OBJECTIVE The purpose of this study was to determine the hemodynamic effects of recreational/toxic doses of ethanol, or cocaine, or ethanol followed by cocaine. METHODS Prospective, randomized study. METHODS University research laboratory. METHODS Eighteen healthy, adult mongrel dogs. METHODS Dogs were randomized to receive ethanol (1 g/kg iv) over 20 mins and a 10-mL bolus of 0.9% sodium chloride, or 5% dextrose in water, over 20 mins, and then a cocaine bolus (7.5 mg/kg), or ethanol (1 g/kg iv), over 20 mins, and then a cocaine bolus (7.5 mg/kg). RESULTS Arterial, left ventricular, and pulmonary arterial pressures, mixed venous blood oxygen saturation, and heart rate (HR) were continuously recorded in each dog. The maximal rate of left ventricular pressure increase (dP/dtmax) and decrease (dP/dtmin), stroke volume, HR, pulmonary artery occlusion pressure (PAOP), and plasma concentrations of ethanol and cocaine were measured at baseline, after ethanol or placebo infusions, and then after a cocaine or placebo bolus at specific time intervals over a 5-hr study period. The plasma ethanol concentration increased to 160 +/- 8 mg/dL at 30 mins after the start of the infusion, and then decreased to 30 +/- 8 mg/dL at 180 mins. The plasma cocaine concentration increased to 4587 +/- 383 ng/mL within 2 mins of the bolus injection, and then decreased and approached the baseline at 240 mins. Immediately after injection, ethanol plus cocaine synergistically decreased dP/dtmax by 70% and dP/dtmin by 81% (both p < .001). In addition, immediately after injection, ethanol plus cocaine maximally decreased the stroke volume by 34% (p < .05) and maximally increased the HR by 89% and PAOP by 127% (both p < .002). The dP/dtmax and the stroke volume remained decreased by 15% to 20% for 5 hrs (p < .05). Cocaine alone, immediately after injection, maximally decreased dP/dtmax and dP/dtmin by 40% (p < .02), and caused a 26% decrease in stroke volume (p = .05), a 48% increase in HR (p < .02), and a 75% increase in PAOP. The decrease in dP/dtmax persisted for approximately 60 to 90 mins. Ethanol alone produced transient 6% to 13% decreases in dP/dtmax, dP/dtmin, and stroke volume (NS) and small (9%) increases in the HR (NS) during the first hour after injection. CONCLUSIONS Cocaine combined with ethanol produces a significant synergistic depression of ventricular contraction and relaxation that substantially exceeds the arithmetic sum of the depressive effects of either cocaine or ethanol alone.