The antidiarrheal drugs loperamide and diphenoxylate were tested for their ability to potentiate central nervous system depression induced by ethanol in mice and nethohexital in rats. Oral diphenoxylate potentiated the loss of righting reflex (hypnosis) at 10 mg/kg in mice and at 5 mg/kg in rats, doses which were considerably lower than those required to induce morphine-like behavior in mice and rats. Oral loperamide did not potentiate hypnosis. Increased incidence and duration of hypnosis was observed with loperamide only at very high, nearly toxic doses (100 mg/kg in mice and 80 mg/kg in rats) and these doses induced only nonspecific central nervous system depression. The failure of loperamide to potentiate the action of hypnotics confirms data from clinical trials which showed that loperamide is essentially free of central depressant effects when given orally.