie,
those described in the original clinical
trials as “tremor,” “twitching,” “jitteri-
ness,” “insomnia,” “difficulty sleep-
ing,” “increased sweating,” “increased
perspiration,” and “sweating;” (3) up-
per gastrointestinal symptoms, ie, those
described in the original clinical trials
as “nausea,” “vomiting,” “abdominal
pain,” “upset stomach,” “heartburn,”
and “gastroesophageal reflux;” (4) pal-
pitations, ie, those symptoms de-
scribed in the original clinical trials as
“palpitations,” “irregular heartbeat,”
“loud heartbeat,” “heart pounding,” and
“increased or stronger heartbeat;” (5)
tachycardia, ie, those symptoms de-
scribed in the original clinical trials as
“tachycardia” and “slightly elevated
heart rate;” (6) hypertension, ie, those
symptoms described in the original
clinical trials as “hypertension,” “in-
creased systolic blood pressure,” and
“increased diastolic blood pressure;”
and (7) headache.
TABLE 3presents the pooled esti-
mate of the OR for each of those ad-
verse events for which there were
sufficient data to justify attempting
meta-analysis. The OR will slightly
overestimate the risk ratio for these
events, because they occur in 10% to
20% of participants. Participants in ac-
tive treatment had between 2.2 and 3.6
increased odds for the adverse events
of psychiatric symptoms, autonomic
hyperactivity, upper gastrointestinal
symptoms, and heart palpitations.
There was a trend toward an increase
of similar magnitude in the report of hy-
pertension, but this increase was not
statistically significant. In our dose
analysis, there was a trend toward
higher risk of adverse events with
higher doses of ephedrine, but data were
sparse and these differences were not
statistically significant (for example, ad-
justed ORs of autonomic hyperactiv-
ity were 2.7 and 10.4 for medium- and
high-dose ephedrine, respectively, but
the 95% CIs overlapped). It is not pos-
sible to estimate the degree to which
caffeine contributes to these results, be-
cause there were too few trials of ephed-
rine alone or ephedra alone to support
Table 2. Summary of Exercise Trials by Bell and Colleagues
Source
Compounds Received by
Comparison Groups Exercise Type Results
Bell et al,34 1998 Placebo
Ephedrine (1 mg/kg)
Caffeine (5 mg/kg)
Ephedrine (1 mg/kg) and
caffeine (5 mg/kg)
Cycle ergometer trials to
exhaustion
Ephedrine and caffeine significantly
increased time to exhaustion
compared with placebo. Heart rate
during exercise was significantly
increased for ephedrine and caffeine,
caffeine groups.
Bell and Jacobs,35 1999 Placebo
Ephedrine (75 mg) and
caffeine (375 mg)
Canadian Forces Warrior Test
(3.2-km run wearing 11 kg of
equipment)
Run times for ephedrine and caffeine trial
were significantly faster than those
for control and placebo trials.
Bell et al,36 1999 Placebo
Ephedrine (1 mg/kg) and
caffeine (5 mg/kg)
Treadmill walking at 50% VO2
peak, 40°C climate, 30%
relative humidity
Ephedrine and caffeine did not
significantly change tolerance times
when compared with placebo.
Ephedrine and caffeine did not affect
skin or rectal temperature, sweat
rate, or sensation of thermal comfort.
Bell et al,37 2000 Placebo
Caffeine (5 mg/kg) and
ephedrine (0.8 mg/kg)
Caffeine (4 mg/kg) and
ephedrine (1 mg/kg)
Caffeine (4 mg/kg) and
ephedrine (0.8 mg/kg)
Cycle ergometer trials to
exhaustion at 85% VO2peak
A lower dose of ephedrine and caffeine
resulted in ergogenic effect similar in
magnitude as reported previously
with a higher dose, while fewer
adverse effects were reported.
