The effects of naloxone on narcosis and/or lethality induced by diazepam, lithium, methaqualone and phenobarbital either alone or in combination with ethanol were studied in mice. Interaction toxicities between ethanol and the various psychotropic drugs were dose-dependent and so was the degree of antagonism by naloxone. Treatment with phenobarbital (10 mg/kg) or methaqualone (50 mg/kg) or lithium (4 meq/kg) prolonged the narcosis induced by ethanol (5 g/kg) by 45, 269 and 107% respectively. Naloxone (10 mg/kg) shortened the ethanol (5 g/kg) induced narcosis by 38%. Naloxone (10 mg/kg) also shortened narcosis induced by ethanol (5 g/kg) in combination with phenobarbital (10 mg/kg) or methaqualone (50 mg/kg) or lithium (2meq/kg) by 31, 12 and 38% respectively. At 10 mg/kg of naloxone, the LD50 due to methaqualone was increased from 240 mg/kg to 416 mg/kg, and the LD50 due to ethanol was increased from 9.2 g/kg to 10.8 g/kg. Multiple injections of naloxone significantly (p less than 0.01) protected against the lethality of phenobarbital but not that of lithium. These findings provide further evidence of naloxone antagonism towards various CNS depressants.