Background: Histamine is an ancient "tissue amine" preceding multicellular organisms. In the central nervous system (CNS), its fibers originate solely from the tuberomammillary nucleus and travel throughout the brain. It is mainly responsible for wakefulness, energy homeostasis, and memory consolidation. Recently, several studies suggest a potential role of histamine in migraine pathogenesis and management.

Methods: Narrative review of current literature regarding histamine and migraine.

Results: Histamine plays a crucial role in migraine pathogenesis: sustaining the neurogenic inflammation pathway. Interaction between mast cells (MC) and calcitonin-gene related protein (CGRP) results in sensitization of trigeminal afferents and trigeminal ganglia (TG). Histamine binds with differing affinities to four different histaminergic G-protein coupled receptors, activating protein kinases, or triggering calcium release with subsequent mode of actions. Histamine 1 receptor (H₁ R) and histamine 2 receptor (H₂ R) antagonists are frequently used for the treatment of allergy and gastric acid secretion, respectively, but their antagonism is probably ineffective for migraine. Histamine 3 receptor (H₃ R) and histamine 4 receptor (H₄ R) have a threefold higher affinity than H₁ R/H₂ R for histamine and are found almost exclusively on neurons and immune tissues, respectively. H₃ R acts as an autoreceptor or as a heteroreceptor, lowering the release of histamine and other neurotransmitters. This is a potential target for anti-nociception and anti-neurogenic inflammation. To date, several small clinical trials using low dose histamine or N^α -methylhistamine have demonstrated migraine prophylactic efficacy, probably via H₃ R or other undetermined pathways.

Conclusion: The histamine system interacts with multiple regions in the CNS and may hypothetically modulate the migraine response. Low dose histamine may be a promising option for migraine prevention.