Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by Miller, S. C. Articles by Waite, C. Search for Related Content PubMed Citation Articles by Miller, S. C. Articles by Waite, C. Miscellaneous Addictive Disorders

Ephedrine-Type Alkaloid-Containing Dietary Supplements and Substance Dependence

Received Feb. 24, 2003; accepted March 17, 2003. From Wright Patterson Medical Center. Address reprint requests to Dr. Miller, 74MDOS/SGOHE, Wright Patterson Medical Center, 4881 Sugar Maple Dr., Wright Patterson AFB, OH 45433; Shannon.miller{at}wpafb.af.mil (e-mail).

Dietary supplements are less regulated than medications and food additives and are widely marketed and consumed in the United States. The dietary supplement market has been growing at an average rate of well above $500 million per year.¹ It has been estimated that approximately 2.5 million Americans use ephedrine-type alkaloid-containing dietary supplements.² These products are commonly purchased for their mood elevating and energizing psychoactive effects and are used to lose weight, boost energy, and enhance concentration. Ephedrine-type alkaloid-containing dietary supplements are similar in structure and action to amphetamine and can produce similar medical and psychiatric complications. These products are often combined with caffeine or other (sometimes illegal) sympathomimetics, and such combinations can result in dangerous synergism.^3,4 Published case reports of complications of ephedrine use include descriptions of seizures,⁵ myocarditis,^6–8 acute hepatitis,⁹ and a variety of other cardiovascular and neurological problems. Over the last decade, the Food and Drug Administration (FDA) has received more than 1,000 adverse event reports involving ephedrine-type alkaloid-containing dietary supplements. Approximately 10% of these reports were related to products marketed as alternatives to illicit street drugs or used for euphoric purposes.^4,10 The United States Government Accounting Office has pointed out that, while the symptoms described in these adverse event reports were consistent with available scientific evidence and known physiologic effects of ephedrine-type alkaloids, the adverse events were poorly documented.¹¹ Numerous states have passed regulations for these products that are stricter than the federal regulations, including the requirement that these products be made available by prescription only and addition of these products to schedules of controlled substances. Medical journals and the popular press have published several articles about the cardiovascular and neurological problems associated with these products, but, to our knowledge, no previous, well-documented cases of substance abuse or dependence associated with these products have been published, although some previous reports have suggested this potential complication.^4,12–16

We present a well-documented case of use of an ephedrine-type alkaloid-containing dietary supplement that resulted in an adverse reaction in a young, healthy, active-duty military member. His history suggests the development of substance dependence.¹⁷ This case supports the inclusion of substance abuse or dependence, with both medical and psychiatric sequelae, in the list of potential complications of these supplements.

Case Report

A 20-year-old single Caucasian male active-duty enlisted intelligence technician reassigned temporarily to armed guard duty at a United States Air Force Base gate within 1 month of the September 11th terrorist attacks was brought to the emergency room by his commanding officer after confiding to his supervisor that he could not stay awake and alert on duty. Further interview revealed the patient had not slept in the past 36 hours due to the overuse of an ephedrine-type alkaloid-containing dietary supplement (Efedrin Plus, Hammer Corp., Atlanta; bottle batch number A03B). He was taking this product during the day to enhance his energy in support of physical workouts and then again at night to stay alert while inspecting cars entering the base. His initial blood pressure was 152/74 mm Hg, his pulse was 114 bpm, and his temperature was 100.1°F (repeat measures, obtained in the emergency room less than 1 hour later while the patient was sleeping: blood pressure, 154/90 mm Hg; pulse, 96 bpm). EKG results showed sinus tachycardia. His well-documented medical record showed no prior hypertension. He was admitted for observation with a diagnosis of ephedra toxicity by internal medicine department staff. The psychiatry consultant concurred. The patient incurred no further complications and experienced normalization of vital signs with monitored abstinence from ephedrine-type alkaloid-containing products overnight.

