Objective: Previous attempts to develop a pragmatic human model for testing new anti-migraine drugs, have failed. Calcitonin gene-related peptide (CGRP) induces a mild headache in healthy volunteers and migraine-like headache in migraine patients. The induced headache must respond to already established migraine treatment for validation. Thus, the objective of the study was to test the effect of sumatriptan against CGRP-induced symptoms in an attempt to validate CGRP-induced headache as a model for drug testing. Methods: Thirty healthy volunteers were recruited to receive a 2-hour infusion of CGRP on 2 separate days. The participants were pretreated with sumatriptan 1 day and with placebo the other day in a randomized double-blind cross-over fashion. During the infusion, a questionnaire about headache and side effects was administered. Electrocardiography, heart rate, blood pressure, dermal blood flow, and diameter of peripheral arteries were monitored during the infusion. Participants were carefully instructed to fill out a headache questionnaire at home until 12 hours after the infusion start. Primary endpoints are difference between the sumatriptan day and the placebo day in area under the headache score curve (AUC) 0-2 hours after infusion start and in headache intensity 2 hours after infusion start. The study was conducted at the Danish Headache Center in Glostrup, Denmark. Results: CGRP-induced headache in 86% (25/29) of the participants on the sumatriptan day and in 96% (28/29) of the participants on the placebo day. There was no difference in AUC_{headache, 0-2 hours} between the days (P =.794). There was a statistically significant decrease in mean atrial pressure (MAP) over time on both days with a16.2% reduction on the sumatriptan day and a 14.8% reduction on the placebo day (P <.001) and a statistically significant increase in heart rate (HR) over time on both days (from mean 57.5 at baseline to mean 105.4 at 120 minutes on the sumatriptan day and from mean 60.2 at baseline to 105.8 at 120 minutes on the placebo day, P <.001). The diameter of peripheral arteries increased statistically significant on both days (P <.001). Conclusion: Sumatriptan does not influence headache score, accompanying symptoms or other symptoms induced by CGRP. Furthermore, a 2-hour CGRP infusion causes a wide range of side effects and does not induce more headache than the usual 20-minute infusion. Thus, the prolonged infusion of CGRP in healthy volunteers is not a valid and pragmatic model for testing new anti-migraine drugs.