We assessed the effect of two regimens of lithium treatment (3 days and 2 weeks) on brain serotonin (5-HT) function in healthy subjects by measuring the prolactin (PRL) responses to the 5-HT releasing agent, d-fenfluramine (30 mg) before and after lithium administration. Neither regime of lithium treatment altered d-fenfluramine-induced PRL release. These results are in contrast to the facilitation produced by lithium of the PRL responses to the 5-HT precursor L-tryptophan. The data suggest that the ability of lithium to increase brain 5-HT neurotransmission in humans may depend on interactions with particular 5-HT receptor subtypes or specific mechanisms of 5-HT release.