Pasternak et al,38 1999 Placebo
Ephedrine (0.8 mg/kg)
Caffeine (4 mg/kg)
Ephedrine (0.8 mg/kg) and
caffeine (4 mg/kg)
Three supersets of leg press and
bench press, to exhaustion
Ephedrine and ephedrine and caffeine
increased muscular endurance, but
only in the first set. Systolic blood
pressure was increased with
ephedrine and with ephedrine and
caffeine.
Bell et al,39 2001 Placebo
Ephedrine (1 mg/kg)
Caffeine (5 mg/kg)
Ephedrine 1 (mg/kg) and
caffeine (5 mg/kg)
Two different cycle ergometer
tests, with 1 to exhaustion at
125% VO2peak
Ephedrine improved performance during
Wingate test of anaerobic power.
Caffeine increased time to
exhaustion in second test.
EPHEDRA AND EPHEDRINE FOR WEIGHT LOSS AND ATHLETIC PERFORMANCE
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stratified analyses. The 1 trial of herbal
ephedra without herbs containing caf-
feine reported a statistically signifi-
cant 2-fold increase in gastrointestinal
symptoms.
If we consider all 1706 patients in the
treatment groups of all 52 trials, these
trials have at least 80% power to dis-
tinguish a serious adverse event rate of
1.0 per thousand or higher. Thus,
though we observed no serious ad-
verse events in any of these trials, the
relatively small aggregated sample size
across the treatment groups in all trials
limits the strength of our conclusions.
Safety Assessment: Case Reports
We reviewed 71 case reports in the pub-
lished literature, 1820 case reports in
the FDA MedWatch files, and 15951
cases reported to 1 manufacturer of
ephedra-containing dietary supple-
ments. The majority of case reports are
insufficiently documented to make an
informed judgment about a relation-
ship between the use of ephedrine- or
ephedra-containing dietary supple-
ments and the adverse event in ques-
tion. From the unpublished reports, 284
concerned serious adverse events and
had sufficient evidence to warrant de-
tailed review. We identified 2 deaths,
3 myocardial infarctions, 9 cerebrovas-
cular accidents, 3 seizures, and 5 psy-
chiatric cases as sentinel events with
prior ephedra consumption; and 3
deaths, 2 myocardial infarctions, 2 cere-
brovascular accidents, 1 seizure, and 3
psychiatric cases as sentinel events with
prior ephedrine consumption. We iden-
tified an additional 43 and 7 cases as
possible sentinel events with prior ephe-
dra and ephedrine consumption, re-
spectively. About half of sentinel events
occurred in persons aged 30 years or
younger (TABLE 4). Full details are
Table 3. Summary of Meta-analysis of Adverse Events Reporting in Controlled Trials
Adverse Event*No. of Studies
Sample Size, No.
Adverse Events
No.
Pooled OR (95% CI)Placebo Intervention Placebo Intervention
Psychiatric symptoms 8 273 351 16 59 3.64 (1.91-7.31)
Autonomic hyperactivity 13 365 587 39 138 3.37 (2.19-5.31)
Heart palpitations 11 386 563 18 51 2.29 (1.27-4.32)
Hypertension 5 257 305 3 7 2.19 (0.49-13.34)
Upper GI symptoms 10 432 568 46 88 2.15 (1.39-3.38)
Headache 5 123 185 8 16 1.64 (0.62-4.68)
Tachycardia 1 45 90 0 6 NR
Abbreviations: CI, confidence interval; GI, gastrointestinal; NR, not reported; OR, odds ratio.
*A study may contribute adverse events to more than 1 category.
Table 4. Summary of Adverse Events With Consumption of Ephedra or Ephedrine
Demographics
Death
Myocardial
Infarction/Other
Cardiac
Cerebrovascular
Accident/
Other Neurologic Seizure
Psychiatric
Symptoms
Ephedra Ephedrine Ephedra Ephedrine Ephedra Ephedrine Ephedra Ephedrine Ephedra Ephedrine
Total events, No.