He described using ephedrine-type alkaloid-containing dietary supplements intermittently since the age of 17, with his use escalating in the past 7 months (while he was training for his fitness run) to approximately 60 capsules per week, as many as 10 per day (more than four times the recommended dose shown on the product label, which was one capsule two times per day). According to the product label, each capsule purportedly contained 313 mg of ephedra extract (8% concentration, 25 mg of ephedrine group alkaloids) and 50 mg of anhydrous caffeine. At times he had also used another supplement containing caffeine and ephedra alkaloids (Ripped Fuel, Twinlab, Hauppauge, N.Y.), which is available at most base exchanges. His only other drug use included tobacco, acetaminophen and diphenhydramine tablets (Tylenol PM), and oxycodone and acetaminophen tablets (Percocet) obtained from his girlfriend. He had used the oxycodone and acetaminophen tablets exclusively to self-medicate his ephedrine withdrawal symptoms over a 2-month period. This use did not meet the DSM-IV-TR criteria for opiate abuse or dependence. Caffeine use included two to 10 cans of soda per day. It is important to note that his complications, described in the next paragraph, continued to occur at times when his intake of caffeinated sodas was as little as none to one can per day and without a history of rapid reduction in caffeine use.

In direct relation to the timing of consumption of these products, he had experienced chest pain, palpitations, dizziness, sweating, visual illusions, and headache. Although he refused to provide specific details regarding his self-reported withdrawal symptoms (perhaps because of his obvious fear of losing his security clearance), he did endorse a history of tolerance (moving from one pill per dose, to two, to sometimes three to get the same desired effect). Although he originally used these products for energy and alertness, he found that higher doses could give him a high, this relaxing amount of energy, and good mood. He felt his use of these products was a problem. He admitted to continued use despite being aware of the complications described herein, spending a considerable amount of time using and recovering from these dietary supplements, and having made multiple, failed attempts to cut back. Moreover, he admitted to a history of recurrent panic attacks that directly correlated with his consumption of ephedrine-type alkaloid-containing dietary supplements. His family history was notable only for his mother's probable pathological gambling.

It is interesting to note that a more exhaustive review of his medical record conducted after his discharge revealed that he had presented to the same emergency room 4 days earlier because of a heavy feeling in his body and dizziness 4 hours after consuming four capsules of Efedrin Plus. His blood pressure had been 145/80 mm Hg; his pulse, 105 bpm; and his temperature, 98.7°F. His EKG, urinalysis, and oxygen saturation test results were within normal limits. He had received a diagnosis of ephedrine toxicity/abuse from the emergency room physician and had been instructed in writing, You are ordered to stop taking ephedrine.

Several weeks later, at one of his addiction psychiatry appointments (scheduled due to the history described earlier), he turned in his bottle of Efedrin Plus, stating he desired to never use that stuff again. Since abstaining from all ephedrine-type alkaloid-containing dietary supplements (and obtaining addiction counseling), he has had no further medical or psychiatric problems. The patient was later reevaluated, which included collection of collateral history data and serial observation of the patient while he participated in an intensive outpatient clinic over several weeks. His diagnoses remained unchanged. One-year follow-up confirmed his abstinence and lack of medical or psychiatric problems.

Multiple psychiatric and physical examinations failed to show any other explanation for the presentations described in this case report. The results of laboratory tests done at the time of presentation and serially were all negative. These tests included CBC, urinalysis, liver function tests, thyroid panel test, tests of electrolyte levels, RPR, HIV antibody test, measurement of blood alcohol, urine drug screen (for amphetamines, methamphetamines, 3,4-methylenedioxymethamphetamine, barbiturates, benzodiazepines, cocaine, marijuana, opiates, and phencyclidine), and gamma hydroxybutyrate toxicology screen.

