Health Professionals

Steven B. Karch, M.D.

September 28, 2000

I am an assistant medical examiner in San Francisco where my practice is confined to the investigation of deaths related to heart disease, particularly those involving drug toxicity. I have published extensively on that topic and my textbook, The Pathology of Drug Abuse, 2nd edition 1996, is widely used. It is generally considered the standard text on the investigation of drug related deaths, and the third edition is to be published next year.

I have been asked by the Ephedra Education Council (EEC) to be a member of the Expert Panel and review the information released by the Food and Drug Administration (FDA) on April 3, 2000 as well as other information relevant to an evaluation of the safety of dietary supplements containing ephedrine alkaloids. My review focused on the purported cardiovascular toxity of ephedra, and my findings are contained in this statement.

Introduction

The Food and Drug Administration (FDA) continues to maintain that the unrestricted use of ephedrine constitutes an ongoing public health menace. In support of this position, they offer four types of evidence: (1) Adverse Events Reports (AERs) submitted between June 1, 1997 and March 1, 1999, which purport to demonstrate medical complications caused by ephedrine, (2) a systematic analysis of the new AERs, (3) a literature review summarizing the existing peer-reviewed literature on ephedra toxicity, and (4) an analysis of the first three items provided by a panel of independent reviewers. The documents have been assembled in a report entitled "Assessment of Public Health Risks Associated with the Use of Ephedrine Alkaloid-Containing Dietary Supplements," released on April 3, 2000 (hereinafter "FDA Report"). A detailed review of all four elements clearly shows that the FDA has failed to make a case for the toxicity of ephedra- containing dietary supplements, though it has made a stronger case against over-the-counter (OTC) drugs such as phenylpropanolamine (PPA) and pseudoephedrine (PE).

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I. AER Overview

Between June 1, 1997 and March 31, 1999, FDA received 140 reports of adverse events allegedly associated with the use of ephedrine-containing dietary supplements that contain, or that were suspected of containing, ephedrine alkaloids. After review, FDA analysts felt there was a clear connection to ephedrine alkaloids in 60 of the cases, approximately one-third of which involved the cardiovascular system. The 60 cases were submitted to medical reviewers who analyzed them separately, and then jointly, before determining that a nexus existed between the episode described and the use of ephedrine alkaloids. Drs. Page and Farber, also EEC Expert Panel members, have prepared an analysis of the entire case series, and the reader is referred to their report. This report deals only with FDA claims of cardiovascular toxicity.

Two general considerations about AERs bear mention. The first is the AER system itself. The detection of adverse drug reactions has traditionally been the role of the medical community in general, and of peer-reviewed medical journals in particular. Published case reports function to alert the medical community, and to prompt others to seek additional cases, or carry out experiments designed to answer the question of whether there really is an association between a drug and a particular adverse clinical event such as ephedrine use and cardiomyopathy.

Past experience suggests that the medical community is usually more observant than any government agency, and very few case reports describing ephedrine-related toxicity have been published in the peer-reviewed medical literature. One explanation for the disparity in the number of case reports published in the peer-reviewed literature, and the very large number of case reports received by FDA, is that papers submitted to peer-reviewed medical journals are scrutinized far more critically than those submitted to FDA. An equally plausible explanation is that significant numbers of ephedrine-related complications are simply not occurring and therefore no one is writing papers about them. The likelihood of the alternate explanation is reinforced by the lack of evidence to be found in government surveys not commissioned by FDA, particularly surveillance of drug abuse patterns and complications sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA). Neither the Medical Examiner (1) nor the Emergency Room (ER) components of the Drug Abuse Warning Network (DAWN) (2), nor the National Household Drug Abuse Survey (NHDAS) (3) contain any data suggesting that ephedrine toxicity is nearly the problem which FDA perceives it to be.

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II. Individual AERs

Only episodes of cardiac arrest deemed by FDA to be "attributable" or "supporting" are examined here. Of 14 cases of cardiac arrest reported, the FDA panel placed only four in the "attributable" or "supporting" groups. In three of the cases, other, much more plausible explanations for the adverse event seem likely. In one case, a dieting, overweight woman who had been fasting, vital information (electrolyte status) was never reported.

Cardiac Arrest/Sudden Cardiac Death

12485: This case describes a 38-year-old man who suffered from obesity, hyperlipidemia, and cardiomegaly, which had been diagnosed long before he ever took dietary supplements. He died shortly after jogging - one of the more common scenarios in sudden cardiac death (SCD). At autopsy he was found to have severe coronary artery disease (>75% obstruction of the distal obtuse marginal branches of the left anterior descending artery (LAD), 75% obstruction of the proximal right coronary (RCA), and 75% narrowing of the proximal circumflex). There was marked cardiomegaly, with a heart weight of 490 grams, and four-chamber dilatation. FDA reviewers dismissed the degree of enlargement as "mild." In fact, the individual's heart was two standard deviations greater than predicted (4). Heart size is an extremely potent predictor, and independent risk factor, for sudden death. The relationship was one of the earliest findings of the Framingham Study, published nearly 30 years ago (5). The connection was recently reaffirmed in a New England Journal of Medicine article on patients with hypertrophic cardiomyopathy who were followed over a 20 year period (6): individuals with wall thickness of 19 mm or less had a cumulative mortality risk close to zero, whereas those with wall thickness of over 30 mm had a risk of close to 40 percent.

The coroner ruled the cause of death to be acute cardiac arrhythmia secondary to cardiovascular disease, but amended his diagnosis to include a possible contribution from ephedrine, which was present in a concentration of 111 ng/ml. Because of the problem of postmortem redistribution, concentrations of basic drugs like ephedrine, when measured in blood samples obtained at autopsy, are generally higher than they were just before death. Concentrations noted here are slightly higher than those that would be expected after taking a 20 to 30 mg dose of ephedrine, a dose which has been shown to have minimal or no effect on blood pressure.

Conclusion: To dismiss both severe coronary artery disease and cardiomegaly as incidental findings, and attribute death to modest concentrations of ephedrine, is to suggest a bias on the part of the FDA. Individuals with heart weights more than two standard deviations above normal are at risk for SCD at any time, with or without taking dietary supplements.

12851: This case describes a 22-year-old man with a history of asthma, who sustained a cardiac arrest while exercising in the gym. At the time, he was taking Theodur™ (aminophylline) and Ventolin™ (albuterol). A urine drug screen at the time of hospital admission was positive for opiates and theophylline (11 µg/ml), but not ephedrine or amphetamines. Echocardiography demonstrated a decreased ejection fraction and increased end diastolic dimensions. A second urine specimen was tested by FDA/CFSAN, which found 12,000 ng/ml ephedrine, 380 ng/ml of pseudoephedrine (PE), 22 ng/ml of methylephedrine, and 410 ng/ml of phenylpropanolamine (PPA). Interestingly, no caffeine was detected, even though the product the deceased had been witnessed taking lists caffeine as an ingredient.

The FDA investigator misread the product label, confusing the guarana content with the ephedrine content and the caffeine content with the guarana content. Thus, the data on the front page of the MedWatch report (CFSAN-KAN 6540) includes the statement that the product contains 1000 mg of caffeine and 340 mg of ephedrine, when it actually contains 340 mg of ma huang with 6% (20.4 mg) of ephedrine and 1000 mg of guarana containing 10% (100 mg) of caffeine. FDA did not confirm the positive opiate screen. Further, the FDA investigator indicates in her report that the morphine had been administered in the hospital, but no mention is made of morphine administration during or after resuscitation. Ativan was given, presumably to control seizures, but it also was not detected.

The attending cardiologist explained to the FDA investigator that cardiac arrest had most likely been the result of ephedrine and caffeine taken in combination with Theodur™ and Ventolin™. Such a scenario is plausible; however, it should be noted that cardiac arrest is associated with the use of asthma inhalers. Long-term use of drugs such as albuterol is associated with an increased risk of SCD, and evidence suggests that frequent use of inhaled beta 2-agonists has a deleterious effect on the control of asthma (9).

In addition, it also appears that the attending physicians suspected testosterone abuse. Testosterone abuse is associated with myocardial fibrosis and SCD, particularly in bodybuilders (7). Unfortunately, the correct tests were not done to rule this possibility in or out. Free testosterone concentration was ordered at hospital admission and it was within the normal range, but since the urine testosterone/epitestosterone ratio was not measured and neither were sex binding globulins, no conclusion can be reached.

Conclusion: Blood ephedrine concentrations were not measured and cannot be inferred from urine concentrations. Attempts to do so have been described by one well-known toxicologist as foolhardy (8). There could well have been no ephedrine in the individual's circulation at the time of the cardiac arrest. Furthermore, asthmatics occasionally die of cardiac arrhythmia because they abuse their inhalers by taking amounts far in excess of the recommended doses (9).

