Background Dietary supplements that contain ephedra alkaloids(sometimes called ma huang) are widely promoted and used inthe United States as a means of losing weight and increasingenergy. In the light of recently reported adverse events relatedto use of these products, the Food and Drug Administration (FDA)has proposed limits on the dose and duration of use of suchsupplements. The FDA requested an independent review of reportsof adverse events related to the use of supplements that containedephedra alkaloids to assess causation and to estimate the levelof risk the use of these supplements poses to consumers.
Methods We reviewed 140 reports of adverse events related tothe use of dietary supplements containing ephedra alkaloidsthat were submitted to the FDA between June 1, 1997, and March31, 1999. A standardized rating system for assessing causationwas applied to each adverse event.
Results Thirty-one percent of cases were considered to be definitelyor probably related to the use of supplements containing ephedraalkaloids, and 31 percent were deemed to be possibly related.Among the adverse events that were deemed definitely, probably,or possibly related to the use of supplements containing ephedraalkaloids, 47 percent involved cardiovascular symptoms and 18percent involved the central nervous system. Hypertension wasthe single most frequent adverse effect (17 reports), followedby palpitations, tachycardia, or both (13); stroke (10); andseizures (7). Ten events resulted in death, and 13 events producedpermanent disability, representing 26 percent of the definite,probable, and possible cases.
Conclusions The use of dietary supplements that contain ephedraalkaloids may pose a health risk to some persons. These findingsindicate the need for a better understanding of individual susceptibilityto the adverse effects of such dietary supplements.
Source Information
From the Division of Clinical Pharmacology and Experimental Therapeutics, Departments of Medicine and Biopharmaceutical Sciences, University of California, San Francisco, and the California Poison Control System, San Francisco Division — both in San Francisco.
Address reprint requests to Dr. Benowitz at the Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, Box 1220, San Francisco, CA 94143-1220, or at nbeno{at}itsa.ucsf.edu.
Hallas, J., Bjerrum, L., Stovring, H., Andersen, M.
(2008). Use of a Prescribed Ephedrine/Caffeine Combination and the Risk of Serious Cardiovascular Events: A Registry-based Case-Crossover Study. Am J Epidemiol
168: 966-973
[Abstract][Full Text]
Wallace, R. B, Gryzlak, B. M, Zimmerman, M B., Nisly, N. L
(2008). Application of FDA Adverse Event Report Data to the Surveillance of Dietary Botanical Supplements. The Annals of Pharmacotherapy
42: 653-660
[Abstract][Full Text]
DiPaola, R. S., Gallo, M. A.
(2008). Hearsay Medicine Is Not Evidence-Based Medicine. Clin. Cancer Res.
14: 337-338
[Full Text]
Grippo, A. A, Capps, K., Rougeau, B., Gurley, B. J
(2007). Analysis of Flavonoid Phytoestrogens in Botanical and Ephedra-Containing Dietary Supplements. The Annals of Pharmacotherapy
41: 1375-1382
[Abstract][Full Text]
Ma, G., Bavadekar, S. A., Davis, Y. M., Lalchandani, S. G., Nagmani, R., Schaneberg, B. T., Khan, I. A., Feller, D. R.
(2007). Pharmacological Effects of Ephedrine Alkaloids on Human {alpha}1- and {alpha}2-Adrenergic Receptor Subtypes. J. Pharmacol. Exp. Ther.
322: 214-221
[Abstract][Full Text]
Ashar, B. H., Rice, T. N., Sisson, S. D.
(2007). Physicians' Understanding of the Regulation of Dietary Supplements. Arch Intern Med
167: 966-969
[Abstract][Full Text]
Diepvens, K., Westerterp, K. R., Westerterp-Plantenga, M. S.
(2007). Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea. Am. J. Physiol. Regul. Integr. Comp. Physiol.
292: R77-R85
[Abstract][Full Text]
Visalyaputra, S.
(2006). Is Ephedrine the Best Vasopressor for Treating Spinal Anesthesia-Induced Hypotension in Patients with Pre-Eclampsia?. Anesth. Analg.
103: 1584-1585
[Full Text]
Schubiner, H., Hassunizadeh, B., Kaczynski, R.
(2006). A controlled study of autonomic nervous system function in adults with attention-deficit/hyperactivity disorder treated with stimulant medications: results of a pilot study.. J Atten Disord
10: 205-211
[Abstract]
Developed in Collaboration With the European Heart, , Zipes, D. P., Camm, A. J., Borggrefe, M., Buxton, A. E., Chaitman, B., Fromer, M., Gregoratos, G., Klein, G., Moss, A. J., Myerburg, R. J., Priori, S. G., Quinones, M. A., Roden, D. M., Silka, M. J., Tracy, C., Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Antman, E. M., Anderson, J. L., Hunt, S. A., Halperin, J. L., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B., Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L.
