Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide that has emerged as one of the most important regulators of vascular, neurological, and inflammatory physiology.1 Initially identified in the early 1980s through alternative RNA splicing of the calcitonin (CALCA) gene, CGRP was first recognized for its potent vasodilatory properties.2 Subsequent research has demonstrated that CGRP is widely distributed throughout the central and peripheral nervous systems, particularly in sensory neurons of the dorsal root and trigeminal ganglia, where it acts as both a neurotransmitter and neuromodulator.3 Over the past four decades, advances in molecular biology, physiology, and clinical medicine have transformed the understanding of CGRP from a simple vasoactive peptide to a multifunctional signaling molecule involved in maintaining cardiovascular homeostasis, pain transmission, immune regulation, metabolism, and tissue repair.4

Under normal physiological conditions, CGRP contributes significantly to the maintenance of vascular tone and organ perfusion.5 It is considered one of the most potent endogenous vasodilators known, acting primarily through activation of the calcitonin receptor-like receptor (CLR) in association with receptor activity-modifying protein-1 (RAMP1).6 Activation of this receptor complex stimulates cyclic adenosine monophosphate (cAMP)-dependent signaling pathways, resulting in relaxation of vascular smooth muscle cells and improved blood flow.7 Beyond its vascular actions, CGRP participates in neurogenic communication by modulating synaptic transmission, sensory perception, and autonomic nervous system function.8 It also influences gastrointestinal motility, renal sodium excretion, pulmonary circulation, pancreatic hormone secretion, and bone remodeling, highlighting its diverse physiological roles across multiple organ systems.

The biological effects of CGRP extend beyond normal physiology into numerous pathological conditions.9 Dysregulation of CGRP signaling has been implicated in migraine, hypertension, ischemic heart disease, heart failure, stroke, diabetes mellitus, inflammatory disorders, chronic pain syndromes, and gastrointestinal diseases.10 Among these conditions, migraine has been the most extensively studied, where excessive release of CGRP from trigeminal sensory neurons induces vasodilation, neurogenic inflammation, and pain sensitization.11 The recognition of CGRP as a central mediator of migraine has revolutionized headache management through the development of highly specific monoclonal antibodies and small-molecule CGRP receptor antagonists (gepants), representing one of the most significant therapeutic advances in modern neuropharmacology.12 These clinical successes have stimulated growing interest in investigating the broader physiological and pathological significance of CGRP in other organ systems.

Recent evidence suggests that CGRP also serves as a critical link between the nervous, cardiovascular, endocrine, and immune systems.13 It regulates endothelial function by enhancing nitric oxide bioavailability, suppresses excessive inflammatory cytokine production, modulates oxidative stress, and influences interactions between immune cells and peripheral nerves.14 Conversely, impaired CGRP signaling may contribute to endothelial dysfunction, vascular stiffness, and chronic inflammation, thereby increasing susceptibility to cardiovascular and metabolic diseases.15 These findings have established CGRP as an important integrative molecule that coordinates communication between multiple physiological systems rather than functioning solely as a neurotransmitter.

Advances in molecular genetics, proteomics, receptor pharmacology, and translational medicine continue to reveal novel functions of CGRP in human health and disease. Emerging research indicates potential roles for CGRP in wound healing, tissue regeneration, cancer biology, host immune responses, aging, and neurodegenerative disorders. At the same time, the long-term physiological consequences of chronic CGRP inhibition remain an area of active investigation, particularly regarding cardiovascular protection and systemic homeostasis. These developments emphasize the need for a comprehensive understanding of CGRP biology from both physiological and pathophysiological perspectives.

This study aims to provide an updated overview of the molecular biology, receptor mechanisms, and physiological functions of CGRP, while critically examining its involvement in major human diseases. In addition, it highlights recent therapeutic advances targeting the CGRP pathway, discusses current knowledge gaps, and outlines future research directions that may facilitate the development of precision medicine strategies based on CGRP signaling. By integrating evidence from basic science and clinical research, this review presents CGRP as a multifunctional regulatory peptide with broad implications for human physiology and modern medical practice.

