CGRP and Migraine: Real-World Insights and Future Therapeutic Directions.

Medical advances in the past 25 years have redefined migraine as a neurological condition. Foremost among these advances have been basic and clinical studies on the neuropeptide calcitonin gene–related peptide (CGRP). Therapeutics that target CGRP or its receptor to acutely treat or prevent migraine represent a success story that began with the basic science of CGRP. CGRP was discovered in 1982 as the product of the second example of cellular alternative RNA processing ( 1 ). The physiological significance of CGRP was quickly established by showing ( a ) that CGRP is the most potent vasodilatory peptide known ( 2 ) and ( b ) that CGRP is highly expressed in nociceptive sensory fibers, including the trigeminal nerve ( 3 ). For an in-depth review of these and other CGRP activities, we refer the reader to Reference 4 . The vascular and nociceptive properties of CGRP laid the foundation for the CGRP and migraine story. In the early 1990s, Goadsby & Edvinsson ( 5 ) discovered that CGRP in the jugular outflow was elevated during migraine and reduced by treatment, coincident with pain relief. Elevated CGRP has since been detected in saliva and tears and in the plasma of chronic migraine patients, even between attacks ( 4 ). However, CGRP elevation is not consistently detected and thus cannot serve as a reliable biomarker of migraine ( 6 ). The second line of evidence for this connection came from a risky but rewarding study in 2002 by Olesen and colleagues ( 7 ) that established a causal link between elevated CGRP and migraine. They found that intravenous infusion of CGRP into people caused migraine-like headaches. Subsequent research corroborated this groundbreaking finding ( 8 ). The third demonstration of the connection between CGRP and migraine was provided by the advent of drugs that target CGRP for both acute and preventive treatments ( 9 ). Numerous clinical trials have clearly demonstrated that these drugs are safe and effective. After several years on the market, there are now real-world data that confirm the efficacy of these medications. Indeed, the American Headache Society recently issued an opinion that CGRP drugs should be considered a first-line preventive treatment for migraine ( 10 ).

Given that current CGRP-based drugs are effective only in approximately half the patients, the question arises as to whether CGRP therapies can be effectively combined within the class (e.g., mAb plus gepant) and across classes (e.g., mAb plus onabotulinumtoxinA). Similarly, should therapeutics target other members of the CGRP family (e.g., amylin and its receptor AMY 1 )? Considering the multifactorial nature of migraine, a combinatorial therapeutic approach seems logical. There is significant interest in combining two CGRP therapies. Evidence is emerging that adding an acute gepant to a preventative mAb regimen is effective for some individuals. A small, randomized trial supports the safety of this approach ( 124 , 125 ), but the long-term effects of dual treatments are unknown. The idea of providing an acute boost to the mAbs’ inhibitory actions makes sense, especially toward the end of the antibody treatment when its protective effect may be waning ( 126 ). Similarly, a recent study found that taking ubrogepant acutely while taking atogepant for migraine prevention was safe and well tolerated ( 127 ). Regarding dual treatments of a CGRP-based drug and another therapeutic, evidence from open-label and anecdotal reports suggests that adding onabotulinumtoxinA to a CGRP mAb further reduces migraine days for some patients ( 128 – 130 ). This aligns with evidence that CGRP antibodies inhibit trigeminal nerve Aδ fibers, while onabotulinumtoxinA primarily inhibits vesicular fusion and the release of neuropeptides, including CGRP, from trigeminal nerve C fibers ( 131 ). Thus, combining onabotulinumtoxinA with CGRP-targeted therapies may benefit some patients with chronic migraine. Another question is whether the failure of one anti-CGRP agent is prognostic for the efficacy of another CGRP agent or a triptan (or vice versa). A recent study found that prior positive responses to a CGRP mAb and onabotulinumtoxinA injections predict a good response to the CGRP receptor antagonist ubrogepant ( 132 ). Conversely, a lack of response to the antibody or onabotulinumtoxinA predicted a poor response to ubrogepant. Given the shared mechanisms of CGRP mAbs and