(2006). ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). J Am Coll Cardiol
48: e247-e346
[Full Text]
Writing Committee Members, , Zipes, D. P., Camm, A. J., Borggrefe, M., Buxton, A. E., Chaitman, B., Fromer, M., Gregoratos, G., Klein, G., Moss, A. J., Myerburg, R. J., Priori, S. G., Quinones, M. A., Roden, D. M., Silka, M. J., Tracy, C., ESC Committee for Practice Guidelines, , Priori, S. G., Blanc, J.-J., Budaj, A., Camm, A. J., Dean, V., Deckers, J. W., Despres, C., Dickstein, K., Lekakis, J., McGregor, K., Metra, M., Morais, J., Osterspey, A., Tamargo, J. L., Zamorano, J. L., ACC/AHA Task Force Members, , Smith, S. C. Jr, Jacobs, A. K., Adams, C. D., Antman, E. M., Anderson, J. L., Hunt, S. A., Halperin, J. L., Nishimura, R., Ornato, J. P., Page, R. L., Riegel, B.
(2006). ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Europace
8: 746-837
[Full Text]
Avois, L, Robinson, N, Saudan, C, Baume, N, Mangin, P, Saugy, M
(2006). Central nervous system stimulants and sport practice. Br. J. Sports. Med.
40: i16-i20
[Abstract][Full Text]
Grippo, A. A., Hamilton, B., Hannigan, R., Gurley, B. J.
(2006). Metal content of ephedra-containing dietary supplements and select botanicals. Am J Health Syst Pharm
63: 635-644
[Abstract][Full Text]
Lopez-Garcia, E., van Dam, R. M, Rajpathak, S., Willett, W. C, Manson, J. E, Hu, F. B
(2006). Changes in caffeine intake and long-term weight change in men and women. Am. J. Clin. Nutr.
83: 674-680
[Abstract][Full Text]
Calfee, R., Fadale, P.
(2006). Popular Ergogenic Drugs and Supplements in Young Athletes. Pediatrics
117: e577-e589
[Abstract][Full Text]
Liles, J. T., Dabisch, P. A., Hude, K. E., Pradhan, L., Varner, K. J., Porter, J. R., Hicks, A. R., Corll, C., Baber, S. R., Kadowitz, P. J.
(2006). Pressor Responses to Ephedrine Are Mediated by a Direct Mechanism in the Rat. J. Pharmacol. Exp. Ther.
316: 95-105
[Abstract][Full Text]
Bui, L. T, Nguyen, D. T, Ambrose, P. J
(2006). Blood Pressure and Heart Rate Effects Following a Single Dose of Bitter Orange. The Annals of Pharmacotherapy
40: 53-57
[Abstract][Full Text]
Smolinske, S. C.
(2005). Herbal Product Contamination and Toxicity. Journal of Pharmacy Practice
18: 188-208
[Abstract]
Woodward, K N
(2005). The potential impact of the use of homeopathic and herbal remedies on monitoring the safety of prescription products. Hum Exp Toxicol
24: 219-233
[Abstract]
Howden, R., Hanlon, P. R., Petranka, J. G., Kleeberger, S., Bucher, J., Dunnick, J., Nyska, A., Murphy, E.
(2005). Ephedrine plus caffeine causes age-dependent cardiovascular responses in Fischer 344 rats. Am. J. Physiol. Heart Circ. Physiol.
288: H2219-H2224
[Abstract][Full Text]
Richard, C. L, Jurgens, T. M
(2005). Effects of Natural Health Products on Blood Pressure. The Annals of Pharmacotherapy
39: 712-720
[Abstract][Full Text]
Kelly, J. P., Kaufman, D. W., Kelley, K., Rosenberg, L., Anderson, T. E., Mitchell, A. A.
(2005). Recent Trends in Use of Herbal and Other Natural Products. Arch Intern Med
165: 281-286
[Abstract][Full Text]
Nyska, A., Murphy, E., Foley, J. F., Collins, B. J., Petranka, J., Howden, R., Hanlon, P., Dunnick, J. K.
(2005). Acute Hemorrhagic Myocardial Necrosis and Sudden Death of Rats Exposed to a Combination of Ephedrine and Caffeine. Toxicol Sci
83: 388-396
[Abstract][Full Text]
Curtis, P., Gaylord, S.
(2005). Safety Issues in the Interaction of Conventional, Complementary, and Alternative Health Care. Complementary Health Practice Review
10: 3-31
[Abstract]
Maglione, M., Miotto, K., Iguchi, M., Jungvig, L., Morton, S. C., Shekelle, P. G.
