Pain & nerve

PACAP-38

Also called Pituitary adenylate cyclase-activating polypeptide 38, PACAP38, PACAP (1-38), ADCYAP1

PACAP-38 is a natural nerve peptide, closely related to VIP, that widens blood vessels and acts on nerves in the head. Given by IV drip in research studies, it reliably causes headache and sets off migraine-like attacks in many people with migraine. Because of this, it is used as a research tool, and drugs that block PACAP are being tested to prevent migraine. PACAP-38 itself is not a treatment.

Early human dataSome small human studies exist; evidence is limited.

New · under editorial review. Added October 31, 2026 by our automated research, with every claim sourced. A person has not checked this page yet; treat it with extra care. How we research

Drawn from its published sequence: 38 residues, one bead each.

Overview

How it works

Established: PACAP-38 switches on three related receptors, the PAC1 receptor and the VIP receptors VPAC1 and VPAC2, which raise cAMP inside cells ³⁴. Its first part is 68% similar to VIP, but it was at least 1000 times more potent at stimulating adenylate cyclase in pituitary cells ⁴. It is found in sensory (trigeminal) and parasympathetic nerve fibers around blood vessels and is a strong vasodilator ¹. Proposed: PACAP-38 triggers migraine much more often than VIP, even though both dilate arteries outside the skull. Researchers think this is because PACAP-38 binds the PAC1 receptor far more strongly, and they point to longer-lasting artery widening and higher blood PACAP-38 before attacks ². In lab and animal work it also protects nerve cells and affects insulin release ³.

What research shows

Human randomized double-blind crossover provocation study (12 healthy people, 12 migraine patients; IV infusion vs placebo): headache in all healthy subjects and 11 of 12 patients; 7 of 12 patients had migraine-like attacks after PACAP-38 vs none after placebo, mostly about 6 hours later ¹.
Human randomized double-blind crossover study (24 women with migraine without aura, 22 completed): migraine-like attacks in 73% after PACAP-38 vs 18% after VIP; both widened arteries outside the skull, but PACAP-38's effect lasted over 2 hours ².
Human mechanism study (25 healthy volunteers): the anti-PACAP antibody Lu AG09222 blocked PACAP-38-induced artery widening, faster heart rate and mild headache ⁵.
Phase 2 RCT of anti-PACAP antibody (n=237, hard-to-treat migraine): a single 750 mg infusion of Lu AG09222 cut monthly migraine days by 6.2 vs 4.2 on placebo over 4 weeks ⁶.
Phase 2b PROCEED, intravenous part (431 patients in 14 countries, 1-4 previous preventive treatments failed): intravenous bocunebart met the main goal of a greater fall in monthly migraine days than placebo over weeks 1-12, with no new safety signals; company data, with full results not yet published ⁷⁹.
PACAP-38 itself has not been tested as a treatment in people; its human use is as a research trigger for migraine ¹².

Doses studied in people

Study or label	Dose used	Source
Migraine provocation study (research tool used to trigger an attack under medical supervision, not a treatment), 12 healthy subjects and 12 migraine patients	10 pmol/kg/min PACAP-38 by IV infusion vs placebo	¹
Migraine provocation study vs VIP (research tool used to trigger an attack, not a treatment), 24 women with migraine without aura (22 completed)	10 pmol/kg/min PACAP-38 by IV infusion over 20 minutes (VIP 8 pmol/kg/min as comparator)	²

Both figures are research infusion rates used to deliberately provoke headache and migraine attacks in a hospital setting, so that the attacks could be studied. They are not treatment doses, and PACAP-38 has no approved or therapeutic use.

Read this first: these are the amounts given to participants in published studies or written on official prescribing labels, reported for reference. They are not recommendations. Trial doses were chosen for specific patients under medical supervision, and a dose that is safe in one person can be harmful in another.

Vial math

Many research vials hold 5 or 10 mg of powder. This table shows how much ends up in each mark on a U-100 insulin syringe for common amounts of added liquid. It is arithmetic only, not a dose.

