What is PACAP and why is it important in neuroscience?

PACAP (Pituitary Adenylate Cyclase-Activating Peptide) is a highly conserved neuropeptide with potent neuroprotective, neuromodulatory, and anti-inflammatory properties. It is important in neuroscience because it influences numerous brain functions including neuroprotection, stress responses, circadian rhythms, and pain signalling. Its role in migraine has led to the development of anti-PACAP antibodies as novel migraine preventive therapies.

How is PACAP related to migraines?

PACAP-38 infusion reliably triggers migraine-like attacks in migraine-susceptible individuals, establishing it as a key migraine mediator alongside CGRP. PACAP causes vasodilation of cranial blood vessels, activates trigeminal pain pathways, and promotes neurogenic inflammation in the meninges. Anti-PACAP and anti-PAC1 receptor antibodies are being developed as migraine preventive treatments, similar to the successful anti-CGRP antibody class.

Is PACAP used as a treatment for any condition?

No. PACAP itself is not used therapeutically due to its extremely short half-life (3–5 minutes), potent vasodilatory effects, and ability to trigger migraines. However, its biology is being exploited therapeutically in reverse — anti-PACAP and anti-PAC1 receptor antibodies are in clinical trials as migraine preventive therapies. PACAP's neuroprotective properties are also being explored for potential applications in neurodegenerative diseases, though these remain in early research stages.

What is the difference between PACAP-38 and PACAP-27?

PACAP-38 and PACAP-27 are both derived from the same precursor gene. PACAP-38 (38 amino acids) is the predominant form in mammalian tissues, whilst PACAP-27 (the N-terminal 27 amino acids) is present in lower quantities. Both forms activate all three PACAP/VIP receptors (PAC1, VPAC1, VPAC2), but PACAP-38 shows somewhat greater potency at the PAC1 receptor and has additional C-terminal residues that may influence receptor binding kinetics and biological activity.

Does PACAP play a role in stress and anxiety?

Yes. PACAP is a key mediator of the stress response. It is released during stress and acts at multiple levels — stimulating CRH release from the hypothalamus, enhancing ACTH secretion, and promoting catecholamine production in the adrenal glands. In the amygdala, PACAP/PAC1 signalling is involved in fear conditioning and anxiety behaviours. Dysregulation of the PACAP system has been linked to post-traumatic stress disorder (PTSD) and anxiety disorders in human genetic studies.

Fact-checked by the Peptide Authority Editorial Board · Last reviewed: 25 September 2026

Corrected 25 September 2026: The PACAP-38 migraine study summary said attacks occurred in "15% of healthy controls". Per the trial abstract (Schytz et al., Brain 2009), migraine-like attacks occurred in 2 of 12 (17%) healthy subjects, only during the infusion/hospital phase (not delayed, unlike the migraine-patient attacks). The summary has been rewritten to match.

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Neuropeptides•Updated 2026-09-25•7 min read

What Is PACAP (Pituitary Adenylate Cyclase-Activating Peptide)? Benefits, Research & Safety

A highly conserved neuropeptide with 38 or 27 amino acid forms, researched for neuroprotection, stress response modulation, circadian rhythm regulation, immune modulation, and involvement in migraine pathophysiology.

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Also known as:

PACAP-38

PACAP-27

Pituitary Adenylate Cyclase-Activating Polypeptide

ADCYAP1

BModerate human evidenceUK: Sold as 'research only' (UK)WADA: Sport status unclear

UK summary: Endogenous neuropeptide. Research on PACAP is informing migraine drug development (anti-PACAP antibodies are in late-stage trials). Native PACAP is not a UK medicine.

