PACAP38 Triggers Migraine Independently of CGRP: A New Peptide Pathway Discovered
Randomized trial showed PACAP38-induced migraine attacks occur independently of CGRP signaling, revealing a separate neuropeptide pathway that anti-CGRP drugs cannot block.
Quick Facts
What This Study Found
PACAP38-induced migraine attacks were not blocked by CGRP signaling inhibition, demonstrating an independent neuropeptide migraine pathway that represents a new drug target.
Key Numbers
Not detailed in available abstract — the key finding is the independence of the two pathways.
How They Did This
Randomized, controlled human provocation trial. Administered PACAP38 to trigger migraine with and without CGRP pathway blockade. Assessed migraine occurrence, characteristics, and CGRP independence.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- CGRP-independent migraine PACAP38 triggers migraine through a pathway that anti-CGRP drugs cannot block — revealing a new target for non-responding patients
- Evidence Grade:
- Strong evidence: randomized controlled human provocation trial demonstrating CGRP independence of PACAP38-induced migraine.
- Study Age:
- Published in 2025. Landmark study identifying a new drug target for migraine beyond CGRP.
- Original Title:
- PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial.
- Published In:
- The journal of headache and pain, 26(1), 79 (2025)
- Authors:
- Al-Karagholi, Mohammad Al-Mahdi(3), Zhuang, Zixuan Alice, Beich, Signe, Ashina, Håkan, Ashina, Messoud
- Database ID:
- RPEP-09824
Evidence Hierarchy
Frequently Asked 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 More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-09824APA
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
MLA
Al-Karagholi, Mohammad Al-Mahdi, et al. "PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial.." The journal of headache and pain, 2025. https://doi.org/10.1186/s10194-025-02022-2
RethinkPeptides
RethinkPeptides Research Database. "PACAP38-induced migraine attacks are independent of CGRP sig..." RPEP-09824. Retrieved from https://rethinkpeptides.com/research/al-karagholi-2025-pacap38induced-migraine-attacks-are
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.