CGRP, VIP, and PACAP-38 are all elevated in migraine patients, with highest levels in migraine with aura | Research

The takeaway

All three neuropeptides (CGRP, VIP, PACAP-38) were significantly elevated in 199 migraine patients versus 97 controls, with migraine-with-aura showing the highest levels and non-significant trends toward greater attack frequency and disability.

Three neuropeptides elevated
CGRP, VIP, and PACAP-38 are all significantly elevated in migraine patients, with migraine-with-aura showing the highest levels across all three

What the researchers found

All three neuropeptides (CGRP, VIP, PACAP-38) significantly elevated in migraine vs controls (p<0.001). MA > MO for all three. MA trends: higher attack frequency (p=0.06), HIT-6 (p=0.08). 296 participants.

Why it matters

While anti-CGRP drugs dominate migraine treatment, this study shows VIP and PACAP-38 are equally elevated. Multi-target approaches blocking multiple neuropeptides could provide better migraine control than single-target therapies.

How the study worked

Case-control study: 101 MA + 98 MO + 97 HC. Serum ELISA for CGRP, VIP, PACAP-38. Clinical assessment: attack frequency, HIT-6.

What this study cannot tell us

Serum levels may not reflect brain concentrations. Interictal measurements. Cross-sectional. Predominantly female sample. Effect sizes not detailed.

How to read the evidence

Case-control study with reasonable sample size. Good biomarker exploration but needs prospective validation.

When this study was published

Published in 2025.

The bigger picture

The migraine neuropeptide landscape extends well beyond CGRP. VIP and PACAP-38 may represent additional therapeutic targets, and multi-neuropeptide panels could serve as diagnostic biomarkers.

Questions still open

Would blocking VIP or PACAP-38 alongside CGRP improve migraine outcomes?
Can a multi-neuropeptide panel diagnose migraine subtypes?
Are these elevations cause or consequence of migraine attacks?

Common questions

Are there other neuropeptides involved in migraine besides CGRP?

Yes. This study confirmed that VIP and PACAP-38 are just as elevated as CGRP in migraine patients. All three were highest in people with migraine with aura. This suggests migraine involves multiple neuropeptide systems, not just CGRP.

Could targeting multiple neuropeptides treat migraine better?

Potentially. Since all three neuropeptides are elevated, blocking just CGRP (as current drugs do) may not be enough for all patients. Drugs targeting VIP or PACAP-38—or combinations—could provide additional relief, especially for patients who do not respond fully to anti-CGRP therapy.

Read the original research

Comparative Analysis of CGRP, VIP and  PACAP-38 Levels in Migraine with and  Without Aura: A Case-control Study.

Annals of neurosciences, 09727531251340156

View on PubMed ↗Publisher’s paper ↗

Citation

Sreevani, N; Ramesh, B; Maheshkumar, K; Thanalakshmi, J. (2025). Comparative Analysis of CGRP, VIP and  PACAP-38 Levels in Migraine with and  Without Aura: A Case-control Study.. Annals of neurosciences, 09727531251340156. https://doi.org/10.1177/09727531251340156