Correspondence

Dietary Supplements Containing Ephedra Alkaloids

N Engl J Med 2001; 344:1095-1097April 5, 2001

Article

To the Editor:

As an anatomical pathologist and paid consultant to the Ephedra Education Council, I reviewed 22 reports of adverse events received by the Food and Drug Administration (FDA) in which death had occurred and assessed the likelihood that death was related to the use of ephedrine-type alkaloids. My review, reported August 8, 2000, at the Department of Health and Human Services's Public Meeting on the Safety of Dietary Supplements Containing Ephedrine Alkaloids, in Washington, D.C., showed no consistent clinical or pathological features of the reported adverse events and showed that ephedrine-type alkaloids were not likely to have been causative or contributing factors in the deaths.1

The report by Haller and Benowitz (Dec. 21 issue)2 included eight of the cases I had reviewed and interpreted these adverse events as related to the use of ephedrine-type alkaloids. Table 4 of the report by Haller and Benowitz lists adverse events that were definitely or probably related to the use of ephedrine-type alkaloids, but in the column labeled “preexisting conditions or concurrent risks,” the authors have omitted the following data: Patient 4 had chest pain, Patient 5 hypertension, and Patient 7 severe coronary artery disease. Table 5, which lists events possibly related to the use of ephedrine-type alkaloids, omits the fact that Patients 2 and 6 collapsed during extreme exercise and fasting for rapid weight loss. In addition, Patient 7 did not have an adverse event; her premature infant died from necrotizing enterocolitis. An autopsy in Patient 9 demonstrated the anomalous origin of the left coronary artery from the pulmonary trunk, a well-known cause of sudden death. With an adequate explanation of the reported adverse events, the implication of ephedrine-type alkaloids in deaths from a wide variety of conditions that occur in the general population is no more than idle speculation.

Grover M. Hutchins, M.D.
1 Stratford Rd., Baltimore, MD 21218

2 References

1. 1

   The National Women's Health Information Center. Public Meeting on the Safety of Dietary Supplements Containing Ephedrine Alkaloids, Washington, D.C., August 8 and 9, 2000. (See http://www.4woman.gov/owh/public.)
   

2. 2

   Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833-1838
   Full Text | Web of Science | Medline

To the Editor:

We wish to report on a previously healthy, 19-year-old male bodybuilder who had a myocardial infarction after using ephedra.

The patient reported chest pain of 30 minutes' duration that had begun shortly after the use of Dymetadrine Xtreme. He dissolved the recommended dose (two tablets, each reported to contain 24 mg of ephedra alkaloids and 100 mg of caffeine1) in water and drank the solution, as he had done in the past. Severe chest pain, radiating to the left arm, developed 15 minutes later. He had no history of chest pain or cardiac disease and reported that he had no other cardiac risk factors, including cocaine use. Vital signs were as follows: pulse, 116 per minute and regular; blood pressure, 147/84 mm Hg; respirations, 22 per minute; temperature, 37.3°C (99.1°F). The physical examination was otherwise unremarkable except for diaphoresis.

The electrocardiogram showed evidence of an inferolateral myocardial infarction. The patient was given oxygen, aspirin, heparin, and nitroglycerin, and his ST-segment elevation resolved. Five hours later, inferolateral ST-segment elevation recurred. After treatment with phentolamine and labetalol, the electrocardiographic findings again returned to normal. The creatine kinase level was initially 351 U per liter, with an MB fraction of 23 ng per milliliter; it peaked at 1271 U per liter, with an MB fraction of 104 ng per milliliter. The value for troponin I peaked at 256.1 ng per milliliter. A toxicologic test of a urine specimen was negative for cocaine. Echocardiography revealed hypokinesis of the inferior wall. Cardiac catheterization demonstrated only minimal intimal disease of the distal left anterior descending artery. The patient recovered and was doing well at follow-up.

The temporal association between the use of the supplement and the infarction, the absence of clinically significant findings on cardiac catheterization, and the negative test for cocaine led us to conclude that the myocardial infarction was caused by the use of ephedra.

This case highlights the potential dangers of ephedra use by presumably healthy persons. Given the growing numbers of reports of ephedra-related adverse events, both the general public and the medical community should be alerted to the dangers posed by over-the-counter products containing ephedra. Furthermore, we urge greater regulation of these potentially lethal products.

