Neurotransmitter Imbalance in Cluster Headache: A Systematic Review of Mechanisms and Therapeutic Targets.

Introduction: Cluster headache (CH) causes brief but extremely severe head pain, yet we still do not fully understand the molecules that trigger these attacks. Many studies have looked at changes in neurotransmitters and neuropeptides, but their results do not always agree. This systematic review brings together all the available data on neurochemical changes in CH, with the goal of clarifying current knowledge gaps and highlighting promising targets for future research.

Methods: We searched PubMed, Embase (Ovid), and Scopus for studies reporting quantitative measurements of neurotransmitters in human biological samples from individuals with CH, as well as provocation studies in which neurotransmitters or neurotransmitter-related compounds were administered to trigger attacks. Thirty-eight eligible studies were identified. For each, we extracted information on design, participant characteristics, sampling matrix (e.g., plasma, saliva, cerebrospinal fluid, platelets), and the neuromodulators assayed, and then synthesized the findings narratively.

Results: Altered levels of histamine and sensory neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P were documented, especially during active headache attacks. Conflicting data were reported for serotonin, whereas nitric oxide (NO), pituitary adenylate cyclase-activating peptide (PACAP), and vasoactive intestinal peptide (VIP) provoked CH attacks in experimental studies. Data on orexins and their receptors were inconclusive.

Conclusions: The evidence emphasize several potential therapeutic targets, including CGRP, substance P, histamine, VIP, and PACAP. However, interpretation is hampered by heterogeneity across studies and methodological limitations, particularly the large variance and uncertainties of CGRP assays, which make cross-study comparisons difficult. Further research is needed to elucidate the exact molecular mechanisms driving CH and to identify effective therapeutic interventions.