Quick Facts

Overview

PACAP (Pituitary Adenylate Cyclase-Activating Peptide) is a pleiotropic neuropeptide belonging to the VIP (vasoactive intestinal peptide)/secretin/glucagon superfamily. It exists in two biologically active forms: PACAP-38 (38 amino acids, the predominant form in mammals) and PACAP-27 (the N-terminal 27-amino-acid fragment). First isolated from ovine hypothalamus in 1989, PACAP is one of the most highly conserved peptides in evolution, with over 90% amino acid identity across vertebrate species — suggesting critical biological functions. PACAP is widely distributed throughout the central and peripheral nervous systems, as well as in non-neuronal tissues including the adrenal glands, gastrointestinal tract, immune system, reproductive organs, and cardiovascular system. It functions as both a neurotransmitter and a neuromodulator, exerting effects through three G-protein-coupled receptors: PAC1 (PACAP-specific), VPAC1, and VPAC2 (shared with VIP). The peptide has garnered significant research interest across multiple domains. In neuroscience, PACAP is studied for its potent neuroprotective effects against excitotoxicity, oxidative stress, and ischaemic damage. In migraine research, PACAP has emerged as a key mediator, with intravenous PACAP-38 reliably inducing migraine-like attacks in susceptible individuals. In immunology, it functions as an endogenous anti-inflammatory agent. In chronobiology, PACAP plays a role in circadian rhythm entrainment through its action in the suprachiasmatic nucleus. PACAP is an endogenous peptide and a subject of active research. It is not approved as a therapeutic agent, and synthetic PACAP is used solely in research settings. Information presented here is for educational purposes.

Evidence standards summary

PACAP (Pituitary Adenylate Cyclase-Activating Peptide) — evidence and risk at a glance

Twenty standard modules scored against the Peptide Authority evidence grading methodology. Missing modules indicate the field has not yet been characterised editorially — treat absences as uncertainty rather than reassurance.

01Evidence snapshot

BModerate human evidenceOverall grade against our evidence grading methodology.

Endogenous neuropeptide. Research on PACAP is informing migraine drug development (anti-PACAP antibodies are in late-stage trials). Native PACAP is not a UK medicine.

02Human evidence grade

BModerate human evidenceStrength of evidence from published human trials.

03Preclinical evidence grade

AStrong human evidenceAnimal-model and in-vitro evidence quality.

04Regulatory status

UK: Not licensed for any therapeutic indication. Used exclusively as a research tool. Anti-PACAP antibodies are in clinical development for migraine.
EU: Not authorised for therapeutic use. Research compound only. Anti-PACAP/PAC1 receptor antibodies under clinical investigation.
Notes: PACAP itself is not being developed as a therapeutic agent due to its extremely short half-life and pleiotropic effects. The primary translational application is the development of anti-PACAP and anti-PAC1 receptor monoclonal antibodies for migraine prevention, analogous to the successful anti-CGRP antibody approach. Several pharmaceutical companies have programmes in this area.

05Approved medical uses

None in the UK or EU as a finished medicine. (Or: not yet documented; treat as absence rather than approval.)

06Unapproved / promotional claims

PACAP supplements treat migraine.
PACAP injection treats depression.

07Common internet claims

Sold by some research-peptide vendors as 'migraine-pathway peptide' (paradoxical — IV PACAP triggers migraines).

08Claim vs evidence

Claim	Evidence	Human evidence?	Regulatory concern	Safer wording
“PACAP supplements relieve migraine”	E	No	High	Paradoxically, IV PACAP triggers migraines in susceptible people; therapeutic development targets PACAP-blocking antibodies, not supplementation.

09Safety uncertainty score

Moderate

Safety profile partly characterised; some signals from observational or preclinical data.

10Known adverse signals

IV PACAP TRIGGERS migraines in susceptible individuals — therapeutic development targets PACAP-blocking antibodies, not PACAP supplementation.

11Drug-interaction uncertainty

Moderate

Some interaction data published; check with a prescriber for your specific medicines.

12Anti-doping status

WADA: Sport status unclearWADA strict-liability framing applies.

13UK legal position

UK: Sold as 'research only' (UK)

Not licensed for any therapeutic indication. Used exclusively as a research tool. Anti-PACAP antibodies are in clinical development for migraine.

Read the full UK legal guide → Research peptides and UK law

14EU legal position

Not authorised for therapeutic use. Research compound only. Anti-PACAP/PAC1 receptor antibodies under clinical investigation.

15What this page cannot tell you

Whether grey-market 'PACAP' contains the labelled compound.
Long-term safety of exogenous PACAP signalling in healthy adults.

16Last reviewed

Last reviewed: 25 September 2026

Next review due: 25 September 2027

Spotted an error or something out of date? Send a correction.

