PACAP
The neuropeptide that sets off migraine, and the new drugs that block it
PACAP, pituitary adenylate cyclase-activating polypeptide, is a natural neuropeptide. When researchers infuse it into people with migraine, many develop a migraine-like attack, and blocking CGRP does not stop it. That makes PACAP a separate route into migraine, and in 2024 an antibody against it reduced monthly migraine days in a phase 2 trial. PACAP itself is not a treatment.
What is it?
Migraine research has a useful tool: give a substance by infusion and see whether it provokes an attack in people who get migraines. CGRP passed that test, and drugs that block CGRP are now standard treatments. PACAP passes it too. In a randomised crossover study, PACAP-27 provoked migraine-like attacks in 55% of patients against 10% after placebo, and PACAP-38 does the same, making it one of the few molecules shown to trigger attacks in a controlled setting.
The key question was whether PACAP acts through CGRP. In a 2025 trial, 38 migraine patients received the CGRP antibody eptinezumab or placebo before a PACAP-38 infusion; attacks followed in 53% and 63%, a difference that was not significant. Blocking CGRP did not block PACAP, so the two can be targeted separately. Early sumatriptan did reduce PACAP-38-induced attacks, from 42% to 15%, and constricted the dilated temporal artery. Glibenclamide, a potassium-channel blocker, did not change PACAP-38 headache in healthy volunteers.
In cluster headache, PACAP-38 and VIP infusions provoke attacks in up to half of patients in an active phase, and those attacks came without changes in blood CGRP or mast-cell markers.
These findings led to drugs that block PACAP. In a 2024 phase 2 trial in 237 people, a single infusion of the antibody Lu AG09222 at 750 mg cut migraine days over four weeks by 6.2 a month against 4.2 with placebo. PACAP itself is used only as a research agent in these provocation studies; it is not sold or prescribed as a treatment.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Educational information, not medical advice. The doses on this page come from approved labels, published studies and, where no study exists, amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Published Research
Studies of PACAP, from their PubMed abstracts.
PACAP-38 attacks with CGRP blocked
In 38 migraine patients, PACAP-38-induced migraine attacks occurred in 10 of 19 after eptinezumab and 12 of 19 after placebo (P = 0.74), and headache intensity did not differ.
Sumatriptan and PACAP-38 migraine
Of 26 patients, 15% developed a PACAP-38-induced attack on sumatriptan versus 42% on placebo (p = 0.016); sumatriptan constricted the PACAP-38-dilated superficial temporal artery.
PACAP-27 provocation
PACAP-27 provoked migraine-like attacks in 11 of 20 patients (55%) versus 2 after placebo (10%; p = 0.022), with greater headache intensity and duration.
PACAP antibody for migraine prevention
In 237 participants, a single 750 mg infusion of the PACAP antibody Lu AG09222 reduced migraine days over weeks 1-4 by 6.2 versus 4.2 with placebo (difference -2.0; P = 0.02).
Glibenclamide and PACAP-38 headache
In 20 healthy volunteers, PACAP-38-induced headache occurred in 95% after glibenclamide and 90% after placebo (P = 0.698), with no difference in artery diameters or blood flow.
Provoked cluster headache attacks
In 44 cluster headache patients given PACAP-38 (10 pmol/kg/min) or VIP for 20 minutes, provoked attacks were not accompanied by changes in plasma CGRP, tryptase or histamine.
Side Effects & Contraindications
Reported Side Effects
From the infusion studies above, where provoking these effects was the point.
Contraindications & Cautions
There is no label; PACAP is a research agent.
Legal Status
PACAP is used only in research.
Frequently Asked Questions
?What is PACAP?
Pituitary adenylate cyclase-activating polypeptide, a natural neuropeptide that exists as PACAP-38 and a shorter PACAP-27. In research it is infused to provoke migraine and cluster headache attacks.
?Does PACAP cause migraine?
Infusing it provokes migraine-like attacks in many people with migraine, which is evidence it takes part in migraine. Whether it causes everyday attacks is still being studied.
?Is PACAP the same pathway as CGRP?
No. Blocking CGRP with eptinezumab did not stop PACAP-38 from triggering attacks, which is why PACAP-blocking drugs are being developed as a separate option.
?Is there a PACAP drug for migraine?
Not yet approved. The antibody Lu AG09222, which blocks PACAP, reduced migraine days in a 2024 phase 2 trial.
References
- [other] PubChem CID 91935803, PACAP-38: formula C203H331N63O53S, molecular weight 4534. Read October 3, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/91935803
- [fda] FDA. Drugs@FDA (openFDA): no application on record for PACAP. Read October 3, 2026.
- [clinical-trial] Al-Karagholi MA, et al. "PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial." J Headache Pain, 2025;26(1):79. PMID: 40229719.
- [clinical-trial] Wienholtz NKF, et al. "Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial." Cephalalgia, 2021;41(6):731-748. PMID: 33567890.
- [clinical-trial] Ghanizada H, et al. "PACAP27 induces migraine-like attacks in migraine patients." Cephalalgia, 2020;40(1):57-67. PMID: 31299857.
- [clinical-trial] Ashina M, et al. "A Monoclonal Antibody to PACAP for Migraine Prevention." N Engl J Med, 2024;391(9):800-809. PMID: 39231342.
- [clinical-trial] Kokoti L, et al. "Effect of K(ATP) channel blocker glibenclamide on PACAP38-induced headache and hemodynamic." Cephalalgia, 2022;42(9):846-858. PMID: 35301859.
- [pubmed] Pellesi L, et al. "PACAP38- and VIP-induced cluster headache attacks are not associated with changes of plasma CGRP or markers of mast cell activation." Cephalalgia, 2022;42(8):687-695. PMID: 34822741.
Sources & Citations
Studies were read from their PubMed records, October 3, 2026.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Consult a licensed healthcare provider before making health decisions.