Peptide directoryBrain, hypothalamus & pituitary

PACAP-38

A neuropeptide of stress, migraine and neuron survival, the next target after CGRP.

Where it comes from

Made in
Hypothalamus, trigeminal and sympathetic ganglia, adrenal medulla, retina, gut, and immune cells
Sent out by
Stress through the sympathetic system; trigeminal activation; light to the retina’s clock pathway
Acts on
  • Adrenal medulla (the stress hormone output)
  • Cranial vessels and dura
  • Amygdala and hypothalamus
  • The suprachiasmatic nucleus
  • Neurons under threat

What it does

  • Carries sustained stress signals to the adrenal medulla and the brain’s fear circuits 1
  • Provokes migraine when infused, through vessels and mast cells, independently of CGRP 2
  • Protects neurons from injury; resets the body clock to light

In medicine

  • No medicine yet. An antibody against PACAP (bocunebart, Lu AG09222) reduced migraine days in a phase 2 trial in 2024 and again in a larger phase 2b trial in 2026; it has not reached phase 3 3
  • A PAC1 receptor antibody failed in phase 2, which points to the other receptors 4

Beyond the body’s own use

  • An infusion of PACAP-38 brings on a migraine-like attack in people who have migraine, the experiment that put it on the list of targets after CGRP 2
  • A PACAP and PAC1 variant is linked with post-traumatic stress disorder in women; that finding is genetic rather than therapeutic, and nothing has been built on it
  • Nothing containing PACAP is approved or obtainable outside the laboratory. The open question is whether blocking the peptide helps the people CGRP blockade does not, which is what the phase 2 trials were built around 3

Sources

  1. Miyata et al., Isolation of a novel 38-residue hypothalamic polypeptide that stimulates adenylate cyclase, Biochemical and Biophysical Research Communications 1989
  2. Schytz et al., PACAP38 induces migraine-like attacks in patients with migraine without aura, Brain 2009
  3. Ashina et al., A monoclonal antibody to PACAP for migraine prevention, New England Journal of Medicine 2024
  4. Ashina et al., A phase 2 trial of AMG 301, a PAC1 receptor antibody, for migraine prevention, Cephalalgia 2021

This card describes what a medicine is for and what the evidence says; it recommends nothing. Talk to your clinician about anything you read here.