5-HT is considered to play a role in the migraine mechanism; its decrease in the midbrain during migraine attacks has been postulated. CSF TP and plasma and platelet 5-HT levels in migraine and cluster headache sufferers have been evaluated; the values registered were compared to those of neurological and carcinoid patients, respectively. The following results were obtained: (a) no significant difference in the time course of free and total TP after l-TP intravenous loading, (b) increased levels of CSF TP during migraine and cluster headache attacks, (c) impressively increased levels of plasma 5-HT only in carcinoid patients. These findings suggest the existence of a positive 5-HT central feedback mechanism during attacks of migraine and cluster headache and thus exclude peripheral 5-HT effects in the generation of pain.