(2005). Psychiatric Effects of Ephedra Use: An Analysis of Food and Drug Administration Reports of Adverse Events. Am. J. Psychiatry
162: 189-191
[Abstract][Full Text]
Adamson, P. B., Suarez, J., Ellis, E., Kanaly, T., Vanoli, E.
(2004). Ephedrine increases ventricular arrhythmias in conscious dogs after myocardial infarction. J Am Coll Cardiol
44: 1675-1678
[Abstract][Full Text]
Fugh-Berman, A., Myers, A.
(2004). Citrus aurantium, an Ingredient of Dietary Supplements Marketed for Weight Loss: Current Status of Clinical and Basic Research. Exp. Biol. Med.
229: 698-704
[Abstract][Full Text]
Xue, Y., Cohen, S. S.
(2004). Dietary Supplements: Policy and Research Implications for Nurses. Policy Politics Nursing Practice
5: 149-159
[Abstract]
Halsted, C.
(2004). The ABC Clinical Guide to Herbs: edited by Mark Blumenthal, 2003, 480 pages, hardcover, $69.95. American Botanical Council, Austin, TX.. Am. J. Clin. Nutr.
79: 1127-1128
[Full Text]
Rhee, S. M., Garg, V. K., Hershey, C. O.
(2004). Use of Complementary and Alternative Medicines by Ambulatory Patients. Arch Intern Med
164: 1004-1009
[Abstract][Full Text]
Pittler, M. H, Ernst, E.
(2004). Dietary supplements for body-weight reduction: a systematic review. Am. J. Clin. Nutr.
79: 529-536
[Abstract][Full Text]
Naik, S. D, Freudenberger, R. S
(2004). Ephedra-Associated Cardiomyopathy. The Annals of Pharmacotherapy
38: 400-403
[Abstract][Full Text]
Miller, S. C., Waite, C.
(2003). Ephedrine-Type Alkaloid-Containing Dietary Supplements and Substance Dependence. Psychosomatics
44: 508-511
[Full Text]
Rothman, R. B., Vu, N., Partilla, J. S., Roth, B. L., Hufeisen, S. J., Compton-Toth, B. A., Birkes, J., Young, R., Glennon, R. A.
(2003). In Vitro Characterization of Ephedrine-Related Stereoisomers at Biogenic Amine Transporters and the Receptorome Reveals Selective Actions as Norepinephrine Transporter Substrates. J. Pharmacol. Exp. Ther.
307: 138-145
[Abstract][Full Text]
Cantu, C., Arauz, A., Murillo-Bonilla, L. M., Lopez, M., Barinagarrementeria, F.
(2003). Stroke Associated With Sympathomimetics Contained in Over-the-Counter Cough and Cold Drugs. Stroke
34: 1667-1672
[Abstract][Full Text]
Brust, J. C.M.
(2003). Editorial Comment--Over-the-Counter Cold Remedies and Stroke. Stroke
34: 1673-1673
[Full Text]
Woolf, A. D.
(2003). Herbal Remedies and Children: Do They Work? Are They Harmful?. Pediatrics
112: 240-246
[Abstract][Full Text]
Weigle, D. S.
(2003). Pharmacological Therapy of Obesity: Past, Present, and Future. J. Clin. Endocrinol. Metab.
88: 2462-2469
[Full Text]
Brown, D L
(2003). Deaths associated with platelet glycoprotein IIb/IIIa inhibitor treatment. Heart
89: 535-537
[Abstract][Full Text]
Heyneman, C. A.
(2003). Preoperative Considerations: Which Herbal Products Should Be Discontinued Before Surgery?. Crit Care Nurse
23: 116-124
[Full Text]
Halsted, C. H
(2003). Dietary supplements and functional foods: 2 sides of a coin?. Am. J. Clin. Nutr.
77: 1001S-1007
[Abstract][Full Text]
Shekelle, P. G., Hardy, M. L., Morton, S. C., Maglione, M., Mojica, W. A., Suttorp, M. J., Rhodes, S. L., Jungvig, L., Gagne, J.
(2003). Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A Meta-analysis. JAMA
289: 1537-1545
[Abstract][Full Text]
Fontanarosa, P. B., Rennie, D., DeAngelis, C. D.
(2003). The Need for Regulation of Dietary Supplements--Lessons From Ephedra. JAMA
289: 1568-1570
[Full Text]
Bent, S., Tiedt, T. N., Odden, M. C., Shlipak, M. G.
(2003). The Relative Safety of Ephedra Compared with Other Herbal Products. ANN INTERN MED
138: 468-471
[Abstract][Full Text]
Chyka, P. A.
