Lysergic acid diethylamide-25 (LSD) and N,N-dimethyltryptamine (DMT) abolish food-rewarded, fixed-ratio bar pressing by rats in a dose-related fashion. Adult male Holtzman rats trained to press a bar (respond) for milk reward on a 4-response fixed-ratio schedule were given i.p. injections of 3.2 or 10 mg/kg of DMT every 2 hours for 21 days. Every 24 hours the animals were placed in operant chambers for 30 minutes before a scheduled injection and were left in the chambers for 30 to 80 minutes after. During the first week of chronic treatment, daily bar pressing worsened progressively until the 6th day of the series, at which time rats in the 10 mg/kg group did not bar press at all. As the chronic injections continued, rates of bar pressing gradually increased until responding was not disrupted at all by an injection of DMT. Rats in the 3.2 mg/kg group showed cross-tolerance to an injection of LSD (0.1 mg/kg). Another group of rats was made partially tolerant to the disruptive effects of LSD (0.1 mg/kg i.p.) on bar pressing with a series of injections given once per day for 21 days and then three times per day for the next 4 days. Cross-tolerance was not demonstrated to a challenge injection of 10 mg/kg of DMT. The LSD injections were continued for another 3 to 5 days until the animals were completely tolerant to the LSD. They then displayed cross-tolerance to 3.2 mg/kg of DMT.