17Citation quality score

AStrong human evidenceQuality of the sources we cite, graded against the evidence grading methodology.

18Research gaps

Anti-PACAP antibody Phase 3 trials in migraine are the productive direction; native-PACAP therapeutic use is essentially non-viable.

19Safer alternatives / established care pathways

NICE CG150 / NG217 migraine pathway via GP / neurology.
Anti-CGRP antibodies (NICE-approved) for chronic migraine after preventive failures.

20Doctor discussion prompts

Questions to ask a qualified clinician

These are starter questions you can adapt for a GP, specialist, pharmacist, or anti-doping advisor. The aim is to help you have a better-informed conversation — not to replace one.

What licensed UK migraine treatments should I consider, and are anti-PACAP antibodies an option?

Discovery & History

PACAP was first isolated in 1989 by Professor Akira Arimura and colleagues at Tulane University in New Orleans, Louisiana. The peptide was identified from ovine hypothalamic tissue extracts based on its ability to stimulate adenylate cyclase activity in rat anterior pituitary cell cultures — hence its name. The 38-amino-acid form (PACAP-38) was characterised first, followed shortly by the identification of the 27-amino-acid form (PACAP-27). The gene encoding PACAP (ADCYAP1) was subsequently cloned, revealing that PACAP is produced as a larger precursor protein (prepro-PACAP) that is processed to yield the mature peptides. The remarkable evolutionary conservation of PACAP became apparent as homologues were identified across vertebrates from fish to humans, with sequence identity exceeding 90%. This extraordinary conservation — unusual even among neuropeptides — pointed to essential physiological functions. Throughout the 1990s and 2000s, the three PACAP receptors (PAC1, VPAC1, VPAC2) were identified and characterised, each with distinct tissue distributions and signalling properties. The PAC1 receptor, which shows high selectivity for PACAP over VIP, was found to be particularly abundant in the brain. Research expanded rapidly into diverse areas including neuroprotection (demonstrating that PACAP could protect neurons from a wide range of insults), stress biology (revealing PACAP's role as a stress-response mediator), migraine (showing that PACAP infusion triggers migraine attacks), circadian regulation (establishing PACAP's role in light-dark cycle entrainment), and immune modulation (characterising its anti-inflammatory properties). The migraine field has been particularly productive, with anti-PACAP antibodies entering clinical trials as novel migraine preventive therapies, representing a direct translational application of basic PACAP research.

Mechanism of Action

PACAP exerts its diverse biological effects through a complex receptor signalling network and multiple downstream pathways: **Receptor Binding and Signalling** PACAP activates three G-protein-coupled receptors with distinct pharmacological profiles: - **PAC1 receptor** — selective for PACAP (binds PACAP with ~1000-fold higher affinity than VIP). Highly expressed in the brain, adrenal medulla, and sensory ganglia. Signals through multiple pathways including Gs (cAMP/PKA), Gq (PLC/IP3/Ca²⁺), and MAPK cascades. - **VPAC1 receptor** — binds PACAP and VIP with equal affinity. Expressed in the brain, lungs, liver, and immune cells. Primarily signals through Gs/cAMP. - **VPAC2 receptor** — also binds PACAP and VIP equally. Expressed in the brain (particularly suprachiasmatic nucleus), smooth muscle, and immune tissues. Signals through Gs/cAMP. **Neuroprotective Mechanisms** PACAP's neuroprotective effects involve multiple complementary pathways: - Upregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL) and suppression of pro-apoptotic factors (Bax, caspases) - Activation of the PI3K/Akt survival pathway - Stimulation of neurotrophic factor expression (BDNF, NT-3) - Reduction of excitotoxic glutamate signalling - Antioxidant effects through upregulation of superoxide dismutase and glutathione pathways **Stress Response Modulation** PACAP is released during stress and modulates the hypothalamic-pituitary-adrenal (HPA) axis: - Stimulates CRH (corticotropin-releasing hormone) release from the hypothalamus - Enhances ACTH secretion from the anterior pituitary - Acts directly on adrenal chromaffin cells to promote catecholamine synthesis and release - Modulates fear conditioning and anxiety-related behaviours via amygdala PAC1 receptors **Migraine Pathophysiology** PACAP's role in migraine involves: - Vasodilation of cerebral and meningeal blood vessels - Activation of trigeminal sensory neurons and trigeminovascular pain pathways - Mast cell degranulation and neurogenic inflammation in the meninges - Central sensitisation through effects on second-order trigeminal neurons **Circadian Rhythm Regulation** PACAP is released from retinal ganglion cells projecting to the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract, where it modulates photic entrainment of the circadian clock through PAC1 and VPAC2 receptor signalling. **Immune Modulation** PACAP acts as an endogenous anti-inflammatory agent by: - Inhibiting production of pro-inflammatory cytokines (TNF-α, IL-6, IL-12) - Promoting production of anti-inflammatory cytokines (IL-10) - Shifting macrophage polarisation toward the M2 reparative phenotype - Modulating T-cell differentiation and function