Stephen J. Traub, M.D.
New York City Poison Control Center, New York, NY 10016

Wissam Hoyek, M.D.
Staten Island University Hospital, Staten Island, NY 10305

Robert S. Hoffman, M.D.
New York City Poison Control Center, New York, NY 10016

1 References

1. 1

   AST sports science Web site. (See http://www.ast-ss.com.)
   

Author/Editor Response

The authors reply:

To the Editor: Dr. Hutchins argues that because several of the patients who had severe cardiovascular events while taking ephedra-alkaloid–containing dietary supplements had underlying disease, it is idle speculation to implicate the dietary supplements as the cause of these events. Before addressing the individual cases mentioned by Dr. Hutchins, we would like to restate our point that ephedra-related events are uncommon but are most likely to occur in vulnerable populations. Persons with underlying cardiovascular disease are an obviously vulnerable population. The effects of ephedrine and caffeine — constricting blood vessels, increasing blood pressure, and releasing catecholamines — would be most likely to cause injury in persons with underlying cardiovascular disease. In such persons, ischemia, infarction, or arrhythmias, or a combination of these events, could well be precipitated by the sympathomimetic effects of ephedrine and caffeine. Most important, these cases illustrate that people with unrecognized cardiovascular disease are using products that are potentially hazardous to them.

In response to Dr. Hutchins's comments on individual cases, it should be noted that in some cases the information provided to us by the FDA differed from that cited by Dr. Hutchins. In any case, assuming that the information provided by Dr. Hutchins is correct, one should be concerned about a 43-year-old man with chest pain (Patient 4 in Table 4 of our article) or a patient with known hypertension (Patient 5 in Table 4) who is taking a supplement that contains an ephedra alkaloid. These circumstances raise questions about the adequacy of warnings about contraindications. The fact that two patients collapsed and died during extreme exercise and dieting underscores another serious concern about the use of ephedrine-containing dietary supplements, which are recommended for increased energy and weight loss. On the basis of the known pharmacologic characteristics of ephedrine and caffeine, these drugs might be likely to have more injurious effects in the context of intense exercise. Likewise, a person with a congenital anomaly of a coronary artery might be more likely to have ischemia in the presence of a sympathomimetic drug. With respect to Patient 7 in Table 5 of our article, the adverse event was fetal death, which was presumed to be due to premature delivery, which in turn may have been induced by the consumption of ephedrine-containing dietary supplements.

Thus, it is likely that unrecognized cardiovascular disease confers a predisposition to adverse events associated with the use of ephedrine-containing dietary supplements. The fact that several persons had underlying cardiovascular disease does not mean there were no adverse reactions to these dietary supplements. Even if appropriate warning statements were listed on the product labels, users with unrecognized risk factors could not be expected to respond to such warnings. Until there is a way to identify persons who are at risk for adverse effects, supplements containing ephedra alkaloids should be considered unreasonably dangerous. Perhaps one solution is to perform coronary angiographic screening of all patients before they take these products.

Finally, our report describes a series of cases in which the use of ephedrine-containing dietary supplements was associated with adverse cardiovascular events. Our report does not prove causation, nor does it provide quantitative information with regard to risk. A large-scale case–control study similar to the Hemorrhagic Stroke Project for phenylpropanolamine1 is needed to determine the risks associated with these dietary supplements.

Christine A. Haller, M.D.
Neal L. Benowitz, M.D.
University of California, San Francisco, San Francisco, CA 94143-1220

1 References

1. 1

   Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826-1832
   Full Text | Web of Science | Medline

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   Leonard Bielory. (2004) Complementary and alternative interventions in asthma, allergy, and immunology. Annals of Allergy, Asthma & Immunology 93:2, S45-S54
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   IRA JACOBS, HARLEY PASTERNAK, DOUGLAS G. BELL. (2003) Effects of Ephedrine, Caffeine, and Their Combination on Muscular Endurance. Medicine & Science in Sports & Exercise 35:6, 987-994
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   G. M. Hutchins. (2002) Ma Huang Toxicity. Mayo Clinic Proceedings 77:7, 733-733
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   Linn Goldberg, Diane Elliot, Kerry Kuehl. (2002) Letters to the Editor-in-Chief. Medicine & Science in Sports & Exercise 34:1, 181
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