Discussion

Ephedrine-type alkaloid-containing dietary supplements have been widely marketed as legal recreational drugs—with aggressive marketing tactics that include naming these products after well-known illegal street drugs (e.g., Herbal Ecstasy, Black Beauties). Ephedrine-type alkaloids readily cross the blood-brain barrier and impart mild central nervous system stimulation. Psychiatric complications generally result in affective disturbances and psychosis.^18,19 Psychosis may result with doses averaging 510 mg of ephedrine.²⁰ Ephedrine has been reported to cause mania^4,20 and to induce a subjective sense of well-being and an elevation of mood.¹² The Physician's Desk Reference for Herbal Medicines¹⁴ states that users of ephedrine-type alkaloids can develop dependence on these substances. It has also been suggested that individuals using ephedrine-type alkaloids for asthma may spontaneously increase the dose of the drug because of its mood-elevating effect.¹³

Investigations of actual versus claimed content of ephedrine-type alkaloid dietary supplements have found substantial amounts of (+)-norpseudoephedrine, a Schedule IV controlled substance. Known as cathine (kat), (+)-norpseudoephedrine is associated with a substance abuse syndrome in East Africa and the Arab Peninsula. The United States Drug Enforcement Agency has requested the FDA to restrict over-the-counter availability of ephedrine-type alkaloid-containing products because 1) it is known that misuse and abuse of ephedrine-type alkaloid products can cause harm and 2) these products have been used as the primary precursor in the synthesis of methamphetamine and methylcathinone.⁴ Conflicting findings regarding the safety and efficacy of ephedrine-type alkaloid-containing dietary supplements have restrained the FDA's efforts to provide more strict controls on the marketing and consumption of these products by the American public.

The FDA has established five criteria for evaluating adverse event reports relating to ephedrine-type alkaloid-containing dietary supplements:⁴

1. Are the observed signs and symptoms (alleged adverse effects) consistent with those previously reported to the FDA for ephedrine-type alkaloid-containing dietary supplements?
   
2. Are the patterns of the signs and symptoms consistent with the available scientific evidence and known physiological and pharmacological effects of ephedrine-type alkaloid-containing dietary supplements?
   
3. Does a temporal, causal relationship exist between substance exposure and the development of the observed pattern of signs and symptoms?
   
4. Is there other evidence of causality, even in the absence of controlled trials (i.e., dechallenge results in improvement, rechallenge results in reoccurrence of signs and symptoms)?
   
5. Considering the totality of the available information, is there a biologically plausible explanation for the adverse events?
   

This case appears to meet all of these criteria, including criterion 4. Moreover, the medical and psychiatric findings in this case were believed by multiple physicians from multiple specialties at multiple points in time to be a direct consequence of use of ephedrine-type alkaloid-containing dietary supplements. To our knowledge, this article presents one of the earliest reported and best-documented cases of such use that progressed to substance abuse and quite possibly substance dependence.

ACKNOWLEDGMENTS

The views expressed in this article are those of the author(s) and do not reflect the official policy or position of the United States Air Force, Department of Defense, or the U.S. Government.