Researched Benefits

Based on preclinical and clinical research findings:

1
Potent neuroprotective effects against excitotoxicity, oxidative stress, and ischaemic brain injury in extensive preclinical models
2
Anti-inflammatory properties through modulation of cytokine production and macrophage polarisation
3
Circadian rhythm regulation through retinohypothalamic tract signalling to the suprachiasmatic nucleus
4
Stress response modulation through HPA axis and sympathoadrenal system regulation
5
Potential therapeutic target in migraine — anti-PACAP antibodies are in clinical trials as migraine preventives
6
Neurotrophic factor stimulation including BDNF upregulation
7
Cardioprotective effects observed in models of myocardial ischaemia
8
Potential roles in neurodegenerative disease protection (Alzheimer's, Parkinson's models)

Claim vs Evidence

How popular claims about PACAP (Pituitary Adenylate Cyclase-Activating Peptide) stack up against the current research, graded using our public evidence grading methodology.

Claim	Evidence	Human evidence?	Regulatory concern	Safer wording
“PACAP supplements relieve migraine”	E	No	High	Paradoxically, IV PACAP triggers migraines in susceptible people; therapeutic development targets PACAP-blocking antibodies, not supplementation.

Theoretical Dosing & Protocols

⚠️ Educational Only: The following information is derived from research literature and is not a prescription or recommendation. No standardised human dosing exists. Always consult a qualified healthcare professional.

Theoretical Dosage	Research doses vary widely by application; intravenous infusion of 10–20 pmol/kg/min used in migraine provocation studies
Frequency	Variable depending on research application; not established for therapeutic use
Duration	Acute infusion studies (minutes to hours); chronic administration protocols not well established in humans
Notes	PACAP is used exclusively as a research tool and is not available for therapeutic use. Its very short plasma half-life (~3–5 minutes for PACAP-38) and pleiotropic effects make therapeutic application challenging. The primary translational interest is in developing anti-PACAP or anti-PAC1 antibodies for migraine prevention, rather than administering PACAP itself. No therapeutic protocols exist.

Administration Routes

Routes studied in research settings (educational only):

Intravenous infusion (research and migraine provocation studies)
Intracerebroventricular injection (preclinical neuroscience research)
Intranasal administration (investigated in limited research for CNS delivery)

Half-Life	Stability
Approximately 3–5 minutes for PACAP-38 in plasma (rapidly degraded by dipeptidyl peptidase-IV); PACAP-27 has a slightly shorter half-life	Highly susceptible to enzymatic degradation, particularly by DPP-IV; lyophilised form should be stored at -20°C; reconstituted solution requires immediate use or storage at -80°C

Safety Profile & Known Risks

Commonly Reported Side Effects

Facial flushing and warmth (vasodilatory effect, very common with IV infusion)
Headache and migraine induction (well-documented in migraine-susceptible individuals)
Palpitations and transient tachycardia
Nausea during intravenous infusion
Transient hypotension due to vasodilation

Rare Risks & Concerns

Severe migraine attacks in susceptible individuals following IV administration
Theoretical concerns regarding chronic PACAP manipulation affecting stress responses and immune function
Unknown effects of long-term exogenous PACAP administration
Potential cardiovascular effects at higher doses

Contraindications

History of migraine (PACAP infusion reliably triggers attacks in migraine sufferers)
Cardiovascular instability or significant hypotension
Pregnancy and breastfeeding (no safety data for exogenous administration)
Known hypersensitivity to PACAP or related peptides
Active brain tumours (neuropeptide effects on tumour biology not fully characterised)

UK & EU Regulatory Context

🇬🇧 United Kingdom

Not licensed for any therapeutic indication. Used exclusively as a research tool. Anti-PACAP antibodies are in clinical development for migraine.

