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# Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement

*Evidence Reports/Technology Assessments, No. 76*

Paul Shekelle, MD, PhD, Task Order Director, Sally C Morton, PhD, Senior Statistician, Margaret Maglione, MPP, Project Manager/Policy Analyst, Mary Hardy, MD, Task Order Co-Director, Marika Suttorp, MS, Statistician, Elizabeth Roth, MA, Senior Programmer/Analyst, and Lara Jungvig, BA, Programmer/Analyst. Physician Reviewers: Walter A Mojica, MD, MPH and James Gagné, MD. Staff Assistants: Shannon Rhodes, MFA and Eileen McKinnon, BA.

Agency for Healthcare Research and Quality (US)2003 Mar
Report No.: 03-E0221-58763-135-0

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## Structured Abstract

#### Objectives:

To assess the efficacy of herbal ephedra-containing dietary                supplements and ephedrine on weight loss and athletic performance, through                comprehensive literature review and synthesis of evidence. We also assessed safety                of these products through review of adverse events reported in clinical trials,                published case reports of adverse events, reports on file with the U.S. Food and                Drug Administration (FDA), and a file of reports kept by a manufacturer of ephedra                products, Metabolife.

#### Search Strategy:

We searched for studies of herbal ephedra and                ephedrine using the following electronic databases: Medline, EmBase, BIOSIS, Allied                & Complementary Medicine Database (AMED), MANTIS, the Cochrane Controlled                Clinical Trials Register Database, International Pharmaceutical Abstracts, Pascal,                and SciSearch. We were able to obtain unpublished studies by posting notices in                relevant journals and through contacts on our Technical Expert Panel. The FDA                provided us with copies of over 1,000 adverse event reports (AERs) related to herbal                ephedra and 125 adverse event reports related to ephedrine. The Metabolife files                contained 18,502 cases.

#### Selection Criteria:

Only studies of weight loss that were controlled                trials of human subjects with treatment of at least eight weeks duration were                accepted to assess efficacy. For assessment of athletic performance, only controlled                trials of human subjects were accepted, but no minimum follow-up was specified.                Reports of adverse events from controlled trials were included regardless of                treatment duration. We reviewed all available reports of death, myocardial                infarction (heart attack), cerebral vascular accident (stroke), seizure, and serious                psychiatric illness reported to the FDA prior to September 30, 2001 and contained in                their ephedra or ephedrine files, and all case reports identified in our literature                search.

#### Data Collection and Analysis:

We found 59 articles that corresponded to                52 controlled clinical trials of ephedrine or herbal ephedra for weight loss or                athletic performance. Forty-four were controlled trials assessing ephedra or                ephedrine for weight loss. Of these, 18 were excluded from pooled analysis because                they had treatment durations of less than eight weeks. Thirteen articles                corresponding to six trials were excluded for a variety of reasons. For the outcome                of weight loss the effects of ephedra/ephedrine 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. Only four placebo-controlled trials assessed the                combination of ephedra plus herbs containing caffeine, and only one trial assessed                ephedra without herbs containing caffeine. Because of their small number and                heterogeneity, eight athletic performance trials were compared and contrasted using                only a narrative review and were not synthesized statistically. We also conducted a                pooled meta-analysis on those adverse event symptoms that occurred frequently in the                controlled trials.

In reviewing the individual adverse event reports, we searched for documentation that                an adverse event had occurred, documentation that the subject had consumed ephedra                within 24 hours prior to the adverse event, or a toxicological examination revealing                ephedrine or one of its associated products in the blood or urine. We also sought                evidence that an adequate investigation had assessed and excluded other potential                causes. Cases that met all these criteria were labeled “sentinel events.” Cases that                met the first two criteria but had other possible causes of the event were labeled                “possible sentinel events.” Classification as a sentinel event does not imply a                proven cause and effect relationship. We used clinical judgment of expert clinicians                to assess whether other causes had been adequately evaluated and excluded.

#### Main Results:

*Weight Loss.* Short-term use of ephedrine, ephedrine plus caffeine,                or dietary supplements containing ephedra with or without herbs containing caffeine                is associated with a statistically significant increase in short-term weight loss                (compared to placebo). The addition of caffeine to ephedrine is associated with a                statistically significant modest increase in short-term weight loss. The observed                effects on weight loss of ephedrine plus caffeine and ephedra-containing dietary                supplements with or without herbs containing caffeine are approximately equivalent:                a weight loss 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                ephedrine or ephedra-containing dietary supplements on weight loss; the longest                published treatment duration was six months.