REFERENCES

1. Kurtzweil P: An FDA guide to dietary supplements. FDA Consumer, Jan 1999 (http://www.cfsan.fda.gov/~dms/fdsupp.html)
2. Blanck HM, Khan LK, Serdula MK: Use of nonprescription weight loss products: results from a multistate survey. JAMA 2001; 286:930–935[Abstract/Free Full Text]
3. Samenuk D, Link MS, Homoud MK, Contreras R, Theohardes TC, Wang PJ, Estes NA III: Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 2002; 77:12–16[Medline]
4. Department of Health and Human Services, Food and Drug Administration: Dietary supplements containing ephedrine alkaloids; proposed rule. Federal Register 1997; 62:30677–30724
5. Kockler DR, McCarthy MW, Lawson CL: Seizure activity and unresponsiveness after hydroxycut ingestion. Pharmacotherapy 2001; 21:647–651[CrossRef][Medline]
6. Zaacks SM, Klein L, Tan CD, Rodriguez ER, Leikin JB: Hypersensitivity myocarditis associated with ephedra use. J Toxicol Clin Toxicol 1999; 37:485–489[CrossRef][Medline]
7. Leikin JB, Klein L: Ephedra causes myocarditis. J Toxicol Clin Toxicol 2000; 38:353–354[Medline]
8. Kurt TL: Hypersensitivity myocarditis with ephedra use (letter). J Toxicol Clin Toxicol 2000; 38:351[Medline]
9. Nadir A, Agrawal S, King PD, Marshall JB: Acute hepatitis associated with the use of a Chinese herbal product, ma-huang. Am J Gastroenterol 1996; 91:1436–1438[Medline]
10. 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[Abstract/Free Full Text]
11. Dietary Supplements: Uncertainties in Analyses Underlying FDA's Proposed Rule on Ephedrine Alkaloids: Report to the Chairman and Ranking Minority Member, Committee on Science, House of Representatives: HEHS GGD-99–90. Washington, DC, US General Accounting Office, July 1999
12. Whitehouse A, Duncan J: Ephedrine psychosis rediscovered. Br J Psychiatry 1987; 150:258–261[Free Full Text]
13. Martin WR, Sloan JW, Sapira JD, Jasinski DR: Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther 1971; 12:245–258[Medline]
14. Physician's Desk Reference for Herbal Medicines, 2nd ed. Montvale, NJ, Medical Economics, 2000, p 489
15. Gurley BJ, Gardner SF, Hubbard MA: Content versus label claims in ephedra-containing dietary supplements. Am J Health Syst Pharm 2000; 57:963–969[Abstract/Free Full Text]
16. Keup W: Use, indications and distribution in different countries of the stimulant and hallucinogenic amphetamine derivatives under consideration by WHO. Drug Alcohol Depend 1986; 17:169–192[CrossRef][Medline]
17. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR). Washington, DC, APA, 2000
18. Traboulsi AS, Viswanathan R, Coplan J: Suicide attempt after use of herbal diet pill (letter). Am J Psychiatry 2002; 159:318–319[Free Full Text]
19. Jacobs KM, Hirsch KA: Psychiatric complications of ma-huang. Psychosomatics 2000; 41:58–62[Free Full Text]
20. Capwell RR: Ephedrine-induced mania from an herbal diet supplement (letter). Am J Psychiatry 1995; 152:647

This article has been cited by other articles:

				J. T. Liles, P. A. Dabisch, K. E. Hude, L. Pradhan, K. J. Varner, J. R. Porter, A. R. Hicks, C. Corll, S. R. Baber, and P. J. Kadowitz Pressor Responses to Ephedrine Are Mediated by a Direct Mechanism in the Rat J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 95 - 105. [Abstract] [Full Text] [PDF]

				S. C. MILLER Psychiatric Effects of Ephedra: Addiction Am J Psychiatry, November 1, 2005; 162(11): 2198 - 2198. [Full Text] [PDF]

				A. Nyska, E. Murphy, J. F. Foley, B. J. Collins, J. Petranka, R. Howden, P. Hanlon, and J. K. Dunnick Acute Hemorrhagic Myocardial Necrosis and Sudden Death of Rats Exposed to a Combination of Ephedrine and Caffeine Toxicol. Sci., February 1, 2005; 83(2): 388 - 396. [Abstract] [Full Text] [PDF]

				S. C. Miller Ephedra and FDA Psychiatr News, April 2, 2004; 39(7): 66 - 76. [Full Text]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via HighWire Citing Articles via Google Scholar Articles by Miller, S. C. Articles by Waite, C. Search for Related Content PubMed Citation Articles by Miller, S. C. Articles by Waite, C. Miscellaneous Addictive Disorders

Get information about faster international access.

Privacy Policy

Copyright © 2003 Academy of Psychosomatic Medicine. All rights reserved.

Home | Search | Current Issue | Past Issues | Subscribe | All APPI Journals | Help | Contact Us