The purpose of the present study is to show anomalies of the plasma cyclic nucleotide responses of patients with migraine to intramuscular injections of methacholine (80 μg/kg body wt) and epinephrine (0.4 mg/person). The methacholine- or epinephrine-induced increases in plasma cyclic GMP were much larger in patients with migraine than in controls. In the case of methacholine injection, there was also a small but significant rise of plasma cyclic AMP in patients with migraine, while no change was observed in controls. On the other hand, there was no significant difference in the epinephrine-induced increase in plasma cyclic AMP between patients with migraine and controls. From these findings it may be assumed that cholinergic or a-adrenergic receptor responses are enhanced in patients with migraine.