antagonists, this correlation is logical. However, like with different triptan drugs, there may be patients who respond to one mAb or gepant but not another. Additionally, response to a triptan has been found to predict a positive response to erenumab ( 133 ), which aligns with triptans reducing CGRP release ( 5 ). Preclinical studies show that triptans can block CGRP-induced light aversion ( 134 , 135 ) and that nitroglycerin-induced symptoms can be blocked by both triptans and CGRP mAbs ( 136 ). The potential benefit of dual therapy with an acute gepant and a triptan remains an open question. Migraine is not solely due to altered CGRP signaling. This is evident from the fact that approved drugs targeting CGRP (mAbs and gepants) are effective in only ~50% of patients, and CGRP injections induce migraine-like attacks in only ~65% of patients ( 8 ). Thus, other molecules need to be targeted for novel therapies. As a starting point, other CGRP family members and their receptors should be considered. Two candidates are amylin and the second CGRP receptor, AMY 1 ( 137 ). Infusion of an amylin analog (pramlintide) triggers migraine-like headache in migraine patients ( 138 ), and amylin causes migraine-like symptoms in mice ( 138 , 139 ). Future studies on amylin and the relative roles of AMY 1 and canonical CGRP receptors should prove interesting. Additionally, adrenomedullin’s ability to induce migraine-like attacks ( 138 ) suggests that other CGRP-related receptors, such as AM1 and AM2, might be considered, although based on the severe phenotypes of adrenomedullin knockout mice ( 140 ), targeting AM receptors may prove too risky. Beyond the CGRP family of peptides and receptors, combinatorial therapy that also targets other peptides should be considered. In particular, targeting pituitary adenylate cyclase-activating polypeptide (PACAP) is likely to be a successful strategy. A PACAP mAb has proven effective in a recent clinical trial ( 141 ). A combinatorial treatment targeting both CGRP and PACAP is promising since the two peptides appear to act by independent mechanisms in preclinical models ( 141 , 142 ) and in a recent small clinical study ( 143 ).

Clinical trials revealed remarkably few adverse effects for the CGRP mAbs and gepants. In the clinical trials, common side effects for CGRP mAbs included injection site reactions (rash and pruritus) and constipation ( 23 ). Common side effects for gepants included nausea, constipation, and fatigue/somnolence ( 11 ). Subsequent reports prompted the FDA in March 2025 to update safety labeling for all CGRP mAbs and gepants to include the potential of developing or worsening preexisting hypertension and Raynaud’s phenomenon, and for erenumab, to include constipation. Fortunately, these symptoms are readily reversible upon stopping drug use. Nonetheless, there remain concerns about the safety risks of long-term use of these drugs, and as more patients take the medications, there are emerging possible adverse side effects ( Figure 1 a ). CGRP is a key compensatory vasodilatory peptide that maintains vascular tone and plays a key cardioprotective role. It facilitates reperfusion in the event of arterial occlusions causing myocardial or cerebral ischemia. Thus, there has been concern that inhibiting CGRP or its receptor may pose an increased risk for adverse cardio and cerebrovascular events ( 58 – 60 ). The initial clinical trials did not demonstrate an increased risk for hypertension ( 9 , 39 ), but subsequent real-world data suggest that there may be a mild increased risk for developing or worsening hypertension ( 61 ). In a study involving US veterans, CGRP inhibitors did not increase the incidence of hypertension in those with no prior history; however, those with preexisting hypertension were found to have a slight increase in the number of antihypertensive medications prescribed over a 4-year period ( 62 ). A prospective study of patients receiving erenumab and fremanezumab found a mild increase in blood pressure (5.2 mm Hg systolic, 3.5 mm Hg diastolic), and 3.7% of normotensive patients required antihypertensive treatment after initiation of erenumab ( 63 ). The exposure-adjusted incidence of hypertension was relatively low at 0.144 per 100 patient years, and it is still too early to determine if this applies to other mAbs or gepants ( 61 ). Therefore, despite the relatively safe hypertension adverse effects profile, continued caution is advised, especially in patients with