The effect on nocturnal melatonin secretion of acute administration of the indirectly acting serotonin (5-HT) receptor agonists d-fenfluramine (30 mg) and paroxetine (20 mg) and a partial 5-HT1A receptor agonist ipsapirone (20 mg) was investigated in healthy male volunteers and compared to a placebo condition. Each subject (n = 8) received each drug on one occasion over a 4 week study period, with drug administration separated by 1 week. A randomized, counter-balanced design was used. Drugs or placebo were administered at 2,000 hours in the light, and all blood samples were collected throughout the night in the dark at regular intervals until 0600 hours. Neither d-fenfluramine, paroxetine, or ipsapirone following acute dosage had a statistically significant effect on nocturnal melatonin synthesis. The lack of effect seen with d-fenfluramine, paroxetine, and ipsapirone may be due to limitations imposed by the dose requirements.