Study Design: A hospital-based comparative cross-sectional study was conducted over a period of 12 months to evaluate serum calcitonin gene-related peptide (CGRP) levels in patients with migraine and healthy controls. Study Setting: The study was carried out in the Departments of Physiology and Neurology at a tertiary care teaching hospital after obtaining approval from the Institutional Ethical Review Committee. \Study Population: A total of 100 participants were enrolled, including 50 patients diagnosed with migraine according to the International Classification of Headache Disorders (ICHD-3) criteria and 50 age- and sex-matched healthy controls. Inclusion Criteria: Adults having age 18–60 years, Patients with a confirmed diagnosis of migraine and Individuals willing to provide written informed consent are included. Exclusion Criteria: Pregnancy or lactation, cardiovascular, renal, hepatic, or autoimmune diseases, diabetes mellitus, active infection or inflammatory disorders, current use of CGRP-targeted therapy or corticosteroids and other neurological disorders are excluded. Sample Collection: After an overnight fast, 5 mL of venous blood was collected from each participant. Serum was separated by centrifugation at 3000 rpm for 10 minutes and stored at −80°C until analysis. Laboratory Analysis: Serum CGRP concentrations were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer's instructions. Routine laboratory investigations, including complete blood count, fasting blood glucose, and C-reactive protein, were performed using standard automated analyzers. Clinical Assessment: Migraine severity was evaluated using the Visual Analog Scale (VAS) for pain intensity and the Migraine Disability Assessment (MIDAS) questionnaire. Blood pressure, body mass index (BMI), age, and demographic characteristics were also recorded. Outcome Measures: The primary outcome was the comparison of serum CGRP levels between migraine patients and healthy controls. Secondary outcomes included the association of CGRP levels with migraine severity, attack frequency, and disability scores. Statistical Analysis: Data were analyzed using IBM SPSS Statistics version 26.0. Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables as frequencies and percentages. Independent-samples t-tests were used to compare continuous variables, while the Chi-square test was applied for categorical data. Pearson's correlation coefficient was used to assess the relationship between serum CGRP levels and migraine severity. A p-value <0.05 was considered statistically significant.

Table 1. Baseline Demographic and Clinical Characteristics of the Study Population

Interpretation: The two groups were comparable in age, sex, and BMI, while migraine-related clinical characteristics were recorded only for the patient group.

Table 2. Comparison of Serum CGRP Levels

Interpretation: Serum CGRP concentrations were significantly higher in migraine patients than in healthy controls.

Table 3. Comparison of Clinical Severity Between Groups

Interpretation: Migraine patients had significantly greater pain intensity and disability compared with healthy controls

Table 4. Correlation Between Serum CGRP Levels and Clinical Variables in Migraine Patients

Interpretation: Serum CGRP levels showed significant positive correlations with migraine attack frequency, pain severity, disability, and disease duration.

The present study evaluated serum calcitonin gene-related peptide (CGRP) levels in patients with migraine and compared them with healthy controls. The findings demonstrated significantly higher serum CGRP concentrations in migraine patients, supporting the role of CGRP as a key mediator in migraine pathophysiology. Furthermore, elevated CGRP levels showed significant positive correlations with migraine attack frequency, pain intensity, disability scores, and disease duration, indicating that increased CGRP activity is associated with greater disease severity. CGRP is a potent neuropeptide released primarily from trigeminal sensory neurons during migraine attacks. It induces vasodilation of intracranial blood vessels, enhances neurogenic inflammation, and promotes transmission of pain signals within the trigeminovascular system. Excessive CGRP release activates peripheral and central pain pathways, contributing to headache generation and prolonged neuronal sensitization. The significantly higher CGRP levels observed in the present study are consistent with these physiological mechanisms and reinforce the concept that CGRP is a major contributor to migraine development. The positive correlation between serum CGRP levels and migraine severity observed in this study suggests that CGRP may serve as a useful biomarker for assessing disease activity. Patients with more frequent attacks and higher pain scores demonstrated greater circulating CGRP concentrations, indicating that sustained activation of the trigeminovascular system may increase peptide release. Similar associations have been reported in previous clinical studies, where elevated CGRP levels were linked to chronic migraine, longer disease duration, and reduced quality of life. The findings also have important therapeutic implications. The success of recently developed CGRP-targeted monoclonal antibodies and small-molecule CGRP receptor antagonists (gepants) has transformed migraine management. By inhibiting CGRP signaling, these therapies reduce neurogenic inflammation, prevent vasodilation, and decrease pain transmission, resulting in fewer migraine attacks and improved patient outcomes. The elevated serum CGRP levels observed in the present study further support the rationale for targeting the CGRP pathway in migraine treatment. This study has several strengths, including a well-defined study population, inclusion of age- and sex-matched healthy controls, and quantitative measurement of serum CGRP using ELISA. However, some limitations should be considered. The relatively small sample size and single-center design may limit the generalizability of the findings. In addition, serum CGRP was measured at a single time point, which may not fully reflect fluctuations during different phases of migraine. Future multicenter longitudinal studies with larger populations are recommended to validate these findings and determine the prognostic value of CGRP as a biomarker for disease progression and treatment response. Overall, the present study provides evidence that increased serum CGRP levels are closely associated with migraine severity and disability. These findings highlight the central physiological and pathophysiological role of CGRP in migraine and support its use as both a potential diagnostic biomarker and a therapeutic target in the management of this common neurological disorder.