13031: This case describes a 28-year-old woman who was overweight and suffered SCD while playing baseball. She had taken an ephedrine-containing diet pill in the morning. She had not eaten during the day and had experienced, for the first time in her life, palpitations. While playing baseball she collapsed with ventricular fibrillation. She was successfully resuscitated and had an extensive cardiac workup, including cardiac catheterization. Electrophysiology studies were negative. Even though a screening toxicology test was done, the panel did not include any abused drugs, such as cocaine or amphetamine. Ephedrine was not detected in the urine-screening sample and was not measured in the blood. The record supplied by FDA does not include any electrolyte measurements, which ordinarily would have been done in the emergency room. She was treated with an implanted defibrillator and discharged. There is no proof in this case that the individual had any ephedrine in her body at the time of her collapse, and there is no documentation that her serum potassium and magnesium levels were normal. The absence of both measures is a glaring omission, especially since the woman was dieting and could well have been deficient of either or both electrolytes, a situation known to produce SCD.

Conclusion: Even though extensive electrophysiologic studies were undertaken, biopsy was not. Either undiagnosed myocarditis or an electrolyte imbalance are possible explanations for this event, especially given the absence of proof that there was any ephedrine in her body at the time of the cardiac arrest.

13096: This report describes a 37-year-old woman, six months postpartum, who had been using an ephedra-based product, intermittently, along with other products, including some type of "herbal" phen-fen. She collapsed and could not be resuscitated, even after treatment with massive doses of epinephrine (5 mg every three minutes for a total of 30 mg). Plasma electrolytes drawn during resuscitation showed a profoundly low potassium level of 1.9. A screening test for abused drugs was negative. At autopsy, her heart weighed 350 g vs. a predicted heart weight of 260 g but was otherwise unremarkable. The medical examiner ruled her death was due to a cardiac arrhythmia provoked by severe hypokalemia (1.6 mmol/L).

In the past, because the antibodies used in urine screening tests cross-reacted both with amphetamine and ephedrine, a negative urine amphetamine screening test would have usually sufficed to rule out the presence of ephedrine. However, in the newer tests now in use, there is very little cross-reaction between amphetamine and ephedrine, so it is possible that ephedrine in small amounts could have been present (a very high concentration would have probably caused a cross-reaction and given a positive test). Unfortunately, no specific tests were undertaken to rule that possibility in or out. The severe hypokalemia noted during cardiac arrest could have been the result of the enormous amounts of ephedrine administered during resuscitation, or it could have been the result of her use of potassium wasting laxatives or diuretics - both are used to promote weight loss. The markedly elevated plasma sodium noted during resuscitation, and confirmed by vitreous measurements made at autopsy, is difficult to explain. The only thing that can be said with certainty is that hypernatremia is not a recognized consequence of the use of any "ephedrine alkaloid."

Conclusion: It is unclear why FDA and its panel of experts feel there is a clear connection between the use of ephedrine alkaloids and the unfortunate outcome in this case given the lack of proof that ephedrine was even present and the fact that the extreme hypokalemia alone was more than sufficient to cause a fatal arrhythmia.

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Myocardial infarction/angina; myocardial necrosis;

Hypersensitivity myocarditis

There were a total of 12 AERs in this category. The six cases viewed by the FDA panel as "attributable" or "supporting" cases are discussed below. Of the six cases FDA included, two were thought by their physicians to have chest wall or rib inflammation, two tested positive for amphetamine abuse, and one was an asthmatic taking other sympathomimetics besides ephedrine ‚ in other words, none of the cases demonstrated clear cut ephedrine toxicity.

12452: This report describes a 59-year-old woman with a 15 year history of hypertension, hyperlipidemia, and renal insufficiency who sustained an antero-septal infarct and required a coronary artery bypass graft (CABG). Severe four-vessel disease was present. Prior to the infarct she was taking beta blockers (a kind of drug which would have countered some of the effects of ephedrine, but perhaps exaggerated others, providing that ephedrine was, indeed, present) and lipid lowering agents. She had been using an ephedrine-containing product (20 mg ephedrine three times a day) for three weeks prior to her infarct. Toxicology testing was not performed.

Conclusion: This individual had most of the known risk factors for coronary artery disease and could easily have sustained an infarct without taking any supplements.

13009: This report describes a 38-year-old woman with an acute myocardial infarction (AMI), successfully treated with thrombolytics. She had begun to use an ephedra containing remedy two days prior. She had no risk factors; however, cardiac catheterization showed 70% narrowing of the mid portion of the intermediate coronary artery and total obstruction of the posterior descending, with presumed spasm of the RCA. The cardiologist who did the study felt the patient had "routine coronary artery disease," but that because of the EKG changes, she must have had vasospasm as well. A urine screening test was positive for amphetamine.

Conclusion: The type of screening test used was not specified, but by 1998, the urine screening tests that were in general hospital use had little cross reactivity with ephedrine, indicating either that a great deal of ephedrine had been ingested or that the woman was taking amphetamine. Plasma concentrations were not determined. The coronary lesions would have taken months, if not years, to develop and could not be related to ephedrine use. Spasm in ephedrine users has only been reported in patients with high spinal anesthetics.

13110: This report describes a 42-year-old woman who presented with uncontrolled seizures found to be the result of cardiomyopathy. Arteriograms were negative but there was biventricular enlargement and marked decrease in ejection fraction. Biopsy was not performed. Urine screening drug test in the ER was positive for amphetamine. Symptoms began about one week after starting a weight loss program with a product containing ephedra (333 mg and guarana 250 mg). It was not established with certainty how many pills she had taken. The type of screening test performed was not specified, but by 1998, urine screening tests in general hospital use had little cross reactivity with ephedrine, indicating that either a great deal of ephedrine had been ingested or that the woman was taking amphetamine. Plasma concentrations were not determined.

Conclusion: Without a biopsy, all that can be unequivocally stated is that the woman had heart failure. The diagnosis could have been myocarditis just as easily as drug-induced cardiomyopathy. The only previously reported cases of ephedrine cardiomyopathy have been in three chronic users taking multi-gram per day doses.

13256: This report describes a 39-year-old woman who had experienced several hours of chest pain. She was treated and released from an emergency room where she had presented with chest pain. A 12 lead EKG and an echocardiogram were both unremarkable, as was a chest x-ray. Toxicology testing was not performed. She was discharged with prescriptions for an anti-inflammatory and a pain pill.

Conclusion: There was no evidence of ischemia and no evidence that this individual was taking ephedrine at the time she experienced chest pain. She did not have ischemia.

13414: This report describes a 19-year-old woman who started taking an ephedra supplement about two weeks before developing chest pain. She was seen at an outpatient clinic. An electrocardiogram was performed with normal results. The attending physician thought she had costochondritis. Toxicology testing was not performed. She was discharged from the clinic.

Conclusion: It is not apparent why this AER is considered an "attributable" or "supporting" case.

13463: This report describes a 51-year-old asthmatic woman taking Ventolin™ and Claritin D™ (which contains pseudoephedrine) who started taking an ephedrine containing herbal supplement and developed chest pain. She was seen in an emergency room and a thallium scan was performed. It revealed no abnormalities, nor were there significant enzyme or EKG changes. The cardiologist felt that the combination of Claritin D™ and ephedra might have provoked spasm.

Conclusion: The possibility exists, but without provocation testing, there is no way to tell whether the patient actually had spasm.

III. Literature Review

A. Description and Overview

Part C of the FDA Report is comprised of three sections: (1) pharmacology and mechanisms of action of ephedrine and related alkaloids, (2) the pharmacokinetics of ephedrine alkaloids and, (3) the adverse effects of ephedrine alkaloids. The section dealing with adverse reactions is further divided into two subsections: one section deals with cardiovascular disease and one with neurologic disorders. The section dealing with cardiovascular disease is supported by 94 literature citations.

Of the 94 references cited, 38 (40%) do not refer to the primary literature. There are quotations from meetings, working groups, textbooks and review articles, all of which describe what others have said about ephedrine. The remaining 56 citations are comprised of letters and case reports of alleged drug toxicity. Of these, 12 (21%) are about PE, 19 (34%) are about ephedrine, and the remainder, not quite half of all the reports cited, are about phenylpropanolomine (PPA) toxicity. Nearly half of the reports describing ephedrine toxicity involve individuals who had taken massive overdoses of ephedrine or who were chronic abusers, or both.

