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Previous Volume 343:1833-1838 December 21, 2000 Number 25 Next

Abstract PDF Editorial by Fleming, G. A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Dietary supplements that contain ephedra alkaloids (sometimes called ma huang) are widely promoted and used in the United States as a means of losing weight and increasing energy. In the light of recently reported adverse events related to use of these products, the Food and Drug Administration (FDA) has proposed limits on the dose and duration of use of such supplements. The FDA requested an independent review of reports of adverse events related to the use of supplements that contained ephedra alkaloids to assess causation and to estimate the level of risk the use of these supplements poses to consumers.

Methods We reviewed 140 reports of adverse events related to the use of dietary supplements containing ephedra alkaloids that were submitted to the FDA between June 1, 1997, and March 31, 1999. A standardized rating system for assessing causation was applied to each adverse event.

Results Thirty-one percent of cases were considered to be definitely or probably related to the use of supplements containing ephedra alkaloids, 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 ephedra alkaloids, 47 percent involved cardiovascular symptoms and 18 percent involved the central nervous system. Hypertension was the single most frequent adverse effect (17 reports), followed by palpitations, tachycardia, or both (13); stroke (10); and seizures (7). Ten events resulted in death, and 13 events produced permanent disability, representing 26 percent of the definite, probable, and possible cases.

Conclusions The use of dietary supplements that contain ephedra alkaloids may pose a health risk to some persons. These findings indicate the need for a better understanding of individual susceptibility to the adverse effects of such dietary supplements.

We conducted an in-depth review of 140 reports of adverse events involving dietary supplements containing ephedra alkaloids that were submitted to the FDA between June 1, 1997, and March 31, 1999, and applied a standardized rating system for assessing causation. We also evaluated factors that might increase the risk to consumers and the adequacy of warnings about potential risks included on product labels. The full report of our review of adverse events is available elsewhere.⁷ Here, we summarize our findings.

Methods

The objective of the review was to determine the likelihood that ephedra alkaloids (which were usually combined with caffeine) caused the reported adverse events on the basis of the information provided in the FDA MedWatch report, along with supplemental medical records. We independently reviewed each of the 140 cases. Causation was assessed according to the criteria described by Blanc et al.⁸ and included an evaluation of the timing of the event in relation to the dose and duration of use of a product; an assessment of the pattern of response to determine whether it constituted a recognized reaction to the substance on the basis of previous reports of ephedrine or similar stimulants in the medical literature; and a determination of the contribution of any underlying diseases or medical conditions.

In general, we defined an adverse event as definitely related to the use of supplements containing ephedra alkaloids only if the symptoms recurred with the reintroduction of ephedra alkaloids or when the onset of symptoms coincided with the expected peak plasma concentration of the drug and resolved within an interval that was consistent with the expected duration of the effect of ephedrine. An adverse event was defined as probably related to the use of supplements containing ephedra alkaloids when the majority of the evidence supported the existence of a causal link but one or more aspects of the case, such as time since the last dose, were unknown or there was a minor inconsistency in the supporting evidence, such as a low reported dose. An adverse event was designated as possibly related to the use of supplements containing ephedra alkaloids when it was equally likely that the adverse event was not related to the use of ephedra alkaloids; for example, in the case of effects that have not been reported in the literature in association with ephedra alkaloids but that are pharmacologically plausible. Reports of adverse events that included scant medical history and incomplete information about the product involved were usually considered to have insufficient information to be assessed. This category was reserved for events in which the evidence was not substantial enough to consider them as possibly related to the use of supplements containing ephedra alkaloids. Adverse events were defined as probably unrelated to the use of supplements containing ephedra alkaloids if the evidence that ephedra alkaloids were the cause was weak or if the likelihood was strong that there was some other cause, either medical or toxicologic. When the scientific evidence or course of events was highly inconsistent with the known effects of ephedra alkaloids, the event was considered definitely unrelated; for example, in the case of symptoms that persisted long after the use of ephedra alkaloids had been discontinued or in the case of symptoms that had no association with the known pharmacodynamic effects of ephedra alkaloids. However, the event was considered related if the patient had a preexisting condition such as hypertension that could have been aggravated by the use of ephedra alkaloids and if the pattern of use met the criteria for causation.

In determining the likelihood of a causal link, we evaluated aspects of the medical history, dietary patterns, and social habits as possible contributing or causative factors. For example, we noted when events occurred while patients were fasting or in conjunction with high intakes of caffeine. We recognized that in the case of adverse events that were most likely not related to the use of supplements containing ephedra alkaloids one or more of the other ingredients in the supplement may have been causally related to the event.

