The effects of dextromethorphan and its metabolite dextrorphan on morphine, methamphetamine and nicotine self-administration and on responding for a nondrug reinforcer (water) were assessed in rats. Both dextromethorphan and dextrorphan decreased morphine self-administration at 10-30 mg/kg, s.c., decreased methamphetamine self-administration at 20 and 30 mg/kg, s.c., and decreased nicotine self-administration at 5-30 mg/kg, s.c.; doses of both drugs less than 40 mg/kg, s.c. did not affect responding for water. The equal potencies of dextromethorphan and dextrorphan suggest mediation of these effects by a non-NMDA receptor mechanism, possibly involving blockade of alpha3beta4 nicotinic receptors. The results also suggest that dextromethorphan should be tested extensively as a potential treatment for diverse populations of drug-abusing patients.