CGRP (Calcitonin Gene-Related Peptide): The Migraine Connection

Key Takeaways

• Biomarker identity: A 37-amino-acid neuropeptide produced in trigeminal ganglion cells, dorsal root ganglia, and perivascular sensory nerve terminals; widely expressed throughout the peripheral nervous system.
• Condition link: Plasma CGRP levels rise significantly during migraine attacks and return to baseline after successful treatment, supporting a causal role in migraine pathophysiology rather than merely correlational status.
• Elevated in: Migraine patients during attacks, cluster headache patients, individuals with post-traumatic headache, and individuals with other chronic pain disorders involving sensitized sensory pathways.
• Drug classes targeting it: Anti-CGRP monoclonal antibodies (targeting the CGRP ligand or its receptor) and CGRP receptor antagonists known as gepants (small-molecule oral agents). As of April 2026, four monoclonal antibodies and four gepants are FDA-approved for episodic or chronic migraine.
• Testing: Plasma CGRP testing is available in research settings; it is not yet a standard clinical diagnostic panel. No Superpower test currently exists for CGRP as a routine clinical biomarker.
• As of April 2026: Four anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) and four gepants (rimegepant, ubrogepant, atogepant, zavegepant) are FDA-approved for episodic or chronic migraine prevention or acute treatment.

What CGRP Is

CGRP (calcitonin gene-related peptide) is a 37-amino-acid neuropeptide that functions primarily as a vasodilator and sensory signaling molecule in the peripheral nervous system. It is among the most potent endogenous vasodilators in the cerebrovascular system. CGRP is encoded by the CALC1 gene through alternative splicing of the calcitonin gene — the same gene that encodes calcitonin — and belongs to the calcitonin peptide family, which also includes adrenomedullin and amylin.

Molecular identity

Alpha-CGRP (αCGRP), the predominant isoform in the trigeminal system, is a 37-amino-acid peptide encoded by the CALC1 gene on chromosome 11. A second isoform, beta-CGRP (βCGRP), is encoded by the CALC2 gene and is expressed primarily in the enteric nervous system and sensory neurons of the dorsal root ganglia. The two isoforms share 94% amino acid sequence identity but differ in their regional distribution and relative abundance in headache-relevant neural circuits.

Where it comes from

CGRP is stored in dense-core secretory vesicles within the terminals of small-diameter sensory neurons. In the context of migraine, the critical source is the trigeminal ganglion — a cluster of sensory neurons whose fibers innervate the meningeal blood vessels, including the dural sinuses and middle meningeal artery. These perivascular trigeminal fibers release CGRP in response to neuronal activation. CGRP is not a continuously circulating hormone at high concentrations under normal physiological conditions; it is released episodically from nerve terminals on stimulation. Eftekhari, Warfvinge, Blixt, and Edvinsson, in a 2013 paper in The Journal of Pain, mapped CGRP fibers in the trigeminovascular system in detail, providing the anatomical map for understanding where therapeutic blockade acts.

What it does in the body under normal conditions

Under physiological conditions, CGRP serves protective and regulatory functions. Its potent vasodilatory action maintains microvascular tone in peripheral tissues and provides ischemic protection to the heart. It plays roles in thermoregulation, wound healing, bone remodeling, and sensory signal modulation in the gut. Benemei and colleagues, in a 2009 review in Current Opinion in Pharmacology, reviewed CGRP receptors in pain and inflammation, noting that CGRP functions as a neuromodulator that amplifies pain signaling under pathological conditions, even though it serves important homeostatic roles under normal conditions. This dual nature — protective under physiological conditions, amplifying pain under pathological activation — helps explain why blocking CGRP in migraine has not produced the cardiovascular harms once anticipated. Post-marketing safety monitoring for cardiovascular effects is ongoing, particularly in patients with pre-existing cardiovascular disease.

CGRP and Migraine: What the Science Shows

Migraine affects approximately 1 in 7 adults, based on data summarized by Ashina in a 2020 review in The New England Journal of Medicine. Ashina describes migraine as a complex neurological disorder involving dysfunction in sensory processing, pain modulation, and autonomic regulation — with CGRP occupying a central position in the pathophysiological cascade. Ashina 2020 also documents that women experience migraine approximately three times as often as men, with peak prevalence between ages 25 and 55. The mechanism by which CGRP drives migraine is now understood in considerable molecular detail.