poorly controlled hypertension ( 64 ). The effects of CGRP in the female reproductive system are generally positive for both fetal and maternal health, including for fetal–maternal blood flow, implantation, uterine receptivity, and placentation ( 65 ). CGRP helps maintain low vascular resistance in the fetoplacental circulation during normal pregnancies; thus, there is concern that an insufficient CGRP vasodilatory response may contribute to hypertensive disorders in pregnancy ( 66 ). This is particularly troubling, as those with migraine have an increased risk of developing gestational hypertension and preeclampsia/eclampsia ( 67 ). Some limited preclinical data have demonstrated increased blood pressure and fetal mortality with CGRP inhibition ( 68 ). The World Health Organization database of suspected adverse events from maternal exposure to these mAbs revealed similar rates of adverse maternal and fetal outcomes to the general population ( 69 ). Although it is hoped that these medications may be considered safe in pregnancy, CGRP inhibitors remain contraindicated in pregnancy until more safety data are available. The long half-life of the CGRP mAbs thus dictates that they should ideally be discontinued at least 5 months prior to conception. It is important to discuss these issues with individuals with the capacity for pregnancy prior to the initiation of anti-CGRP therapies During cerebral and cardiac ischemic events, CGRP-induced vasodilation facilitates tissue reperfusion. Thus, CGRP inhibition could worsen outcomes of heart attacks and strokes, leading to larger areas of ischemia, as observed in a rodent model of stroke ( 70 ). There have been multiple case reports of stroke in the setting of CGRP inhibitors ( 71 – 74 ). Consequently, there remains concern about prescribing CGRP inhibitors to patients with a history of cardiovascular or cerebrovascular disease. This includes patients with small ischemic vessel diseases, such as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), who often experience migraine ( 75 ). Additionally, it has been suggested that even those without a prior risk of ischemia should be carefully monitored ( 71 ). CGRP appears to play a key role in mitigating vasospasm, such that CGRP has been proposed as a therapy for cerebral vasospasm following subarachnoid hemorrhage (SAH) ( 76 ). A meta-analysis of preclinical studies confirmed that CGRP can improve cerebral vascular tone after SAH but found insufficient data to conclude whether this improved clinical outcomes ( 77 ). Thus, blocking CGRP-induced vasodilation may pose risks in the setting of various disorders involving vasospasm. One case report found that a patient who received fremanezumab for presumed chronic migraine experienced multifocal ischemic and hemorrhagic strokes in the setting of unrecognized reversible cerebrovascular vasospasm syndrome (RCVS) ( 73 ). Similarly, a patient developed an ischemic stroke in the setting of RCVS following erenumab administration ( 74 ). Furthermore, the use of anti-CGRP drugs for migraine has led to some case reports of worsened or new-onset Raynaud’s phenomenon, a vasospasm-related disorder. In Raynaud’s phenomenon, vasospasm of small vessels in the fingers and toes can cause ischemia, leading to dysesthesias, pain, and even tissue damage if prolonged. CGRP has been associated with this condition in several ways. Skin biopsy samples show that perivascular CGRP immunoreactivity is lower in patients with Raynaud’s phenomenon compared to healthy individuals ( 78 , 79 ). Interestingly, these patients may be more sensitive to CGRP ( 80 ) and can respond to CGRP injections with increased blood flow ( 81 ). However, their responsiveness at low temperatures appears to be reduced ( 82 ). The World Health Organization’s pharmacovigilance database found a disproportionate number of reports of Raynaud’s phenomenon associated with anti-CGRP drugs compared to triptans and beta-blockers, which are other migraine treatments used for comparison ( 83 ). Thus, caution and close monitoring should be used in individuals with a history or at risk of Raynaud’s phenomenon and avoided in severe cases requiring medical management. However, despite these risk considerations, a recent study of US medical claims found that erenumab was not associated with an increased risk of hypertension, myocardial infarction, or stroke as compared to other CGRP mAbs, onabotulinumtoxinA, or other standard oral preventive medications