January 2026 Clinical Research Update: The Latest Findings in Migraine

Highlights include successful phase 4 trials, new studies on psychedelics, migraine in men, and more.

Editor’s note: This is Part 2 of a two-part update on select recent findings from clinical studies in the migraine and headache field published in 2025 (see Part 1 here). This update describes studies that were published through the end of the year.

Two Phase 4 studies
Successful Phase 3 clinical trials of new drugs generate a lot of excitement, and for good reason, since those are the key studies that result in approval of new medications by regulatory bodies. But the clinical trial process does not end there. After regulatory approval, Phase 4 trials provide additional evidence about the efficacy and safety of new drugs. Recently, the migraine field saw two such Phase 4 trials, each offering additional information about rimegepant, an oral, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist approved for the prevention and treatment of migraine. The trials, both of which appeared in Cephalalgia, focused on what role this gepant could play in treating migraine in people who had not fared well previously with traditional treatments.

In one of the Phase 4 studies, researchers investigated the efficacy and tolerability of rimegepant in people with episodic migraine who responded inadequately to two to four different categories of oral preventive medications, out of eight categories in total considered in the study (the anticonvulsant valproic acid, other anticonvulsants, beta-blockers, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, calcium channel blockers, angiotensin blockers, and other locally approved or recognized preventive medications). An inadequate response was defined as a lack of drug efficacy, or drug intolerance, in the previous 10 years, or when the drug was contraindicated. Thirty-five percent of study participants showed a previous inadequate response to drugs in at least three of the categories.

This multinational, randomized, double-blind, placebo-controlled trial included 328 people randomized to rimegepant, and 324 randomized to placebo, given every other day over a 12-week study period that came after a one-month observational period without treatment. On the study’s primary outcome, which was the average change in monthly migraine days (MMDs) after 12 weeks of treatment compared to the observational phase, those who received rimegepant showed a greater change in MMDs, compared to placebo. Specifically, those treated with the drug exhibited an average reduction of 2.1 MMDs, compared to a reduction of 0.5 MMDs in the placebo group, equating to a 1.6-day greater MMD reduction.

The study had five secondary outcomes, and rimegepant once again outperformed placebo on all of those outcomes. For instance, 20.1% more participants in the drug group showed at least a 50% reduction in MMDs with moderate or severe pain intensity, compared to the observational phase. There were no differences between groups in drug tolerability or safety.

The authors say their study is the first of its kind, and pointed to “the rigorous determination of prior inadequate response, ensuring that the target population was correctly selected for enrollment” as one of the study’s strong suits. There is an ongoing 12-week, open-label extension for this work. Stay tuned…

In the second Phase 4 study, another international group of researchers examined the efficacy and tolerability of rimegepant for the acute treatment of migraine in patients with a previously deemed unsuitability for triptans – the first prospective trial of its kind in this group of individuals. Patients were deemed unsuitable for triptans if they were intolerant to them and/or had a lack of efficacy, or if there were contraindications to taking these drugs.

A total of 633 study participants were randomized to receive one dose of rimegepant to treat a single migraine attack of moderate to severe pain intensity, or placebo. Participants recorded headache pain intensity and other symptoms using an electronic diary, both before receiving study medication and then at various timepoints after drug administration, up to 48 hours post-dose.

On the study’s primary outcome of migraine pain relief two hours after receiving treatment, 55.9% of those who received rimegepant reported relief, compared to 32.7% in the placebo group, a statistically significant difference of 23.2%. Those who received the gepant also responded better on 10 secondary endpoints, compared to the placebo group. Adverse events were mild and similar between groups.

As for future work, this study, too, has an ongoing, 12-week open-label extension phase, to provide information about the safety and efficacy of repeated dosing of rimegepant in patients unsuitable for triptans.

“The key strength of this study,” the authors concluded, “is that it is the first, to our knowledge, prospectively designed trial of a gepant in individuals with a documented history of unsuitability to triptans. Previous analyses of individuals unsuitable to triptans were based on subgroup analyses and not prospectively designed.”

A triumph for TRIUMPH
The advent of CGRP-targeted therapies has transformed migraine care, but how these drugs compare to traditional migraine treatments has been uncertain, considering there are relatively few studies that make direct comparisons between different classes of migraine therapies. New results from TRIUMPH, an international, prospective, observational cohort study of people with migraine initiating or switching to a new preventive migraine medication, now provide valuable data in this regard, in a real-world setting.

