PACAP-38
Pituitary Adenylate Cyclase-Activating Polypeptide-38 (PACAP38; PACAP-38; ADCYAP1; pituitary adenylate cyclase-activating peptide 1-38)
PACAP-38 is an endogenous 38-amino-acid neuropeptide that activates PAC1, VPAC1, and VPAC2 receptors, playing a central role in migraine pathophysiology, neuroprotection, and vasodilation. It is the predominant endogenous form (~90% of total PACAP) and is a validated migraine trigger in human provocation studies (PMC5815979, PMC11998216).
Last updated: 2026-03-13
Safety Summary
The acute safety profile of PACAP-38 is dominated by its potent vasodilatory and headache-inducing properties. In the largest published RCT (n=38), PACAP-38 infusion at 10 pmol/kg/min over 20 minutes induced mild-to-moderate headache in ~79-84% of participants and migraine-like attacks in a majority of migraine-susceptible individuals (PMC11998216). Flushing, warmth, and palpitations are near-universal during infusion. No treatment-related serious adverse events (SAEs) have been reported in PACAP-38 peptide infusion challenge studies, though these studies are small (n=6-45) (PMC11998216;). Mast cell degranulation mechanisms are implicated in headache responses, though cluster headache attacks induced by PACAP-38 were not associated with changes in plasma CGRP or mast cell activation markers (IHS podcast;). For PACAP-pathway therapeutics (anti-PACAP antibodies, distinct from the peptide itself): isolated SAEs include one B-cell lymphoma in the LY3451838 program (causality not established, PMID 40836866) and one sympathetic posterior cervical syndrome in the Lu AG09222 Phase II study (PMC10210362). No tolerance, tachyphylaxis, or withdrawal effects have been documented. No formal carcinogenicity studies exist. Long-term safety data (>6 months) are not available. PACAP-38 is an endogenous peptide with low immunogenicity risk when administered exogenously.
Known Side Effects
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Who Should NOT Use This
PACAP-38 reliably induces migraine-like attacks in 58-73% of migraine patients. Exogenous administration in migraine-susceptible individuals will likely trigger attacks (PMC11998216; PMC5815979)
PACAP-38 causes significant vasodilation, tachycardia (HR increase up to 62%), and palpitations. Cardiovascular effects suggest caution in patients with cardiac disease, though no formal contraindications have been established
PACAP-38 infusion can provoke cluster headache attacks in susceptible patients (NCT03814226; PMC12465007)
Clinical trials excluded pregnant women. No pregnancy exposure data or pregnancy-category labeling exists (NCT05635604 exclusion criteria;)
Talk to Your Doctor
Before considering PACAP-38, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-10]
Evidence Assessment
PACAP-38 itself has been used in multiple Phase I-equivalent human provocation/challenge studies (n=12-45 per trial) demonstrating consistent physiological effects (migraine induction, vasodilation) but has never been developed as a therapeutic drug product. No Phase II or Phase III trials exist for PACAP-38 as a treatment. The clinical trials that exist (NCT03814226, NCT05635604, NCT05378061, NCT02364453, NCT00380263) are mechanistic provocation studies, not efficacy trials for a therapeutic indication. Anti-PACAP antibodies (separate agents targeting the PACAP pathway) have reached Phase 2b (Lu AG09222/bocunebart by Lundbeck, NCT05133323, n=237) but these are distinct molecules, not PACAP-38 itself. Evidence tier 4 reflects limited human data as a challenge agent with no therapeutic development.
1PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trialNCT05635604PMID 40229719
Al-Karagholi et al. - The Journal of Headache and Pain (2025) - Randomized controlled trial (double-blind, placebo-controlled, parallel-group) - 38
PACAP-38 infusion induced migraine-like attacks in 53% of eptinezumab-pretreated subjects vs 63% placebo (p=0.74), demonstrating PACAP-38-induced migraine is independent of CGRP signaling. Headache occurred in 79-84% of participants. Validates PACAP as a distinct therapeutic target from CGRP.
Limitations: Small sample size (n=38). Single-dose design. Short observation period.
2Hypersensitivity to PACAP-38 in post-traumatic headache: a randomized clinical trialNCT05378061
Not specified in raw data - Brain (2024) - Randomized clinical trial - 21
PACAP-38 induced migraine-like attacks in 95% of post-traumatic headache patients vs 10% placebo, demonstrating extreme hypersensitivity to PACAP-38 in PTH.
