To determine whether calcitonin gene-related peptide (CGRP) provokes typical idiopathic intracranial hypertension (IIH) headache attacks compared with placebo.

CGRP is a key mediator in migraine pathophysiology. IIH headache phenotype is now understood to be typically migraine-like, but it is unclear whether CGRP directly provokes IIH headaches or alters intracranial pressure (ICP) dynamics.

We conducted a randomised, double-blind, placebo-controlled, two-way crossover provocation study to address this question. Twenty women with IIH and no prior migraine were randomly assigned to receive a 20-min continuous intravenous infusion of CGRP (1.5 μg/min) or placebo (isotonic saline). Primary outcome was the difference in the proportion of participants who developed a provoked migraine-like headache between CGRP and placebo during the 12h observation after infusion. Secondary outcomes included the area under the curve (AUC) for headache intensity from 10-min to 12h, the timing and duration of headache features, and baseline-adjusted changes for vital signs, cerebrovascular haemodynamics and ICP.

Seventeen participants with mean(SD) age 26.7(6.4) years completed both visits. Twelve (71%) participants developed a typical IIH headache attack with migraine-like features after CGRP compared with three (18%) after placebo (risk difference 53%; 95% CI, 26–79; P=0.004). The AUC_-10min-12h for headache intensity was higher after CGRP than after placebo (P=0.016). The mean ICP remained unchanged, whereas ICP amplitude increased significantly after CGRP (P=0.005). Vital signs and cerebrovascular haemodynamics AUC_-10min-90min were significantly altered after CGRP (increased: heart rate (P<0.001), tissue oxygenation index (P=0.041), oxygenated haemoglobin (P<0.001) and decreased: mean arterial pressure (P=0.010), middle cerebral artery blood velocity (P=0.006)).

CGRP reliably provoked typical IIH headache attacks (which have migraine-like features) and increased ICP pulse amplitude (a measure of intracranial compliance) without altering mean pressure. These findings provide mechanistic support for CGRP involvement in headache attributed to IIH and justify prospective evaluation of CGRP pathway blockade in this population.