We have recently demonstrated dose-dependency of caffeine metabolism under multiple dosing conditions. Whether there are persistent pharmacodynamic actions of caffeine under such circumstances is the focus of this report. Nine healthy subjects were given, in randomized 5 day blocks, placebo, 4.2 (low) and 12 (high) mg.kg-1.day-1 of caffeine in 6 divided doses. After 5 days, complete tolerance developed to the effects of caffeine on blood pressure, heart rate and plasma glucose concentrations. The 24-h area under the curve (AUC) for plasma norepinephrine and the AUC for the total sum of free fatty acids (FFA) both demonstrated a trend to increase with the high dose caffeine treatment. When the AUC for norepinephrine was split into 12 h time periods, a significant difference between the placebo and the high dose treatment block was seen. We conclude that regular consumption of 12 mg.kg-1 of caffeine per day (equivalent to approximately 6 to 11 cups of coffee per day) may produce pharmacodynamic effects not completely compensated for by the development of tolerance. Mechanisms of tolerance may be overwhelmed by the nonlinear accumulation of caffeine and other methylxanthines in the body when caffeine metabolism becomes saturable.