Trigeminovascular activation: the triggering event

Migraine begins with activation of the trigeminovascular system — the sensory nerve network connecting meningeal blood vessels to the brainstem's trigeminal nucleus caudalis. What triggers this activation varies between individuals and may include cortical spreading depolarization (the electrical wave underlying migraine aura), environmental or metabolic triggers acting on sensitized peripheral nociceptors, or central brainstem disinhibition. Once activated, these neurons release CGRP from their perivascular terminals into the meningeal tissue. Iyengar, Ossipov, and Johnson, in a 2017 paper in Pain, described CGRP's role in pain mechanisms, establishing the two-tier mechanism that explains why migraine can be both throbbing (peripheral) and associated with widespread sensory hypersensitivity (central).

What CGRP does once released: vasodilation and neurogenic inflammation

Released CGRP binds to the CLR/RAMP1 receptor heterodimer on meningeal blood vessel smooth muscle and on neurons throughout the trigeminovascular system. This binding triggers profound vasodilation of the meningeal arteries, increases vascular permeability, and activates mast cells to release additional inflammatory mediators. Benemei and colleagues in 2009 described how CGRP receptor activation on sensory neurons amplifies pain signal transmission, contributing to the pulsating quality of migraine pain. The dilation of meningeal arteries and the activation of perivascular nociceptors together produce the characteristic throbbing headache. Wattiez, Sowers, and Russo, in their 2020 review in Expert Opinion on Therapeutic Targets, identified CGRP as the primary pain mediator.

Causality evidence: CGRP as a driver, not just a marker

The causal role of CGRP in migraine is supported by several lines of evidence that go beyond correlation. Plasma CGRP concentrations have been shown in human studies to rise during spontaneous migraine attacks and to decline after successful abortive treatment, a finding that helped establish CGRP as a migraine-specific biomarker. A complementary line of evidence comes from the CGRP infusion model: administering exogenous CGRP intravenously triggers migraine-like attacks in migraine patients but not in healthy controls, as reviewed by Wattiez, Sowers, and Russo in 2020. This asymmetric biological response — patients are sensitized to CGRP in ways controls are not — provides direct evidence for CGRP's causal role rather than mere secondary elevation.

Central sensitization: why attacks escalate and become chronic

Repeated peripheral CGRP release, if not resolved, can drive central sensitization — a progressive lowering of the pain threshold in central trigeminal pathways. Once central sensitization is established, allodynia (pain from normally non-painful stimuli) and heightened sensory sensitivity persist beyond the acute attack. Iyengar, Ossipov, and Johnson in 2017 described this amplification loop as the mechanism underlying the transition from episodic to chronic migraine, noting that each attack may lower the threshold for the next. Emerging safety data on combining CGRP inhibitors is discussed later in this article (see Alsaadi 2024).

Extension to related conditions

CGRP's role in pain signaling extends beyond migraine. Edvinsson, writing in Headache in 2018, documented CGRP's involvement in cluster headache and related primary headache disorders. Emerging research suggests CGRP pathway involvement in persistent post-traumatic headache, though the clinical evidence base in that setting remains limited.

Who Has Elevated CGRP Levels

A 2020 systematic review and meta-analysis in Headache analyzed serotonin and neuropeptides in blood from episodic and chronic migraine and cluster headache patients, documenting consistently elevated plasma CGRP in migraine patients during attacks. Elevated interictal plasma CGRP levels have been reported in chronic migraine patients compared with controls in multiple observational studies. Plasma CGRP has been investigated as a potential biomarker for migraine diagnosis and therapeutic response, including in pediatric populations, suggesting the marker's utility extends to younger populations.

Demographic factors associated with elevated CGRP and migraine risk include female sex (as noted above, migraine is approximately three times more prevalent in women than men per Ashina 2020), hormonal fluctuations (estrogen has been shown to modulate CGRP release and may contribute to the perimenstrual migraine pattern observed in many women), genetic predisposition, and stress exposure. Non-disease factors that may transiently elevate CGRP include vigorous exercise, heat exposure, and certain dietary compounds — though these are typically transient elevations rather than the sustained release associated with migraine attacks.

Some observational research, synthesized in the 2020 Headache systematic review, has reported elevated interictal CGRP levels in chronic migraine patients (15 or more headache days per month) compared with controls, though this remains an area of ongoing investigation, and direct head-to-head comparative benefit between chronic and episodic populations is not established.

