Effects of substance P on headache induction and arterial dilation in healthy adults

Objective To determine whether intravenous infusion of substance P elicits headache and arterial dilation in healthy adults. Methods In a double-blind, placebo-controlled, two-way crossover study, we randomly allocated healthy adults to receive either substance P (1.5 pmol/kg/min) or placebo (isotonic saline) by 20-minute intravenous infusion on separate experiment days. The primary endpoint was the incidence of headache within 12 hours after the infusion. Other endpoints included the area under the curve (AUC) for headache intensity scores over the 12-hour observation period and AUC changes in the superficial temporal artery (STA) diameter from baseline to 120 minutes post-infusion. Results Twenty-one participants underwent randomization and completed both experiment days. Headache was reported by 15 (71%) of 21 participants following substance P, compared with two (10%) after placebo ( p < 0.001). The AUC for headache intensity scores was significantly higher after substance P infusion than after placebo ( p = 0.03). In addition, there was a significant STA diameter increase with substance P, compared with placebo ( p = 0.005). Conclusions Among healthy adults, substance P infusion elicited headache and arterial dilation. These findings support a role for substance P in headache pathogenesis and encourage further investigation in migraine and other headache disorders. Additional research is also needed to explore new therapeutic strategies targeting substance P or its downstream signaling. Trial Registration: CT identifier: NCT06632080.