¹Department of Medicine, Division of Clinical Pharmacology, University of California, San Francisco, San Francisco General Hospital, San Francisco, Calif, USA

Correspondence: Christine A. Haller, MD, University of California, San Francisco, Box 1220, San Francisco, CA 94143, USA. E-mail: dchaller@worldnet.att.net

^*This work was supported by United States Public Health Service grants K23AT00069-01 (National Center for Complementary and Alternative Medicine) and DAO2277 and DA012393 (National Institute on Drug Abuse), as well as a General Clinical Research Center Award (5-MO1-RR-00083-40).

Received 12 June 2003; Accepted 13 November 2003.

Abstract

Objective: Herbal weight loss and athletic performance–enhancing supplements that contain ephedrine and caffeine have been associated with serious adverse health events. We sought to determine whether ephedrine and caffeine have clinically significant pharmacologic interactions that explain these toxicities.

Methods: Sixteen healthy adults ingested 25 mg ephedrine, 200 mg caffeine, or both drugs in a randomized, double-blind, placebo-controlled crossover study. Plasma and urine samples were collected over a 24-hour period and analyzed by liquid chromatography–tandem mass spectrometry for ephedrine and caffeine concentrations. Heart rate, blood pressure, and subjective responses were recorded. Serum hormonal and metabolic markers were serially measured during a 3-hour fasting period.

Results: Ephedrine plus caffeine increased systolic blood pressure (peak difference, 11.7 9.4 mm Hg; compared with placebo, P = .0005) and heart rate (peak difference, 5.9 8.8 beats/min; compared with placebo, P = .001) and raised fasting glucose, insulin, free fatty acid, and lactate concentrations. Ephedrine alone increased heart rate and glucose and insulin concentrations but did not affect systolic blood pressure. Caffeine increased systolic blood pressure and plasma free fatty acid and urinary epinephrine concentrations but did not increase heart rate. Compared with ephedrine, caffeine produced more subjective stimulant effects. Clinically significant pharmacokinetic interactions between ephedrine and caffeine were not observed. Women taking oral contraceptives had prolonged caffeine elimination (mean elimination half-life, 9.7 hours versus 5.0 hours in men; P = .05), but sex differences in pharmacodynamic responses were not seen.

Conclusions: The individual effects of ephedrine and caffeine were modest, but the drugs in combination produced significant cardiovascular, metabolic, and hormonal responses. These enhanced effects appear to be a result of pharmacodynamic rather than pharmacokinetic interactions.