Cyclazocine is a kappa-opioid receptor agonist and mu-opioid receptor antagonist that was studied in the 1960s as a potential treatment for heroin addicts. Based on the evidence that opioid mechanisms modulate the reinforcing effects of cocaine, it has been suggested that cyclazocine be reconsidered for use in treating cocaine dependence. In the present study, the effects of orally administered (+/-)-cyclazocine, (+)-cyclazocine and (-)-cyclazocine on intravenous cocaine self-administration were assessed in rats. (+/-)-Cyclazocine produced a dose-related (2-8 mg/kg) decrease in cocaine intake without affecting bar-press responding for water. Neither enantiomer significantly altered responding for either cocaine or water. The efficacy of orally administered (+/-)-cyclazocine on cocaine self-administration was comparable to that previously observed using the intraperitoneal route. Distinct actions of the enantiomers of cyclazocine that might contribute to the unique efficacy of the racemate are discussed. Although the mechanistic basis for the results are not entirely understood, the data suggest that (+/-)-cyclazocine should be considered as a potential treatment for cocaine dependence.