Ephedra and Ephedrine for Weight Loss and Athletic Performance Enhancement. Clinical Efficacy and Side Effects. Review of Evidence Report/Technology Assessment No. 76. AHRQ Publication No. 03-e022. Rockville, MD: Agency for Healthcare Research and Quality; March 2003. Available at: www.ahrq.gov/clinic/epcsums/ephedsum.htm.
Editor’s Note: A federal ban on the sale of ephedra-containing products is scheduled to take effect within days, and the evidence presented in the above named RAND Report provides clear rationale for such action. The authors of this impressive report offer a balanced, thorough exploration of a topic equally complex and controversial. A distillation of the information contained in the report follows. Save for introductory and concluding comments offered by this editor, all the information presented below is taken directly, and in some instances verbatim, from the RAND Report.—Russell H. Greenfield, MD
"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy."—Paracelsus
Ephedra-containing supplements are scheduled to be taken off the shelves this month as a result of precedent-setting action by the U.S. Food and Drug Administration (FDA). Notwithstanding high profile headlines and direct attempts to reach consumers with precautionary information, an estimated $500 million worth of ephedra was sold in 2003, down from $1.3 billion in 2002, according to the Nutrition Business Journal.1 Most retail chains have already stopped selling ephedra-containing products, and only a handful of major producers are still in this short-term market.
The rise of ephedra as a dietary supplement closely parallels the increase in waistlines of the U.S. population, and rising levels of frustration over the inability to lose a significant amount of weight easily. Over the past 40 years the prevalence of obesity (defined as body mass index [BMI] greater than or equal to 30.0 kg/m2) has increased from 13% to 31% in adults, while the prevalence of overweight (BMI of 25.0-29.9 kg/m2) has increased from 31% to 34%.2 According to 1999 NHANES data, 13% of children and adolescents currently are seriously overweight and displaying increasing rates of obesity-related chronic diseases, such as non-insulin dependent diabetes mellitus, not previously seen in children.3 The United States is not alone—in Canada between 1985 and 1998 overall prevalence of obesity increased in adults from 5.6% to 14%, and from 1981 to 1996 it tripled in children.4-8
Obesity is a risk factor for major causes of death, including cardiovascular disease, numerous types of cancer, and diabetes,9 and is linked with markedly decreased life expectancy.10,11 Other serious health risks associated with obesity include Syndrome X, hypertension, hyperlipidemia, coronary artery disease, stroke, gall bladder disease, sleep apnea, osteoarthritis, the development of certain cancers, and social stigmatization.12 Obesity increases both morbidity and mortality rates, especially those associated with heart disease and diabetes.13 Allison and colleagues estimated that in 1991 approximately 280,000 deaths were attributable to excess weight. Patients with BMI greater than 30.0 kg/m2 accounted for more than 80% of the obesity-attributable deaths.14
Fortunately, weight loss of but 5-10% of body weight that is followed by long-term weight maintenance can significantly improve health outcomes.15 Despite this fact, less than half of obese people report that their doctor recommended weight-loss interventions to them. In course, many have turned to agents like ephedra.
Stimulant use has long been popular among high performance athletes as well, and dietary supplement use by athletes overall is very common. In reviews, 56% of athletes16 and 42% of college athletes17 use dietary supplements, most notably elite male athletes.
History and PharmacologyThere is a remarkably long, rich history of medicinal use of ephedra as documented in treatises from China, and later in India. Branches of the small shrub traditionally have been used to treat colds, fevers, and wheezing, and as a diaphoretic.18 Ephedra has been approved by the German Commission E for treatment of diseases of the respiratory tract with mild bronchospasm in patients older than age 6.19
Also known as ma huang, ephedra is the common name for any of three species grown medicinally in China and recognized in the Chinese Materia Medica: Ephedra sinica, Ephedra equisentina, and Ephedra intermedia. Other species may be used for the preparation of commercial products, including Ephedra distachya and Ephedra gerardiana. North American species of ephedra, such as Ephedra nevadensis (known as mormon tea), reportedly contain little or no ephedrine.20,21
The alkaloid ephedrine, first isolated from ma huang in 1887, is defined as a mixed sympathomimetic agent that acts indirectly by enhancing the release of norepinephrine from sympathetic neurons, and directly by stimulating alpha- and beta-adrenergic receptors.22 Other alkaloids derived from ephedra act similarly but are less potent than ephedrine (see Table 1). Thus, the pharmacologic activity of a given ephedra sample depends on its alkaloid composition (see Table 2).