For the new study, published in Headache, 1,105 adult patients with migraine received the anti-CGRP monoclonal antibody galcanezumab, and 1,293 received traditional oral preventive medications for migraine (which could include anticonvulsants, tricyclic antidepressants, beta-blockers, calcium channel blockers, or angiotensin II receptor antagonists). The study’s primary outcome was the proportion of patients who, at three months, showed a clinically meaningful response, in particular a reduction from baseline in monthly migraine headache days of 50% or more for those with episodic migraine, and 30% or more for individuals with chronic migraine.

For all patients, approximately 47% of those taking galcanezumab achieved a clinically meaningful response at three months, compared to roughly 35% of those taking the traditional medications, representing a statistically significant difference. Similarly, 52% of those with episodic migraine who took the antibody showed at least a 50% reduction in monthly migraine headache days, compared to 31% of those taking traditional medications; similar findings were observed for those with chronic migraine. Those who took galcanezumab also showed better responses on secondary outcomes, including a better improvement in function.

The authors acknowledged the limitations of observational studies, as well as the study’s strength of providing data from real-world settings on how galcanezumab and the traditional medications stack up against each other. “These findings are representative of clinical practice settings and may help physicians in making treatment decisions,” they concluded.

Worrying findings about opioid use
Opioids are not a recommended treatment for migraine. Yet many people with the condition do use them. To get a better idea of how extensive opioid use is in the migraine population, researchers recently looked to data from the long-running Observational Survey of the Epidemiology, Treatment, and Care of Migraine (OVERCOME) study, which is a longitudinal web survey that gathers data about various aspects of migraine, including treatment.

Almost 62,000 US-based survey respondents with active migraine were included in the new analysis, which was published in Pain and Therapy. Notably, over one-fifth of these respondents said they were currently using opioids as a migraine treatment. The researchers wanted to know what lay behind this finding, including the factors that predicted opioid use. According to a machine learning analysis, the strongest predictors were currently taking recommended acute treatment for migraine (those doing so were, strikingly, 10 times more likely to also be taking opioids [an odds ratio of 10.1]); currently taking medications containing barbiturates (an odds ratio of 2.18); and having sought care at an emergency department/urgent care over the past year (an odds ratio of 1.75).

In their discussion, the study authors pointed to another very concerning finding from the study – one that suggests that many people living with migraine are not benefiting from currently available treatments: “[It] is striking that 22.7% of those using opioids were prescribed opioids for migraine by specialists who should be most knowledgeable that they are not recommended for migraine. This suggests that more than one in five patients with active migraine may have attacks that are either unresponsive to or have contraindications/intolerance to recommended medications or that some specialists continue to prescribe opioids that were initiated by a prior prescriber.”

A migraine research tool performs poorly
Could CGRP serve as a biomarker of migraine – as an objective indicator of the disease or of the risk of developing it? For a CGRP biomarker to achieve this role, researchers must have tools to reliably detect and measure the peptide in patient samples. But, according to an article recently published in Headache, an assay kit commonly used in the migraine field to measure CGRP appears unreliable, raising questions about findings from previous studies that used this tool.

The authors tested a commercially available CGRP assay (from a company called Cusabio). The assay is an enzyme-linked immunosorbent assay (ELISA) kit, a type of assay that relies on antibodies for detection. The ELISA used in the current study (which the researchers call Kit A) is thought to detect mature, bioactive β-CGRP, which is one of the two isoforms of CGRP, with the other being α-CGRP. To see if that was actually the case, the investigators compared Kit A to a control CGRP ELISA kit (Kit B) that is non-selective for the different CGRP isoforms and is known to accurately detect them.

The findings are troubling: While Kit B reliably detected both CGRP isoforms – both mouse and human versions – Kit A was unable to detect either bioactive isoform, whether mouse or human. The researchers confirmed this finding using two separate lots of the kits.