B. General Considerations

Throughout the report, FDA persists in using the neologism it coined for the first proposed rulemaking - "ephedrine alkaloids." Ephedrine is a molecule and has four separate isomers. Ephedra is a plant, and it contains dozens of different chemical compound. Because there are so few references in the peer-reviewed literature documenting cases of ephedrine toxicity, FDA has lumped all of the ephedrine enantiomers (isomers) as equivalent. Based on an inspection of the literature citations discussed above, it appears that FDA believes that the metabolism, pharmacokinetic behavior, and receptor affinity of all ephedra isomers are equivalent and interchangeable. This view, however, is incorrect and untenable. Modern research, using cloned receptors expressed in tissue culture, show that each of the isomers has different binding properties. Simply put, at the molecular level, ephedrine and phenylpropanolamine exert very different effects. Action at the molecular level is what determines effects seen by clinicians. To suggest that molecules that behave differently at the molecular level exert exactly the same clinical effects, is simply not tenable.

The ephedrine molecule possesses two asymmetric carbon atoms, allowing it to exist as four different isomers. These are designated as 1R,2S and 1S,2R-ephedrine and 1R,2R-, 1S,2R- pseudoephedrine. The only two isomers that occur naturally as plant alkaloids are 1R,2S ephedrine and 1S,2S PE. Synthetic PE, 1R,2S-PE, is a widely used over-the-counter (OTC) nasal decongestant (10). One of the ways that ephedrine isomers (and other ephedra alkaloids such as PPA and methylephedrine) exert their effects is by binding to beta receptors. Human beta receptors have been cloned and can be expressed in tissue culture. Thus it becomes possible to measure the relative potency of each isomer against each type of human beta receptor (ß1, ß2, and ß3). Naturally occurring 1R,2S ephedrine has twice the activity at the ß1 and ß2 receptor as synthetic PE, and the 1R,2S form was the only form to bind the ß3 receptors - the receptors thought to be responsible for fat mobilization (one of the justifications for taking ephedrine) (10).

The same structural features that give ephedrine greater affinity for ß receptors also give it less affinity for alpha receptors. In general, the larger the group attached to the amino terminal group, the greater the affinity for ß receptors, and less the affinity for alpha receptors (11). This explains why PPA has a much more marked affinity for alpha than for beta receptors, and also explains why PPA causes much greater elevation in blood pressure than either PE or ephedrine, even though all of these are, in FDA's terms, ephedrine alkaloids. Even FDA's own document confirms the different receptor affinities of the various isomers, although the citations quoted are from older data, and somewhat inaccurate. One consequence of these differences is that unlike PPA, ephedrine and PE, unless taken in massive doses, are unlikely to cause any significant increase in blood pressure. This is an extremely important difference because many, if not most, of the cardiovascular complications attributed to the ephedrine alkaloids are a consequence, in one way or another, of elevated blood pressure, especially the reported neurologic complications, such as ruptured arteriovenous malformation and berry aneurysm, that are said to be related to ephedrine use.

There are also differences in metabolism, tissue disposition and excretion. PPA increases caffeine plasma levels and decreases theophylline clearance, while there is no evidence that such an effect is exerted either by ephedrine or PE (12). Modest amounts (less than 15%) of ephedrine and PE are both demethylated to active metabolites (PPA and norpseudoephedrine). But in humans, PPA is hardly metabolized at all. Excretion times vary as well. Although the rate of urinary excretion of ephedrine and PPA is pH dependent, that of PE is not. None of these differences can be made to go away by adherence to the incorrect belief that ephedrine and PPA, not to mention norpseudoephedrine and methylephedrine, are all the same molecule. They are not. And therein lies the fundamental weakness of the FDA analysis - nearly one-half of their citations do not deal with ephedrine at all, but with PPA, a completely different compound.

The inappropriate citation of PPA articles is misleading. Even more misleading is the reliance upon overdose data. In the section of the FDA report dealing with cardiovascular disorders, reference is made to only 19 case reports involving ephedrine, a sizable number of which were cases of accidental or suicidal overdose.

While the ephedrine molecule lacks the catechol moiety, it still behaves in many ways like a catecholamine, and massive doses of catecholamines are toxic. Having said that, the issue is not a patient who has taken massive doses of ephedrine, but rather, individuals who take recommended servings of the drug. There can be little doubt that taking thousands of grams of ephedrine every day for years will cause cardiomyopathy. Such an occurrence (there are three in the reported world literature) only proves it is not a good idea to abuse any substance. It does not prove that ephedrine, in physiologically relevant doses, is cardiotoxic.

C. Specific Misstatements

Part C of the FDA report relates to cardiovascular disease, and it contains a large number of misstatements, omissions, and inaccuracies. Many of the misstatements are relatively inconsequential but, in aggregate, they convey a false impression. For example, FDA is correct when it says that "PPA is the major metabolite of ephedrine." Having read that statement, one might suppose that ephedrine is cleared from the body by conversion to PPA. In fact, ephedrine is mostly excreted unchanged in the urine. Only a very small amount (<10%) is converted to PPA. Readers of the report who accept FDA's contention that PPA and ephedrine are both ephedrine alkaloids, exerting the same effects, might suppose that converting one alkaloid into another would just enhance toxicity, even though that is clearly not the case, because so little PPA is formed. Some of the more obvious inaccuracies in the FDA report are listed below in the order of their appearance.

1. "Ephedrine [and] phenylpropanolamineÖ are listed as commonly abused stimulant drugs" (FDA Report at 30).

In support of this statement FDA cites the 1994 issue of Conn's Current Therapy (FDA Reference #61), which, in turn, cites no supporting sources whatsoever. FDA does not inform readers that there are no mentions of ephedrine or PPA in the most recent (1998) National Household Drug Abuse Survey (NHDAS)(3) or in the ER component of the 1999 midyear Drug Abuse Warning Network (DAWN) report (2), or that ephedra and/or PE were detected at autopsy in less than one percent of the drug-related deaths reported in the U.S. In many of these cases, the presence of ephedrine probably reflected methamphetamine abuse (ephedrine is the starting material used by illicit methamphetamine makers and sometimes ephedrine appears in the final product). For purposes of comparison, 560 diphenhydramine-related deaths were reported during the same period, making diphenhydramine, an OTC antihistamine, the eighth most common cause of drug-related deaths in the U.S. Ephedrine ranked 47th; PE, 52nd; and PPA, 59th (1).

Conclusion: If none of the other national surveys detected a problem, then most likely there is no abuse problem. It should be noted that reports made to DAWN and NHDAS are never financially motivated. Often AERs are filed on an attorney's advice, or after a particularly inflammatory television "expose." I agree with Dr. Edgar Adams, one of the other members of our panel, that there is no evidence of significant ephedra abuse despite widespread use.

2. "Ephedrine increases arterial blood pressure in humans both by peripheral vasoconstriction and by cardiac stimulation" (FDA Report at 27), and "[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" (FDA Report at 31, citing FDA Reference #82).

The sole support for the latter statement is a review paper that lists seven earlier studies in normotensive volunteers and two in hypertensive individuals. (See FDA Reference #82.) In more than half of those studied, no change was detected, and in others, the increase was less than 10 mm systolic.

Furthermore, FDA is either unaware, or chose not to mention, the multiple studies that have failed to demonstrate that ephedrine, caffeine, or PE exert any effect whatsoever on healthy volunteers, even when they underwent maximal exercise testing. Much of this data is not new. In 1981, Bright et al. evaluated the effects of 60 and 120 mg doses of PE in six healthy normal males, both at rest and during submaximal exercise. No statistically significant increase was seen in the amount of time required to reach 85% maximal predicted heart rates on treadmill tests. Nor was there a significant difference seen in the amount of time required for heart rate to return to baseline rates (an important, indirect measure of cardiac function). Absolutely no drug effect on blood pressure, either at rest or during exercise, was observed with either the high or low dose of PE (13). The study was prompted partially by recommendations made by FDA's own Advisory Review Panel on OTC Cold, Allergy, Bronchodilator and Anti-Asthmatic products. The panel had recommended that the dose of PE be increased from 30 mg to 60 mg every four hours, not to exceed 360 mg per day (14). It appears that this recommendation has never been rescinded.

Essentially the same results were found when ten healthy female athletes were tested on treadmills, using the standard Bruce protocol. Each participant was administered 60 mg of PE in a double blind, placebo-controlled study. Heart rates were found to be slightly higher at the end of Stages II, III, and IV, but not at maximal exertion. There was no effect on either systolic or diastolic blood pressure at rest, or during maximal exercise (which was very maximal indeed - participants had VO2 values of close to 60 ml/kg/min)! (15)

A more recent study evaluated the effects of PE and PPA on maximum oxygen uptake and time to exhaustion in 20 male cyclists, randomized to receive 0.33 mg/kg PPA, 0.66 mg/kg PPA, placebo, 1 mg/kg PE, or 2 mg/kg PE, with a one week washout between tests. Although these individuals underwent maximal exercise testing, no significant differences were found between placebo and maximum oxygen uptake, maximum systolic, or maximum diastolic pressure, or peak pulse pressure (16).

