An Examination of the Literature FDA Used in Evaluating the Physiological and Pharmacological Effects of Ephedrine Alkaloids

Issue: Whether the Food and Drug Administration�s (FDA�s) literature review supports FDA�s claim that dietary supplements containing ephedrine alkaloids cause adverse health effects.

Findings: FDA�s literature review fails to demonstrate an association between the consumption of dietary supplements containing ephedrine alkaloids and adverse effects and includes data contradicting the agency�s own conclusions. In addition, FDA�s literature review is replete with misstatements, and the agency made erroneous assumptions to arrive at its incorrect conclusions.

Methodology: Dr. Steven B. Karch and Dr. Norbert P. Page, both members of the Ephedra Education Council (EEC) Expert Panel, examined FDA�s literature review entitled "Review of the Published Literature on the Physiological, Pharmacological and Toxic Effects of Ephedrine Alkaloids."

Analysis:

• FDA�s literature review consisted mainly of information that had little or no relevance to ephedra

Dr. Karch and Dr. Page found that the principal conclusions of FDA�s literature review were based on many references that were irrelevant to an analysis of the effects of dietary supplements containing ephedrine alkaloids. For example, Dr. Karch noted that of the 94 references FDA cites as dealing with cardiovascular disease, 38 (40%) of them do not refer to the primary literature. Rather, they consist of quotations from meetings, working groups, textbooks, and review articles, all of which describe what other people have stated about ephedrine.

The remaining 56 citations consist of letters and case reports of alleged drug toxicity. Of these, 12 (21%) are about pseudoephedrine (PE) and 19 (34%) are about ephedrine, both of which are contained in ephedra. The remainder, not quite half of all the reports cited, are about phenylpropanolomine (PPA) toxicity. PPA is rarely a constituent of ephedra, and when it is, it is present in extremely small amounts. In addition, nearly half of the reports describing ephedrine toxicity involved individuals who had taken massive overdoses of ephedrine or who were chronic abusers, or both.

As stated above, Dr. Karch and Dr. Page noted that nearly one-half of FDA�s citations deal with PPA, which is a completely different compound than ephedrine. PPA is different from ephedrine in its structure, metabolism, tissue disposition, and excretion. In addition, PPA causes a greater elevation in blood pressure than ephedrine and PE. Nevertheless, FDA relies heavily (and inappropriately) on its citations to PPA articles as showing a relation between ephedrine and adverse events.

• FDA�s literature review mischaracterized and misstated data and studies to support the agency�s concerns about ephedra

Dr. Karch found that FDA�s literature review contains a considerable number of misstatements and inappropriate citations:

• FDA cited to two cases in which ephedra was not even ingested to support its statement that vasculitis is "particularly (likely) when used in combinations with PPA and/or caffeine."

• FDA�s statement that "[a] significant increase in both systolic and diastolic blood pressure occurs in normotensive subjects with oral doses of ephedrine equal to, or greater than, 60 mg," is misleading. The only support for this statement is a review paper that lists seven earlier studies in normotensive volunteers and two in hypertensive individuals. In more than half of those studies, no change was detected, and in others, the increase was less than 10 mm systolic. Furthermore, FDA did not mention the multiple studies that have been conducted that have failed to demonstrate that ephedrine, caffeine, or PE exert any effect whatsoever on healthy volunteers, even when they underwent maximal exercise testing.

• FDA states that "cardiac damage may result from coronary artery spasm induced by stimulation of adrenergic receptors." However, one of the two cases FDA cites to support this statement involved a cocaine user. Furthermore, patients in both cases had received high spinal anesthetics and were given ephedrine by intravenous bolus to treat dangerously low blood pressure. As one of the authors of the cases pointed out, all that this really proves is that the "administration of adrenergic agonists may induce coronary artery spasm during high spinal anesthesia." The cases have no relevance to users of dietary supplements containing ephedrine alkaloids.

• FDA states that "shifting of potassium to skeletal muscle following use of adrenergic agents like �ephedrine alkaloids� may predispose certain individuals to cardiac dysrhythmias." All three cases that FDA cites to support this proposition involved individuals who attempted suicide. Further, only one of the individuals was known to have actually consumed ephedrine (some 375 mg of it in combination with 3,000 mg caffeine and 750 mg PPA).

• FDA states that "[e]phedrine and pseudoephedrine have been implicated in cerebrovascular events secondary to intracranial hemorrhage and subarachnoid hemorrhage and vasculitis." However, only half of the cases cited involved ephedrine, and most of those cases involved drug overdoses or IV abusers.

• FDA states that "[c]ardiomyopathy has been reported . . . with the use of ephedrine." The only four cases in the world literature that support this statement include (1) a 35-year-old male who was taking 400 mg of ephedrine a day along with liberal doses of prednisolone for 14 years; (2) a 28-year-old female who weighed 321 pounds, smoked, and took more than 2,000 mg of ephedrine per day for over eight years; (3) a 33-year-old woman who took more than 1,000 mg of ephedrine a day for 10 years; and (4) a 14-year-old who developed heart failure after taking 225 mg of PPA in a suicide attempt. To suggest that individuals who consume ephedrine in physiologically appropriate amounts are at the same risk for cardiomyopathy as those who consume massive doses of ephedrine is inappropriate.

• FDA states that "myocardial ischemia and infarction have also been reported." However, seven of FDA�s eight citations are cases involving PPA. The only case relating to ephedrine involved a nose drop abuser.

Conclusion � FDA Has Mischaracterized the Published Literature to Support the Agency�s Case against Ephedra:

FDA�s literature review does not support its finding of an association between dietary supplements containing ephedrine alkaloids and adverse events. FDA�s review contained serious misstatements and incorrect citations and was predominantly composed of PPA literature based on the apparent but incorrect assumption that PPA and ephedrine are the same in terms of their effects and toxicity.

The consequence of FDA�s actions is a literature review that creates the false impression that dietary supplements containing ephedrine alkaloids are linked to adverse health effects.