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SYNOPSISCBF and cerebral vasomotor responses to 5% CO2 and 100%O2 inhalation were evaluated in 88 patients with headache (56 migraineurs, 17 cluster, 15 non-vascular) before and during acute versus chronic administration of (1) methysergide (single dose 0.047 mg/kg for acute and 0.071 mg/kg/day for chronic) or (2) cyproheptadine (single dose 0.092 mg/kg for acute and 0.139 mg/kg/day for chronic). Acute treatment with methysergide produced decreases [−4.5%] in F1 values (fast or gray matter flow). Chronic treatment (3–12 weeks) produced increases (%7.9%). These CBF changes only occurred among migraineurs and were not seen in cluster and non-vascular headache patients. In migraineurs methysergide induced F1 increases were asymmetric between hemispheres. This asymmetry was not seen in patients with non-vascular headache. Methysergide induced biphasic F1 changes specific for migraineurs, implies rapid and excessive stimulation of cerebrovascular serotoninergic receptors, followed by excessive and asymmetric blockade. Acute treatment with cyproheptadine produced increases (+3.9%) in F1 values. Chronic treatment (3–12 weeks) produced decreases (−8.6%) Since cyproheptadine is Known to alter cholinergic, histaminergic and serotonergic receptors, it is concluded that acute cyproheptadine treatment may stimulate and chronic treatment may block both cholinergic and histaminergic receptors so that any serotonergic effects in the opposite direction are masked. Vasomotor responses were not altered in any of the headache groups by either methysergide or cyproheptadine, so that serotoninergic receptors do not appear to participate in excessive cerebral vasodilator CO2 responses seen in migraineurs.