Results

Features of the Cases

The age and sex of the users of products containing ephedra aklaloids and the reported reasons for use are shown in Table 1. Although the labels of most such products state that they are not intended for use by persons less than 18 years of age, adverse events were recorded in at least 10 persons under this age. The youngest was 15 years old. Overall, 43 cases (31 percent) were considered to be definitely or probably related to the use of supplements containing ephedra alkaloids, 24 cases (17 percent) were considered to be unrelated to the use of such supplements, 44 cases (31 percent) were deemed possibly related to the use of such supplements, and in 29 cases (21 percent) the information provided was insufficient to assess causation. The types of adverse events that were definitely or probably related to the use of supplements containing ephedra alkaloids and those that were possibly related are summarized in Table 2.

View this table: [in this window] [in a new window]   Table 1. Age and Sex of Users of Supplements Containing Ephedra Alkaloids and Reasons for Use, According to Adverse-Event Reports.

 

View this table: [in this window] [in a new window]   Table 2. Types of Adverse Events That Were Definitely, Probably, or Possibly Related to the Use of Supplements Containing Ephedra Alkaloids.

 
Cardiovascular symptoms made up 47 percent of the adverse events that were definitely, probably, or possibly related to the use of supplements containing ephedra alkaloids. Hypertension was the single most frequent adverse effect, followed by palpitations, tachycardia, or both. Eighteen percent of related and possibly related adverse events involved the central nervous system. Strokes (n=10) and seizures (n=7) were the most frequent type of central nervous system event reported. The clinical outcomes of the definite, probable, and possible cases are listed in Table 3.

View this table: [in this window] [in a new window]   Table 3. Clinical Outcomes of Adverse Events That Were Definitely, Probably, or Possibly Related to the Use of Supplements Containing Ephedra Alkaloids.

 
Ten events resulted in death (including 1 neonatal death and 1 fetal death), and 13 events resulted in permanent impairment, which represented 26 percent of the definite, probable, and possible cases. Nine serious adverse events occurred in persons who were taking relatively low doses of ephedra alkaloids (range, 12 to 36 mg per day) and who had no important medical risk factors. Features of the definite or probable and possible cases that resulted in death or permanent impairment or that necessitated substantial medical intervention are given in Table 4 and Table 5, respectively.

View this table: [in this window] [in a new window]   Table 4. Outcome in 11 Patients with Adverse Events That Were Definitely or Probably Related to the Use of Supplements Containing Ephedra Alkaloids.

 

View this table: [in this window] [in a new window]   Table 5. Outcome in 15 Patients with Adverse Events That Were Possibly Related to the Use of Supplements Containing Ephedra Alkaloids.

 
Of the sudden catastrophic cerebrovascular and cardiovascular events, 11 occurred in previously healthy persons. Some of these cases, which were definitely or probably related to the use of supplements containing ephedra alkaloids, are described in detail in the following sections.

Examples of Severe Cerebrovascular Adverse Events

            Patient 1

Patient 1 was a healthy 35-year-old woman who had taken aerobic-exercise classes for several years without incident (Table 4). In July 1997, she began taking one capsule of Shape-Fast Plus (according to the label, each capsule contained 15 mg of ephedra alkaloids and 40 mg of caffeine) three times a day before meals for weight loss; she was taking no other medications. She had been taking the product for one week when she collapsed during an aerobics class. Bystanders observed that her arms and legs were flexing and tensing. In the emergency department, her blood pressure was 110/38 mm Hg and the heart rate was 104 beats per minute. A computed tomographic scan of the head showed a subarachnoid hemorrhage. Cerebral angiography showed no evidence of a vascular aneurysm. A urine toxicology screen was positive for amphetamine, a result presumed to reflect a cross-reaction with the ephedrine and therefore to be false positive. Neurogenic pulmonary edema rapidly developed, necessitating endotracheal intubation and mechanical ventilation. Electrocardiographic findings and cardiac-enzyme levels were consistent with the occurrence of a small myocardial infarction. The treating cardiologist and neurologist thought that ephedrine induced the subarachnoid hemorrhage. The finding of amphetamine on the urine toxicology test supports the presence of ephedrine at the time of the event. Laboratory analysis of the supplement determined that the ephedrine content was 12.0 mg per capsule. At that time, the FDA's recommendation was a maximal dose of 8 mg per serving.⁷

