Intranasal cocaine (COC) and oral ethanol (ETOH) were administered to one group of seven research volunteers during daily experimental sessions. Following the determination of baseline subjective and performance measures, an ETOH cocktail (0, 19.4, 38.7 or 58.1 g of ETOH in lemonade) was consumed over a 10-min period. COC hydrochloride (4, 48, 96 mg) was inhaled 35-min after the start of ETOH drinking. In a separate experiment, seven research volunteers received intravenous cocaine and smoked marijuana (MJ), alone and in combination during daily experimental sessions. Following the determination of baseline measures, a 1-g MJ cigarette (0-2.7% delta 9-THC, w/w) was smoked and 13 min after the start of MJ smoking COC hydrochloride (0, 16, 32 mg) was given intravenously. ETOH increased simple-reaction time and decreased DSST trials. COC decreased DSST trials, increased incorrect responses on a list-learning task and attenuated the effect of ETOH on DSST performance. Only combinations of the high COC dose and the high MJ dose increased errors on a repeated acquisition task. Intranasal COC increased ratings of 'Stimulated,' and 'High' and LSD scores on the ARCI which were unaffected by ETOH. Increased ratings of 'Sedated' following ETOH alone were attenuated by intranasal (i.n.) COC. Intravenous COC and smoked MJ alone both increased ratings of 'Stimulated' and 'High.' There was a trend for combinations of i.v. COC and MJ to prolong these elevations. The results suggest that the interactive effects of COC in combination with ETOH or MJ, after acute administration, are subtle and in need of further analyses to better understand polydrug abuse.