Enhanced stimulant and metabolic effects of combined ephedrine and caffeine

Clin Pharmacol Ther. 2004 Apr;75(4):259-73. doi: 10.1016/j.clpt.2003.11.375.


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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Area Under Curve
  • Biological Availability
  • Blood Pressure / drug effects
  • Caffeine / administration & dosage*
  • Caffeine / pharmacokinetics*
  • Cardiovascular System / drug effects*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / adverse effects*
  • Central Nervous System Stimulants / pharmacokinetics
  • Confidence Intervals
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Interactions
  • Ephedrine / administration & dosage*
  • Ephedrine / pharmacokinetics*
  • Female
  • Heart Rate / drug effects
  • Hemodynamics / drug effects
  • Humans
  • Male
  • Middle Aged
  • Risk Assessment
  • Sensitivity and Specificity


  • Central Nervous System Stimulants
  • Caffeine
  • Ephedrine