Finally, a 1999 study evaluated the safety of 120 mg of PE taken every 12 hours during simulated conditions of weightlessness (-6 degrees of head down tilt). Ten healthy male volunteers were studied and no significant cardiovascular effects (pulse or systolic or diastolic pressure or maximal oxygen uptake) were observed (17). It is important to note that statistically significant does not mean the same thing as clinically significant. Even though an 8 mm rise in systolic blood pressure did occur, changes of that magnitude are almost certainly innocuous, probably even in someone with an undiagnosed arteriovenous malformation (AVM) or berry aneurysm (18).

Conclusion: If maximal exercise testing does not cause clinically significant blood pressure increases after dosing with ephedrine alkaloids, then it is illogical to suppose that such changes occur at rest, or that they become clinically significant in uncontrolled settings. FDA has no rational basis for asserting any such association.

3. "Potentially life-threatening effects of ephedrine and related alkaloids are its acute cardiovascular and central stimulant effects, which are seen with excessive dosages or in susceptible individuals" (FDA Report at 29).

There is no question that excessive doses of ephedrine alkaloids, particularly potent alpha adrenergic agonists like PPA, can cause heart attack, stroke, and even myocardial necrosis. It does not follow, however, that physiologically relevant doses do the same thing to otherwise normal individuals.

FDA implies that some individuals may be more susceptible to the effects of ephedrine alkaloids than others. Drug effects are altered by rates of drug absorption and excretion, tissue distribution, and protein binding, not to mention age, sex, and bodyweight. Since ephedrine is not metabolized to any significant degree, genetic heterogeneity of the cytochrome system is about the only factor that could not be invoked to explain an altered or unexpected response. There is, however, no evidence to suggest that any of the other possible factors, while quite real, have much of an impact, at least not within the general population.

Individual susceptibility could also be the result of severe, undiagnosed, heart disease. This condition is widely prevalent in the U.S. and other developed countries, and for hundreds of thousands of people each year, the first manifestation of its presence is SCD. Coronary arteries are supplied with both alpha and beta receptors. All of the ephedrine alkaloids stimulate both, though PPA is far more potent in this regard than ephedrine. It is certainly possible that an individual with an undiagnosed 90% LAD blockage could precipitate an infarct just by taking a modest dose of an ephedrine.

Conclusion: The key issue here is that FDA considers all the ephedrine alkaloids to be equivalent. If they are equivalent, how can the OTC sale of PE- and PPA-containing products be permitted, especially when these products (a) are more likely to cause vasospasm than ephedrine and (b) contain many more "ephedrine alkaloids" than found in food supplements.

4. "Chronic administration of ß-receptor agonists has been associated with muscle fatigue and stress" (FDA Report at 29, citing FDA Reference #41).

The source for this statement never actually discusses, or defines, stress, so it is unclear whether the "stress" the FDA document is talking about is oxidative stress, which could be quantitated by measurement of excess allantoin production (the uric acid breakdown product produced by free radical trapping), or psychological stress with increased production of catecholamines. In any case, the citation does not provide any evidence to support "ephedrine alkaloid"-related stress or muscle weakness, and neither does the FDA report, other than to simply assert, that it occurs.

In fact, chronic administration of beta receptor agonists leads to receptor down-regulation, which is why ephedrine is not a particularly good drug for treating asthma; after a few weeks it loses its effect (tachyphylaxis) (19). The body sequesters beta receptors so that ephedra cannot bind to the muscle cells of the bronchi and make them dilate. Presumably this happens in other parts of the body as well, but the phenomena is not well studied.

Conclusion: FDA has failed to demonstrate a relationship.

5. "[T]he adrenergic system plays in the regulation of serum potassium levels via mediation by a ß2 receptor, and which results in a decline in serum potassium that is independent of insulin, aldosterone and renal excretion," (FDA Report at 30, citing FDA Reference #32), and "[t]he consequent marked hypokalemia due to compartment shifting of potassium to skeletal muscle following use of adrenergic agents like ephedrine alkaloids may predispose certain individuals to cardiac dysrhythmias" (FDA Report at 30, citing FDA References #42-44).

There is no evidence in the peer-reviewed literature to support the notion that ephedrine alkaloids, taken in physiologically relevant doses, cause anything of the sort. Even the citations offered by FDA refute their own claims. Reference #42 is a case report describing a 17-year-old who attempted suicide by taking an unknown amount of PE and theophylline. The case was cited to prove that hypokalemia in users of ephedrine alkaloids "is independent of insulin." But it actually states quite the opposite: "This suggests that the sympathomimetics provoked a compartmental shift of potassium perhaps indirectly by inducing hyperglycemia and hyperinsulinaemia." References #43 and #44 are equally irrelevant. Reference #43 describes another attempted suicide, this time with a minimum of 375 mg ephedrine, 3000 mg caffeine, and 750 mg PPA. Reference #44 described the case of a 43-year-old obese, hypertensive female who took an unknown amount of PPA and caffeine (toxicology testing was not performed). These three case reports (only one of which actually involved ephedrine) appear to form the sole basis for FDA's claim that relevant physiologic doses of "ephedra alkaloids" can predispose to arrhythmias.

Conclusion: There is no question that a massive overdose with sympathomimetics can cause life-threatening hypokalemia (see AER 13096), but major potassium shifts simply do not occur at physiologically relevant doses.

6. "[M]yocardial ischemia and infarction have also been reported" (FDA Report at 30, citing FDA References #45-51). The citations provided to support this claim are equally unconvincing.

Reference #45 described a 50-year-old woman with anginal symptoms. She also had nasal polyps and had become addicted to nose drops containing 1% ephedrine and 0.1% xylometazalone (Otrivinic™). She used the drops every half-hour for months, perhaps even years. Assuming that she was placing 2-3 drops in each nostril, she was taking 3 mg of ephedrine every half-hour, or 6 mg per hour, or 70-100 mg every day, and had been using it for months or years.

Reference #46 actually disproves FDA's contention that ephedrine causes myocardial ischemia. It compares the long-term consequences of treating asthma with terbutaline versus ephedrine. The authors concluded that "[n]o evidence of cardiac, hepatic, renal, or ophthalmologic toxicity or change in need for other bronchodilator agents was noted during the study with either drug."

Reference #47 describes a 28-year-old man said to have taken 60 mg of PE. There was clear clinical evidence of coronary artery spasm, but toxicology testing was not performed, and blood PE concentrations were not measured, so there is no way to actually determine which ephedrine alkaloids were involved, if any.

Reference #48 is about myocardial ischemia, but as a consequence of PPA ingestion, not ephedrine. Two of the cases were suicidal overdoses. (One individual took 2 grams of PPA and 8 grams of caffeine. A third individual developed ischemic symptoms after taking one pill, containing 50 mg PPA.) Bearing in mind that PPA is a much more potent alpha agonist than ephedrine, coronary artery spasm would not be particularly surprising, particularly given a dose of 2000 mg, although it does seem that in the third case, a relatively small dose of PPA was the cause.

Reference #49 describes a 34-year-old woman who took two 75 mg timed-release PPA capsules, and then developed symptoms consistent with coronary spasm. Urine drug abuse screening tests were negative, and blood concentrations were not quantitated.

Reference #50 describes two cases, a 17-year-old woman who had been taking 75 mg of PPA each morning for a month, and a 26-year-old woman who attempted suicide by taking 750 mg PPA (toxicology screen otherwise negative). Both had typical anginal symptoms.

Reference #51: Actually, this citation is not even a case report; it is only a letter to the editor describing a case where an episode of angina was thought to have been the result of PE ingestion. Angina did not recur, even though the individual was given an additional PE challenge while in the hospital. The failure to reproduce symptoms with a second challenge would suggest that PE was not responsible.

Conclusion: Of the eight cases FDA presents to prove that ephedrine causes angina and/or infarction, seven cases actually were about PPA-related cases. The one ephedrine case cited was that of a chronic ephedrine abuser. Many people would interpret the data as suggesting a link between PPA ingestion and coronary spasm leading to angina or infarction. The data also suggest that one episode of coronary spasm in an ephedrine abuser does not form a sufficient basis for any generalization about ephedrine use and heart disease.

7. "Cardiomyopathy has been reported also with use of ephedrine" (FDA Report at 30, citing FDA References #52-55).

Technically, FDA is correct. However, this observation has no relevance to any proposed rulemaking for the general population. Three of these cases are the same ones included in the earlier version of FDA's proposed rulemaking, with the addition of one new case attributed to PPA. These cases include (1) a 35-year-old male asthmatic taking 400 mg of ephedrine per day and "liberal doses" of prednisolone for 14 years; (2) a 28-year-old woman who weighed 321 pounds, smoked cigarettes, and had been taking 2000 mg of ephedrine per day for eight years, and (3) a 33-year-old woman with symptoms of congestive heart failure who had been taking >1000 mg of ephedrine per day for 10 years. The PPA case involved a 14-year-old child who developed heart failure after taking 225 mg PPA as a suicide attempt. Neither arteriography nor biopsy was performed in any of the four cases. Each of the cases cited involved massive and usually prolonged over use of ephedrine. Even in the single experimental reference cited (FDA Reference #57), where rats were injected with PPA, necrosis did not occur until at least 8 mg/kg had been administered. (This would equate to a dosage of 600 mg of PPA in an average-sized man.)