for migraine ( 84 ). Similarly, another recent US study of Medicare beneficiaries did not find an increased risk of cardiovascular disease events (including myocardial infarction, stroke, hypertensive crisis, peripheral revascularization, Raynaud’s phenomenon) for patients receiving CGRP mAbs as compared to those receiving onabotulinumtoxinA for migraine ( 53 ). While these studies are reassuring, further investigation and ongoing caution in patients with high-risk cardiovascular disease are warranted. Constipation has been reported by a small but notable percentage of patients in clinical trials following treatment with the CGRP receptor antibody erenumab (3–4%) ( 23 ) or the CGRP receptor antagonist atogepant (7–8%) ( 85 ). Real-world data with erenumab, however, suggest much higher rates (14–43%) ( 85 ). Nausea has been a commonly reported side effect in gepant clinical trials ( 11 ). Both of these symptoms likely reflect the significant, but complex, role of CGRP in gastrointestinal (GI) motility ( 85 ). A recent review addressed how CGRP might be responsible for the clinical comorbidity of GI symptoms and migraine ( 85 ). Symptoms of migraine include nausea and vomiting, affecting 73% and 29% of patients, respectively ( 86 ). Other GI symptoms can accompany migraine, such as diarrhea, constipation, gastroesophageal reflux, and gastroparesis ( 86 , 87 ). These symptoms may be linked to CGRP ( 4 , 85 ). Furthermore, genetic association studies ( 88 , 89 ) and recent gut barrier physiological studies ( 90 ) further point to a possible role of CGRP in GI health and disease and highlight the need to consider the long-term effects of reducing CGRP actions. While not reported in clinical trials, there is developing real-world data suggesting that alopecia (hair loss) is a possible adverse event for CGRP inhibitors ( 91 ). CGRP has known roles in bone development, which is particularly relevant to CGRP-targeted therapy use in children and the elderly ( 57 ). One study examined bone turnover in 45 patients receiving CGRP mAbs, but further studies are needed to better understand any potential risk ( 92 ). Preclinical data have implicated CGRP in wound healing; there is one case report of impaired wound healing in an individual receiving erenumab, but the risk remains unclear ( 93 ).

Other potential therapeutic uses for CGRP manipulation have been suggested, as described in the following subsections ( Figure 1 b ). The role of CGRP in trigeminal nociception suggests that CGRP therapies may be effective in facial pain disorders, such as trigeminal neuralgia and temporomandibular disorders. CGRP is also critical in other noncephalic chronic pain disorders, such as neuropathy, osteoarthritis, and endometriosis. Inhibition of CGRP may be beneficial in other systemic disorders, such as hot flashes and inflammatory bowel disease. For trigeminal neuralgia (TN), one case series observed that 9 out of 10 TN patients reported a reduction in pain severity after a 6-month course of erenumab (REF). Similarly, another case series observed that 5 out of 6 TN patients with comorbid migraine reported a reduction in pain severity after a 3-month course of erenumab (REF). However, a double-blind, randomized, placebo-controlled study found erenumab to be ineffective at reducing pain intensity or paroxysmal pain over a 4-week period ( 94 ). Nevertheless, there remains interest in CGRP as a potential target for trigeminal neuralgia, perhaps with a longer treatment course. Preclinical models of temporomandibular disorders suggest that CGRP may be a relevant therapeutic target ( 95 ). Clinical studies are needed to assess whether CGRP drugs are effective for temporomandibular disorders. There is evidence that CGRP accumulates in synovial fluid and contributes to osteoarthritis, with preclinical models indicating that reducing CGRP activity would be beneficial ( 96 , 97 ). Notably, CGRP expression in knee osteoarthritis patients was higher in women than men and correlated positively with pain severity in women ( 98 ). One trial has been done with a CGRP mAb (galcanezumab) in patients with mild to moderate knee osteoarthritis ( 99 ), but the study was terminated following an interim analysis showing inadequate efficacy. Nevertheless, it is too early to rule out CGRP as a target for arthritis, as factors such as disease stage, length of dosing, and the number of trial participants need consideration. Preclinical studies have implicated increased CGRP