*Athletic Performance.* The effect of herbal ephedra-containing                dietary supplements on athletic performance has not been assessed. The few studies                that assess the effect of ephedrine on athletic performance have included only small                samples of fit individuals (young male military recruits) and have assessed its                effect only on very short-term immediate performance. These data support a modest                effect of ephedrine plus caffeine on very short-term athletic performance. One study                reported the addition of caffeine to ephedrine is necessary to produce an effect on                athletic performance. No studies have assessed the sustained use of ephedrine on                performance over time.

*Safety Issues.* There is sufficient evidence from controlled trials                to conclude that the use of ephedrine and/ or the use of ephedra-containing herbal                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 controlled trials studied relatively                few people and in aggregate were insufficient to evaluate events with a risk of less                than 1.0 per one thousand.

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. Prior ephedra consumption was                associated with two deaths, three myocardial infarctions, nine cerebrovascular                accidents, three seizures, and five psychiatric cases as sentinel events. Prior                consumption of ephedrine was associated with 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 with prior ephedrine consumption. About half the sentinel events occurred in                persons aged 30 years or younger.

#### Conclusions:

Ephedrine, ephedrine plus caffeine, and ephedra-containing                dietary supplements with or without herbs containing caffeine all promote modest                amounts of weight loss over the short term. There are no data regarding long-term                effects on weight loss. Single-dose ephedrine plus caffeine has a modest effect on                athletic performance. The available trials do not provide any evidence about                ephedrine or ephedra-containing dietary supplements, as they are used by the general                population, to enhance athletic performance. Use of ephedra or ephedrine plus                caffeine is associated with an increased risk of gastrointestinal, psychiatric, and                autonomic symptoms. The adverse event reports contain a sufficient number of cases                of death, myocardial infarction, cerebrovascular accident, seizure, or serious                psychiatric illness in young adults to warrant a hypothesis-testing study, such as a                case-control study, to support or refute the hypothesis that consumption of ephedra                or ephedrine may be causally related to these serious adverse events.

## Contents

                          - Expand All
                          - Collapse All

                        - Preface
                        - Acknowledgment
                        - Summary
                        - 1. Introduction                           - Purpose
                          - Scope of Work
                          - Background
                          - History and Pharmacology
                        - 2. Methods                           - Original Proposed Key Questions
                          - Technical Expert Panel
                          - Literature Search
                          - Article Review
                          - Meta-Analysis
                          - Safety Assessment
                          - Peer Review
                        - 3. Results                           - Results of Literature Search
                          - Efficacy
                          - Safety Assessment
                        - 4. Limitations
                        - 5. Conclusions                           - Efficacy
                          - Adverse Consequences
                        - 6. Future Research
                        - References
                        - Evidence Tables
                        - Acronyms
                        - Appendix 1. Bibliography
                        - Appendix 2. Metabolife Serious Adverse Events
                        - Appendix 3. Reviewer Comments

                          - Expand All
                          - Collapse All

Prepared for: Agency for Healthcare Research and                            Quality, U.S. Department of Health and Human Services.1             Contract No. 290-97-0001, Task Order No. 9. Prepared by: Southern California Evidence-Based Practice Center, RAND.

#### Suggested citation:

Shekelle P, Morton, S., Maglione M, et al. Ephedra and Ephedrine for Weight Loss and                Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Evidence                Report/Technology Assessment No. 76 (Prepared by Southern California Evidence-based                Practice Center, RAND, under Contract No 290-97-0001, Task Order No. 9). AHRQ                Publication No. 03-E022. Rockville, MD: Agency for Healthcare Research and Quality.                February 2003.

This report may be used, in whole or in part, as the basis for development of                clinical practice guidelines and other quality enhancement tools, or a basis for                reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human                Services endorsement of such derivative products may not be stated or implied.

AHRQ is the lead Federal agency charged with supporting research designed to improve                the quality of health care, reduce its cost, address patient safety and medical                errors, and broaden access to essential services. AHRQ sponsors and conducts                research that provides evidence-based information on health care outcomes; quality;                and cost, use, and access. The information helps health care decisionmakers—patients                and clinicians, health system leaders, and policymakers—make more informed decisions                and improve the quality of health care services.

The authors of this report are responsible for its content. Statements in the report              should not be construed as endorsement by the Agency for Healthcare Research and              Quality or the U.S. Department of Health and Human Services of a particular drug,              device, test, treatment, or other clinical service.

                        - 1
                        - 
2101 East Jefferson Street, Rockville, MD 20852. www​.ahrq.gov

Copyright Notice

Bookshelf ID: NBK36915

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                    - Cite this Page Shekelle P, Morton SC, Maglione M, et al. Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects. Rockville (MD): Agency for Healthcare Research and Quality (US); 2003 Mar. (Evidence Reports/Technology Assessments, No. 76.)

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