Combination formulations often are used for weight loss, and pharmaceutical preparations of ephedrine frequently include caffeine and/or aspirin. Caffeine alone has been shown to stimulate both thermogenesis and weight loss, both as an isolated alkaloid and as a botanical tea.23-25 Furthermore, caffeine potentiates the thermogenic effects of ephedrine by acting as an adenosine receptor antagonist and inhibiting phosphodiesterase activity.26,27 Botanical preparations often mimic these combined formulations by including caffeine—or salicylic acid-containing herbs, or those herbs (see Table 3) containing sympathomimetic amines such as Citrus aurantium (bitter orange). Other herbs frequently included in botanical weight-loss formulas include those with diuretic or laxative actions.
Regulatory History in the MakingA 2000 survey by manufacturers of ephedra-containing supplement products estimated that 3 billion servings of these products were consumed in the prior year (revealed during testimony at the Public Meeting on the Safety of Dietary Supplements Containing Ephedrine Alkaloids held Aug. 8, 2000). According to Michael McGuffin, an industry spokesman, this figure represented a 65% increase in sales over the previous five years, and would correspond to approximately $6.8 billion in total sales.28
Herbal ephedra has been used in China to treat respiratory conditions for more than 5,000 years; however, the herb is not used for weight loss or physical performance enhancement in Eastern medicine. Its active alkaloid, ephedrine, was first used in Western medicine as an asthma treatment in the 1930s. Since then, ephedrine and other sympathomimetic alkaloids have been used in many over-the-counter decongestants and cold medicines. It was not until the early 1990s that herbal ephedra and other products containing ephedrine began to be promoted as weight-loss aids in the United States.
In response to a growing number of adverse event reports submitted to the FDA about ephedra-containing products (more than 300 at the time), the FDA convened an open meeting of the Special Working Group on Food Products Containing Ephedrine Alkaloids (a working group of the Food Advisory Committee) in October 1995. 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. The working group found sufficient evidence to suggest adverse events were associated with the use of ephedrine alkaloids, that safe levels should be established, and that warning labels should appear on products containing ephedrine alkaloids regardless of source.
In August 1996, the FDA convened a meeting of its Food Advisory Committee to continue discussion of the safety of ephedrine-containing foods and supplements, by which time the number of adverse events reported to the FDA had doubled from the year before to more than 600. In 1997, the FDA published a proposed rule on the use of dietary supplements containing ephedrine alkaloids, advancing a dose limit of 8 mg ephedrine alkaloid per serving, a daily limit of 24 mg, a duration limit of seven days, and various label warnings. In July 1999, the General Accounting Office reported that the FDA had insufficient evidence to support dosage and duration limits. As a result, in early 2000 the FDA withdrew a large part of the 1997 proposal.
The American Herbal Products Association, for its part, did respond to safety issues surrounding the use of ephedra and ephedrine-containing supplements by drafting guidelines for dosage levels and label warnings in 1994, and revising them in 2000. Recommended dosing limits were 3-4 times higher than those proposed by the FDA in 1997.
From 1992 to 2002, more than 1,000 health-related problems were reported to the FDA. This, in large part, led the non-profit group Public Citizen to file a petition in 2001 asking the FDA to ban production and sale of ephedra products. In the fall of 2001, the National Football League banned ephedra following the deaths of several high school and college athletes after alleged use of ephedra-containing products.
In June 2002, the U.S. Department of Health and Human Services proposed an expanded scientific evaluation of ephedra.
The ReportUltimately, an evidence report by the RAND Corporation was published in 2003 detailing methodology, reports, and conclusions on the efficacy and safety of whole herb or extracts of the herb ephedra and the isolated alkaloid ephedrine, either alone or in combination with other substances, to promote weight loss or to enhance athletic performance (see Table 4). Conclusions were arrived at through a comprehensive literature review (see Tables 5-7) and subsequent synthesis of evidence.
In selecting studies for the meta-analysis of weight-loss efficacy, only those trials of at least eight weeks treatment duration were considered. In selecting studies on athletic performance, only those controlled trials addressing human subjects were chosen. As pertains to the latter, studies varied widely with respect to intervention. In light of such heterogeneity, studies on athletic performance were compared and contrasted in a narrative view, rather than performing a statistical synthesis.
Safety was assessed via review of clinical trials and compared to event rates for placebo groups, and meta-analysis was performed where appreciable numbers of adverse events were noted. All reports of adverse events were included in the analysis regardless of treatment duration. Adverse event reports on file with the FDA, published case reports, and reports to a major manufacturer of ephedra-containing products also were reviewed in depth. All available reports of death, myocardial infarction, cerebrovascular accident, seizure, or serious psychiatric illness filed before Sept. 30, 2001, were reviewed.
