The effect of lithium salts administered chronically to bipolar patients on peripheral measures of the serotoninergic system has been studied. Plasma free serotonin (5HT), whole blood 5HT, plasma 5-hydroxyindoleacetic acid (5HIAA) and plasma total tryptophan (TP) have been analyzed in 22 patients treated with lithium carbonate (mean daily dose: 1280 mg, mean serum concentration: 0.73 mmol/l) and compared to 14 healthy controls and 11 patients treated chronically with antipsychotic drugs. Lithium salts induced significant increases in plasma free 5HT (+159% with respect to control values) and in plasma 5HIAA (+39%) without affecting 5HT contained in platelets. Plasma TP was also unchanged by chronic lithium treatment. The ratio between 5HT stored in platelets and 5HT free in plasma, a variable reduced after uptake inhibitors like clomipramine, was decreased in lithium-treated patients (-50%). These results are compatible with an enhanced synthesis of 5HT in the periphery (mainly enterochromaffin cells) as well as with an inhibition of platelet 5HT uptake (or increased 5HT efflux from intracellular stores) induced by lithium. The lack of effect of several antipsychotic drugs upon these variables is consistent with their predominant effect on the dopaminergic system and reinforces the specificity of the effect observed with lithium salts. Taken together, these results support the usefulness of using this "in vivo" 5HT peripheral model for the study of the actions elicited by drugs acting on the presynaptic components of the 5HT system.