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EE: Ephedra (2005)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
  • This evidence report details the methodology, results, and conclusions of a comprehensive literature review and synthesis of evidence on the efficacy and safety of ephedra and ephedrine, either alone or in combinations with other substances, to promote weight loss or to enhance athletic performance. Meta-analysis was performed where appropriate.
Inclusion Criteria:
  1. All study designs
  2. Discussion of ephedra, ephedra + caffeine, or ephedra (herbal preparations) to outcome measures.
Exclusion Criteria:
  1. Editorials
  2. Letters to the editor
  3. Animal studies.
Description of Study Protocol:

Search procedures

  • Very extensive database searches: Medline, EMBASE, BIOSIS, AMED, MANTIS, Cochrane Controlled Clinical Trials Register Database; International Pharmaceutical Abstracts, Pascal, and SciSearch International data bases.
  • Study quality assessed using a standardized form.

Outcomes

  1. Weight loss
  2. Improved athletic performance
  3. Additive effects of ephedra
  4. Safety assessment of ephedra.
Data Collection Summary:
  1. Author, year
  2. Design,
  3. Study quality
  4. Population
  5. Jadad Score
  6. Co-morbidies
  7. Intervention to include total daily dose, route of administration and duration
  8. Sample size
  9. Summary of results.

Analysis:

  1. Pooled average percent weight loss
  2. Sensitivity analysis suing Jadad score
  3. Pooled effect score
  4. Publication bias analysis
  5. Dose analysis.
Description of Actual Data Sample:
  • 59 articles included
  • 530 articles identified.

Number and type of studies reviewed: 59 reported results from randomized clinical trials or controlled clinical trials that assessed the effects of either ephedrine or herbal ephedra on weight loss or athletic performance.

Articles that did not go on to initial data abstraction included 71 case reports or case series articles that reported adverse events.

149 articles were rejected from further review for “topic” i.e., articles did not discuss ephedra or ephedrine; 100 were rejected for “subject”; 68 articles were rejected for population (i.e., majority were animal studies); 4 articles were government documents or public testimony and rejected; 75 were rejected for design (i.e., editorials, commentaries, letters to journal editors, etc).

Summary of Results:

PHYSIOLOGY OF EPHEDRA AND ADVERSE EFFECTS

Ephedrine is defined as a mixed sympathomimetic agent, which acts indirectly by enhancing the release of norepinephrine from sympathetic neurons and directly by stimulating alpha and beta adrenergic receptors. In the cardiovascular system, ephedrine increases heart rate and therefore cardiac output. Because of its peripheral vasoconstriction activity, ephedrine increases peripheral resistance and can lead to a sustained rise in blood pressure. Ephedrine acts as a bronchodilator in the lung and crosses the blood-brain barriers where it acts as a central nervous system stimulant.

Ephedrine is readily absorbed from the gastrointestinal tract, with peach concentrations of an oral, immediate-release dose achieved at approximately two to three hours. The half-life of ephedrine in the blood (the time required to reach half the peak concentration) is six hours. The pharmacokinetics of pseudoephedrine and phenylpropanolamine (norephedrine) are similar.

Reported adverse events involved primarily the cardiovascular and central nervous systems. Most events occurred in young to middle-aged women, often those using the products for weight loss or to increase energy.

EPHEDRA AND WEIGHT LOSS

44 of the 52 unique controlled trials assessed the effects of ephedra, ephedrine, or ephedrine and other compounds on weight loss. Criteria had to have a treatment duration of >8 weeks. The interventions were sorted as follows:

  1. Ephedrine versus placebo
  2. Ephedrine plus caffeine versus placebo
  3. Ephedrine plus caffeine versus ephedrine alone
  4. Ephedrine versus another active pharmaceutical for weight loss
  5. Ephedra versus placebo
  6. Ephedra plus herbs containing caffeine versus placebo.

For the 16 reported baseline sample sizes, the attrition rate in the treatment arms averaged 27%, whereas the attrition rate in the placebo arms averaged 29 percent. This difference was not statistically significant. No significant association was found between the frequency of favorable results and the relative proportion of dropouts in the treatment and placebo groups.

EPHEDRINE VERSUS PLACEBO (n= 5 trials with 6 comparisons)

Pooled average percent weight loss in the ephedrine-treated patients, compared to pretreatment weight, was 11% at 4 months.

A sensitivity analysis on only those trials that scored 3 or > on the Jadad scale had an attrition rate >20% and yielded a pooled estimated of effect substantially lower than the main analysis (effect size=-0.20); this difference was stastistically significant (P=0.049).

