The endocannabinoid system plays a central role in headache disorders, and targeting it could offer new treatments

The endocannabinoid system modulates trigeminovascular firing, CGRP release, neurogenic inflammation, cortical spreading depression, and glial activation after brain injury. Drugs that inhibit endocannabinoid breakdown (FAAH, MAGL, COX-2 inhibitors) consistently reduce headache-like behaviors in animal models. Endocannabinoid system dysregulation contributes to central sensitization in medication overuse headache. Females show distinct hormonal regulation, receptor expression, and glial activation that influence responses to cannabinoid-based therapies.

Comprehensive narrative review synthesizing preclinical and translational research on the endocannabinoid system across multiple headache types: migraine, tension-type headache, trigeminal autonomic cephalalgias, post-traumatic headache, and medication overuse headache.

Headache disorders affect over a billion people globally and remain difficult to treat. The endocannabinoid system offers multiple therapeutic targets that could complement or replace existing treatments, particularly for patients who do not respond to conventional therapies.

Rather than using whole cannabis for headaches, this review points toward more targeted strategies: enhancing the body's own endocannabinoid tone through enzyme inhibition. This approach could provide therapeutic benefit without the psychoactive effects of THC.

Mostly based on preclinical data. Clinical evidence for endocannabinoid-targeted headache treatments is limited. Sex differences are documented but not yet integrated into clinical protocols. Individual variation in endocannabinoid tone may complicate treatment.