How Glutamate May Trigger CGRP Release in Migraine — and Why Targeting Both Could Help More Patients | Research

The takeaway

Glutamate may act as an upstream trigger for CGRP release in migraine, and targeting the glutamate-CGRP interaction could help the one-third of patients who don't respond to CGRP-blocking treatments alone.

~33% non-response to CGRP therapy
About one-third of migraine patients don't respond to CGRP-blocking treatments, possibly because glutamate — the upstream trigger — continues to drive migraine through other pathways

What the researchers found

The review synthesizes evidence that glutamate acts as an upstream trigger for CGRP release in the trigeminovascular system. Elevated glutamate levels contribute to both peripheral sensitization (nerve activation around blood vessels) and central sensitization (amplified pain processing in the brain), potentially driving the transition from episodic to chronic migraine. The CGRP-glutamate relationship is bidirectional, with CGRP also capable of enhancing glutamate signaling, creating a feedforward loop that perpetuates migraine.

Why it matters

About one-third of migraine patients don't respond to CGRP-targeting therapies — the most important advance in migraine treatment in decades. Understanding that glutamate may be the upstream driver of CGRP release explains why blocking CGRP alone isn't always sufficient. This points to glutamate-targeting strategies as a complementary or alternative approach, potentially expanding effective treatment options for treatment-resistant migraine patients.

How the study worked

This is a narrative review examining the scientific literature on CGRP and glutamate interactions in migraine pathophysiology, covering evidence from preclinical studies, neuroimaging, and clinical observations. The review integrates findings on peripheral excitation, central sensitization, and therapeutic implications.

What this study cannot tell us

As a narrative review, this does not include systematic methodology or meta-analysis. The glutamate-CGRP interaction model is largely based on preclinical data and has not been fully validated in clinical trials targeting glutamate for migraine. The complexity of glutamate signaling (essential for normal brain function) makes targeting it therapeutically challenging without side effects.

How to read the evidence

This is a narrative review synthesizing preclinical and clinical evidence. While it provides a compelling mechanistic framework, the proposed glutamate-CGRP interaction model awaits direct clinical validation through randomized trials targeting the glutamate component.

When this study was published

Published in 2025 in The Journal of Headache and Pain, this review reflects the current state of migraine neuroscience and addresses an important clinical gap in CGRP-era treatment.

The bigger picture

The migraine field has been dominated by CGRP for the past decade, with multiple antibodies and small molecules approved. This review redirects attention to glutamate — the brain's primary excitatory neurotransmitter — as a potentially more fundamental target. If the glutamate-CGRP axis can be disrupted at the glutamate level, it could prevent not just the CGRP-mediated component but also other downstream effects of excessive glutamate that contribute to migraine and central sensitization. This could reshape the next wave of migraine drug development.

Questions still open

Could glutamate-lowering dietary interventions complement CGRP-blocking drugs for migraine patients?
Would targeting glutamate receptors directly prove effective as a migraine preventive for CGRP non-responders?
Is excessive glutamate signaling the reason some patients transition from episodic to chronic migraine?

Common questions

What is CGRP and why is it important in migraine?

Calcitonin gene-related peptide (CGRP) is a signaling molecule released by nerves around brain blood vessels during migraine attacks. It causes blood vessel dilation and inflammation that contributes to migraine pain. Drugs that block CGRP or its receptor (like erenumab, fremanezumab, and rimegepant) have become major migraine treatments, but about a third of patients don't respond to them.

Could diet affect the glutamate-CGRP migraine pathway?

This review suggests glutamate triggers CGRP release, so reducing glutamate levels could theoretically help. Some migraine patients report that foods high in glutamate (like MSG) trigger attacks. A low-glutamate diet has shown promise in preliminary studies and could complement CGRP-blocking medications, particularly for patients who don't fully respond to CGRP therapies alone.

Read the original research

Unmasking the relationship between CGRP and glutamate: from peripheral excitation to central sensitization in migraine.

The journal of headache and pain, 26(1), 101

View on PubMed ↗Publisher’s paper ↗

Citation

Martami, Fahimeh; Holton, Kathleen F. (2025). Unmasking the relationship between CGRP and glutamate: from peripheral excitation to central sensitization in migraine.. The journal of headache and pain, 26(1), 101. https://doi.org/10.1186/s10194-025-02043-x