Conclusion: One could legitimately question the inclusion of these cases in the report. Perhaps they were used to support FDA's contentions that "necrosis is commonly seen with other phenylisopropylamines such as PE and PPA." There is no dispute that a massive dose of catecholamines, or catecholamine-like drugs (ephedrine is not a catecholamine, but does directly stimulate adrenergic receptors and does cause the release of norepinephrine, which is a catecholamine) cause myocardial necrosis and produce a distinctive type of cardiomyopathy (20-22). To suggest that someone taking 40 to 60 mg (less than a milligram per kilogram) of ephedrine a day for a few weeks or months is at the same risk as anyone with a cumulative dose of 5.8 kilograms (2000 mg x 365 x 8 years) is simply bad science.

8. "In addition to direct cardiac toxicity, including immune mediated mechanisms, cardiac damage may result from coronary artery spasm induced by stimulation of alpha-adrenergic receptors" (FDA Report at 30, citing FDA References #58, 59).

The suggestion is not logically impossible, but taking into account ephedrine's strong ß agonist properties and relatively weak alpha agonist properties, it is not very likely either. FDA offers two citations to support its suggestion. Both involved patients who had received high spinal anesthetics (one was a regular cocaine user), had been given an intravenous injection of ephedrine to treat dangerously low blood pressure, and subsequently developed coronary artery spasm. The sympathetic nerves of the heart arise from mainly Tl-T4; therefore, administration of a high spinal anesthetic would lead to unopposed parasympathetic stimulation of the coronary arteries, enhancing the effects of ephedrine and making coronary artery spasm much more probable. As the authors of one of the reports point out, all this really proves is that the "administration of adrenergic agonists may induce coronary artery spasm during high spinal anesthesia."

Conclusion: The relevance of this observation to anesthesiologists is clear, but the relevance to average users of dietary supplements is difficult to imagine. Anyone who did not understand the sympathetic innervation of the heart might actually suppose that ephedrine could cause spasm in the average, healthy person, which is highly unlikely.

9. "Ephedrine and pseudoephedrine have been implicated in cerebrovascular events secondary to intracranial hemorrhage and subarachnoid hemorrhage and vasculitis" (FDA Report at 31, citing References #64-66, 67-69, 70 (English abstract), 71).

FDA's Report makes it appear that this claim is supported by a large number of citations. However, the citations are not relevant to ephedra when consumed according to label directions. Reference #64 is a case report describing a 20-year-old woman with a subarachnoid hemorrhage (SAH) and immune complex deposition evident on skin biopsy. The patient was a known drug abuser whose symptoms began acutely within one hour after ingestion of an unknown quantity of "speed." Urine was positive (qualitative test only) for ephedrine, but blood concentrations were not measured, and the amount taken was never estimated. Initial angiograms were unremarkable, but repeat studies showed the typical pattern of "beading" that was at the time thought to be diagnostic for "vasculitis." Many experts (such as the author of Reference #72) feel that "beading" only represents the vascular reaction to subarachnoid hemorrhage. No similar cases with immune complex deposition in the skin have been reported in the last 17 years.

Reference #65: This report describes three cases. The first was an abuser who took at least 150 mg of ephedrine orally and sustained a thalamic infarct. The second patient had been taking 150-300 mg per day for more than 20 years and experienced a fatal brain hemorrhage. The postmortem blood concentration was 2.7 mg/L. Presuming the individual was a 70 kg man, a concentration of 2.7 mg/L would have required a dose of 70 kg x 3 l/kg x 2.7 mg = 560 mg of ephedrine. The third patient had a ruptured berry aneurysm. Ephedrine was identified in postmortem blood but quantitative results were not reported.

Reference #66: This case report describes a 17-year-old female with a history of amphetamine abuse who took 20 PE tablets (1200 mg) in an attempted suicide. She sustained an intercerebral hemorrhage. Blood and urine levels were not quantitated. Angiography showed "beading."

Reference #67: A case report which describes a 20-year-old woman with an arteriovenous malformation who sustained an intercerebral hemorrhage after taking 50 mg of PPA orally. PPA was the only drug detected, but neither urine nor blood concentrations were quantitated. Angiography did not show any evidence of vasculitis, though vasculitis was apparent in the surgical specimen.

Reference #68: A case report which describes a 68-year-old man who had been taking pills containing a total of 60 mg ephedrine, 150 mg theophylline, and 90 mg caffeine per day, every day for ten years. He sustained an intracerebral hemorrhage. Angiography did not show "beading," but necrotizing vasculitis was evident in a surgical specimen. Urine toxicology testing was not performed and blood concentrations were not determined.

Reference #69: A case report which describes a 44-year-old woman who had been given a spinal anesthetic. She developed hypotension requiring the administration of an unknown amount of ephedrine administered in an unknown medium, intravenously over an undetermined period of time. She subsequently developed multiple cerebral infarcts and the angiogram showed "beading." No toxicology testing was done.

Reference #70: A case report, which describes three women who used PPA and sustained hemorrhagic strokes. The paper is in Spanish. The abstract states there were no angiographic abnormalities. The results of toxicologic testing, if any, were not mentioned. The outcome was not mentioned, and the dosage of the PPA pills was not specified.

Reference #71 is not a case report. It is a letter to the editor disputing the diagnosis of ephedrine-vasculitis offered by the authors in Reference #64.

Conclusion: Only half of the cases cited were in ephedrine abusers, and most of those involved cases of drug overdose or intravenous bolus administration. In only two of the cases were there histologic evidence of necrotizing angiitis. The appearance of "beading" is non-specific and has been associated with many conditions and diseases (e.g., meningitis, encephalitis, aneurysmal subarachnoid hemorrhage, closed head injury, and postpartum disease) (23). As the authors of FDA Reference #71 point out, the observation of this pattern does not prove that vasculitis is present. From the minimal amount of data presented, it would appear that, if "ephedrine alkaloid"-related vasculitis does occur, it is much more likely to occur when large amounts of drug are taken, or when the drug is given parenterally, or when the vessels are in some way presensitized, as in chronic cocaine abuse. Also, as noted above, high spinal anesthesia, which leaves the parasympathetic to the heart unopposed, may well increase the chances of ephedrine-related coronary artery vasospasm. Even if vasculitis is a real risk, it has not been established that use of any other drugs, particularly caffeine or PPA, makes the likelihood of vasculitis occurring any greater (see below).

10. Vasculitis is "particularly (likely) when used in combinations with PPA and/or caffeine" (FDA Report at 31, citing FDA References #72-74).

Reference #72: This is neither a case report or a research paper, but rather a review of PPA AERs published more than 10 years ago. The author states "it appears that although 75 mg of sustained-release PPA or less may have little cardiovascular impact in resting, healthy subjects (unless other sympathomimetic drugs such as caffeine are coingested), 150 mg of PPA (contained in two diet pills) does raise BP to statistically and clinically relevant levels." The paper also states "[t]here are conflicting conclusions from controlled studies investigating the effects of PPA and caffeine on blood pressure in humans; three reports . . . found no BP effects while another group showed significant BP increases after 75 mg of sustained-release PPA and 400 mg of caffeine." Except for a listing of AERs, neither ephedrine nor ephedrine in combination with any other drug is discussed anywhere in this paper.

Reference #73: This is a case report about a 35-year-old woman who was three weeks postpartum when she experienced a subarachnoid hemorrhage (SAH). Symptom onset was 1.5 hours after taking one Dexatrim tablet. Angiography showed "beading." Other than to mention that ephedrine and amphetamine have structural similarities to PPA, the paper does not mention ephedrine. Caffeine is not discussed either, except to mention a 1984 experiment showing that when PPA was combined with caffeine and given to rats, the chances for brain hemorrhage were increased. Toxicology testing had not been performed.

Conclusion: Subarachnoid hemorrhage (SAH) due either to ruptured arteriovenous malformation (AVM) or aneurysm accounts for 4.4% of all maternal deaths and is the third most common nonobstetric cause of maternal death. Increased risk of AVM-related SAH appears to correlate with the augmented cardiac output of pregnancy, as well as with other coagulation, hemodynamic and endocrine changes. These changes usually occur between 20 weeks gestation and six weeks postpartum (32). Furthermore, postpartum angiopathy occurs spontaneously and has been documented in women who were taking no drugs whatsoever (33). There is just as much reason to suppose this particular patient suffered from one of the natural complications of pregnancy as from "ephedrine alkaloid" toxicity.

