Review surveys headache targets beyond CGRP, including early endocannabinoid…

OBJECTIVES/BACKGROUND: This narrative review summarizes novel applications for the use of calcitonin gene-related peptide (CGRP)-targeted therapies that go beyond migraine, the latest updates with respect to targeting pituitary adenylate cyclase-activating peptide (PACAP) as therapeutic in migraine, as well as exploring other more recently discovered targets that are undergoing preclinical through advanced clinical development, for the prevention and treatment of headache disorders. Headache disorders affect over one billion individuals worldwide and represent a major public health burden. Although CGRP-targeted therapies have transformed migraine care, a substantial proportion of patients do not achieve adequate relief or remain untreated. Therefore, there is the need to identify and validate novel mechanistic targets across the full spectrum of headache disorders. METHODS: This narrative review reports preclinical and clinical evidence for emerging therapeutic targets in headache, with a focus on those presented at the 2025 Scottsdale meeting of the American Headache Society, during the Advanced Science session. Literature searches were performed on specific topic areas using PubMed/Scopus to find relevant peer-reviewed literature, as well as studies in ongoing clinical trial registries. RESULTS: In addition to their established efficacy in migraine, CGRP-targeted therapies are increasingly being explored across other headache disorders, reflecting their broader relevance to headache pathophysiology. Beyond CGRP, several promising targets have emerged. PACAP has been identified as a CGRP-independent headache mediator, supported by robust preclinical data and two phase 2 trials demonstrating preventive efficacy with a PACAP monoclonal antibody in migraine. The endocannabinoid system shows antinociceptive potential, particularly through multitarget modulation of cannabinoid receptors and endocannabinoid-degrading enzymes. Several therapeutic targets in earlier stages of development are also gaining attention. Among these, prolactin signaling and orexin-2 receptor pathways represent sex-specific mechanisms, demonstrating female-specific and male-specific relevance in headache-related nociception, respectively. Additionally, protease-activated receptor-2 is implicated in dural-trigeminovascular nociceptive sensitization and advancing through early clinical development. Finally, modulation of reactive nitroxidative species with peroxynitrite has emerged as an early-stage strategy given its role in trigeminovascular sensitization and central pain maintenance. CONCLUSION: Altogether, these emerging targets expand the therapeutic landscape for headache disorders beyond CGRP and support a shift toward alternative, sex-informed, and potentially combinatorial approaches for headache prevention and treatment, with the potential to benefit the untreated portion of patients. Calcitonin gene‐related peptide (CGRP)‐targeted drugs have been a major success in migraine treatment and are now being studied for use in other headache disorders, yet many patients still struggle to adequately manage their migraine. Several new treatment targets, which work differently than CGRP, show promise in early research and clinical studies. These findings suggest that expanding beyond CGRP, and developing more personalized or combinatorial treatments, could improve care for people whose headaches remain inadequately treated.