PACAP38 Triggers Migraine Independently of CGRP: A New Peptide Pathway Discovered | Research

The takeaway

Randomized trial showed PACAP38-induced migraine attacks occur independently of CGRP signaling, revealing a separate neuropeptide pathway that anti-CGRP drugs cannot block.

CGRP-independent migraine
PACAP38 triggers migraine through a pathway that anti-CGRP drugs cannot block — revealing a new target for non-responding patients

What the researchers found

PACAP38-induced migraine attacks were not blocked by CGRP signaling inhibition, demonstrating an independent neuropeptide migraine pathway that represents a new drug target.

Why it matters

About 30-40% of migraine patients do not respond to anti-CGRP drugs. Discovering that PACAP38 triggers migraine independently of CGRP reveals a new drug target for these non-responders.

The numbers in context

Not detailed in available abstract — the key finding is the independence of the two pathways.

How the study worked

Randomized, controlled human provocation trial. Administered PACAP38 to trigger migraine with and without CGRP pathway blockade. Assessed migraine occurrence, characteristics, and CGRP independence.

Who was studied

Migraine patients in an experimental provocation study

What this study cannot tell us

Human provocation model — PACAP38-induced migraine may differ from spontaneous migraine. Sample size typical for provocation studies. Anti-PACAP drugs are still in early development.

How to read the evidence

Strong evidence: randomized controlled human provocation trial demonstrating CGRP independence of PACAP38-induced migraine.

When this study was published

Published in 2025. Landmark study identifying a new drug target for migraine beyond CGRP.

The bigger picture

This landmark finding means the migraine field needs to look beyond CGRP. Anti-PACAP drugs could become the next generation of migraine treatments, specifically helping patients who fail anti-CGRP therapy. Multiple neuropeptide pathways likely contribute to migraine, and targeting more than one could provide broader relief.

Questions still open

Will anti-PACAP drugs help the 30-40% of patients who fail anti-CGRP therapy?
Could combining anti-CGRP and anti-PACAP treatments provide synergistic migraine prevention?
Are there additional neuropeptide pathways beyond CGRP and PACAP that drive migraine?

Common questions

Why don't anti-CGRP drugs work for everyone?

This study reveals why — PACAP38 triggers migraine through a completely separate pathway. If your migraines are driven by PACAP rather than CGRP, anti-CGRP drugs won't block them. Anti-PACAP drugs are being developed for these patients.

What is PACAP38?

PACAP38 (pituitary adenylate cyclase-activating peptide) is a 38-amino-acid neuropeptide that causes blood vessel dilation and triggers migraine. It works independently of CGRP, meaning it represents a separate drug target for migraine prevention.

Read the original research

PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial.

The journal of headache and pain, 26(1), 79

View on PubMed ↗Publisher’s paper ↗

Citation

Al-Karagholi, Mohammad Al-Mahdi; Zhuang, Zixuan Alice; Beich, Signe; Ashina, Håkan; Ashina, Messoud. (2025). PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial.. The journal of headache and pain, 26(1), 79. https://doi.org/10.1186/s10194-025-02022-2