            Patient 10

Patient 10 was an apparently healthy 39-year-old man who experienced numbness of the right arm and leg on March 17, 1998, 90 minutes after drinking Ultimate Orange, which according to the label contained 415 mg of ma huang (ephedra alkaloids) per serving as well as guarana (a source of caffeine), and 5 minutes after running 3 miles (4.8 km) (Table 4). He also regularly took multivitamins and amino acid supplements, but no other medications. On presentation at a nearby hospital, his blood pressure was 140/78 mm Hg and his pulse was 60 beats per minute. A computed tomographic scan of the head revealed a left-sided intrathalamic hemorrhage. Cerebral angiography showed no evidence of vascular anomalies. The patient had gradual clinical improvement, and his symptoms resolved except for persistent sensory loss on the right side of his face. Chemical analysis of the Ultimate Orange product confirmed the presence of ephedrine, as well as of pseudoephedrine, norephedrine, and norpseudoephedrine.

Examples of Severe Cardiovascular Adverse Events

            Patient 2

Patient 2 was a 22-year-old man with a history of asthma who collapsed while lifting weights at a gym on March 31, 1998 (Table 4). His medications included theophylline (Theo-Dur; 300 mg twice daily), albuterol (Ventolin; administered as necessary through a metered-dose inhaler), and a combination of chlorpheniramine maleate, phenylephrine hydrochloride, and phenylpropanolamine hydrochloride (Atrohist Plus SR). According to friends, he had consumed one 18-oz bottle of Ripped Force (which is listed as containing 20 mg of ephedrine alkaloids, 100 mg of caffeine, 250 mg of l-carnitine, and 240 µg of chromium) before working out and was regularly drinking three bottles of Ripped Force per day. He also took creatine and protein supplements. Witnesses reported that he had a seizure. Paramedics initially found him apneic and in ventricular fibrillation. He was successfully resuscitated. Computed tomography of the head showed cerebral edema but no hemorrhage or masses. An initial electrocardiogram showed atrial flutter, which subsequently converted to sinus rhythm. An echocardiogram revealed mild left ventricular hypertrophy. The plasma theophylline level was 11 µg per milliliter (therapeutic range, 10 to 20), and urinalysis revealed 12 µg of ephedrine per milliliter, 0.38 µg of pseudoephedrine per milliliter, and 0.41 µg of phenylpropanolamine per milliliter. The treating cardiologist thought that the combination of ephedra alkaloids and caffeine in Ripped Force and the theophylline and albuterol medications caused a ventricular arrhythmia that resulted in cardiac arrest. The patient suffered anoxic encephalopathy and remained in a vegetative state for several weeks. After one month in an acute care facility and six weeks at a rehabilitation facility, he was discharged with substantial residual neurologic impairment.

            Patient 7

Patient 7 was an apparently healthy 38-year-old man who had been taking two capsules of Ripped Fuel (according to the label each capsule contains 10 mg of ephedrine and 100 mg of caffeine) each morning for one year as directed on the product label (Table 4). On June 6, 1996, he took his usual dose along with a cup of coffee and went jogging for 20 minutes. After returning home, he was talking with his family when he suddenly collapsed and appeared to have a tonic–clonic seizure. He had not reported any symptoms before collapsing. He was in full cardiac arrest when paramedics arrived and could not be resuscitated. Autopsy showed mild cardiomegaly with four-chamber dilatation and coronary artery disease, with narrowing of 50 to 75 percent in four vessels. The cause of death was acute arrhythmia resulting from atherosclerotic cardiovascular disease. Subsequent toxicology testing showed blood levels of 110 ng of ephedrine per milliliter (the therapeutic range used for bronchodilation is 20 to 80).⁹ An addendum to the autopsy report included the comment, "ephedrine is a stimulant medication, and as such may have contributed to a fatal arrhythmia in the decedent."

Discussion

Ephedrine and related alkaloids have been associated with adverse cardiovascular events, including acute myocardial infarction, severe hypertension, myocarditis, and lethal cardiac arrhythmias.^10,11 Constriction of coronary arteries and, in some cases, vasospasm are believed to be the mechanisms of myocarditis and myocardial infarction. The adrenergic effects of ephedrine shorten cardiac refractory periods, permitting the development of reentrant cardiac arrhythmias. Ephedrine can predispose patients to both hemorrhagic and ischemic stroke.¹² Subarachnoid hemorrhage is thought to be a result of the hypertensive action of ephedrine, which can be short lived, or of cerebral vasculitis, which has been described in association with a variety of sympathomimetic drugs.^13,14 Thrombotic stroke is presumably related to vasoconstriction of large cerebral arteries, which leads to local thrombosis as a result of stasis and sympathomimetic-induced platelet activation.

