CGRP
CGRP; α-CGRP (CALCA gene, the same gene as calcitonin) and β-CGRP (CALCB); receptor is CLR paired with RAMP1 plus the intracellular protein CGRP-RCP
1What it is
CGRP is one of your own neuropeptides, discovered in 1982 as an unexpected product of the calcitonin gene: splice the CALCA transcript one way in the thyroid and you get calcitonin, splice it another way in neurons and you get CGRP.
It is found in sensory nerves throughout the body and is, weight for weight, the most powerful vasodilator of small blood vessels in humans. In the trigeminal system it does something more specific: released from trigeminal nerve endings around the meningeal vessels, it dilates them, sensitises the nerve, and transmits a pain signal. That sequence is now understood to be the core of a migraine attack.
The evidence chain here is unusually clean, and it is worth laying out because it is rare in neuroscience. CGRP rises in jugular blood during a migraine attack. Infusing CGRP into people with migraine triggers an attack. Blocking CGRP or its receptor prevents and treats attacks. That chain produced the gepants and the anti-CGRP antibodies, the first genuinely mechanism-based migraine drugs.
As with substance P (#158), this is a profile about a molecule you want less of. Community use: essentially none documented — exogenous CGRP causes headache and flushing, which is the opposite of what anyone would seek.
2How it's thought to work
3What the research shows
CGRP infusion triggers migraine
Elevated CGRP during attacks
Gepants (small-molecule receptor antagonists)
Anti-CGRP monoclonal antibodies
Cluster headache
Long-term safety of blocking the pathway
CGRP as a therapy (rather than a target)
4Reported side effects and interactions
Literature-reported
Literature (the peptide). CGRP infusion causes facial flushing, a feeling of heat, a fall in blood pressure, tachycardia and headache — including provoked migraine. These are its pharmacological actions.
Literature (the blockers, for context). Gepants — nausea, somnolence, dry mouth; nasal discomfort and dysgeusia with zavegepant. Antibodies — injection-site reactions, constipation (sometimes severe with erenumab), hypertension (erenumab label), and rare hypersensitivity. Constipation and raised blood pressure are the two that most often change management.
Community-reported
None for the peptide. Not in self-directed use.Theoretical. Giving exogenous CGRP would be expected to provoke headache and hypotension. The more interesting theoretical question runs the other way — what sustained removal of a protective vasodilator does over decades.
Interactions. Gepants are CYP3A4 substrates, so strong CYP3A4 inhibitors and inducers matter clinically; rimegepant and ubrogepant have specific co-administration restrictions on their labels. The antibodies, being proteins, have essentially no CYP-mediated interactions — one of their practical advantages.
Markers researchers commonly monitor
The monitoring here belongs to the blockers in clinical use, not to the peptide:
| Marker | Why it's watched |
|---|---|
| Monthly migraine days and headache days | the primary endpoint in every trial and the practical measure of whether a preventive is working; a headache diary is the instrument. |
| Blood pressure | hypertension was added to the erenumab label after post-marketing reports; worth checking at baseline and after starting. |
| Bowel function | constipation is common with erenumab and occasionally severe; a symptom to ask about rather than a test. |
| Liver enzymes (ALT/AST) | historically relevant because telcagepant failed on hepatotoxicity; not routinely required for the current gepants, but the reason the class is watched. |
| Acute medication use days | tracked to detect medication-overuse headache, which is the main confounder in migraine management. |
| Plasma or jugular CGRP | research assays only; not a clinical test and not usable to guide treatment. |
Free for everyone. Safety information is never behind a paywall.
5Reconstitution and handling
Not applicable as a consumer practice for the peptide: human CGRP is prepared as a sterile infusion for experimental provocation studies under monitoring, and its effects are deliberately unpleasant. No vial format, no community practice, no calculator preset. The approved blockers are conventional prescription products — oral tablets or orally disintegrating tablets (gepants), a nasal spray (zavegepant), prefilled autoinjectors stored refrigerated (erenumab, fremanezumab, galcanezumab) and an intravenous infusion given quarterly (eptinezumab) — and should be handled per their labels.
6Commonly studied alongside
Substance P (#158 — co-released from the same sensory fibres), adrenomedullin (#151) and amylin (shared receptor family and accessory proteins), PACAP (the other migraine-provoking peptide and the target of the next wave of migraine drugs), triptans as the prior standard of acute care.
Informational cross-links. Not stack recommendations.
7Regulatory status by region
| Region | Status (checked —) |
|---|---|
| United States | The peptide: not FDA-approved, research use only. Blockers approved: erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), eptinezumab (Vyepti), ubrogepant (Ubrelvy), rimegepant (Nurtec ODT), atogepant (Qulipta), zavegepant (Zavzpret) |
| European Union | Peptide not authorised. Erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant and atogepant are EMA-authorised; ubrogepant and zavegepant EU status should be checked † |
| United Kingdom | Peptide not licensed. The antibodies and rimegepant/atogepant are MHRA-licensed with NICE guidance on use after prior preventives have failed † |
| Australia | Peptide not approved. Galcanezumab, erenumab, fremanezumab and some gepants are TGA-registered, with PBS listing conditions † |
| South Africa | Peptide not registered. Availability of the anti-CGRP antibodies should be confirmed with SAHPRA † |
| Sport | CGRP is not listed by WADA, and neither the gepants nor the anti-CGRP antibodies are prohibited. Exogenous CGRP, as an unapproved peptide, would fall under S0 |
8Open questions
- What are the long-term cardiovascular consequences of blocking a protective vasodilator for years, particularly in people with vascular disease who were excluded from the trials?
- Is CGRP blockade safe in pregnancy? Data are minimal and the antibodies have long .
- Why do roughly a third of patients not respond, and can responders be predicted?
- How do CGRP and PACAP pathways relate, and will blocking both do better than either?
- Does CGRP have a therapeutic role of its own in Raynaud's or pulmonary vascular disease, or is the half-life insurmountable?
9References
- 1Amara SG et al. (1982). Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature. PubMed · DOI
- 2Goadsby PJ, Edvinsson L, Ekman R (1990). Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. PubMed · DOI
- 3Lassen LH et al. (2002). CGRP may play a causative role in migraine. Cephalalgia. PubMed · DOI
- 4Goadsby PJ et al. (2017). A controlled trial of erenumab for episodic migraine (STRIVE). NEJM. PubMed · DOI
- 5Lipton RB et al. (2019). Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. NEJM. PubMed · DOI
- 6Dodick DW et al. (2018). Effect of fremanezumab compared with placebo for prevention of episodic migraine. JAMA. PubMed · DOI
- 7Edvinsson L, Haanes KA, Warfvinge K, Krause DN (2018). CGRP as the target of new migraine therapies — successful translation from bench to clinic. Nat Rev Neurol. PubMed · DOI
† Being confirmed by our reviewers against current sources.
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Self-reported side effects Phase 2
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