How CGRP Is Measured

CGRP is measurable in plasma using immunoassay-based techniques (enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay platforms). Samples are typically collected in EDTA plasma tubes, processed promptly, and stored frozen to prevent degradation. Plasma CGRP concentrations are low under baseline conditions — typically in the picomolar range — and rise measurably during migraine attacks.

Despite its scientific utility, plasma CGRP testing is not yet a standard clinical diagnostic for migraine. It is used primarily in research settings and clinical trials. CGRP's potential as a clinical biomarker for diagnosis and treatment monitoring has not yet been translated into routine clinical use due to challenges in assay standardization and reference range establishment across populations. At present, the diagnosis of migraine and the assessment of treatment response rely on clinical criteria rather than biomarker measurement. Plasma CGRP testing is not currently available as a routine clinical panel through Superpower.

Reference ranges vary by assay platform and individual characteristics. Provider interpretation in clinical context is always required.

Drug Classes That Target CGRP

Two distinct classes of medications have been developed to block CGRP signaling in migraine. Both were designed based on the biology described in the sections above: if CGRP drives migraine by activating meningeal nociceptors and triggering central sensitization, blocking either the peptide itself or its receptor should interrupt the cascade. Tepper, in a 2018 historical review in Headache, traced CGRP discovery to approved drugs, documenting the decades of translational research that connected the basic science to therapeutic applications.

Anti-CGRP monoclonal antibodies

Anti-CGRP monoclonal antibodies are large protein molecules designed to bind either the CGRP peptide directly or its receptor (the CLR/RAMP1 heterodimer), preventing CGRP from activating the signaling cascade that drives migraine. Administered by subcutaneous injection (monthly or quarterly, self-administered) or intravenous infusion (quarterly, clinic-administered), they have durations of action measured in weeks due to the pharmacokinetics of antibody clearance. This sustained blockade makes them suitable as preventive therapies rather than acute treatments. As of April 2026, four monoclonal antibodies are FDA-approved: erenumab (targets the receptor), fremanezumab and galcanezumab (target the CGRP ligand), and eptinezumab (targets the CGRP ligand, administered intravenously). FDA has described these therapies collectively as a new drug class with a novel mechanism for migraine.

In phase 3 randomized controlled trials summarized in the 2022 European Headache Federation guideline by Sacco and colleagues in The Journal of Headache and Pain, anti-CGRP antibodies reduced monthly migraine days compared with placebo across both episodic and chronic migraine populations. European Headache Federation clinical guidelines, updated by Sacco and colleagues in 2022 in The Journal of Headache and Pain, now recognize anti-CGRP monoclonal antibodies as first-line preventive therapies for appropriate migraine patients. A 12-week trial period is typically recommended before assessing therapeutic response. Common adverse effects at the class level include injection site reactions, constipation, and fatigue. Barbanti and colleagues, in a 2022 multicenter prospective study in The Journal of Headache and Pain, reported efficacy in chronic migraine with medication overuse — a clinically important secondary benefit in patients who have overused acute medications.

Gepants (CGRP receptor antagonists)

Gepants are small-molecule oral CGRP receptor antagonists that bind the CLR/RAMP1 receptor heterodimer reversibly, blocking CGRP from activating it. Unlike monoclonal antibodies, their reversible binding and short half-life make them suitable for acute treatment — taken at the onset of a migraine attack. Some gepants have also received FDA approval for preventive use with regular dosing. First-generation CGRP receptor antagonists (telcagepant, olcegepant) showed promising efficacy in trials but were discontinued due to hepatotoxicity signals observed in longer-duration studies. The approved second-generation gepants have not demonstrated the same hepatotoxicity, as reviewed by Rissardo and Caprara in a 2022 narrative review in Brain Sciences. Rissardo and Caprara describe rimegepant, ubrogepant, and zavegepant with their respective efficacy and safety profiles in detail.

As of April 2026, four gepants are FDA-approved: rimegepant (approved for both acute treatment and prevention), ubrogepant (acute treatment), atogepant (prevention), and zavegepant (acute treatment, nasal spray formulation). Caronna and colleagues, in a 2024 chapter in Handbook of Clinical Neurology, reviewed monoclonal antibodies and gepants as the two established drug classes in the anti-CGRP treatment landscape.

Combination and sequencing

The question of whether anti-CGRP monoclonal antibodies and gepants can be used together has been addressed in emerging safety data. Berman and colleagues, in a 2020 paper in Headache, found combination use was generally well-tolerated in observational data. Alsaadi and colleagues, writing in Neurology and Therapy in 2024, reviewed safety of combined use and found no major safety signals in the available evidence. As of April 2026, combination use is not established as standard first-line management but may be considered in appropriate patients under specialist supervision. This approach should not be interpreted as a general recommendation.