Caffeine is present in many products that contain ephedra alkaloids, and those who take these products might also be consuming considerable quantities of caffeine in coffee, tea, and soft drinks. Caffeine is likely to enhance the cardiovascular and central nervous system effects of ephedrine. Caffeine acts by competitively antagonizing the receptors for adenosine, a hormone released by endothelial cells that dilates blood vessels.¹⁵ By inhibiting adenosine-mediated dilatation of blood vessels, caffeine constricts blood vessels and may increase blood pressure in persons prone to hypertension. Caffeine also augments the release of catecholamines, an effect that, when combined with that of ephedrine, could lead to increased stimulation of the central nervous system and cardiovascular system.¹⁶

Phenylpropanolamine, another ephedrine alkaloid, was marketed with caffeine in various weight-reducing aids until 1983, when the combination was banned by the FDA after numerous reports of adverse effects. Several studies have shown that caffeine and phenylpropanolamine have an additive effect on blood pressure.¹⁷ These interactions between phenylpropanolamine and caffeine support the idea that the combination of ephedrine and caffeine in a dietary supplement could increase the risk of adverse effects.

The quantity of ephedrine in dietary supplements, as reported on package labels, is typically about 20 mg per serving, and the usual dose frequency is two to three times per day. These products may contain larger or smaller amounts of ephedra alkaloids than are listed on the product label. For example, 11 of 20 supplements tested by Gurley et al.¹⁸ either failed to list the alkaloid content on the label or had more than a 20 percent difference between the amount listed on the label and the actual amount.

Often, the dose of ephedrine that was associated with an adverse event was less than a typical dose of ephedrine used for bronchodilation (25 to 50 mg). Experimental studies show that ephedrine has only moderate effects on heart rate and blood pressure at these doses.^19,20 The discrepancy between such data and our findings of serious adverse events reported with the use of dietary supplements containing ephedra alkaloids may be due to individual susceptibility, the additive stimulant effects of caffeine, the variability in the contents of pharmacologically active chemicals in the products, or preexisting medical conditions.

Many of the cases we reviewed involved side effects such as anxiety, tremulousness, insomnia, palpitations, and personality changes that are well known to occur with the use of stimulant drugs. When ephedrine is used for medical purposes, these types of reactions are considered side effects and must be included in the assessment of risks and benefits. In fact, ephedrine is rarely prescribed today for medical purposes, because newer drugs have more specific actions and fewer side effects. The risks of taking ephedra alkaloids as a dietary supplement, however, are difficult to justify because the alkaloids have no demonstrated benefit. Unlike vitamins and minerals, ephedra alkaloid supplements are not essential for proper nutrition. People who take these products to increase their exercise capacity or to lose weight place themselves at risk without a substantial likelihood of benefit.

A limitation to the use of reports of adverse events as an indicator of a product's safety is that the number of people at risk for the event is unknown. Manufacturers of dietary supplements that contain ephedra alkaloids reported that 3 billion servings were sold in 1999.²¹ The number of servings that were actually consumed is difficult to determine. Assuming that the products were consumed as directed — three doses per day for 12 weeks — then approximately 12 million people used these supplements in 1999.

Another limitation is that adverse events are known to be underreported. Several studies have shown that spontaneous reporting of adverse events to MedWatch is not routine, and the rate of reporting may be less than 15 percent.^22,23 The frequency of reports of adverse reactions to herbal products is thought to be even lower.^7,24 Therefore, the frequency of serious adverse events associated with the use of supplements containing ephedra alkaloids cannot be precisely determined with the use of current reporting mechanisms.

Because of the severity of the adverse events that we reviewed and, in particular, the occurrence of events that caused permanent disability and death, we conclude that dietary supplements that contain ephedra alkaloids pose a serious health risk to some users. Although the incidence of serious adverse effects cannot be determined from our analysis, our findings arouse concern about the risks of these products, given that they have no scientifically established benefits. Our findings indicate the need for a better understanding of the determinants of individual susceptibility to the serious adverse effects of dietary supplements containing ephedra alkaloids so that appropriate dosing guidelines and warnings can be devised.

Supported by funds from the Food and Drug Administration and by grants (DA02277 and DA12393) from the National Institute on Drug Abuse, National Institutes of Health. Dr. Haller was supported by a Veterans Affairs Medical Toxicology fellowship and by a National Research Service Award (T32GM07546) from the National Institutes of Health.

