PACAP-38
Evidence: CCognitive / Neuro
Evidence Snapshot
What this grade covers
Repeated controlled human administration studies establish substantial human pharmacology and migraine/headache-provocation biology. This does not establish therapeutic efficacy of administered PACAP-38.
Regulatory Context
PACAP-38 is an endogenous human neuropeptide studied in research and controlled human-challenge settings; it is not an FDA-approved drug. No subject-specific FDA regulatory action has been identified in the current source set, and the absence of FDA approval does not itself indicate that PACAP-38 is unsafe.
Research Takeaway
PACAP-38 is a mature bioactive peptide generated from the human ADCYAP1 precursor and is distinct from PACAP-27, another mature product of the same precursor.
Evidence boundary: Shared precursor origin does not make PACAP-27 evidence automatically applicable to PACAP-38.
See all 6 evidence claims →Quick Summary
PACAP-38 is an endogenous human neuropeptide and one of two mature signaling peptides (alongside PACAP-27) produced from the ADCYAP1 precursor. Repeated randomized, placebo-controlled human challenge studies show that intravenous PACAP-38 reliably produces headache, provokes migraine-like attacks in migraine patients, and causes measurable vascular and cardiovascular effects. This body of evidence establishes human pharmacology and disease-relevant mechanism; it does not establish that administering PACAP-38 is a therapeutic treatment.
Mechanism & Research Overview
Controlled human challenge trials support a role for PACAP-38 signaling in migraine and headache pathophysiology: intravenous PACAP-38 has induced headache in nearly all studied subjects and migraine-like attacks in a substantial proportion of migraine patients, along with prolonged dilation of the middle meningeal artery and marked heart-rate increases. A head-to-head human study found that PACAP-38 and VIP, despite sharing overlapping receptor biology, produce different migraine-related and vascular responses. A 2025 trial found that blocking CGRP signaling with eptinezumab did not significantly reduce PACAP-38-induced migraine incidence, suggesting PACAP-38 acts through mechanisms at least partly independent of CGRP.
Evidence Claims
Individual scientific statements drawn from the sources cited below, each shown with the specific evidence boundary that statement does not establish.
Supported
PACAP-38 is a mature bioactive peptide generated from the human ADCYAP1 precursor and is distinct from PACAP-27, another mature product of the same precursor.
Does not establish
Evidence boundary: Shared precursor origin does not make PACAP-27 evidence automatically applicable to PACAP-38.
Sources: ADCYAP1 - Pituitary adenylate cyclase-activating polypeptide - Homo sapiens (Human)
Supported
Intravenous PACAP-38 has repeatedly produced measurable physiological effects in controlled human studies, including headache, vascular changes, and marked cardiovascular responses.
Does not establish
Evidence boundary: These are experimental human pharmacology findings, not evidence that PACAP-38 is a therapeutic treatment.
Sources: PACAP38 induces migraine-like attacks in patients with migraine without aura; Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers; The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers
Supported
Controlled human challenge studies support a role for PACAP-38 signaling in migraine and headache pathophysiology.
Does not establish
Evidence boundary: Provoking a disease-like phenotype establishes mechanistic relevance, not clinical benefit from administering PACAP-38.
Sources: PACAP38 induces migraine-like attacks in patients with migraine without aura; Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38; Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial; PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial
Supported
PACAP-38 and VIP can produce different migraine-related responses in humans despite overlapping receptor biology.
Does not establish
Evidence boundary: VIP is comparator evidence only and cannot substitute for PACAP-38-specific evidence.
Supported
Human PACAP-38 challenge studies have reported headache and significant transient physiological effects, including tachycardia and cranial vascular responses.
Does not establish
Evidence boundary: Small controlled challenge studies do not establish the safety of chronic, repeated, non-study, or vendor-supplied PACAP-38 use.
Sources: Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers; The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers
Supported
No regulatory claim is frozen beyond a neutral investigational/research status statement until a specific official regulatory source is supplied.
Does not establish
Evidence boundary: Do not infer safety or danger from absence of approval.
Safety & Evidence Limitations
Considerations reported in the sources cited on this page — not a complete list of every possible risk, and not medical advice.
