Mazindol is a catecholamine reuptake inhibitor that blocks binding of cocaine at the dopamine reuptake site. This study was conducted to determine whether the acute administration of mazindol modulates the pharmacological effects of intravenous cocaine in humans. In a crossover study, twelve acute drug conditions were tested in randomized order under double-blind, double-dummy conditions in eight cocaine abusers. Cocaine (0, 12.5, 25 and 50 mg, i.v.) was administered in combination with mazindol (0, 1 and 2 mg given orally 2 hr before the cocaine injection). Physiological and subject- and observer-rated responses were measured. Cocaine and mazindol alone both significantly increased heart rate and blood pressure. Cocaine increased ratings on stimulant-like subjective effect measures, including desire for cocaine; mazindol had mild, stimulant-like subjective effects. There were significant interactions between the effects of cocaine and mazindol on heart rate and blood pressure, with combinations producing significantly large and more sustained increases compared with cocaine alone. There was no evidence that mazindol substantially altered the magnitude or profile of the subjective effects of cocaine, including cocaine-induced craving for cocaine. These results do not support the utility of acute administration of mazindol in the treatment of cocaine abusers through a mechanism of modulation of cocaine's subjective effects. Furthermore, mazindol treatment may increase the cardiovascular risks of cocaine.