Submitted by
Wanda K. Jones, Dr.P.H.
Deputy Assistant Secretary for Health (Women's Health)
Director, Office on Women's Health

The Office on Women's Health, U.S. Department of Health and Human Services (HHS), convened a public meeting August 8-9, 2000, to discuss available information about the safety of dietary supplements containing ephedrine alkaloids (EADS). These products are promoted for uses such as weight loss, body building, and increased energy. A planning group representing components of HHS developed four questions on which abstracts were solicited from interested parties. A panel of experts (attached-Tab A) from both HHS and the U.S. Army assisted OWH in clarifying information presented during the workshop.

Two industry panels and 18 individuals or organizations submitted abstracts for presentations; an additional 34 individuals or organizations requested time to make remarks during the public comment sessions. The next section contains a summary of the information presented at the meeting, organized according to the questions. It does not reflect interpretation by, or opinions of, the panel of experts. The last section of this report consists of the observations and concerns of the Office on Women's Health stemming from the meeting.

A schedule (Tab B) and participant list (Tab C) is appended to this report for reference. All speakers were asked to report the source of funding for their research, their travel, or their presentation; these disclosures are contained in the transcript of the meeting. A complete transcript is available from:

Freedom of Information Office (HFI-35)

Food and Drug Administration

5600 Fishers Lane, Rm. 12A-16

Rockville, MD 20857

(Cost is 10 cents per page, and there are approximately 700 pages)

The transcript can also be viewed on the internet at http://www.fda.gov, and at http://www.4woman.gov. A copy of the transcript is available for examination at the Dockets Management Branch, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852 between 9:00 a.m. and 4:00 p.m., Monday through Friday.

MEETING SUMMARY

Question 1. What positive and adverse physiologic actions would be expected of ephedra based on its known constituents? Does the available information show an association between the use of dietary supplements containing ephedrine alkaloids and adverse events (i.e., cardiovascular, central nervous system, psychotropic, etc.) when used as directed?

Information Presented

Six different ephedrine alkaloids are found in Ephedra spp., known in traditional Chinese medicine as ma huang. "Ephedrine", used here to refer to the main active ingredient in ephedra, may be either plant-derived or chemically synthesized. Ephedra is used to refer to the group of botanical preparations classified as dietary supplements and which contain variable amounts and types of ephedrine alkaloids. Historically, these compounds have been used as nasal decongestants and bronchodilators (in fact, numerous over-the-counter ¬OTC| cold and sinus medications containing ephedrine are available); secondary uses have been for urticaria, enuresis, narcolepsy, and chronic postural hypotension.

Ephedrine acts by stimulating a, ß₁, and ß₂ adrenergic receptors, and indirectly by releasing norepinephrine from body stores. Depletion of these stores at least partially accounts for the reduced efficacy of ephedrine observed with repeated dosing. The cardiovascular effects of ephedrine last 10 times longer than those of epinephrine, and consist primarily of increased heart rate and peripheral vascular resistance (hypertension). In the central nervous system (CNS), ephedrine has a longer duration of action than epinephrine. A psychoactive effect evidenced by a feeling of well-being has been reported to accompany ephedrine use; however, research with ephedrine in subhuman primates suggests evidence of dopaminergic neuron damage similar to that caused by methamphetamine. A central anorectic effect and a peripheral thermogenic effect also have been noted (although some presenters suggested caffeine is a more potent thermogenic agent).

Both benefits and adverse effects can be predicted reasonably from the known metabolic actions of these compounds. Whether these events are seen in practice is not always clear, since few clinical studies have been performed to address either the positive or the negative impact of EADS. Studies reported to date have been small and of short duration, although study dropout has been attributed to adverse effects such as palpitations, high blood pressure, irritability, and insomnia. The available evidence for adverse effects, particularly from the adverse event reports (AERs) submitted to FDA, is very circumstantial. While these reported adverse events give cause for concern, the AER data set is not robust. Subject matter experts at the meeting pointed out inherent weaknesses of a passive reporting system. Certain rare adverse events plausibly and temporally may be related to use of EADS, but opinion was divided on the value of the AER system in assessing the strength of the association. Information presented at, and contained in the transcript of, this meeting indicates a need for enhanced AER capability, including engaging industry to improve the quality of the system.

Question 2. Are there any circumstances for which there are well-established indications for the use of dietary supplements containing ephedrine alkaloids? What dose and duration of use are needed for those indications? What is the quality of any data to support such use?

Information Presented

Traditional Chinese medicine (TCM) has used ma huang (plant-derived ephedrine) for short durations to treat upper respiratory conditions; however, indications are not well-established except through the practices handed down and recorded in textbooks of TCM. Numerous OTC medications for colds and sinus congestion containing ephedrine are available. A related compound, phenylpropanolamine (PPA), is an ingredient in numerous OTC and dietary supplement products marketed for weight loss and as a decongestant. Both synthetic and naturally derived forms of PPA are available; OTC products contain synthetic PPA, while dietary supplements containing PPA can be synthetic, naturally derived, or some combination thereof.

The efficacy of ephedra or EADS for weight loss or body building specifically is not supported by a large number of high quality, randomized controlled clinical trials. The few trials and studies reported at the meeting consisted primarily of small groups (fewer than 150) and short durations of use (6-8 weeks); data on long-term weight loss and maintenance are scarce and may be confounded by calorie-restricted diets. A number of presenters did suggest that the results of newer studies to be published this fall show that EADS may be effective and safe for short term weight loss. Doses and durations of use as recommended by industry are empiric, not supported by clinical evidence. Moreover, dosage recommendations vary by proponent and by study. Studies reported at the meeting varied from use of 8 to 25 mg total alkaloids per dose, for a total of 72 to 150 mg total per day, and sometimes in a formulation combined with caffeine.