Sentinel 2 3 3 2 9 2 3 1 5 3
Possible sentinel 9 3 9 1 11 2 7 0 7 1
Events by sex, No.
Women
Sentinel 1 1 0 2 5 2 3 1 2 1
Possible sentinel 3 1 4 1 8 0 5 0 4 0
Men
Sentinel 1 2 3 0 4 0 0 0 3 2
Possible sentinel 6 2 5 0 3 2 2 0 3 1
Events by age, No.
13-30 y
Sentinel 2 2 2 1 3 2 2 0 3 2
Possible sentinel 5 0 1 1 2 1 3 0 5 0
31-50 y
Sentinel 0 1 1 1 5 0 1 1 2 0
Possible sentinel 4 2 7 0 5 1 3 0 1 1
51-70 y
Sentinel 0 0 0 0 1 0 0 0 0 1
Possible sentinel 0 1 1 0 4 0 1 0 1 0
EPHEDRA AND EPHEDRINE FOR WEIGHT LOSS AND ATHLETIC PERFORMANCE
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, March 26, 2003—Vol 289, No. 12 1543
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available at http://www.ahrq.gov/clinic
/evrptfiles.html#ephedra.
COMMENT
We found sufficient evidence to con-
clude that the short-term use of ephed-
rine at high doses, or of ephedrine and
caffeine, ephedra, and ephedra with
herbs containing caffeine, promotes
weight loss in selected patient popula-
tions. These results satisfy, with 1 ex-
ception, published criteria42 for the
evaluation of weight loss products, as
they are randomized, blinded, placebo-
controlled, and resulted in a weight loss
of at least 5% of pretreatment weight.
The criterion not met is duration of
treatment, as all trials but 3 reported less
than 6 months duration of treatment.
Trials assessing 1 year of treatment are
considered desirable, as are trials as-
sessing what happens to weight after the
weight loss product is discontinued.
We can also conclude that caffeine
adds additional efficacy to ephedrine in
promoting weight loss, and the effects
of ephedrine and caffeine and ephedra
with or without herbs containing caf-
feine are approximately equivalent, each
resulting in about 0.9 kg per month of
weight loss above that lost with pla-
cebo, extending out to 4 months. To help
put these data in context, placebo-
controlled studies of some FDA-
approved weight loss pharmacothera-
pies have reported losses 2.7 to 4.5 kg
greater than losses with placebo over 6
to 12 months for patients taking sibutra-
mine43-46 or orlistat47-51; or 7.2 kg greater
than with placebo at 9 months for pa-
tients taking phentermine.52 There are
no data regarding weight loss beyond 6
months’ use of ephedrine or ephedra.
Regarding athletic performance, we
were unable to identify any controlled
trials of ephedra. The few identified
trials of ephedrine did not study it as
used by the general population, that is,
repeated use. Therefore, the effect of
ephedra or ephedrine as it is used to
promote enhanced athletic perfor-
mance is unknown.
We found sufficient evidence to con-
clude that ephedrine and ephedra are
associated with 2 to 3 times the risk of
psychiatric symptoms, autonomic symp-
toms, upper gastrointestinal symp-
toms, and heart palpitations. It is not pos-
sible to separate out the effect caffeine
may contribute to these events. As most
ephedra-containing dietary supple-
ments also contain herbs with caffeine,
this issue may be moot. We also found
a number of case reports of serious ad-
verse events that occurred in young
adults without apparent causes. Similar
observations have been made by oth-
ers2and raise the possibility that there
may be a causal relationship between
ephedrine or ephedra use and rare seri-
ous adverse events. A recent case-
control study reported an adjusted OR
of 3.59 (95% CI, 0.70-18.35) for hem-
orrhagic stroke in persons taking more
than 32 mg/d of ephedra. We note that
we found no studies of ephedra where
participants consumed less than 32 mg/d
of ephedra.53 In addition, another re-
cent report linked ephedra use to an in-
creased risk of adverse events reported
to poison control centers, relative to other
herbal products.54
Our study has several limitations.
