Health Professionals

An Analysis of FDA's Concern That Dietary Supplements Containing Ephedrine Alkaloids May Cause Adverse Nervous System Effects

Issue: Whether the Food and Drug Administration's (FDA's) adverse event reports (AERs) or the world literature establish that dietary supplements containing ephedrine alkaloids are causally related to adverse health effects.

Findings: Based on the review of the AERs by FDA and its two consultants, not a single AER supports the proposition that ephedrine alkaloids cause nervous system adverse effects. Furthermore, the world literature does not support the proposition that dietary supplements containing ephedrine alkaloids cause adverse health effects.

It is reasonable to conclude that ephedrine alkaloids contained in dietary supplements are safe if used in doses recommended by AHPA (not to exceed 25 mg ephedrine per serving, four servings per day), and if used in keeping with all other AHPA-recommended label instructions. - Dr. John W. Olney

Methodology: Dr. John W. Olney, a member of the Ephedra Education Council (EEC) Expert Panel, reviewed the 28 AERs that FDA singled out as relating to the nervous system. He also reviewed FDA's and its two consultants' causality analysis of the AERs as well as the world literature pertaining to neurotoxic side effects of ephedrine alkaloids.

Analysis: Dr. Olney found that FDA, in its review of the 28 AERs purportedly related to the nervous system, disqualified 12 of them because they provided insufficient information in order to make a causality analysis. FDA rejected another AER on the basis of it being irrelevant. Of the remaining 15 AERs, FDA classified 12 as "supportive" of a possible ephedrine alkaloid link to an adverse event and three as "attributable," meaning that FDA considered that there was a likely association between the adverse event and the consumption of a dietary supplement containing ephedrine alkaloids.

No Agreement among FDA and Its Consultants

FDA's two consultants, Drs. Ricaurte and Stoll, also reviewed the same 28 AERs, which included the 13 AERs that FDA had disqualified. Dr. Olney noted that Dr.ÝRicaurte classified eleven cases as "attributable" while Dr. Stoll classified only five as "attributable." Only two of the consultants' findings overlapped ‚ that is, there were only two cases that both Dr. Ricaurte and Dr. Stoll agreed should be categorized as "attributable."

The only two cases that Drs. Ricaurte and Stoll agreed were "attributable" to an ephedrine alkaloid-related adverse event were two of the 12 AERs that FDA disqualified because of "insufficient information." Thus, the number of reports on which the three separate reviewers, FDA, Dr. Stoll and Dr. Ricaurte, agree, referred to as the "inter-rater reliability," is zero. There is not a single case that all three reviewers rated as having a highly probably causal association with ingestion of ephedrine alkaloids.

In medical research, if the inter-rater reliability in the use of a rating method is not in a range approaching 100%, then the rating method is rejected as being unreliable. FDA has, in its own review of the AERs, provided the best example of the lack of reliability of these reports as a basis for making scientific conclusions.

FDA's Consultants Have Used Inappropriate Standards for Assessing the Safety of Ephedra

Dr. Olney observed that Dr. Ricaurte stated in his March 20, 2000 letter to FDA, in which Dr. Ricaurte provided his analysis of the AERs, that his concern about ephedrine-containing dietary supplements does not relate to the general population, but rather to specific individuals who have an increased vulnerability to certain illnesses or to those persons abusing the products or using them in combination with other stimulants. Dr. Olney emphasized in his presentation that Dr. Ricaurte's concern is "in the same category as sodium chloride (common table salt), which poses a health risk not to the general public, but to individuals who are predisposed to high blood pressure. There are many such food-related substances that FDA considers so harmless for the general public that they require no regulatory attention."

Therefore, FDA's own experts have, by their own admission, assessed the safety of ephedra using standards that FDA does not apply to other regulated products.

FDA Cannot Reconcile Its Position on Ephedra-Containing Dietary Supplements and Ephedra-Containing OTC Drugs

FDA regards over-the-counter (OTC) drug products containing ephedrine as "generally recognized as safe and effective" at higher doses than the national industry standards for dietary supplements containing ephedrine alkaloids. OTC ephedrine-containing drug products have been sold for many years, during which time, through the lack of reports of adverse events or of abuse, they have confirmed that FDA's regulatory treatment is appropriate.

FDA has repeatedly been asked, but has never been able to explain, how its "concerns" over the safety of ephedra can be consistent with its lack of concern over OTC ephedrine products. Dr. Olney finds that FDA's position is self-contradictory. For may years, ephedrine and its analogs have been marketed as OTC drugs, and FDA has shown no concern about the adverse effect potential or abuse potential of these agents, even when consumed together with various sources of caffeine (coffee, tea, caffeinated soft drinks, etc.).

According to available evidence, ephedrine in dietary supplement form is at least as safe as ephedrine in OTC form.

The logical conclusion, arguing from FDA precedent, is that FDA does not really believe that ephedrine, either alone or in combination with caffeine, poses a public health hazard.

The World Literature Does Not Support the Notion That Ephedra Is Neurotoxic

Dr. Olney also reviewed the world literature pertaining to neurotoxic side effects of ephedrine alkaloids. Based on this review and his review of the AERs, Dr. Olney concluded that FDA's allegation that ephedrine alkaloids are neurotoxic "is not supported by a single AER" and is "not supported by the world literature."

Conclusions:

Neither FDA nor its two outside consultants were able to identify a single AER reporting an alleged neurologic effect that they can agree is closely related to the consumption of dietary supplements containing ephedrine alkaloids. Furthermore, two of the cases that FDA's consultants agreed were "attributable" were among the 12 that FDA disqualified as having "insufficient information." Thus, it is clear that the method used by FDA and its consultants is not reliable and does not provide a sound basis for establishing a link between the consumption of dietary supplements containing ephedrine alkaloids and adverse events.

Moreover, the world literature does not support FDA's opinion that dietary supplements containing ephedrine alkaloids, when consumed in appropriate amounts, cause adverse neurological health effects. Dr. Olney's review confirms that dietary supplements containing ephedrine alkaloids are safe when consumed according to national standards.

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