Safety Consideration
In controlled challenge trials, intravenous PACAP-38 produced headache in nearly all healthy subjects and migraine patients, and triggered migraine-like attacks in a majority of migraine patients versus none after placebo.Safety Consideration
PACAP-38 has markedly increased heart rate and produced prolonged dilation of the middle meningeal artery in controlled human studies.Safety Consideration
All human PACAP-38 evidence comes from small, single-dose or short experimental challenge studies. Safety of repeated, chronic, or non-study use has not been established.
Research Areas Being Studied
Research areas discussed on this page reflect the Cognitive / Neuro category and the sources cited below.
Findings Reported in Studies
Educational summary only — reported in cited studies, not a claim of proven benefit.
- PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial (2025):
- Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial (2023):
- Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38 (2014):
- Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers (2012):
- PACAP38 induces migraine-like attacks in patients with migraine without aura (2009):
- The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers (2007):
Study Tables by Evidence Type
Human Studies & Clinical Data
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial | 2025 | 38 adults with migraine without aura; double-blind randomized eptinezumab vs placebo before PACAP-38 challenge | CGRP-ligand blockade with eptinezumab did not significantly reduce PACAP-38-induced migraine incidence, supporting partially independent PACAP signaling in this model. | ||
| Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trial | 2023 | 21 adults with persistent post-traumatic headache; randomized double-blind placebo-controlled crossover | 20/21 participants developed migraine-like headache after PACAP-38 versus 2/21 after placebo. | ||
| Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38 | 2014 | 24 female migraine patients; randomized double-blind crossover PACAP-38 vs VIP | Head-to-head human provocation study showed PACAP-38 and VIP differ in migraine-inducing and vascular effects despite biological relatedness. | ||
| Headache and prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers | 2012 | 14 healthy volunteers; randomized double-blind placebo-controlled study | PACAP-38 induced headache and prolonged middle meningeal artery dilation, without significant middle cerebral artery dilation. | ||
| PACAP38 induces migraine-like attacks in patients with migraine without aura | 2009 | 12 healthy subjects + 12 migraine patients; randomized double-blind crossover PACAP-38 vs placebo | PACAP-38 caused headache in all healthy subjects and 11/12 migraine patients; 7/12 migraine patients had migraine-like attacks after PACAP-38 and none after placebo. | ||
| The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers | 2007 | 12 healthy volunteers; crossover double-blind PACAP-38 vs placebo | PACAP-38 markedly increased heart rate; apparent cerebral blood-flow changes were largely explained by reduced end-tidal CO2, with no major direct effect on regional cerebral blood flow after correction. |
Animal / Cell / Preclinical Data
No Animal / Cell / Preclinical Data Listed Yet
This section will be updated as sources are added.
Regulatory Documents & Official Trial Registries
No Regulatory Documents & Official Trial Registries Listed Yet
This section will be updated as sources are added.
Review Articles / Secondary Sources
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| ADCYAP1 - Pituitary adenylate cyclase-activating polypeptide - Homo sapiens (Human) | Homo sapiens curated identity record | Human ADCYAP1 precursor; documents PACAP-27 and PACAP-38 as separate mature chains. | No source link available |
Anecdotal Reported Patterns — Not Medical Advice
Anecdotal Reported Patterns — Not Medical Advice
Reported dosing patterns are included for educational context only. They are self-reported, unverified, not medical advice, and not instructions for human use. Community-submitted patterns are not yet available in this Phase 1 prototype; this section is a placeholder reserved for moderated, aggregated community data.
Lab Markers to Discuss With a Clinician
Educational topics only — not self-monitoring instructions.
FAQ
Disclaimer
Educational information only. This page summarizes published and official research and does not provide medical advice, a recommendation, or instructions for human use.
Educational use only. This content is provided for informational and research-summary purposes only. It is not medical advice, not a treatment recommendation, not a dosing guide, and not a substitute for care from a licensed medical professional. Nothing here is intended to diagnose, treat, cure, prevent, or mitigate disease. Reported dosing patterns, when shown elsewhere on the site, must be labeled either as Study / Trial Dosing or Anecdotal Reported Patterns — Not Medical Advice. Community reports are self-reported, unverified, and not scientific proof.
Community-reported experiences, once enabled, must be displayed only as moderated, anonymized, or aggregated data. They are anecdotal, self-reported, unverified, and should never be presented as proof of safety, efficacy, or expected results.
Content status: Published. Last updated 2026-08-24.
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