Ten healthy adult male research volunteers with histories of smoked and i.v. cocaine use participated in four daily sessions. After resting base line, subjects received the same cocaine dose twice with a 14-min interval between doses. Cocaine hydrochloride (16 and 32 mg) was injected or cocaine base (25 and 50 mg) was smoked. Heart rate, blood pressure, subjective effects and venous blood were sampled repeatedly. The potency of smoked cocaine was about 60% of that of i.v. cocaine, i.e., a 50-mg dose of smoked cocaine had effects similar to a 32-mg dose of i.v. cocaine. Cocaine plasma level increased after each dose up to 425 ng/ml with peaks observed 4 min after the second dose. Plasma levels 44 min after the first dose were similar to plasma levels seen 4 min after the first dose. Smoked and i.v. cocaine produced similar increases in heart rate, blood pressure and rate pressure product at similar cocaine venous plasma levels. VAS ratings of "stimulated" and "high" were greater at similar plasma levels after smoked cocaine compared to i.v. cocaine. In addition VAS ratings of cocaine "liking" were also greater for smoked than i.v. cocaine. Otherwise the subjective effects of smoked and i.v. cocaine were similar. The effects of specific cocaine plasma levels on cardiovascular activity and some subjective reports were diminished across the session, demonstrating the development of acute tolerance to cocaine.