Many of the trials had methods prob-
lems. However, not all trials did, and
our sensitivity analyses of the higher-
quality trials supported our main analy-
sis with respect to ephedrine and caf-
feine and with respect to ephedra. Only
for ephedrine alone did we find evi-
dence that higher-quality trials re-
ported smaller effects, as has been re-
ported in meta-analyses of other clinical
questions.11 Second, while we did not
find any evidence of publication bias,
this does not mean that it does not
exist. There is no way of ever knowing
if all trials conducted have been iden-
tified. We made reasonable efforts to
identify and did identify some unpub-
lished data. Third, we did not observe
significant heterogeneity among the
weight loss trials but acknowledge that
the 2test of heterogeneity is under-
powered. We used a random-effects ap-
proach and sensitivity analysis to try to
incorporate and understand possible
heterogeneity. The heterogeneity
among the athletic performance trials
prevented us from conducting a for-
mal meta-analysis at all. Fourth, 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 preexist-
ing conditions, such as heart disease,
that may predispose subjects to an in-
creased risk of adverse events. Such pa-
tients were then excluded from the
trials. Whether patients taking ephe-
dra or ephedrine without such medi-
cal screening have a similar risk of ad-
verse events is unknown. Finally, the
weight loss trials as a group had lim-
ited duration of treatment times and
thus we cannot draw conclusions about
the association between ephedra and
weight loss over longer and more clini-
cally relevant intervals than about 4
months, nor about what happens to
weight after the ephedra or ephedrine
is stopped.
With these limitations in mind we
found sufficient evidence to conclude
that ephedrine- and ephedra-contain-
ing dietary supplements have modest
short-term benefits with respect to
weight loss and have harms in terms of
a 2- to 3-fold increase in psychiatric
symptoms, autonomic symptoms, up-
per gastrointestinal symptoms, and
heart palpitations. More serious ad-
verse effects from ephedra use cannot
be excluded at a rate less than 1.0 per
thousand, and case reports raise the
possibility that a causal relationship
with serious adverse events may exist.
We did not find sufficient evidence to
support the use of ephedra for enhanc-
ing athletic performance.
Author Affiliations: Southern California Evidence-
based Practice Center–RAND, Santa Monica, Calif
(Drs Shekelle, Morton, Mojica, and Mss Maglione,
Suttorp, Rhodes, and Jungvig); Cedars-Sinai Medical
Center, Los Angeles, Calif (Dr Hardy); Greater Los An-
geles Veterans Affairs Healthcare System (Dr Shek-
elle); and Department of Family Medicine, University
of Southern California, Los Angeles (Dr Gagné).
Author Contributions: Study concept and design:
Shekelle, Hardy, Morton, Maglione, Suttorp.
Acquisition of data: Shekelle, Hardy, Morton,
Maglione, Mojica, Suttorp, Rhodes, Gagné.
Analysis and interpretation of data: Shekelle, Hardy,
Morton, Maglione, Suttorp, Jungvig.
Drafting of the manuscript: Shekelle, Morton, Suttorp,
Rhodes, Jungvig.
Critical revision of the manuscript for important in-
tellectual content: Shekelle, Hardy, Morton, Maglione,
Mojica, Suttorp, Jungvig, Gagné.
EPHEDRA AND EPHEDRINE FOR WEIGHT LOSS AND ATHLETIC PERFORMANCE
1544 JAMA, March 26, 2003—Vol 289, No. 12 (Reprinted) ©2003 American Medical Association. All rights reserved.
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Statistical expertise: Shekelle, Morton, Suttorp.
Obtained funding: Shekelle, Hardy, Morton, Maglione.
Administrative, technical, or material support: Shekelle,
Maglione, Mojica, Suttorp, Rhodes, Jungvig.
Study supervision: Shekelle, Morton, Maglione, Mojica.