We are indebted to Dr. Raymond Woosley for his critical review of the manuscript and to Kaye Welch for editorial assistance.

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.

References

1. Adverse events associated with ephedrine-containing products -- Texas, December 1993-September 1995. JAMA 1996;276:1711-1712. [CrossRef][Medline]
2. Theoharides TC. Sudden death of a healthy college student related to ephedrine toxicity from a ma huang-containing drink. J Clin Psychopharmacol 1997;17:437-439. [CrossRef][Medline]
3. Josefson D. Herbal stimulant causes US deaths. BMJ 1996;312:1378-1379. [Free Full Text]
4. Zahn KA, Li RL, Purssell RA. Cardiovascular toxicity after ingestion of "herbal ecstasy." J Emerg Med 1999;17:289-291. [CrossRef][Medline]
5. 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]
6. Vahedi K, Domigo V, Amarenco R, Bousser MG. Ischaemic stroke in a sportsman who consumed MaHuang extract and creatine monohydrate for body building. J Neurol Neurosurg Psychiatry 2000;68:112-113. [Free Full Text]
7. Dietary supplements containing ephedrine alkaloids. FDA docket no. 00N-1200. Rockville, Md.: Food and Drug Administration, 2000. (See www.accessdata.fda.gov/scripts/oc/ohrms/index.cfm.)
8. Blanc S, Leuenberger P, Berger JP, Brooke EM, Schelling JL. Judgments of trained observers on adverse drug reactions. Clin Pharmacol Ther 1979;25:493-498. [Medline]
9. Costello JF, May CS, Paterson JW, Pickup ME. Pharmacokinetics of ephedrine in asthmatics receiving acute and chronic treatment. Br J Clin Pharmacol 1975;2:180-181. abstract. 
10. Wiener I, Tilkian AG, Palazzolo M. Coronary artery spasm and myocardial infarction in a patient with normal coronary arteries: temporal relationship to pseudoephedrine ingestion. Cathet Cardiovasc Diagn 1990;20:51-53. [Medline]
11. To LB, Sangster JF, Rampling D, Cammens I. Ephedrine-induced cardiomyopathy. Med J Aust 1980;2:35-36. [Medline]
12. Bruno A, Nolte KB, Chapin J. Stroke associated with ephedrine use. Neurology 1993;43:1313-1316. [Free Full Text]
13. Fallis RJ, Fisher M. Cerebral vasculitis and hemorrhage associated with phenylpropanolamine. Neurology 1985;35:405-407. [Free Full Text]
14. Wooten MR, Khangure MS, Murphy MJ. Intracerebral hemorrhage and vasculitis related to ephedrine abuse. Ann Neurol 1983;13:337-340. [CrossRef][Medline]
15. Benowitz NL. Clinical pharmacology of caffeine. Annu Rev Med 1990;41:277-288. [CrossRef][Medline]
16. Robertson D, Frölich JC, Carr RK, et al. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 1978;298:181-186. [Abstract]
17. Brown NJ, Ryder D, Branch RA. A pharmacodynamic interaction between caffeine and phenylpropanolamine. Clin Pharmacol Ther 1991;50:363-371. [Medline]
18. Gurley BJ, Gardner SF, Hubbard MA. Content versus label claims in ephedra-containing dietary supplements. Am J Health Syst Pharm 2000;57:963-969. [Free Full Text]
19. Drew CD, Knight GT, Hughes DT, Bush M. Comparison of the effects of D-(-)-ephedrine and L-(+)-pseudoephedrine on the cardiovascular and respiratory systems in man. Br J Clin Pharmacol 1978;6:221-225. [Medline]
20. White LM, Gardner SF, Gurley BJ, Marx MA, Wang PL, Estes M. Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults. J Clin Pharmacol 1997;37:116-122. [Abstract]
21. Dietary supplement market view. Chevy Chase, Md.: FDC Reports, August 2000.
22. Chyka PA, McCommon SW. Reporting of adverse drug reactions by poison control centres in the US. Drug Saf 2000;23:87-93. [Medline]
23. Spontaneous adverse event reports. (See http://www.fda.gov/ohrms/dockets/ac/99/slides/3558s1e/tsld003.htm.)
24. Barnes J, Mills SY, Abbot NC, Willoughby M, Ernst E. Different standards for reporting ADRs to herbal remedies and conventional OTC medicines: face-to-face interviews with 515 users of herbal remedies. Br J Clin Pharmacol 1998;45:496-500. [CrossRef][Medline]

Abstract PDF Editorial by Fleming, G. A. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

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• 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]