Animal and human studies have suggested a thermogenic synergism between ephedrine (E), a beta-agonist, and caffeine (C), an adenosine antagonist, which may be suitable for the treatment of obesity. To study this phenomenon, the thermogenic effect of single doses of oral placebo, E 10 mg, E 20 mg, C 100 mg, and C 200 mg were compared with the effects of three different combinations of E + C, 10 mg/200 mg, 20 mg/100 mg, and 20 mg/200 mg, measured by indirect calorimetry in six healthy, lean subjects. The thermogenic effect after E + C 20 mg/200 mg was larger than that of any of the other combinations. In this dose ratio, ephedrine and caffeine exerted a supra-additive synergism, whereas the thermogenic effects of the other two combinations were only additive. The 3-hour postintake increase in systolic blood pressure after all three combinations averaged 5 to 7 mm Hg more than placebo (P less than .01), which exceeded the predicted additive effect fivefold to sevenfold. Diastolic blood pressure was not increased by E + C 20 mg/200 mg, whereas the other two combinations increased it by approximately 4 mm Hg more than placebo. E + C 20 mg/100 mg and 20 mg/200 mg increased heart rate more than placebo, while E + C 10 mg/200 mg had no effect on heart rate. As expected, all combinations increased plasma glucose, insulin, and C-peptide from their ephedrine content. No significant effects of the combinations were found on plasma lactate, glycerol, nonesterified fatty acids (NEFA), triglyceride, potassium, or sodium.(ABSTRACT TRUNCATED AT 250 WORDS)