Which Biomarkers Are Worth Testing?

Plasma CGRP testing is not yet a standard clinical panel. But several adjacent biomarkers provide useful context for individuals experiencing migraine or considering anti-CGRP therapies, particularly when ruling out other conditions that produce headache or when assessing broader neurological and inflammatory health.

• TSH (Thyroid-Stimulating Hormone)
  • What it shows: Thyroid function; both hypothyroidism and hyperthyroidism can produce or worsen headache disorders.
  • Why it is relevant: Thyroid dysfunction is one of the most common secondary causes of worsened migraine frequency; ruling it out is an important step in the workup of refractory or escalating migraine.
• hs-CRP (High-Sensitivity C-Reactive Protein)
  • What it shows: Systemic low-grade inflammation, which may intersect with neuroinflammatory processes in migraine.
  • Why it is relevant: Elevated hs-CRP in a migraine patient may indicate a concurrent inflammatory condition contributing to symptom burden; baseline assessment informs clinical interpretation.
• HbA1c
  • What it shows: Average blood glucose control over approximately 3 months.
  • Why it is relevant: Glucose dysregulation and insulin resistance are associated with worsened migraine frequency; metabolic health assessment is a reasonable component of a comprehensive migraine evaluation.
• Complete Blood Count (CBC)
  • What it shows: Red blood cell counts, hemoglobin, white cells, and platelets.
  • Why it is relevant: Anemia — particularly iron deficiency anemia — is a known secondary contributor to headache disorders that is easily detected and addressed before attributing all symptoms to migraine.
• Ferritin
  • What it shows: Iron storage, and by extension, iron deficiency even before anemia develops.
  • Why it is relevant: Low ferritin is associated with increased headache frequency in some populations; correcting iron deficiency may reduce headache burden independently of migraine-specific treatment.

Reference ranges vary by lab and individual characteristics. Your provider will interpret your specific results in context.

Context for Understanding CGRP in Migraine

Because migraine involves CGRP dysregulation at multiple stages — trigeminovascular activation, meningeal vasodilation, neurogenic inflammation, and central sensitization — understanding the adjacent biology that can be measured provides a clearer picture than symptom tracking alone. Plasma CGRP itself is not yet a routine clinical test, but the biomarkers listed above can help rule out secondary contributors to headache, establish a metabolic and inflammatory baseline before any therapeutic decision, and provide objective reference points for interpreting future changes.

The principle underlying that approach is consistent with Superpower's approach to preventive health: objective data about your biological baseline — inflammation, metabolic function, thyroid status — should inform clinical decisions before any therapeutic intervention. In a headache disorder where multiple underlying contributors may exist, a measured baseline across relevant biomarkers is a more durable foundation for decision-making than symptom diaries alone.

IMPORTANT SAFETY INFORMATION

This article discusses drug classes that target CGRP at the class level for educational purposes only. Superpower Health does not prescribe, sell, or facilitate access to any of the medications described. The drug classes discussed — anti-CGRP monoclonal antibodies and gepants — are FDA-approved prescription medications that require evaluation and prescription by a licensed healthcare provider. This content does not constitute medical advice, diagnosis, or treatment recommendations.

Anti-CGRP monoclonal antibodies: As of April 2026, four anti-CGRP monoclonal antibodies are FDA-approved for the preventive treatment of episodic or chronic migraine in adults, administered by subcutaneous injection or intravenous infusion. Common adverse effects at the class level include injection site reactions, constipation, and fatigue. Not recommended during pregnancy; consult your provider.

Gepants (CGRP receptor antagonists): As of April 2026, four gepants are FDA-approved for acute migraine treatment and/or prevention in adults, administered orally (tablet) or intranasally (nasal spray). Common adverse effects at the class level include nausea and dizziness. Not recommended for patients with severe hepatic impairment; consult your provider about contraindications specific to each agent.

It does not replace consultation with a qualified clinician who can evaluate your individual health history, current medications, and clinical picture.

Disclaimer: IMPORTANT: This article discusses prescription drug classes targeting CGRP for educational purposes only. Superpower Health does not prescribe, sell, or facilitate access to anti-CGRP therapies. Always consult a qualified healthcare provider. This page is provided for educational and informational purposes only.