Intravenous challenges with placebo and cocaine doses ranging from 0.125 to 0.5 mg/kg were administered to five subjects using a within subjects design during placebo and active desipramine (DMI) maintenance at a fixed dose of 150 mg daily for at least 10 days. The "high" reported after cocaine infusion was not altered by DMI, but "desire for cocaine" after a single dose was attenuated. Together with the results of clinical trials of DMI for cocaine abuse, these laboratory results suggest that DMI may reduce cocaine craving both during and between cocaine binges. Physiologically, baseline heart rate was higher on DMI, but the incremental heart rate response to cocaine was attenuated.