Cocaine can cause myocardial ischemia or infarction. The incidence of these events, and the influence of specific dosing routes or regimens on their occurrence is not established. In the current study, we obtained frequent 12-lead electrocardiograms (ECGs) and continuous 2 or 3 channel ECGs from 20 subjects participating in a behavioral study of smoked cocaine. Subjects received 10 or 11 doses of cocaine 0.4 mg/kg per dose, or 10 doses of 35 mg per dose at 30 min intervals (range 233-408 mg total dose per session). ECGs were also recorded on control days on which subjects received no cocaine. The mean peak plasma cocaine concentration on cocaine days was 640 ± 262 ng/ml. There were no changes in digitized ST segment amplitude on 12-lead ECGs obtained during cocaine administration (P = 0.098). Of 17 subjects who had technically satisfactory continuous ECGs, four had significant ST segment depression (> 1 mm below the PR segment); two on cocaine days and two on control days (P > 0.5). One subject had frequent premature beats on both cocaine and control days. One subject had an asymptomatic run of 4 ventricular beats 30 s after cocaine administration that could have been due to cocaine. All episodes of ST depression or premature beats were asymptomatic. No evidence of either symptomatic or subclinical cardiac ischemia related to cocaine administration was found. Thus no clinically important adverse events were found as a result of smoked cocaine administered by this dosing regimen to healthy males with a history of heavy cocaine use. Additional study with larger numbers of subjects will be helpful in further assessing the safety of administering smoked cocaine to research subjects.