In a dose analysis, only high doses of ephedrine resulted in a weight loss that was significantly greater than zero, and the difference in weight loss between medium dose trials and high dose trials approached statistical significance (P=0.052). Neither graphical nor statistical tests yielded evidence of publication bias... These data indicate that use of ephedrine is associated with a statistically significant increase in weight loss (1.3 pounds of weight loss per month) compared with that of placebo for up to four months of use.

EPHEDRINE PLUS CAFFEINE VERSUS PLACEBO (12 trials)

Pooled average percent weight loss in the ephedrine-treated patients, compared to pretreatment weight, was 11% at 4 months.

Four sensitivity analyses were performed.

Sensitivity analysis on those that scored =3 on Jadad scale was performed vs. only those that scored =3 Jadad scale AND with <20% drop-out. This yielded a similar pooled estimate effect size of weight loss of -0.74 (95% CI: -1.2, -0.3).

A dose analysis indicated a trend toward increased weight loss with higher doses (i.e., weight loss greater than placebo of 2.0, 2.2, and 2.6 lb per month for low, medium and high doses, respectively) but these differences were not statistically significant (i.e., no difference between).

Data indicate the use of the combination of ephedrine and caffeine is associated with a significantly greater (2.2 pound) weight loss per month than is associated with placebo, for up to four months duration.

EPHEDRINE PLUS CAFFEINE VERSUS EPHEDRINE (3 trials)

All had attrition rates >20%.

The random effects pooled estimate of the rate of weight loss per month was -0.31 (95% CI: -0.61, -0.02) which equates to a weight loss of 0.8 pounds per month more than with ephedrine alone.

EPHEDRINE VERESUS ANOTHER ACTIVE WEIGHT LOSS THERAPY (two Danish trials)

In each of the trials, there were ~40 patients taking ephedrine and 40 patients taking other treatments. Based on a two-sided test of significance level 0.05 and assuming the same variance in both groups, trials of this size have only 59% power to distinguish between an 8.4 kg (18.4 lb in 12 weeks) weight loss in the ephedrine group and a 6.4 kg (14.1 lbs in 12 weeks) weight loss in the active treatment group (i.e., a difference of 30% between the groups. In order to attain 80% power, a study would need 67 ephedrine patients and 67 comparison treatment patients. No statement of effect is made.

EPHEDRA VERSUS PLACEBO (one trial; i.e., Metabolife)

The trial lasted 3 months, and the ephedra arm lost 1.8 pounds more per month than did those in the placebo arm (95% CI: -2.7, -1.0). There was 17% attrition.

EPHEDRA PLUS HERBS CONTAINING CAFFEINE VERSUS PLACEBO (4 trials)

The pooled average percent weight loss in the ephedra-treated patients, compared to pre-treatment weight, was 5.2% at four months. Pooled random effects estimate of the rate of weight loss per month of these four trials was -0.81 (95% CI: -1.12, -0.51), which equates to a weight loss of 2.1 pounds per month more than that for placebo, for up to four months.

META-REGRESSION ANALYSIS

A meta-regression analysis assessing the effects of ephedrine, ephedrine plus caffeine, and ephedra plus herbs containing caffeine on weight loss, shows the following

  • P-value for test vs. ephedra + herbs Pooled monthly wt contain loss vs. placebo (lb) 95% CI caffeine
  • Epehedrine vs. placebo: -1.3 -2.1,-0.43 0.17
  • Ephedra + herbs containing caffeine: -2.1 -2.1,-1.3 NC
  • Ephedrine + caffeine: -2.2 -2.8,-1.7 0.75.

N.C. = Not calculated as this is the comparison group.

Ephedrine plus caffeine and ephedra plus hers containing caffeine are somewhat more effective than ephedrine alone in promoting weight loss and there is no difference in effect between ephedrine plus caffeine and ephedra plus herbs containing caffeine.

To put in context, we note that placebo-controlled trials of some FDA-approved weight loss pharmacotherapies have shown losses of 6-10 lbs more than placebo, over 6-12 months for patients taking sibutramine or orlistat; or 16 lbs more than placebo at 9 months for patients taking phentermine.

ATHLETIC PERFORMANCE

8 published controlled trials of the effects of synthetic ephedrine on athletic performance; one did not report athletic performance outcomes; the remaining 7 trials could not be pooled for analysis because they included various types of exercise and outcome measures.