Reference #74: This is a case report which describes two women with intercerebral hemorrhage following consumption of PPA. Both women had taken "amphetamine look-alikes," which were still popular and readily available in the early 1980s. One of the women had taken a pill containing ephedrine, PPA, and caffeine. The amounts contained in the pill were not quantitated, and toxicology testing was not performed. The pill taken by the second woman contained ephedrine, PPA, PE, and an unspecified barbiturate. The amounts present in the pill were not quantitated, and toxicology testing not performed.

Conclusion: The contention that ephedrine toxicity is increased by coingestion with caffeine or PPA could be correct, but it is not supported by the citations offered. In fact, none of the papers even discuss synergism. The only evidence they provide is derived from an early experimental study with rats that may or may not be relevant to humans.

11. "The potential for cardiac arrhythmias is noted in a description of the use of Ephedra in traditional Chinese medicine, which further states that such reactions are common if contraindications are not observed" (FDA Report at 31-32, citing FDA Reference #88).

Reference #88: This citation is from a textbook of Chinese herbal medicine. It contains no research but only recipes, in this case one for "Wind Chill." Ephedrine-related arrhythmias are described as occurring when "[a]s little as 0.05 quoin, (is) decocted and ingested at one time, has caused cardiac arrhythmias, for which atropine is the antidote. Such reactions are common if the contraindications are not observed. Otherwise, the herb is relatively safe."

Conclusion: FDA fails to define "quoin" or explain or describe what sort of arrhythmias are produced or that anticholinergic poisoning was a consequence of ephedrine ingestion.

12. "Sudden death in a healthy college student was related to ephedrine cardiotoxicity from a ma huang containing protein drink (90). Postmortem cardiac evaluation revealed patchy myocardial necrosis suggestive of multiple ongoing insults resulting in vasoconstriction of the small arteries and mycotoxicity, features reminiscent of experimental and clinical aspects of adrenergic/sympathomimetic agents" (FDA Report at 32).

Reference #90: This is a case report describing secondhand the cardiac changes reported by an unnamed FDA pathologist. The paper itself was written by a pharmacologist whose expertise is in bladder function. In spite of his extensive bibliography, he chose to publish this paper in the Journal of Psychopharmacology, a journal that he had never published in previously, but whose editorial offices are located in the same department as his.

Conclusion: This paper contained a number of forensic errors, such as attempting to infer blood concentrations from postmortem urine concentrations. If such calculations were permissible, they would have indicated massive overdose. Interestingly, FDA did not cite a critical letter to the editor published by the same journal. In addition, FDA failed to indicate that the diagnosis was disputed. The author of the paper acknowledges the help of FDA in preparing the paper.

Note: I have had the opportunity to examine slides from this case and believe the individual died of classic viral myocarditis (illustrations will be supplied upon request).

13. "Zaacks et al. recently reported a case of hypersensitivity myocarditis occurring in a 39 year old male, who had been using a multi-component dietary supplement line, with one product containing ma huang [1-3 tabs tid] for 3 months, along with other supplements, pravastatin and furosemide" (FDA Report at 32, citing FDA Reference #91).

Reference #91: This case describes a 39-year-old hypertensive man with heart failure who was being treated with pravastatin and furosemide. He began self-medicating with multi-component dietary supplements (nearly 100 different herbal extracts which, very likely, contained thousands of other molecules). He previously had had an episode of angioneurotic edema, which could potentially have a great bearing on this case. Angioneurotic edema and eosinophilia have been associated with pravastatin treatment (34, 35). Arteriography and biopsy were performed. The biopsy showed a mixed lymphocytic/eosinophilic infiltrate (the journal illustrations were too poorly reproduced to interpret). The authors concluded that ephedrine (the pills being used by this individual contained 7 mg of ephedrine) was the likely culprit, mainly because "[m]yocarditis has been described with sympathomimetics: primarily cocaine, I-norepinephrine, and PPA."

Conclusion: Eosinophilic myocarditis is an extremely rare disease, and there is no reason to believe that ephedrine could not have been responsible. But given that more than 6.5 billion doses of ephedrine have been sold since 1995, it would hardly seem to constitute a grave public threat, even if ephedrine was the responsible agent. This man was exposed to literally thousands of other molecules contained in the hundred different herbal extracts he consumed, and given that the prescription drugs he was taking are known to be capable of causing eosinophilia, the only way to prove ephedrine was responsible would be to rechallenge. However, the type of "myocarditis" produced by catecholamines only occurs when very large doses are administered. It is not an allergic phenomena but a toxic one. The amounts of ephedrine being taken were trivial, unlikely to have caused catecholamine excess sufficient to produce myocardial necrosis.

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IV. Outside Reviewers

Two of the outside reviewers consulted by FDA devoted more attention to cardiovascular complication than the others, and their reports are considered separately. For the most part, their critiques follow the general outline adapted by FDA in its document. Like FDA, both consultants make statements that are not supported by the published literature; however, they do make some interesting and useful observations.

A. Dr. Neal Benowitz

The report "Review of Adverse Reaction Reports Involving Ephedrine-Containing Herbal Products" (hereinafter "Benowitz Report") was written jointly by Drs. Neal Benowitz and Christine Haller. It has much the same structure as the FDA report, beginning with a review of the pharmacology of ephedrine, then progressing to the toxicity of "ephedrines," a term the authors apparently coined as a substitute for FDA's term "ephedrine alkaloids," an evaluation of the 139 case records supplied by FDA, and a discussion. Unlike the FDA report, Drs. Benowitz and Haller have added a separate section on the pharmacology and toxicology of caffeine, and a more detailed review of some of the cases. Observed medical complications are divided into three groups: cardiovascular toxicity, stroke, and central nervous system. Less common problems, such as skin diseases and rhabdomyolysis, are not discussed. The discussion below follows the same subheadings used by Drs. Benowitz and Haller. Not all of the sections are discussed.

Section 3: "Pharmacology and toxicology of ephedrine"

a. Pharmacology

After listing all the isomers found in naturally occurring ephedra, Drs. Benowitz and Haller state, "[t]he main cardiovascular effect is constriction of arteries and veins. To a lesser extent there is beta adrenergic stimulation producing increased heart and increased forced of contraction" (Benowitz Report at 2).

Conclusion: Absolutely no mention is made of any differences between the isomers. Specifically, no mention is made of PPA's low affinity for beta receptors or ephedrine's relatively low affinity for alpha receptors or the fact that PPA is much more likely to produce blood pressure elevation than ephedrine because beta receptors cause vasodilatation of peripheral resistance vessels. This omission gives a scientifically incorrect picture of ephedrine's actions on the circulatory system.

The same could also be said for Drs. Benowitz and Haller's explanation of how ephedrine causes weight loss, which they attribute to its ability to increase "sympathetic nervous tone." Evidently they are unaware of the literature concerning ß3 and ß4 receptors or they do not believe such interactions play a role. If the latter, they should at least mention these putative receptors if only to reject them.

The remainder of the pharmacology section deals with pharmacokinetics. After devoting several sentences to ephedrine excretion and physical constants, they provide the volume of distribution (Vd) (a physical constant unique for each drug) for PE, but not ephedrine. The reason for so doing is that the Vd of ephedrine has never been determined - it may be quite different from that of PE, and this gap in our knowledge should have been acknowledged.

b. "Toxicity of Ephedrine"

This section begins with the statement that "[a] number of reports of adverse reactions to ephedrine, some producing permanent injury or death, have appeared in the medical literature" (Benowitz Report at 1), but doesn't give the number or, for that matter, any citations. In fact, the number is quite small. As mentioned above, only one of the eight cases of angina/infarction presented by FDA was actually due to ephedrine; the other seven were PPA-related. And even the one ephedrine case cited was in a chronic ephedrine abuser.

Conclusion: Many scientists/physicians would interpret the data as suggesting a link exists between PPA and coronary spasm/angina and/or infarction - not ephedrine.

The phrase "a number of cases. . ." is typically used when an author either (a) cannot find the literature citations needed to support a point being made, or (b) hasn't the time to track down the reference. Drs. Benowitz and Haller utilize the phrase at least four other times in their report, each time failing to supply the citations which would support their point.

1. Benowitz Report at 2: "A number of case reports have described toxic

reactions to ephedrine and [PE]."

2. Benowitz Report at 13: "A problem in assessment of causality in a number of the cases was the lack of quantitative data on ephedrine/caffeine content of the products and amount of daily use."

3. Benowitz Report at 14: "But of great concern were the number of cases of severe adverse events - including sudden death (presumably related to cardiac arrhythmias, with or without cardiac ischemia), acute myocardial infarction, stroke and seizures."

4. Benowitz Report at 15: "A number of different substances are known to inhibit the metabolism of caffeine. Very little systematic research on the clinical pharmacology of herbal products containing ephedrine has been published."

