Studies in which healthy, carefully screened, experienced cocaine users receive cocaine under controlled laboratory conditions, although often overlooked by the medical community, are an excellent source of data on the cardiovascular effects of cocaine. Cocaine is generally self-administered in repeated-dose 'binges', and studies simulating this pattern provide interesting cardiovascular information, such as the selective development of acute tolerance or the unique effects of some drug combinations. Studies with intranasal, intravenous, and smoked cocaine all show that under conditions in which subjects are allowed to take cocaine repeatedly, heart rate generally returns to near baseline levels between doses despite gradually increasing cocaine blood levels. Blood pressure either shows the same pattern, or gradual increases with repeated dosing. Analyses of cardiovascular activity as a function of cocaine plasma level indicate the rapid development of acute (i.e., within session) tolerance to cocaine. Cocaine self-administration often occurs in the presence of behavioral stressors, or in combination with other drugs of abuse or cocaine abuse treatment medications. Performance of a behaviorally-demanding task increases heart rate and blood pressure. When cocaine is taken prior to task performance larger increases in heart rate are observed than with either drug or task alone. An unexpected cardiovascular interaction was observed in subjects who inhaled cocaine and drank ethanol-containing beverages. This combination resulted in heart rate increases that were significantly larger than observed with either drug alone. Combinations of i.v. cocaine and smoked marijuana also increased heart rate above levels seen with either drug alone. A single intravenous dose of cocaine and morphine in combination, however, produced cardiovascular effects similar to those produced by cocaine alone. The effects of these drug combinations on blood pressure were often equal to the effect of one drug alone. Since cocaine is frequently taken in combination with potential treatment drugs, these interactions can be assessed under controlled settings prior to large-scale treatment studies. For instance, maintenance on the antidepressant desipramine increased baseline heart rate and diastolic pressure. Cocaine administration engendered increases in heart rate and blood pressure above the desipramine-elevated baselines. Clearly, drug interactions can have unexpected cardiovascular effects, and laboratory studies provide a controlled setting for understanding and studying these interactions.