activity in various peripheral neuropathic disorders, including peripheral neuropathy, complex regional pain syndrome, and painful neuromas ( 100 ). A small, open-label clinical study of chronic migraine patients with comorbid peripheral neuropathy observed that CGRP mAbs decreased neuropathic pain scores ( 101 ). Larger, placebo-controlled studies are needed to further assess efficacy in neuropathic pain disorders. A recent preclinical study demonstrated that CGRP acting on macrophage immune cells is a significant factor in the pathogenesis of endometriosis ( 102 ). Importantly, blocking CGRP with CGRP mAbs (fremanezumab or galcanezumab) or gepants (rimegepant or ubrogepant) reduced both endometriosis pain and lesion size in mice ( 102 ). A recent clinical study found that CGRP levels decreased following treatment with dienogest, a synthetic progesterone used to treat endometriosis, corresponding with decreased pain levels ( 103 ). Further studies are needed on whether CGRP therapies reduce pain associated with endometriosis. Hot flashes commonly occur during menopause in women and prostate cancer treatment in men, mainly affecting the face, neck, and upper torso. They can last for years. Studies show elevated CGRP levels during hot flashes in women ( 104 ). Studies with ovariectomized mice found that the CGRP receptor antagonist MK-8825 inhibited flash-like temperature increases from exercise. Mice with reduced α-CGRP also showed reduced temperature increases ( 105 ). Rosacea, linked to flushing and neurogenic inflammation, may also involve elevated CGRP levels ( 106 ), and erenumab has shown promise for treating rosacea flushing and erythema ( 107 ). Thus, CGRP-blocking drugs might help prevent hot flashes and rosacea. Migraine presents with a number of GI symptoms and is also associated with a number of GI disorders, implicating CGRP as the underlying mechanism and possible therapeutic target for GI dysfunction ( 85 ). These include irritable bowel syndrome (IBS), inflammatory bowel disease, functional dyspepsia (indigestion), and gastroparesis ( 108 ). GI disorders such as IBS are among the most common comorbidities associated with migraine ( 109 ). There has long been speculation that CGRP receptor antagonists could treat GI diseases ( 110 ). Recent preclinical studies suggest that inhibiting CGRP signaling might benefit patients with IBS ( 111 ). CGRP released from nociceptive neurons has long been implicated in cancer pathogenesis and pain ( 112 , 113 ). An early report linked CGRP and tumor angiogenesis ( 114 ), and this remains a therapeutic possibility ( 115 ). Since then, a deeper role for CGRP in cancer progression has emerged from the complex actions of CGRP on the immune system ( 4 ). CGRP inhibits the activation of cytotoxic T cells that would otherwise have infiltrated melanoma ( 116 ) and head and neck squamous cell carcinoma tumors ( 117 ). CGRP can also disrupt the development of dendritic cells in medullary thyroid carcinoma ( 118 ), which ironically is the neuroendocrine tumor that led to the discovery of CGRP ( 1 ). Recently, it has been reported that CGRP can also directly increase gastric cancer cell proliferation via the Rb/E2F pathway and that treatment with CGRP inhibitors can suppress tumor growth ( 119 ). These preclinical findings all point to CGRP and its receptor as therapeutic targets for cancer. It will be interesting to see whether CGRP mAbs and gepants will be effective in clinical trials for these and other tumors with CGRP in their microenvironment. The CGRP system has been suggested as a potential therapeutic target for diabetes and/or obesity ( 120 , 121 ). However, the somewhat contradictory findings regarding the underlying biology make it unclear how best to proceed ( 4 ). While initial studies did not reveal a trend ( 122 ), a recent report found that atogepant led to weight loss ( 123 ). Clinical trials with sufficient power are needed to draw firm conclusions.

In conclusion, therapeutics targeting CGRP signaling for migraine treatment and prevention have significantly enhanced quality of life for many patients. However, despite their clinical success, we need more preclinical and clinical research to uncover how and where CGRP acts to improve efficacy, help alleviate side effects, and guide development of combinatorial therapies. This need is even greater as evidence is mounting that modulating the CGRP axis could be a beneficial strategy for diseases beyond migraine.