A trial of 12 males (6= 40 mg ephedrine orally/day) vs 6=placebo) studied by Oksbjerg N et al, 1986 showed an increased thermogenic effect of 4.3±1.3 watt was established for the ephedrine group compared to the 1.6±1.6 watt f the placebo. The thermogenic effect in the ephedrine group increased by 100% following aerobic training. (P<0.05).

CASE STUDIES

  • No data abstracted for this report.
Author Conclusion:

Efficacy

The efficacy of herbal ephedra-containing dietary supplements has not been extensively studied in randomized clinical trials.

The majority of studies-of both ephedra and ephedrine-are plagued by methodological problems known to be associated with bias, particularly high attrition rates. All of the conclusions on efficacy need to be considered with these methodological limitations in mind.

WEIGHT LOSS

The short-term use of ephedrine, ephedrine plus caffeine, or the assessed dietary supplements containing ephedra and herbs with caffeine is associated with a statistically significant increase in short-term weight loss (compared to placebo).

There are no sutides assessing the long-term effects of the use of ephedra-containing dietary supplements or ephedrine on weight loss or maintenance.

There are no dat to indicate that the effects of ephedrine plus caffeine are different from the effects of ephedra-containing dietary supplements with caffeine-containing herbs.

The effect of ephedra-containing dietary supplemnts with caffeine-containing herbs or ephedrine plus caffeine is a weight loss that is approximately two pounds per month greater than that of placebo, for up to four to six months duration.

As a percentage of pretreatment weight, the weight losses in these studies average between 5-11% in the treatment groups.

The only two studies that compared ephedrine plus caffeine to prescription weight loss pharmaceutical products reported no differences in effectiveness between products, but these studies were statistically underpowered to detect differences of moderate size.

The addition of caffeine to ephedrine is associated with a statistically significant increase in short-term weight loss. The data suggest a dose-response relationship with respect to ephedrine and weight loss.

All published studies on herbal ephedra and weight loss have used a medium dose of ephedra per day; consequently, no dose-response analysis is possible.

ATHLETIC PERFORMANCE

  • Not reported.

ADVERSE CONSEQUENCES

There is sufficient evidence from short-term controlled trials to conclude that the use of ephedrine and/or the use of ephedra 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. It is not possible to separate out the contribution of caffeine to these events.

There were no reports of serious adverse events in the controlled trials of ephedrine or ephedra, but these studies are insufficient to assess adverse events that occurred at a rate of less than 1.0 per 1000.

A large number of adverse event reports regarding the herbal ephedra-containing dietary supplements have been filed with FDA. The majority of FDA case reports are insufficiently documented to make an informed judgment about the relationship between the use of ephedra-containing dietary supplements and the adverse event in questions.

A very large number of adverse events were reported to one manufacturer of ephedra-containing dietary supplements. Nearly all of the case reports were too poorly documented to permit us to make any judgments about the potential relationship between ephedra use and the event.

About half of the sentinel events occurred in persons aged 30 years or younger.

Scientific studies (not additional case reports) are necessary in order to assess the possible association between consumption of ephedra-containing dietary supplements and those serious adverse events. Given the rarity of such events, a properly designed case control study would be the appropriate next step. Such a study would need to control for caffeine consumption.

Funding Source:
Reviewer Comments:
  • Extremely thorough systematic review with the use of meta-analysis
  • All tools available to abstract and critique process
  • Generalizable to adults in U.S. and Canada.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? N/A
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? N/A
  1.3. Were the target population and setting specified? N/A
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? N/A
  2.2. Were criteria applied equally to all study groups? N/A
  2.3. Were health, demographics, and other characteristics of subjects described? N/A
  2.4. Were the subjects/patients a representative sample of the relevant population? N/A
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) N/A
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? N/A
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) N/A
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) N/A
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? N/A
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? N/A
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? N/A
  7.2. Were nutrition measures appropriate to question and outcomes of concern? N/A
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? N/A
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? N/A
  7.5. Was the measurement of effect at an appropriate level of precision? N/A
  7.6. Were other factors accounted for (measured) that could affect outcomes? N/A
  7.7. Were the measurements conducted consistently across groups? N/A
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? N/A
  8.2. Were correct statistical tests used and assumptions of test not violated? N/A
  8.3. Were statistics reported with levels of significance and/or confidence intervals? N/A
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? N/A
  8.6. Was clinical significance as well as statistical significance reported? N/A
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? N/A
  9.2. Are biases and study limitations identified and discussed? N/A
10. Is bias due to study's funding or sponsorship unlikely? No
  10.1. Were sources of funding and investigators' affiliations described? N/A
  10.2. Was the study free from apparent conflict of interest? N/A