Caffeine acutely modulates CGRP, NO, and endothelin-1 in migraine patients during ictal attacks

Migraine is a debilitating neurovascular disorder characterized by complex interactions between trigeminovascular, endothelial, and neuroimmune pathways. Dysregulation of key mediators like calcitonin gene-related peptide (CGRP), nitric oxide (NO), endothelin-1, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) is central to its pathophysiology. While these mediators are implicated, their phase-dependent dynamics and acute responsiveness to common interventions like caffeine have remained largely undefined, presenting a critical gap in understanding migraine mechanisms and optimizing therapeutic strategies.

This randomized, double-blind, placebo-controlled crossover study included 327 participants (174 migraine patients, 153 healthy controls). Migraine patients were assessed across interictal and ictal phases using a within-subject design. During ictal attacks, participants received a single oral dose of 200 mg caffeine or placebo. Blood samples were collected at baseline (T0) and 60 min post-intervention (T1). Mediator levels were quantified using ELISA and analyzed with linear mixed-effects models to evaluate phase-specific alterations and intra-individual responses to caffeine.

Key neurovascular-immune mediators showed significant phase-dependent alterations in migraine patients. CGRP, NO, IL-6, and TNF-α were significantly elevated during migraine, particularly in the ictal phase, while endothelin-1 levels were reduced. Acute administration of caffeine demonstrated potent modulatory effects on these mediators during an attack. > Caffeine significantly decreased CGRP and NO levels and increased endothelin-1 compared with placebo, promoting a shift toward a more vasoconstrictive vascular balance and reduced trigeminovascular activation. IL-6 and TNF-α also showed modest, though less pronounced, reductions. The individual responses to caffeine varied, with greater effects observed in patients who presented with higher baseline levels of these mediators, underscoring the importance of individual physiological state.