Objective: Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. Methods: Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. Results: Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. Conclusion: A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: ClinicalTrials.gov Identifier: NCT03143465.