In this section, Drs. Benowitz and Haller also suggest that "caffeine is likely to enhance the cardiovascular effects...of the ephedrine." No citations are supplied, although the theoretical basis for the supposition is supplied in Section 4 on the pharmacology and toxicology of caffeine, and is quite convincing.

Conclusion: Drs. Benowitz and Haller also fail to mention that controlled studies have shown that cardiovascular effects, at least in terms of blood pressure, have not been enhanced when assessed in placebo-controlled trials (see above).

Under the subsection entitled "Cardiovascular toxicity" of the "ephedrines," we are told that "ephedrines" have been associated with "myocardial infarction, sudden cardiac death (presumably arrhythmic), myocarditis and severe hypertension" (Benowitz Report at 3, citing References #8-11).

Conclusion: None of the citations listed had anything to do with SCD, myocardial infarction, or myocarditis, and only one of the cases may have involved ephedrine.

Reference 8: A case report about coronary spasm secondary to PE.

Reference 9: A case report of hypertension and arrhythmia in a 19-year-old who overdosed on an unknown amount of PE or ephedrine, or both.

Reference 10: A case report describing a hypertensive emergency that occurred after taking PE.

Reference 11: A paper about a chronic ephedrine abuser with cardiomyopathy.

In the same paragraph, Drs. Benowitz and Haller state that "there is also a report of hypersensitivity myocarditis." However, the reference supplied is about cardiomyopathy in ephedrine abusers (Reference #11 above), not about myocarditis.

In the section devoted to stroke, it is stated that "[e]phedrines have been associated with subarachnoid hemorrhage and thrombotic stroke" (Benowitz Report at 3, citing Reference #12).

Conclusion: Reference #12 is about the neurologic complications of PPA use. The authors go on to add that "cerebral vasculitis has been reported with a variety of sympathomimetic drugs including amphetamine and methylphenidate as well as ephedrine and PPA." But again, the references supplied are both about PPA.

Section 4: "Pharmacology and toxicology of caffeine"

This section is scientifically uncontroversial and generally accurate, except for the statement that "[p]ills containing high doses of caffeine and ephedrine have been marketed as amphetamine look-alikes" (Benowitz Report at 4). Again, no reference is supplied, and the statement gives the impression that such pills are still commonly sold. In fact, the amphetamine "look-alikes" largely disappeared from the marketplace many years ago.

Section 6: "Individual risk factors"

Drs. Benowitz and Haller echo FDA's argument that there is a need for tighter regulations to prevent adverse events that might occur when ephedrine is used by someone who is abnormally sensitive to ephedrine alkaloids or, as Drs. Benowitz and Haller prefer, "ephedrines." Drs. Benowitz and Haller correctly point out that "[m]illions of people use herbal products containing ephedrine, but the number of adverse reactions reported in the U.S. are in the hundreds." However, they then argue that the occasional episode of "severe adverse reactions" must be the result of "individual susceptibility" (Benowitz Report at 4). They offer a list of conditions which might make an individual more "susceptible." These include the presence of preexisting kidney or coronary or cerebrovascular disease, or an utterly obscure, extremely rare disorder known as autonomic insufficiency. Drs. Benowitz and Haller's inclusion of the last condition is somewhat surprising, because alpha 1-sympathomimetic agents, such as ephedrine, are occasionally used to treat refractory orthostatic hypotension resulting from autonomic failure.

Conclusion: Drs. Benowitz and Haller ignore the possibility, supported by a majority of the case reports, that adverse reactions to ephedrine occur when people take too much.

Unintentionally, Drs. Benowitz and Haller may have raised an extremely important issue: because there are so few case reports involving ephedrine toxicity, FDA has had to adopt the position that all ephedrine enantiomers are equally toxic; otherwise they would not be able to cite cases of PPA-related vasculitis or hypertensive crisis as proof that ephedrine causes those same disorders. But if one accepts that all isomers are equivalent, then PPA or PE, the main cold medications in the Western world, are just as likely to cause strokes and heart attacks as ephedrine. In fact, based on the peer-reviewed literature, which is held in considerably higher esteem than FDA's AERs, the other isomers are much more dangerous than ephedrine, particularly for those individuals with underlying heart or cerebrovascular disease. If ephedrine is to be restricted because it might precipitate illness in those with preexisting anatomic lesions, how can PPA and PE be allowed to remain on the market?

Section 8: "Results"

Drs. Benowitz and Haller state that "one of the most disturbing findings was the number of sudden devastating cerebral or coronary vascular events in previously healthy persons who did not appear to be at high risk based on medical history or prior symptomology" (Benowitz Report at 9). Certainly Dr. Benowitz is aware that for several hundred thousand Americans, the first symptoms of coronary artery disease is SCD. The lack of prior symptomology is irrelevant to any rational discussion about ephedrine-related heart disease.

Some of the "sudden devastating cerebral or coronary vascular events in previously healthy persons who did not appear to be at high risk based on medical history or prior symptomology," referred to by Drs. Benowitz and Haller, are described below. Cases 12485, 12851, 13031, 13096, the only cases where FDA felt there was a clear connection between ephedrine use and death, were discussed in more detail above.

Section 9: "Case Examples"

According to Drs. Benowitz and Haller, "serious events frequently occurred during or soon after exercise, as in the following two examples" (Benowitz Report at 11).

Case #12483: This case involved an otherwise healthy woman who sustained a subarachnoid hemorrhage after an aerobics class. She had been taking a tablet containing 15 mg of ephedrine three times a day to promote weight loss. Arteriography showed neither aneurysm nor evidence of vasculitis. Only screening urine toxicology tests were performed and these were positive for barbiturates and amphetamine. Drs. Benowitz and Haller state that this is proof of ephedrine ingestion, which would have been true in the early 1990s since the antibodies used for urine screening tests for amphetamine often cross-reacted with ephedrine. However, this episode occurred in the summer of 1997, and given the operating characteristics of urine screening tests available at that time, the only way for cross-reaction to have occurred would have been for the woman to have taken a massive dose of ephedrine. Barbiturates would, of course, not have contributed to the woman's stroke, but their presence confirms she was a polydrug user and strongly suggests that the screening test for amphetamine, had it been confirmed, would have tested positive for amphetamine, not ephedrine. Drs. Benowitz and Haller fail to mention that barbiturates were detected.

Case #12485: This case describes a 38-year-old man with obesity, hyperlipidemia, and known cardiomegaly long before he ever took dietary supplements. He died shortly after jogging - one of the more common scenarios in SCD. At autopsy, he was found to have severe coronary artery disease (>75% obstruction of the distal obtuse marginal branches of the LAD, 75% obstruction of the proximal RCA, and 75% narrowing of the proximal circumflex). There was marked cardiomegaly, with a heart weight of 490 grams, and four-chamber dilatation. Drs. Benowitz and Haller stated that the decedent had "mild cardiomegaly," which is a bit like saying that the HIV virus causes mild symptoms. A heart weight of 490 grams in a man the size of the decedent is more than two standard deviations above predicted. As the recent publication of the New England Journal of Medicine points out (24), and has been known for more than 40 years, this degree of cardiomegaly carries a greater increased risk for sudden death, even in the absence of ephedrine or other stimulants. Drs. Benowitz and Haller's contention that the role of ephedrine is proven by the fact that the individual was "asymptomatic" is simply ridiculous. Most people with severe coronary artery disease and an enlarged heart are asymptomatic until they experience a cardiac arrest.

Conclusion: Drs. Benowitz and Haller appear to have a much lower threshold for diagnosing ephedrine toxicity than the FDA working group as a whole, which included far fewer cases. Only Case #12485 was deemed by the entire committee to be a direct result of ephedrine-toxicity. The case below is typical of the type of cases where Drs. Benowitz and Haller felt that the illness could be linked to ephedrine use.

Case #12713: This case describes a 64-year-old woman with a previous history of treatment for transient ischemic episodes and hypertension and new onset atrial fibrillation, who sustained a left-sided cerebral infarct in the middle cerebral territory. Treatment with heparin resulted in a small hemorrhage. Her attending physicians felt the stroke was the result of embolization from her atrial fibrillation. Toxicology testing was not performed. She was taking a product called "Fit America," which contained ephedrine. However, she could not remember how many pills she had taken, or if she had taken any at all, the day of her stroke. Routine chest x-ray showed an enlarged heart, and this was confirmed by echocardiography, which showed biventricular enlargement and calcification of the mitral annulus. The patient improved, reverted to sinus rhythm and was discharged to rehabilitation.

Conclusion: This is a classic stroke patient who had every reason to have had a stroke without invoking toxicity from ephedrine, which may or may not have even been present.