Limitations: Very small sample size (n=21). Specific to post-traumatic headache population.
3PACAP38 induces migraine-like attacks in patients with migraine without auraNCT00380263PMID 19220306
Schytz et al. - Brain (2009) - Randomized, double-blind, placebo-controlled crossover - 12
PACAP-38 infusion induced migraine-like attacks in 58% of migraine patients vs 0% placebo. Demonstrated delayed migraine onset hours after infusion. Established PACAP-38 as a migraine provocateur.
Limitations: Very small sample size (n=12). Single-center study.
4The effect of Lu AG09222 on PACAP38- and VIP-induced vasodilation, heart rate increase, and headache in healthy subjectsNCT04976309PMID 37231350
Not specified in raw data - Cephalalgia (2023) - Interventional, randomized, double-blind, parallel-group, placebo-controlled - 25
Lu AG09222 (anti-PACAP mAb) blocked PACAP-38-induced vasodilation, heart rate increase, and headache in healthy subjects. Proof-of-mechanism for PACAP-targeting therapy. One SAE (sympathetic posterior cervical syndrome) reported.
Limitations: Healthy volunteers only (n=25). Single-dose. Short follow-up.
5Lu AG09222 (bocunebart) Phase 2b HOPE trial in treatment-resistant migraineNCT05133323
Lundbeck (sponsor) - Press release / Conference presentation (2026) - Phase 2b randomized, double-blind, placebo-controlled - 237
Single IV dose of 750 mg Lu AG09222 reduced monthly migraine days by -6.2 vs -4.2 placebo (difference -2.0 days, 95% CI -3.5 to -0.6, p=0.01) over weeks 1-4. Largest therapeutic trial targeting PACAP pathway to date.
Limitations: Single-dose design. Short primary endpoint window (4 weeks). Treatment-resistant population may limit generalizability. Industry-sponsored (Lundbeck). Full peer-reviewed publication pending.
6Preclinical and clinical evaluation of LY3451838, a PACAP-neutralizing monoclonal antibody, in randomized, double-blind, placebo-controlled phase 1 and phase 2 studiesPMID 40836866
Johnson MP, Krikke-Workel J, Patel CN, et al. - Cephalalgia (2025) - Phase 1 and Phase 2, randomized, double-blind, placebo-controlled - 38 (Phase 2)
LY3451838 (Eli Lilly anti-PACAP mAb) did not meet primary efficacy endpoint in treatment-resistant migraine (CM -4.7 vs -3.0; EM -1.7 vs -1.2 MMD reduction, not significant). One case of B-cell lymphoma reported (causality not established). ADA rate 5.6%, no neutralizing antibodies.
Limitations: Small Phase 2 (n=38). Treatment-resistant population. Program discontinued or de-prioritized.
7Safety, Tolerability and Pharmacokinetics of ALD1910 in Healthy Men and WomenNCT04197349
Alder BioPharmaceuticals (sponsor) - ClinicalTrials.gov (2020) - Phase 1, safety/PK - 96
Phase 1 safety and PK study of ALD1910 (anti-PACAP antibody). Trial completed. Mixed/negative proof-of-concept results reported.
Limitations: Phase 1 only. Full results not publicly published in peer-reviewed literature.
8PACAP-38 Infusion in Patients With Cluster HeadacheNCT03814226
Danish Headache Center (sponsor) - ClinicalTrials.gov (2019) - Interventional, randomized crossover - 45
PACAP-38 infusion in cluster headache patients to assess physiological and clinical responses. Published results in PMC12465007 confirm PACAP-38 as a prospective case-control study target in cluster headache.
Limitations: Status unknown/ongoing. Limited published results.
9To Evaluate the Blockade of CGRP in Preventing PACAP-38 Induced Migraine-like AttacksNCT02542605
Not specified - ClinicalTrials.gov (2015) - Phase 1, double-blind, randomized, placebo-controlled, crossover - 35
Evaluated whether CGRP blockade prevents PACAP-38-induced migraine attacks. Completed. Results inform the understanding that PACAP and CGRP pathways are independent.
Limitations: Small sample size.
10A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention
Amgen (sponsor) - PMC7786389 (2021) - Phase 2, randomized, double-blind, placebo-controlled - Not specified in raw data
AMG 301 (anti-PAC1 receptor mAb by Amgen) failed to show benefit in migraine prevention. Program discontinued.
Limitations: Negative trial. Program terminated.