Current CGRP drugs fall into two pharmacological categories: monoclonal antibodies (mAbs) that bind either the CGRP ligand or the CGRP receptor and small-molecule CGRP receptor antagonists referred to collectively as gepants ( Table 1 ). Collectively, these drugs have proven effective for both acute and preventive treatment of migraine ( Figure 1 a ). Three gepants have an indication for the acute treatment of migraine: rimegepant, ubrogepant, and zavegepant. These are effective acute medications as compared to placebo ( 11 ), but meta-analyses suggest that they are likely less effective as a class than the triptans, which remain the gold standard for the acute treatment of migraine ( 12 ). Nevertheless, gepants provide a key alternative class of acute treatment options for patients who have not responded or have contraindications to triptans or other acute medications. Moreover, the gepants have several advantages. Acute gepants have a favorable side effect profile, with nausea being the most common side effect ( 13 ). Overall, they are better tolerated than triptans ( 14 ). Recent clinical data with ubrogepant suggest that initiating treatment during the prodrome phase may increase its efficacy and may even terminate the migraine prior to the onset of headache ( 15 ). While frequent triptan use can lead to medication overuse headache (MOH), possibly secondary to trigeminal allodynia, this has not been observed with frequent acute gepant use ( 16 , 17 ). Acute gepants do not cause vasoconstriction, unlike triptans and ergots; thus, they likely pose a safer alternative for individuals with significant cardiovascular disease or risk, but further safety data are needed ( 13 ). Although eptinezumab is currently approved by the US Food and Drug Administration (FDA) only for the prevention of migraine, initial clinical studies suggest it may acutely terminate a migraine attack, which could be an appealing alternative to other therapies for status migrainosus ( 18 ). A significant gap in headache treatment has been the lack of widely effective preventive treatments. Coupled with this gap has been poor compliance, as most previous preventive measures had adverse side effects. The development of CGRP therapeutics has been a major advance in addressing this gap. CGRP therapeutics are highly efficacious for the prevention of migraine and are now recommended by the American Headache Society as first-line therapy ( 10 ). Phase II and III clinical trials and subsequent meta-analyses have consistently demonstrated that CGRP mAbs (erenumab, eptinezumab, fremanezumab, and galcanezumab), and gepants (rimegepant and atogepant) are efficacious in reducing the number of migraine days per month ( 19 ). CGRP mAbs reduced monthly migraine days by 1.27 to 2.36 days, and gepants reduced monthly migraine days by 0.80 to 1.27 days ( 19 ). The ≥50% responder rates for CGRP mAbs ranged from 42 to 59% (with an OR = 1.82 to 3.19), and for gepants, they ranged from 49 to 57% (with an OR = 1.38 to 2.57) ( 19 ). This has been observed in both episodic and chronic migraine, including those with migraine with aura. CGRP mAbs effectively reduce MOH with low relapse rates ( 20 , 21 ). Atogepant also appears effective in reducing MOH ( 22 ). CGRP mAbs often show a rapid onset of action, sometimes within days of initiating treatment, and a progressive reduction in monthly migraine days over the following 6 months ( 23 ). Overall, both CGRP mAbs and preventive gepants have led to improvements in headache-related disability and quality of life ( 24 – 28 ). Patients taking CGRP mAbs were more likely to refill their medication and less likely to discontinue it, leading to higher rates of adherence and persistence compared to other standard-of-care preventive medications ( 29 ). However, persistence to treatment may be higher for onabotulinumtoxinA than CGRP mAbs (except for eptinezumab) ( 30 ). Switching to another CGRP mAb may be beneficial for patients who fail to respond to their initial CGRP mAb. In one study, 15% of patients were able to reduce their monthly headache days by >50% by the sixth month of therapy ( 31 ). However, more evidence is needed to better understand the efficacy of this practice ( 32 ). These positive clinical outcomes appear to correspond to changes in the brain, including reduced cortical thickness ( 33 ) and functional connectivity in numerous brain regions ( 34 – 36 ). Thus, blocking CGRP and subsequently reducing nociceptive input appears to reduce cortical hyperexcitability in migraine ( 36 ). While this may indicate that CGRP mAb therapies could be disease-modifying, headache frequency and quality of life tend to worsen after discontinuing CGRP mAbs ( 37 ), so the improvements appear to be dependent on continued