Blood levels of PACAP in migraine: A systematic review

ObjectiveTo examine whether plasma or serum pituitary adenylate cyclase-activating polypeptide (PACAP) levels differ between people with migraine and healthy controls (HCs), and to assess evidence for dynamic alterations during migraine attacks.MethodsA systematic literature search was conducted in PubMed and Embase from inception to December 19, 2025. Eligible studies measured PACAP in plasma or serum of adult or pediatric participants with migraine and reported comparisons with HCs, and/or between ictal and interictal phases. Two reviewers independently screened articles, extracted data, and assessed risk of bias using the QUADAS-2 tool.ResultsEleven studies met the inclusion criteria, comprising seven adult and four pediatric studies. Findings were inconsistent across studies, with some reporting higher PACAP-38 levels in participants with migraine, while others found no differences or even lower levels compared with HCs. Five studies compared ictal and interictal levels, but results were incongruent and lacked intraindividual measurements. Furthermore, all studies were judged to be at high overall risk of bias, primarily due to limitations in participant selection and index test methodology.ConclusionsCurrent evidence on plasma or serum PACAP-38 levels in migraine is limited and inconsistent. The lack of intraindividual ictal-interictal comparisons and variability in study design and assays further weaken conclusions. Standardized, high-quality studies are essential to resolve existing uncertainties.Trial RegistrationThe study protocol was prospectively registered in PROSPERO (CRD42024601373).