Funding/Support: This research was performed by the
Southern California Evidence-based Practice Center–
RAND, Santa Monica, Calif, under Agency for Health-
care Research and Quality contract 290-97-0001.
Disclaimer: The authors of this article are respon-
sible for its contents. No statement in this article should
be construed as an official position of the Agency for
Healthcare Research and Quality or of the US De-
partment of Health and Human Services.
Acknowledgment: We thank Birgit Danila, MA, for
translation of Danish trials, and Elizabeth Roth for pro-
gramming advice. We also thank the members of our
Technical Expert Panel who advised us on the project
and reviewed our findings. Dr Shekelle was a Senior
Research Associate of the Veterans Affairs Health Ser-
vices Research and Development Service.
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EPHEDRA AND EPHEDRINE FOR WEIGHT LOSS AND ATHLETIC PERFORMANCE
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, March 26, 2003—Vol 289, No. 12 1545
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... Rimedi integrativi con un'azione di tipo adrenergico: Efedra sinica. L'Efedra sinica è una pianta di origini asiatiche il cui estratto contiene efedrina, un alcaloide con proprietà adrenergiche e stimolanti (20). Le prove di ef-ficacia dell'efedra nel favorire il calo ponderale riportate da una meta-analisi suggeriscono un possibile effetto a breve termine (<6 mesi) di −0,9 kg/mese rispetto al placebo (20). ...
... L'Efedra sinica è una pianta di origini asiatiche il cui estratto contiene efedrina, un alcaloide con proprietà adrenergiche e stimolanti (20). Le prove di ef-ficacia dell'efedra nel favorire il calo ponderale riportate da una meta-analisi suggeriscono un possibile effetto a breve termine (<6 mesi) di −0,9 kg/mese rispetto al placebo (20). L'efedrina, però, in virtù delle sue proprietà farmacologiche, risulta scarsamente maneggevole e può causare effetti collaterali anche gravi come aritmie cardiache, alterazioni del sistema nervoso autonomo, turbe psichiatriche e gastrointestinali (20). ...
... Le prove di ef-ficacia dell'efedra nel favorire il calo ponderale riportate da una meta-analisi suggeriscono un possibile effetto a breve termine (<6 mesi) di −0,9 kg/mese rispetto al placebo (20). L'efedrina, però, in virtù delle sue proprietà farmacologiche, risulta scarsamente maneggevole e può causare effetti collaterali anche gravi come aritmie cardiache, alterazioni del sistema nervoso autonomo, turbe psichiatriche e gastrointestinali (20). Citrus aurantium. ...
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Background. Overweight and obesity are conditions characterized by a growing epidemiological trend. Objective. The present review aims to collect evidence on the efficacy and safety of remedies derived from medicinal herbs and mushrooms commonly used for weight loss. Results. Various remedies, grouped on the basis of their mechanism of action, have been analyzed and discussed. Conclusions. Overall, the most interesting integrative remedies which favor weight loss in overweight or obese subjects seem to be Garcinia cambodia, Camellia sinensis, green coffee, Amorphophallus konjac, chitosan, and Phaseolus vulgaris, acting through different mechanisms on metabolism, nutrient absorption and the sensation of hunger. Further studies are needed to better evaluate the efficacy and safety profile of weight-loss supplements. CITE AS: Antonelli, M., & Donelli, D. (2019). Medicinal herbs and mushrooms for weight loss: an overview. Pharmanutrition and Functional Foods, 4(4), 12–17.
... Ephedra sinica (Es), also named ma huang, is commonly used in Asia as a traditional medicine for the treatment of common cold, flu, asthma, arthralgia, and edema for thousands of years [21]. Currently, Es and its principal active constituent, ephedrine, are commonly used as food additives for reducing body weight worldwide due to its powerful sympathomimetic action [22]. Several studies reported on the effects of Es on body weight loss in both obese human subjects and HFD-induced obese animal models associated with alteration of gut microbiota and regulation of adipokines [23,24]. ...
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