SYNOPSISMethysergide is the drug of choice for the prophylaxis of the crises in Episodic Cluster Headache (ECH). Thissubstance is a partial antagonist of both serotonin and histamine. Nevertheless, the classical anti‐histamine drugsdo not have any therapeutic effect in this disease. The etiological role of serotonin has never been taken intoconsideration, because the plasma levels of this mediator have never been found increased. This is not surprising,since serotonin is rapidly degraded in the circulation or immediately bound by circulating platelets. Therefore, apossible role of serotonin cannot be excluded. Serotonin is capable of modulatingin vitrothe motility of humanmonocytes. Our previous studies showed an increase in the number of circulating monocytes in ECH. Therefore,we examined thein vitrointeractions between circulating cells from ECH patients and serotonin.21 ECH patients were studied, in and out of the crisis period. 5 adults were used as normal controls. Circulatingmononuclear cells were tested for their ability to specifically bind 5‐HT, using ( 3 H) labeled 5‐HT.Normal human mononuclear cells bind serotonin in a saturable and specific fashion, and most of this binding isthrough a high affinity site (Kd = 100nM). Conversely, cells from ECH patients lack this high affinity binding siteand only display binding through the low affinity site. The lack of this high affinity binding can be demonstrated inthe patients during the crisis as well as out of it.A possible explanation for the loss of this high affinity binding site could be that the cells of the patients havebeen previously exposedin vivoto high concentrations of serotonin, probably generated during the crisis p