CGRP, or calcitonin gene-related peptide, is a small protein made up of 37 amino acids that is released by sensory nerves throughout your body. Its most well-known job is dilating blood vessels, and it does this with remarkable potency, even at extremely tiny concentrations. CGRP has become a major focus in medicine because of its central role in migraine, and an entire class of medications now exists to block it.
What CGRP Does in the Body
CGRP comes in two nearly identical forms, alpha and beta, which differ by only three amino acids in humans. Both are produced from genes on chromosome 11 and share similar biological effects. The alpha form is generated through an interesting quirk of genetics: the same gene that makes calcitonin (a hormone involved in calcium regulation) can be spliced differently to produce CGRP instead.
The peptide’s primary home is in sensory nerve fibers, the same nerves responsible for detecting pain, temperature, and touch. When these nerves are activated, they release CGRP into surrounding tissue. Once released, CGRP powerfully widens blood vessels, increases blood flow, and plays a role in wound healing and cardiovascular protection. It also participates in pain signaling, which is where its connection to migraine begins.
How CGRP Drives Migraine Attacks
During a migraine, CGRP levels in the blood and saliva rise measurably. The connection runs through the trigeminal nerve, a major nerve that carries sensation from your face and head. When the trigeminal system becomes activated, it releases CGRP in two key locations: around blood vessels in the protective membranes covering the brain (the meninges) and in the brainstem where pain signals are processed.
In the meninges, CGRP triggers what’s called neurogenic inflammation. It causes blood vessels to dilate and promotes the release of other inflammatory molecules, which sensitize the surrounding tissue and amplify pain. In the brainstem, CGRP excites pain-processing neurons directly, helping to establish the sustained, throbbing headache that defines a migraine. These elevated CGRP levels correlate with pain intensity, and reducing them helps stop or prevent attacks.
People with chronic migraine (15 or more headache days per month) tend to have higher baseline CGRP levels than those with episodic migraine, and both groups typically have higher levels than people who don’t get migraines at all. One study found that chronic migraine patients averaged about 75 pg/ml of CGRP in their blood between attacks, compared to roughly 46 pg/ml in episodic migraine patients and 34 pg/ml in healthy controls. This suggests CGRP isn’t just elevated during attacks but may stay elevated in people whose migraines are more frequent.
Medications That Target CGRP
The discovery of CGRP’s role in migraine led to two distinct classes of medication: monoclonal antibodies (injections or infusions given monthly or quarterly) and gepants (oral pills taken as needed or daily). Both aim to shut down CGRP signaling, but they do it differently and are used in different situations.
Monoclonal Antibodies
Four monoclonal antibodies are FDA-approved for migraine prevention:
- Erenumab (Aimovig), approved May 2018, at doses of 70 mg or 140 mg monthly
- Fremanezumab (Ajovy), approved September 2018, at 225 mg monthly
- Galcanezumab (Emgality), approved September 2018, at 120 mg monthly
- Eptinezumab (Vyepti), approved February 2020, given as an intravenous infusion
These antibodies fall into two camps based on what they target. Three of them (fremanezumab, galcanezumab, and eptinezumab) bind to the CGRP molecule itself, essentially soaking it up before it can reach its receptor. Erenumab takes the opposite approach, blocking the CGRP receptor so the peptide has nowhere to land. This distinction matters clinically: some patients who don’t respond to one type may respond when switched to the other, likely because the two approaches affect slightly different signaling pathways inside cells.
Galcanezumab also holds a separate FDA approval for preventing episodic cluster headaches, making it the first drug ever specifically approved for that condition.
Gepants (Oral CGRP Blockers)
Gepants are small-molecule pills that block the CGRP receptor. Three are currently FDA-approved:
- Ubrogepant (Ubrelvy), approved December 2019, for acute migraine treatment and prevention
- Rimegepant (Nurtec ODT), approved February 2020 for acute treatment and May 2021 for prevention
- Atogepant (Qulipta), approved September 2021, developed exclusively for migraine prevention
The gepants filled an important gap because they gave patients an oral option. Rimegepant is notable for being approved both as a treatment you take during a migraine and as a daily preventive, offering flexibility depending on how often attacks occur.
What Treatment Looks Like
If you’re prescribed a monoclonal antibody, the typical approach involves monthly self-injections at home (or quarterly infusions for eptinezumab). Doctors generally evaluate whether the treatment is working after about 12 weeks. European guidelines recommend continuing therapy beyond 12 to 18 months when it’s clearly helping, and long-term studies have tracked patients through three years of use.
Gepants work faster for people who need relief during an attack. Ubrogepant and rimegepant can be taken at the onset of a migraine. Atogepant is taken daily as a preventive. Unlike triptans, which are the older class of acute migraine medications, gepants don’t constrict blood vessels, which made them an appealing option for people with cardiovascular risk factors who couldn’t safely take triptans.
Cardiovascular Safety
Because CGRP is a powerful blood vessel dilator with protective cardiovascular effects, blocking it raised reasonable concerns about heart and blood vessel safety. If you remove something that keeps blood vessels relaxed, could that lead to high blood pressure, heart attacks, or circulation problems?
So far, the data is reassuring. A cohort study of Medicare beneficiaries, a population that skews older and includes people with disabilities, found no increased risk of cardiovascular events, hypertensive crisis, circulation problems requiring procedures, or Raynaud phenomenon (a condition where fingers and toes lose blood flow in the cold) when comparing CGRP antibodies to Botox injections, another common migraine preventive. These findings are encouraging, though they reflect a population that has only been studied over a limited timeframe.
Beyond Migraine
CGRP’s role in the body extends well past headache. Its vasodilating properties appear to protect the cardiovascular system under stress, and it plays a part in wound healing by increasing blood flow to damaged tissue. CGRP is also involved in how your body responds to heat and inflammatory pain, since the sensory nerves that release it are the same ones activated by capsaicin, the compound that makes chili peppers burn. This connection to sensory nerve function means CGRP research touches on pain conditions broadly, though migraine remains the area where targeting it has proven most useful in clinical practice.