Molecular triggers of migraine aura: A systematic review of human pharmacological provocation studies.

BackgroundMigraine aura reflects transient neurological disturbances attributed to cortical spreading depolarization (CSD), yet the upstream molecular events that promote or precipitate this phenomenon remain uncertain. Human pharmacological provocation models provide a controlled approach to identifying endogenous signaling pathways capable of triggering aura and thereby clarifying their mechanistic role in migraine pathogenesis.MethodsThis systematic review was pre-registered in PROSPERO (ID: CRD420250636266) and conducted in accordance with the Synthesis Without Meta-Analysis (SWiM) guideline. PubMed and Embase were searched from database inception through January 1, 2026, without language restrictions, to identify experimental studies administering pharmacological agents to individuals with migraine with aura under controlled lab conditions. Two reviewers independently performed study selection, data extraction, and methodological assessment. Extracted variables included participant characteristics, study design, pharmacological trigger, dosing protocol, and the incidence, timing, and phenotype of provoked aura and headache. Because of substantial heterogeneity, findings were synthesized qualitatively.ResultsFourteen studies met inclusion criteria, examining seven pharmacological agents: calcitonin gene-related peptide (CGRP), levcromakalim (ATP-sensitive potassium (KATP) channels opener), glyceryl trinitrate (GTN), sildenafil, cilostazol, endothelin-1, and histamine. Across studies, aura induction occurred far less frequently than headache induction. CGRP provoked aura in 17 (32%) of 53 participants across three studies, with latencies ranging from 10 to 360 min. Pharmacological opening of vascular KATP channels by levcromakalim elicited aura in 14 (27%) of 52 participants in randomized crossover trials, with onset between 20 and 120 min. Other agents produced minimal or no aura responses.ConclusionsHuman pharmacological provocation provides a reproducible framework for dissecting molecular pathways that can trigger migraine aura. Current evidence implicates CGRP signaling and vascular ATP-sensitive potassium channel activation as the most plausible associated candidate pathways. However, standardized protocols and larger controlled studies are required to confirm these mechanisms and refine experimental models of aura biology.Trial RegistrationPROSPERO (ID: CRD420250636266).