🇪🇺 European Union

Not authorised for therapeutic use. Research compound only. Anti-PACAP/PAC1 receptor antibodies under clinical investigation.

PACAP itself is not being developed as a therapeutic agent due to its extremely short half-life and pleiotropic effects. The primary translational application is the development of anti-PACAP and anti-PAC1 receptor monoclonal antibodies for migraine prevention, analogous to the successful anti-CGRP antibody approach. Several pharmaceutical companies have programmes in this area.

Clinical Studies Summary

PACAP-38 Induces Migraine-Like Attacks in Migraine Patients

Study (n=12 migraine patients, n=12 healthy subjects) demonstrating that intravenous infusion of PACAP-38 induced migraine-like attacks in 7 of 12 (58%) migraine patients versus none after placebo (P=0.016), mostly with delayed onset (mean 6 hours post-infusion, range 2-11). Migraine-like attacks also occurred in 2 of 12 (17%) healthy subjects, but only during the infusion/hospital phase, not delayed — establishing PACAP as a key mediator in migraine pathophysiology.

Brain. 2009View on PubMed

Registered Trials & Regulatory Status

Registered trials

Currently recruiting

Furthest phase

Phase 1

Approved product

10 of 11 completed trials have never posted results. Unreported trials are not neutral: results that go unpublished are more often negative ones.

Induction of Migraine Attacks With Aura Using Pituitary Adenylate Cyclase Activating Polypeptide-38

Status: Not Yet Recruiting · 21 participants · Danish Headache Center

Conditions: Migraine With Aura, Migraine Aura

No results postedNCT07342296

The Effect of Interventional Procedures on Serum CGRP and PACAP-38 Levels in Chronic Migraine

Status: Active Not Recruiting · 100 participants · Aydin Adnan Menderes University

Conditions: Chronic Migraine Headache, Radiofrequency Ablation, Greater Occipital Nerve Block

No results postedNCT07395908

Migraine Induction Properties of PACAP-38 After Eptinezumab in Migraine Without Aura Patients.

Status: Completed · 38 participants · Danish Headache Center

Conditions: Migraine

No results postedNCT05635604

Hypersensitivity to PACAP-38 in Post-Traumatic Headache

Status: Unknown · 21 participants · Danish Headache Center

Conditions: Post-Traumatic Headache

No results postedNCT05378061

The Hemodynamic Effects of PACAP38 After Glibenclamide Administration in Healthy Volunteers

Status: Completed · 22 participants · Danish Headache Center

Conditions: Migraine, Headache, Pain

No results postedNCT04960657

PACAP38 Induced Headache and Rosacea-like Symptoms in Patients With Rosacea

Status: Completed · 38 participants · Danish Headache Center

Conditions: Rosacea

No results postedNCT03878784

The Role of Inflammation and Vasodilatation in PACAP38-induced Headache Using MRI on Healthy Subjects

Status: Completed · 34 participants · Danish Headache Center

Conditions: Headache

No results postedNCT03585894

PACAP38 Induced Headache, Migraine and Flushing in Patients With Migraine

Status: Completed · 37 participants · Danish Headache Center

Conditions: Migraine Without Aura

No results postedNCT03881644

The Effect of PACAP27 on the Extra- and Intracerebral Arteries Assessed by Magnetic Resonance Angiography (MRA) on Healthy Volunteers

Status: Completed · 18 participants · Danish Headache Center

Conditions: Headache, Migraine

No results postedNCT03560024

PACAP-38 Infusion in Patients With Cluster Headache

Status: Unknown · 45 participants · Danish Headache Center

Conditions: Cluster Headache

No results postedNCT03814226

PACAP27 Headache Properties in Migraine Without Aura Patients

Status: Completed · 20 participants · Danish Headache Center