New Reviews Highlight the Endocannabinoid System as a Promising Frontier in Migraine Therapeutics

Delphian Therapeutics is a clinical-stage company developing cannabinoid-based migraine therapeutics. Two recent independent reviews highlight the growing scientific rationale behind the Company's approach: targeting the endocannabinoid system (ECS) for migraine treatment.

​Mapping the ECS Across Migraine Pathways

 A 2026 review published in Neurotherapeutics by Adriana Della Pietra and Andrew F. Russo at the University of Iowa provides an updated map of endocannabinoid components across migraine-relevant brain regions. Della Pietra and Russo show that the cannabinoid receptors CB1 and CB2, the endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degrading enzymes FAAH and MAGL are expressed and active throughout the trigeminovascular system, cortex, hypothalamus, and brainstem regions implicated in migraine. Their analysis supports a multi-target therapeutic approach, as these enzymes are distributed differently across pain-signaling regions, and inhibiting multiple pathways simultaneously may be necessary for broad efficacy.

​The review also explores non-canonical ECS pathways, including TRPV1 ion channels, dopamine D2 receptors, and serotonergic interactions, as well as two emerging directions: ECS modulation of circadian rhythms and glymphatic clearance, the brain's sleep-dependent waste removal system. 

Clinical and Preclinical Evidence for Cannabinoid-Based Migraine Treatment

 A complementary 2025 review by Roger Gregory Biringer in Pain Research and Management surveys both preclinical and clinical evidence for cannabinoid treatment of migraine. Biringer notes that clinical data consistently show patients using cannabinoid-based products report improvements in migraine intensity, duration, and frequency. A randomized, double-blind, placebo-controlled study found that a combination of THC and CBD was superior to placebo for pain relief and pain freedom at two hours, with less cognitive impairment than THC alone.

​Both reviews reference the Clinical Endocannabinoid Deficiency (CED) hypothesis, which proposes that reduced endocannabinoid tone may underlie migraine. Supporting this, cerebrospinal fluid levels of anandamide have been found to be reduced in chronic migraine patients.

​Both Della Pietra and Biringer conclude that combination approaches targeting multiple ECS components represent the most promising direction for next-generation migraine therapeutics.

​Delphian Therapeutics is developing cannabinoid-based migraine treatments that engage the endocannabinoid system through an optimized, multi-target approach. The Company's research has been supported by the U.S. National Institutes of Health and conducted in collaboration with leading academic institutions.