Vial	Liquid added	Concentration	Per unit (0.01 mL)
5 mg	1 mL	5 mg/mL	50 mcg	Open in calculator
5 mg	2 mL	2.5 mg/mL	25 mcg	Open in calculator
5 mg	3 mL	1.67 mg/mL	16.7 mcg	Open in calculator
10 mg	1 mL	10 mg/mL	100 mcg	Open in calculator
10 mg	2 mL	5 mg/mL	50 mcg	Open in calculator
10 mg	3 mL	3.33 mg/mL	33.3 mcg	Open in calculator

More sizes: all vial sizes · How this works: Syringes and units · Reconstitution guide.

Safety

IV PACAP-38 caused headache in all 12 healthy volunteers and 11 of 12 migraine patients, and delayed migraine-like attacks in 7 of 12 patients ¹.
In a second study, 73% of women with migraine had a migraine-like attack after the infusion ².
It widens arteries outside the skull for more than 2 hours and raises heart rate ²⁵.
No data on repeated use or long-term safety in people; it is not used as a therapy ¹².

Report side effects of any drug or product to the FDA through MedWatch. For a possible poisoning in the US, call Poison Control at 1-800-222-1222.

Legal status

FDA: Not FDA-approved; used only as an investigational research agent in human provocation studies ¹². Antibodies that block PACAP (e.g. bocunebart) are investigational ⁷.
Compounding: Not on FDA's 503A bulk drug substances categories list (Categories 1-3, updated May 14, 2026) ⁹¹.
Sports (WADA): Not named on the 2026 WADA Prohibited List. The list's S0 class covers any substance with no current approval by any government health authority for human therapeutic use, and is prohibited at all times ⁹⁰. PACAP-38 has no such approval, so on our reading it would fall under S0 — this is our interpretation of the published list, not a WADA ruling on this peptide.
Other: Not approved as a medicine in any country, based on the sources reviewed ⁶⁷.
Sold online: PACAP-38 is also sold online as an unregulated "research" peptide. These products are not the clinical-grade material used in trials and have unknown purity, dose and contents. US law requires a new drug to be shown safe and effective before it is marketed, and FDA notes that for unapproved products there is no way to know whether the label is complete and accurate ⁹². FDA has separately warned sellers of weight-loss peptides that labelling a product "for research purposes" or "not for human consumption" does not change its status when it is in fact sold for human use ⁹⁴. PACAP-38 is notable because in controlled human studies infusing it reliably caused headache and set off migraine-like attacks ¹². No FDA warning letter, import alert or anti-doping notice naming PACAP-38 specifically was found.

Rules change often. See Legal status of peptides for how these categories work.

History

Miyata, Arimura and colleagues isolated PACAP-38 from sheep hypothalamus and reported it in 1989, naming it for its ability to stimulate adenylate cyclase in pituitary cells ⁴. In 2009, a Copenhagen team (Schytz, Ashina, Olesen and colleagues) showed that an IV infusion caused headache in healthy people and delayed migraine-like attacks in migraine patients ¹; the later head-to-head study describes the same rate given over 20 minutes ². A 2014 head-to-head study found it triggered migraine far more often than VIP ². This led to drugs that block PACAP: Lundbeck's antibody Lu AG09222 (bocunebart) blocked PACAP-38's effects in volunteers ⁵, cut migraine days in a phase 2 trial published in 2024 ⁶, and met the main goal of the intravenous part of the phase 2b PROCEED trial, announced by the company on February 12, 2026 ⁷ and presented in June 2026 ⁹.

Common questions

Is PACAP-38 a migraine treatment?

No, the opposite. Given by IV infusion, it triggers headache and migraine-like attacks, so researchers use it to study migraine ¹². Drugs that block PACAP are the ones being tested as treatments ⁶.

What are anti-PACAP drugs?

They are antibodies that grab PACAP and stop it from working. Lundbeck's Lu AG09222 (bocunebart) cut migraine days in a phase 2 trial ⁶ and the intravenous part of its phase 2b PROCEED trial met its main goal, per company announcements in 2026 ⁷⁹.

How is PACAP-38 different from VIP?

They are closely related, but PACAP-38 triggered migraine in 73% of patients vs 18% for VIP in a head-to-head study, possibly because it binds the PAC1 receptor much more strongly ².

Is PACAP-38 banned in sport?

It is not named on the 2026 WADA list. The S0 class covers substances with no current approval anywhere for human therapeutic use and is banned at all times ⁹⁰; on our reading PACAP-38 fits that description, but WADA has not ruled on it.

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Sources

Last reviewed 2026-10-31 · How we research · Found an error? See our corrections policy.