(2003). Health Risks of Selected Performance-Enhancing Drugs. Journal of Pharmacy Practice
16: 37-44
[Abstract]
Goldschlager, N., Epstein, A. E., Grubb, B. P., Olshansky, B., Prystowsky, E., Roberts, W. C., Scheinman, M. M., for the Practice Guidelines Subcommittee, North Am,
(2003). Etiologic Considerations in the Patient With Syncope and an Apparently Normal Heart. Arch Intern Med
163: 151-162
[Full Text]
Morgenstern, L.B., Viscoli, C.M., Kernan, W.N., Brass, L.M., Broderick, J.P., Feldmann, E., Wilterdink, J.L., Brott, T., Horwitz, R.I.
(2003). Use of Ephedra-containing products and risk for hemorrhagic stroke. Neurology
60: 132-135
[Abstract][Full Text]
Marcus, D. M., Grollman, A. P.
(2002). Botanical Medicines -- The Need for New Regulations. NEJM
347: 2073-2076
[Full Text]
Corns, C, Metcalfe, K
(2002). Risks associated with herbal slimming remedies. The Journal of the Royal Society for the Promotion of Health
122: 213-219
[Abstract]
Skinner, C. M., Rangasami, J.
(2002). Preoperative use of herbal medicines: a patient survey. Br J Anaesth
89: 792-795
[Abstract][Full Text]
Markman, M.
(2002). Safety Issues in Using Complementary and Alternative Medicine. JCO
20: 39s-41
[Abstract][Full Text]
Gilbert, G. J., Petro, D. J., Singhal, A. B.
(2002). Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology
59: 651-652
[Full Text]
Favreau, J. T., Ryu, M. L., Braunstein, G., Orshansky, G., Park, S. S., Coody, G. L., Love, L. A., Fong, T.-L.
(2002). Severe Hepatotoxicity Associated with the Dietary Supplement LipoKinetix. ANN INTERN MED
136: 590-595
[Abstract][Full Text]
Lewis, J. D., Strom, B. L.
(2002). Balancing Safety of Dietary Supplements with the Free Market. ANN INTERN MED
136: 616-618
[Full Text]
Valli, G., Giardina, E.-G. V.
(2002). Benefits, adverse effects and drug interactionsof herbal therapies with cardiovascular effects. J Am Coll Cardiol
39: 1083-1095
[Abstract][Full Text]
Metcalfe, K., Corns, C., Fahie-Wilson, M., Mackenzie, P.
(2002). Chinese medicines for slimming still cause health problems. BMJ
324: 679-679
[Full Text]
Yanovski, S. Z., Yanovski, J. A.
(2002). Obesity. NEJM
346: 591-602
[Full Text]
Ernst, E.
(2001). "Alternative" Therapies For Asthma : Reason For Concern?. Chest
120: 1433-1434
[Full Text]
Blanck, H. M., Khan, L. K., Serdula, M. K.
(2001). Use of Nonprescription Weight Loss Products: Results From a Multistate Survey. JAMA
286: 930-935
[Abstract][Full Text]
Boucher, J. L., Shafer, K. J., Chaffin, J. A.
(2001). Weight Loss, Diets, and Supplements: Does Anything Work?. Diabetes Spectr.
14: 169-175
[Full Text]
Ang-Lee, M. K., Moss, J., Yuan, C.-S.
(2001). Herbal Medicines and Perioperative Care. JAMA
286: 208-216
[Abstract][Full Text]
Margolis, M. L.
(2001). A Survey of the Use of Herbal Agents Among Philadelphia Veterans Affairs Medical Center Pulmonary Outpatients. Chest
119: 1981-1982
[Full Text]
Hutchins, G. M., Traub, S. J., Hoyek, W., Hoffman, R. S., Haller, C. A., Benowitz, N. L.
(2001). Dietary Supplements Containing Ephedra Alkaloids. NEJM
344: 1095-1097
[Full Text]
(2001). Some natural scepticism about the Natural Health Products Directorate. CMAJ
164: 613-613
[Full Text]
(2001). La Direction des produits de sante naturels : un peu de scepticisme naturel. CMAJ
164: 615-615
[Full Text]
(2001). Dangers of Dietary Supplements with Ephedra Alkaloids. Journal Watch Cardiology
2001: 3-3
[Full Text]
(2000). Risks with Phenylpropanolamine and Ephedra Alkaloids. JWatch General
2000: 1-1
[Full Text]
Fleming, G. A.
(2000). The FDA, Regulation, and the Risk of Stroke. NEJM
343: 1886-1887
[Full Text]
Jordan, J., Tank, J., Shannon, J. R., Diedrich, A., Lipp, A., Schroder, C., Arnold, G., Sharma, A. M., Biaggioni, I., Robertson, D., Luft, F. C.
(2002). Baroreflex Buffering and Susceptibility to Vasoactive Drugs. Circulation
105: 1459-1464
[Abstract][Full Text]
Previous