Question 3. How would you characterize the seriousness and/or severity of the risks of ephedrine alkaloids labeled for weight loss and exercise enhancement, taking into account issues such as user demographics (age, sex, race/ethnicity); amount consumed across the population; use with other natural or synthetic stimulants (e.g. caffeine, synephrine, yohimbine); the added stress of exercise; and individual sensitivity to these types of products?

Information Presented

Mild adverse effects that have been reported for ephedrine consist of nervousness, headache, insomnia, dizziness, palpitations, and skin flushing and tingling. Moderate to severe effects include hypertension, arrhythmias, and tachycardia (possibly death), and have been associated with concurrent use of caffeine, phenylpropanolamine, or antihistamines.

The mild adverse effects appear to be more commonly noted than the severe effects, and they accounted for much of the participant dropout reported in various studies presented at the meeting. Presentation of the AERs revealed a preponderance of mild effects, although serious cardiac abnormalities and deaths were also reported. Virtually all of the data for any of the adverse effects and their severity, as represented in the AERs, are anecdotal. However, user demographics, amount consumed, use with other stimulants, stress of exercise, or individual sensitivity have not been adequately addressed in any of the studies or the AERs.

Question 4. Are the outcomes associated with the use of these products affected by:

• Dosage;
• User characteristics (e.g. age, predisposing health conditions) or behaviors (such as combining use with other stimulants or other compounds);
• Duration of exposure; or
• Other means?

Information Presented

Given the many issues raised above, this question remains largely unanswered. High quality, randomized, blinded, controlled clinical trials testing efficacy, and case-control studies of selected adverse events, are critical. Moreover, product labeling may be totally inadequate to influence user behavior, if the results of a single consumer survey on over-the-counter drug use reported at the meeting is accurate. That study of over 1000 adults reported the following: 66% read the label always or nearly every time; 25% find labels are difficult to understand; 32% take more than the recommended dose; and 22% use these products for longer than the recommended time.

OBSERVATIONS AND CONCERNS

Since serious adverse events including death have been linked to use of EADS, and since these products are increasingly popular, careful monitoring for such events is critical. A rigorous process for establishing a causal relationship between the adverse event and the product requires a well-designed, comprehensive, and active surveillance system. Numerous presentations suggested that the extant AERs, while important and serious, appear to be largely anecdotal and of limited scientific usefulness for systematic analysis. However, they form the basis for future research and serve as a starting point for an improved surveillance system. Current marketing data indicating that billions of "servings" (doses) are being sold in the United States are inadequate to estimate the number of actual users (or population exposure) necessary for epidemiologic studies. This lack of reliable information on use further complicates any assessment of the magnitude of risk (including for minor adverse effects) EADS use.

It is not clear whether susceptibility to adverse effects differs among individuals with an underlying sensitivity or an undiagnosed condition (e.g., thyroid or heart disorders). Individuals who use EADS may be unaware that they are at risk for an adverse effect. Improved labeling and increased public education are urgently needed. The known contraindications for ephedrine can serve as a guide for label warnings and consumer education.

The current marketing of ephedra for weight loss and ergogenic purposes has occurred in the absence of strong clinical data supporting such uses. It also goes beyond the traditional applications of the compound, although these effects have been noted in some Chinese medicine texts. Use of EADS for treatment of obesity, as reported by some investigators in this meeting, appears to constitute use for treatment of a health condition, which is beyond the structure and function purposes of dietary supplements.

Overall, the information on appropriate dose is not established, and use of EADS for long-term weight loss would conflict with labeling recommendations for "short-term" use. Well-designed trials of sufficient duration in well-characterized subject populations are needed to address questions of efficacy. Dropout from these studies should be scrutinized for adverse effects experienced by participants.

Several industry presenters called for adherence to good manufacturing practices. This would be a critical first step in assuring consistency in quality and content among products. It would further increase the value of the label information in helping consumers use the products appropriately.

Most of the proposed questions could not be answered because of the lack of data; human exposure and trends could not be quantified. Industry should be stimulated to participate in research on the pharmacokinetics and efficacy of EADS, including use during rest or exercise. In addition, the effects of risk factors such as gender, hypertension, diabetes, and multiple dose regimens should be assessed.

A number of research needs were identified: long term studies of benefits and risks; clinical research on efficacy; exploration of the ephedrine alkaloid and caffeine mechanism and interactions; studies of the isomers and differences between the natural and manufactured products; and studies of the effects of different members of this class of compounds.

CONCLUSION

Despite the established limitations of AERs, many of the adverse effects are biologically plausible based on the known pharmacologic effects of ephedrine alkaloids. The pharmacology of ephedrine is supported by a rich database, in contrast to the paucity of evidence on the benefits or risks of EADS in humans. The level of concern for continued use of EADS must be based on the totality of information available on ephedra and ephedrine alkaloids, including the AERs, results of human and animal studies, as well as what is known about the pharmacology and chemistry of these compounds.

Given the current widespread use of EADS, a consumer education campaign about these products is warranted. Good manufacturing standards are needed, reasonable dose and duration levels determined, and warnings and contraindications clearly indicated on labels. A research agenda should be established. Therefore, the research community should take the next logical step by conducting a systematic review of the world's literature on ephedra. After compiling the state of the science and identifying the limitations and gaps of the current research, an appropriate agenda can be established. In this regard, the National Center for Complementary and Alternative Medicine of the National Institutes of Health already is requesting proposals to study herb-drug interactions (http://nccam.nih.gov/nccam/fi/concepts/rfa/index.html).

This is a mirror of the page at http://www.4woman.gov/owh/public/report.htm