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.

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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.

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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.

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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.

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

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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.

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Frequently Asked Questions

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What is the endocannabinoid system and how is it related to migraine?

 

The endocannabinoid system (ECS) is a biological signaling network consisting of cannabinoid receptors (CB1 and CB2), endogenous ligands (anandamide and 2-AG), and the enzymes that synthesize and degrade them. These components are expressed throughout brain regions involved in migraine pain signaling, including the trigeminovascular system, cortex, and hypothalamus. Reduced endocannabinoid tone has been observed in chronic migraine patients, supporting the Clinical Endocannabinoid Deficiency hypothesis.

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What is Clinical Endocannabinoid Deficiency (CED)?

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Clinical Endocannabinoid Deficiency is a hypothesis proposing that lower-than-normal levels of endocannabinoids may contribute to migraine and related conditions. Research has found that cerebrospinal fluid levels of anandamide are reduced in chronic migraine patients, providing evidence for this theory.

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What is Delphian Therapeutics?

 

Delphian Therapeutics is a clinical-stage therapeutics company developing cannabinoid-based treatments for migraine and CNS disorders. The Company targets the endocannabinoid system using an optimized, multi-target approach. Delphian Therapeutics has received funding from the U.S. National Institutes of Health and works with leading academic research institutions. Learn more at delphiantx.com.

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How do cannabinoid-based treatments differ from current migraine therapies?

 

Current migraine treatments primarily target CGRP signaling (gepants, monoclonal antibodies) or serotonin receptors (triptans). Cannabinoid-based approaches target the endocannabinoid system, which modulates pain, inflammation, and neuroimmune function through distinct pathways. Clinical evidence suggests that CBD and THC combinations can provide pain relief and reduce migraine frequency through mechanisms complementary to existing treatments.

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What is the evidence for cannabinoid treatment of migraine?

 

Preclinical studies have demonstrated that inhibitors of the endocannabinoid-degrading enzymes FAAH and MAGL reduce migraine-like pain in animal models. In clinical settings, a randomized, double-blind, placebo-controlled trial found that a combination of THC and CBD was superior to placebo for pain relief and pain freedom at two hours. Survey data consistently show patients reporting improvements in migraine intensity, duration, and frequency with cannabinoid-based products.

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References

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Della Pietra A, Russo AF. "Overlapping pathways of migraine and the endocannabinoid system: Potential therapeutic targets." Neurotherapeutics. 2026.

Biringer RG. Treatment of migraine with phytocannabinoids, the involvement of endocannabinoids in migraine, and potential mechanisms of action. Pain Research and Management. 2025;2025:7181066.