The present study demonstrates that serum calcitonin gene-related peptide (CGRP) levels are significantly elevated in patients with migraine and are positively associated with disease severity, attack frequency, and disability. These findings highlight the central role of CGRP in migraine pathophysiology and suggest that CGRP may serve as a valuable biomarker and therapeutic target for improving migraine diagnosis and management.

1. Xiong J, Wang Z, Bai J, Cheng K, Liu Q, Ni J. Calcitonin gene-related peptide: a potential protective agent in cerebral ischemia-reperfusion injury. Frontiers in Neuroscience. 2023 Jul 17;17:1184766.
2. SABOOWALA H. Calcitonin Gene-Related Peptide (CGRP): Insights into Its Physiological Functions and Pathological Implications. Dr. Hakim Saboowala; 2024 Nov 12.
3. Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the trigeminal system in migraine. Headache: The Journal of Head and Face Pain. 2019 May;59(5):659-81.
4. Russo AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: migraine and beyond. Physiological reviews. 2023 Mar 6.
5. Kee Z, Kodji X, Brain SD. The role of calcitonin gene related peptide (CGRP) in neurogenic vasodilation and its cardioprotective effects. Frontiers in physiology. 2018 Sep 19;9:1249.
6. Kumar A, Potts JD, DiPette DJ. Protective role of α-calcitonin gene-related peptide in cardiovascular diseases. Frontiers in physiology. 2019 Jul 2;10:821.
7. Favoni V, Giani L, Al-Hassany L, Asioli GM, Butera C, De Boer I, Guglielmetti M, Koniari C, Mavridis T, Vaikjärv M, Verhagen I. CGRP and migraine from a cardiovascular point of view: what do we expect from blocking CGRP?. The journal of headache and pain. 2019 Dec;20(1):27.
8. Owman C. Role of neural substance P and coexisting calcitonin gene-related peptide (CGRP) in cardiovascular function. InNonadrenergic innervation of blood vessels 2019 Jun 4 (pp. 77-100). CRC Press.
9. Affaitati G, Costantini R, Fiordaliso M, Giamberardino MA, Tana C. Pain from internal organs and headache: the challenge of comorbidity. Diagnostics. 2024 Aug 12;14(16):1750.
10. Altamura C, Corbelli I, De Tommaso M, Di Lorenzo C, Di Lorenzo G, Di Renzo A, Filippi M, Jannini TB, Messina R, Parisi P, Parisi V. Pathophysiological bases of comorbidity in migraine. Frontiers in human neuroscience. 2021 Apr 20;15:640574.
11. Iyengar S, Johnson KW, Ossipov MH, Aurora SK. CGRP and the trigeminal system in migraine. Headache: The Journal of Head and Face Pain. 2019 May;59(5):659-81.
12. Özge A, Baykan B, Bıçakçı Ş, Ertaş M, Atalar AÇ, Gümrü S, Karlı N. Revolutionizing migraine management: advances and challenges in CGRP-targeted therapies and their clinical implications. Frontiers in Neurology. 2024 Jun 13;15:1402569.
13. Bonura A, Brunelli N, Marcosano M, Iaccarino G, Fofi L, Vernieri F, Altamura C. Calcitonin gene-related peptide systemic effects: embracing the complexity of its biological roles-a narrative review. International Journal of Molecular Sciences. 2023 Sep 12;24(18):13979.
14. Xiong J, Wang Z, Bai J, Cheng K, Liu Q, Ni J. Calcitonin gene-related peptide: a potential protective agent in cerebral ischemia-reperfusion injury. Frontiers in Neuroscience. 2023 Jul 17;17:1184766.
15. Chen Y, Qi Y, Lu W. Endogenous vasoactive peptides and vascular aging‚Äêrelated diseases. Oxidative Medicine and Cellular Longevity. 2022;2022(1):1534470.