Section 10: "Discussion"

The discrepancy between the large number of AERs received by FDA, and the paucity of published clinical and experimental studies detecting even "modest cardiovascular effects from ephedrine, dosed alone or with caffeine" is explained, according to Drs. Benowitz and Haller, by "differences in individual susceptibility" (Benowitz Report at 14). The failure to demonstrate toxicity in controlled clinical trials with obese patients is, they believe, explained by the "inadequate numbers of subjects to detect uncommon adverse effects that are related to individual susceptibility." (One study involved 29 patients, the other 180.) Furthermore, they argue that "ephedrine and/or caffeine could augment the cardiovascular stress of exercise, and that could provide another explanation for differences in individual susceptibility." Although this statement is unsupported by any citations, others have suggested it as well (See FDA Reference #82).

Conclusion: There are two difficulties with this position. It ignores the possibility that some (or many, or most) of the AERs have nothing to do with ephedrine. And, if they have nothing to do with ephedrine, then the discrepancy between the peer-reviewed literature and the FDA literature disappears. The other difficulty is that it ignores a rather sizable body of literature written by exercise physiologists which shows that neither caffeine nor ephedrine, in relevant physiologic doses, has any effect on the results of maximal exercise testing (13, 15, 16, 17, 25, 26).

B. Dr. R. L. Woosley

The report Dr. Woosley drafted for FDA is entitled "Summary of Analysis of Adverse Event Reports for Dietary Supplements Containing Ephedrine Alkaloids" (hereinafter "Woosley Report").

"Results"

Except to say that Dr. Woosley felt most of the AERs were a consequence of ephedrine use, his assessments are impossible to analyze, since he does not discuss individual cases. He awarded a score of "5" to seven cases of cardiac arrest, two more than were agreed to by the consensus panel.

Conclusion: Since Dr. Woosley doesn't indicate which individuals he is talking about, little more can be said, except that if cardiac arrest occurs, and ephedrine is present, then Dr. Woosley apparently has presumed ephedrine is the cause of death, regardless of any other findings.

"Discussion"

The discussion section is unique in that it contains no supporting scientific references whatsoever. Dr. Woosley's general approach is even broader than that of FDA. While FDA considers all ephedrine alkaloids to be identical, Dr. Woosley considers all sympathomimetic amines to be similar, at least for the purposes of his analysis. The statements below are all unsupported by any scientific citations, and no data contradictory to Dr. Woosley's position is presented.

a. "The major results of the direct cardiovascular actions of ephedrine are an increase in heart rate and blood pressure" (Woosley Report at 3).

Conclusion: While it is true that ß1 stimulation causes increased myocardial contractility, ß1 stimulation also causes coronary artery dilation and dilation of peripheral resistance vessels (27). Since ephedrine has a greater beta agonist than alpha agonist activity, increased blood pressure need not occur. Indeed, in controlled experiments, using physiologically relevant doses of ephedrine, increased blood pressure does not occur. All catecholamines are not equal, and Dr. Woosley is suggesting they are.

b. "The effects of ephedrine on the adrenergic nervous system increase heart rate, shorten cardiac refractory periods and facilitate the development of reentrant cardiac arrhythmias" (Woosley Report at 3).

Conclusion: The latest scientific data suggest that the ability of catecholamines to facilitate reentrant arrhythmias is contingent on the presence of underlying heart disease (28). However, not all catecholamines are alike, and since the electrophysiology of neither ephedra nor ephedrine has never been studied, it is a bit difficult to see how Dr. Woosley reached this conclusion.

c. "These effects are most likely responsible for the cases of atrial fibrillation, sustained symptomatic ventricular tachycardia, and symptoms associated with cardiac arrhythmias, palpitations, dizziness and syncope" (Woosley Report at 3).

Conclusion: There is no published peer-reviewed data that suggest that the use of any catecholamines, let alone ephedrine, causes atrial fibrillation. Furthermore, Dr. Woosley writes in this month's issue of Circulation (Circulation, 2000; 101:2200) that "[t]he prevalence of atrial fibrillation (AF) increases with age and is associated primarily with hemodynamic or mechanical disorders of the heart (i.e., hypertension, mitral valve disease, cardiac failure)," never once mentioning the key role he feels that ephedrine toxicity plays. It is unclear whether Dr. Woosley has changed his mind since he wrote his report for FDA.

d. "The electrophysiologic changes associated with ephedrine can unmask a previously asymptomatic case of cardiac pre-excitation, i.e. Wolfe-Parkinson-White (WPW) Syndrome" (Woosley Report at 3).

Conclusion: There is no published peer-reviewed data which shows that (a) ephedrine, in physiologically relevant doses, causes pre-excitation syndrome, and (b) no evidence that ephedrine use has ever "unmasked" a case of WPW.

Dr. Woosley then concludes his discussion by discussing FDA's two favorite areas of concern - individual variation in sensitivity to ephedrine's effects, and the presence of undiagnosed hypertension. The only difference between Dr. Woosley and FDA, at least on the first point, is that Dr. Woosley's explanation is weaker, suggesting that he may not be aware of how ephedrine is metabolized.

e. "Although ephedrine has been used for many years, the clinical pharmacology of ephedrine has not been studied using modern methods. For example, unlike drugs being marketed today, we do not know which specific enzymes in the bowel and liver metabolize ephedrine. Are there individuals who have exaggerated sensitivity to ephedrine products because they lack a specific cytochrome P450 enzyme?" (Woosley Report at 4).

Conclusion: The metabolic breakdown of ephedrine is well-characterized (29, 30). Very small amounts of ephedrine and PE are demethylated to PPA and norpseudoephedrine, but the vast majority is excreted unchanged in the urine. Since the drug is not metabolized, it is difficult to conceive how any genetic heterogeneity could alter the metabolism of a drug that is not metabolized. It is unclear whether Dr. Woosley is suggesting that some people actually metabolize more ephedrine to PPA than others do, but certainly there is no precedent for such heterogeneity, and it has never been reported in the peer-reviewed literature.

f. "Likewise, receptor polymorphisms are being recognized as potential causes of extreme sensitivity to drugs. Yet, individuals with polymorphisms of adrenergic or other vascular receptors have not been studied for their response to ephedrine" (Woosley Report at 4).

Conclusion: The most common polymorphisms of the human beta2-adrenergic receptor--Arg16-->Gly and Gln27-->Glu-- are associated with alterations in beta2-adrenergic receptor responses, both in vitro and in vivo. Beta2-adrenergic receptor-mediated vascular responses are affected by ethnicity, blood pressure, and genotype. But population studies, while confirming that such variations exist, have also shown that they have absolutely nothing to do with the occurrence of essential hypertension, either in blacks or in whites (31).

g. "There were 12 cases of severe stroke leading to death and/or serious disability. Three of the strokes occurred in young people in their twenties. These are most likely due to either severe increases in blood pressure in normal individuals or even a moderate increase in blood pressure in someone with a predisposition to stroke, i.e., someone with a silent aneurysm. In some cases of stroke the patients had a history of high blood pressure before taking the ephedrine product and in others the high blood pressure was only detected after the stroke. All of the products carried warnings not to take the product if the consumer had high blood pressure. However, some individuals who had a stroke were unaware of their high blood pressure. At least three cases were aware of their high blood pressure and the risk but took the products anyway" (Woosley Report at 3).

Conclusion: Ample evidence suggests that neither ephedrine, nor PE, in relevant physiologic doses, causes hypertension. This means the use of ephedrine or PE does not put people at risk for stroke. On the other hand, individuals with undiagnosed preexisting severe heart disease might be at risk, but they would be equally at risk no matter whether they were taking dietary supplements or OTC cold medications. If one product is to be removed from the market, simple logic requires that they all be removed.

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V. Conclusion

An analysis of (1) the AERs purportedly linked to cardiovascular toxicity, (2) FDA's literature review, and (3) the health assessments made by FDA and its outside consultants does not support FDA's concern that dietary supplements containing ephedrine alkaloids are causing cardiotoxic adverse events.

The AERs I have reviewed in this statement do not show that ephedra, when consumed in appropriate amounts, is causally related to the adverse events. Many other factors likely precipitated these adverse event. It would be scientifically inappropriate to rely on these reports as evidence of cardiotoxicity of ephedra.

Further, FDA's literature review consists of many references that are either irrelevant or inappropriate to an analysis of the safety of ephedra products. Thus, the literature review's relevance in an analysis of the safety of ephedra products is questionable. My review of the relevant literature shows that ephedra products should not be a concern from the standpoint of cardiotoxicity when consumed according to current national standards.

FDA's outside consultants' health assessments of ephedra are based on the AERs and are therefore not reliable. The reviews of these experts to a significant degree are inconsistent with each other and with FDA, showing why AERs are not useful for making health assessments.

In sum, my review of the above information leads me to a very different conclusion than that reached by FDA and its consultants ‚ that ephedra products may be safely consumed when taken in accordance with the current national standards as reflected in the American Herbal Products Association trade recommendation for ephedra products.

______________________

Steven B. Karch, M.D.

September 22, 2000

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