Journal article
Overlapping pathways of migraine and the endocannabinoid system: Potential therapeutic targets
Neurotherapeutics, Vol.23(3), e00833
01/17/2026
DOI: 10.1016/j.neurot.2026.e00833
PMCID: PMC12996789
PMID: 41549028
Abstract
Migraine is a disabling neurovascular disorder with limited therapeutic options, especially for patients unresponsive to current treatments targeting calcitonin gene-related peptide (CGRP) signaling. The endocannabinoid system (ECS) has emerged as a promising alternative for migraine modulation, offering analgesic, anti-inflammatory, and neuroimmune-regulatory effects through its main ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degrading enzymes. This review provides an updated map of endocannabinoid components in central and peripheral migraine-relevant regions, highlighting their spatial distribution and functional regulation in animal models. We summarize the available preclinical evidence supporting the anti-nociceptive effects of endocannabinoid-degrading enzyme inhibitors and cannabinoid receptor agonists/antagonists, with particular emphasis on the therapeutic potential of multi-target compounds. Moreover, we explore non-canonical ECS pathways, including TRPV1, D2 dopamine receptors, serotonergic and ion channel interactions, and their roles in modulating CGRP release and trigeminovascular signaling to treat migraine pathophysiology. Finally, we propose two sleep-related directions for treatments involving ECS modulation of circadian rhythms and glymphatic clearance. Although human translational data are limited, the ECS offers a multifaceted framework for developing next-generation therapeutics targeting migraine pathophysiology.
Details
- Title: Subtitle
- Overlapping pathways of migraine and the endocannabinoid system: Potential therapeutic targets
- Creators
- Adriana Della Pietra - University of IowaAndrew F. Russo - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Neurotherapeutics, Vol.23(3), e00833
- DOI
- 10.1016/j.neurot.2026.e00833
- PMID
- 41549028
- PMCID
- PMC12996789
- NLM abbreviation
- Neurotherapeutics
- ISSN
- 1878-7479
- eISSN
- 1878-7479
- Publisher
- Elsevier Inc
- Grant note
- National Institutes of Health: R01NS129573 Marie Sklodowska-Curie Postdoctoral Fellowship: HORIZON-MSCA-2024-PF-01, 101208555
This work was supported by a research grant from the National Institutes of Health R01NS129573 (AFR) and the Marie Sklodowska-Curie Postdoctoral Fellowship HORIZON-MSCA-2024-PF-01 (proposal 101208555, ADP) .
- Language
- English
- Date published
- 01/17/2026
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center
- Record Identifier
- 9985129653702771
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