The FindingsEfficacy for Weight Loss. After excluding trials for methodological reasons, including short duration of intervention, 20 trials that contained a total of 678 people who consumed ephedra or ephedrine were assessed. The majority of these trials were still plagued by problems, especially high attrition rates (for the 16 weight-loss trials that reported baseline sample sizes, the attrition rate in the treatment arms averaged 27%, whereas the attrition rate in the placebo arms averaged 29%). The authors state the results of their review (see Table 8a) must be interpreted in light of this potential bias.
Nonetheless, the reviewers state evidence points to a definite association between short-term use of ephedrine, ephedrine plus caffeine, or dietary sup- plements that contain ephedra with or without herbs that contain caffeine, and a statistically significant increase in weight loss compared with placebo. Adding caffeine to ephedrine modestly increases the amount of weight loss. There is no evidence that the effect of ephedra-containing dietary supplements with herbs that also contain caffeine differs from that of ephedrine plus caffeine—both result in weight loss of approximately 2 lbs/month more than with placebo for up to 4-6 months.
No studies have assessed the long-term effects of ephedra-containing dietary supplements or ephedrine on weight loss (the longest duration of treatment in a published study was six months).
Efficacy for Athletic Performance. The effect of ephedrine was assessed in seven studies (mostly crossover studies, all but one also including caffeine, and all measuring a variety of exercises as well as outcome measures). These studies focused on small samples of young male military recruits and assessed effects only on very short-term immediate athletic performance. Thus, the studies do not provide particularly useful information on ephedrine as reportedly used in the general population. No studies were identified that assessed the effect of herbal ephedra-containing dietary supplements on athletic performance.
The available data support a modest effect of ephedrine plus caffeine on very short-term athletic performance (see Table 8b). The only trial that assessed the additive effects of these agents reported that ephedrine must be supplemented with caffeine to affect athletic performance. The sustained use of ephedrine on performance over time has yet to be formally assessed.
Safety Issues. Evidence from controlled trials was sufficient to conclude that use of ephedrine and/or use of ephedrine-containing dietary supplements or ephedrine plus caffeine is associated with a two- to three-fold increased risk of nausea, vomiting, psychiatric symptoms such as anxiety and change in mood, autonomic hyperactivity, and palpitations (see Table 8c). A trend toward an increase of similar magnitude was noted for hypertension, but the increase was not statistically significant; a non-significant trend toward an increase in headaches also was identified. The majority of case reports are insufficiently documented to make informed judgment about the relationship between ephedrine and adverse events.
For prior consumption of ephedrine-containing products, the authors identified two deaths, three myocardial infarctions, nine cerebrovascular accidents, three seizures, and five psychiatric cases as sentinel events (see Table 8d). For prior consumption of ephedrine, reviewers identified three deaths, two myocardial infarctions, two cerebrovascular accidents, one seizure, and three psychiatric cases as sentinel events. An additional 43 cases were identified as possible sentinel events with prior ephedra consumption, and seven additional cases as possible sentinel events with prior ephedrine consumption. Approximately half the sentinel events occurred in people aged 30 years or younger. The authors caution that classification as a sentinel event does not imply a proven cause-and-effect relationship.
In dosage analysis, there was a trend toward a higher risk of adverse events with higher doses of ephedrine, but data were sparse, and differences were not statistically significant. The pattern of symptoms with statistically significant findings is consistent with the pharmacology of ephedrine.
Short descriptions of the adverse event cases that were reviewed by the authors are included in the report. The authors also offer their recommendations on future research directions. Limitations of this review can be found in Table 9.
Editor’s Concluding CommentsDespite a time-honored tradition of medicinal use spanning literally thousands of years, the herb ephedra and its alkaloid ephedrine will no longer be available in the United States. The FDA took this action because it is warranted, perhaps even long overdue, but not because the herb is inherently dangerous. Rather, the herb and its alkaloid were being both marketed in high concentrations and misused for maladies as never promoted by traditional healers and herbalists.
Sadly, people across America are scrambling to get their hands on the dwindling supplies of the herb before the March deadline, willing to risk their health and their lives for the promise of 2 lbs/month more weight loss than is offered by placebo, or the lure of short-term gain in athletic performance.
According to consultant Loren Israelsen, however, there will be an exclusion under the ban to allow professionals to use ephedra under traditional Chinese medicine (TCM) principles or traditions. Unscrupulous individuals may try to take advantage of this by selling mock TCM products that contain ephedra. There is, and will remain, a market for ephedra-containing dietary supplements. In addition, patients already may be using or considering many products and services of debatable efficacy and/or safety (see Tables 10a-c).
As health care practitioners we must remain vigilant and steadfast in dissuading our patients from being tempted by the quick, and potentially deadly, fix for overweight and obesity that is ephedra, and partner with them in exploring safe dietary and lifestyle measures for weight control.
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