treatment. While some studies found that, after discontinuation, headache frequency remained below levels prior to therapy, patients were followed only for up to 4 months, which is shorter than the >5-month duration needed for complete antibody elimination ( 37 ). Hence, these brain changes are likely not maintained long-term, and ongoing CGRP blockade is needed to reduce migraine burden. In addition to migraine, CGRP therapies have been investigated for other headache disorders ( Figure 1 a ). The CGRP mAb galcanezumab reduced headache frequency in episodic cluster headache patients, leading to FDA approval ( 38 ). In contrast to episodic cluster, galcanezumab failed to meet primary and secondary endpoints in a double-blind, placebo-controlled trial for chronic cluster headache ( 39 ). However, its use for chronic cluster headache remains under investigation, with real-world data suggesting potential efficacy in reducing headache frequency ( 40 ). The higher dose (300 mg) required for cluster headache appears to be well tolerated and safe; however, the risk of adverse events is significantly higher than that of the 240 mg dose indicated for migraine ( 41 ). While clinical trials for fremanezumab were unsuccessful, the efficacy of other CGRP mAbs for cluster headache remains under investigation ( 42 ). CGRP is likely a beneficial therapeutic target for cluster headache regardless of agent, and the confounding findings likely reflect the challenges of designing clinical trials for cluster headache. Clinical trials with CGRP mAbs for posttraumatic headache (PTH) have yielded mixed results. An open-label trial found erenumab reduced headache frequency in PTH, suggesting that CGRP may be an effective therapeutic for PTH ( 43 ). However, another trial with fremanezumab failed ( 44 ). Nonetheless, a role for CGRP seems likely since PTH patients with migraine-like features (without a preexisting history of migraine) are hypersensitive to infusion of CGRP ( 45 ). Further investigation is warranted. Migraine affects all populations, regardless of age, sex, gender identity, race, or ethnicity. Vulnerable populations like children and adults older than 65 are often excluded from clinical trials due to the potential risk for harm. Here, we discuss evolving data on the potential benefits and risks of CGRP therapies for some of these special populations. The question of why migraine is more prevalent in women than in men has perplexed the field for decades. A role for sex hormone fluctuations is likely, although no clear picture has emerged linking sex hormones and CGRP ( 46 , 47 ). Injection of CGRP causes migraine in both men and women, and the CGRP and CGRP receptor mAbs are effective in both sexes ( 48 ). While it was initially suggested that gepants may not work in men ( 48 ), a larger post hoc analysis recently confirmed that both sexes respond to gepants ( 49 ). Transgender and gender-diverse individuals appear to experience higher rates of migraine ( 50 ). For patients receiving gender-affirming hormone therapy, CGRP mAbs for prevention are particularly attractive options as they pose no risk of drug–drug interactions ( 50 ). For pregnancy, see potential safety concerns discussed in Section 3.1.1 While adults older than 65 years of age were excluded from clinical trials, recent real-world data have suggested that CGRP mAbs are effective at reducing headache frequency and are likely as effective as for people under 65 years ( 51 , 52 ). Trials found CGRP mAbs to be safe, with adverse events comparable to prior reports and to the case-control groups under 65 years of age, with no reports of serious events, including no ischemic events ( 51 , 52 ). However, Muñoz-Vendrell et al. ( 51 ) reported two cases of elevated blood pressure, with one of those leading to hypertensive crisis. Nevertheless, analysis of US Medicare claims did not detect an increased risk of cardiovascular disease for individuals (including older adults) taking CGRP mAbs as compared with those receiving onabotulinumtoxinA ( 53 ). Further investigation is needed to understand the potential risk for patients with significant cardiovascular disease, as outlined in Section 3.1 Children and adolescents under 18 years of age were excluded from the initial trials. However, the first randomized clinical trial in children between 6 and 17 years found that fremanezumab was safe and effective for the prevention of episodic migraine ( 54 ), but the final results have yet to be publishedFurthermore, smaller retrospective trials have also indicated that CGRP mAbs are safe and likely effective in a subset of adolescent patients ( 55 , 56 ). Until further results are available, recommendations and considerations for this population have been published ( 57 ).