The investigators clearly stated what they think their results mean for the field: “Our findings have major implications for headache and headache research. We demonstrate that the widely used Kit A may not be suitable for detecting mature bioactive α- or β-CGRP in clinical samples or otherwise. Although the kit is clearly able to detect an analyte in clinical samples based on the literature, based on our results, this analyte does not appear to be a mature form of CGRP. This affects the conclusions drawn from the clinical studies that have reported data using this kit. The potential impact of our findings warrants further consideration and discussion within the field.”

Understanding migraine in men with a genome-wide association study in veterans
Migraine is two to three times more common in women than in men, but of course men do suffer from this condition, too. A recent investigation, published in Molecular Psychiatry, performed a genome-wide association study (GWAS) in a predominantly male (90% of study participants) sample of veterans from the Million Veteran Program. This work included over 433,000 veterans, including 87,859 cases of migraine, and it was a multi-ancestry study, including people of European, African, and Hispanic ancestry. Considering the extremely difficult circumstances that veterans are often exposed to in the course of duty, the researchers were interested in looking at associations of migraine with traumatic brain injury (TBI), depression, and post-traumatic stress disorder (PTSD).

The investigators reported 49 genome-wide significant loci. Analyzing how their results stacked up with previous migraine studies, the researchers found that 36 of the loci were new, with the remaining 13 loci having been shown in the prior studies to be associated with migraine. Seven of the new loci were replicated with a previous migraine GWAS.

The next task was to determine the genes and biological pathways to which the 49 genome-wide significant loci mapped. That led to the identification of 283 genes associated with migraine, some of which had not been associated with migraine previously. That included, for instance, a gene called MAML3, which had previously been associated with chronic pain. As other examples, a gene called ASXL1 had been associated with decreased circulating triglyceride and glucose levels, while TLR4 had been known to play a role in neuroinflammation and immune signaling.

With regard to biological pathways, the study implicated lipidosis (lipid accumulation), obesity, cholesterol metabolism, fatty acid levels, irritability, and neuroticism, among others. And, the migraine-associated genes were enriched in brain and uterine tissues, but, interestingly, not in vascular tissues, which the authors said could be due to the predominantly male, and veteran, sample.

Further, when the results were stratified by sex, the researchers identified several sex-specific loci. The group also found genetic correlations between migraine and disorders like PTSD, depression, and TBI. However, these were only correlations, as Mendelian randomization, a technique that the researchers used to determine whether there were causal relationships at play, found no such relationships between migraine and the other disorders. Finally, additional analysis of the findings pointed to drugs associated with the study’s novel loci. Here, the authors emphasized losmapimod, a drug known as a kinase inhibitor that has been tested in inflammatory conditions, and TLR4 antagonists, which also target inflammation.

“Our study sets the foundation for future ancestry-specific and sex-specific genomic migraine research and points to the role of neuroinflammatory and immune pathways in migraine pathology, consistent with the existing framework of migraine pathophysiology,” the authors concluded. “This study demonstrated the complex interplay between migraine and neuropsychiatric disorders, highlighting the role of the shared genetic architecture that contributes to this relationship.”

A new psilocybin trial
Psilocybin continues to attract interest as a potential treatment for migraine. Now, a small, exploratory randomized controlled clinical trial of this compound in people with migraine has been published in Headache. The study builds on the group’s earlier work, and had two aims: To test whether a pulsed regimen of psilocybin could be effective and safe, and to determine whether an active placebo could mimic the acute subjective effects of psilocybin, an important consideration if proper blinding in a psilocybin clinical trial is to be achieved.

The trial compared different doses of psilocybin – zero, one, or two doses – to the antihistamine diphenhydramine, the active placebo agent. The 18 adult migraine patients who took part in the study (16 were included in the final analysis) had at least two weekly migraine days at baseline, and received an initial dose of psilocybin, followed by a second dose one week later. Study participants who did not receive psilocybin received the active placebo. The researchers collected headache diary data up to eight weeks after the second drug session.

On the study’s primary outcome of change from baseline in weekly migraine days, the one- and two-dose psilocybin groups showed an approximately two migraine day/week (60%) reduction in migraine days, compared to (a still very notable) 40% reduction in the group receiving only diphenhydramine, at eight weeks; that the placebo group showed such a response raises questions about how much of psilocybin’s positive effects on migraine are actually due to psilocybin itself.

However, despite finding large effect sizes in the one- and two-dose psilocybin groups versus placebo, there were no statistically significant differences between the psilocybin groups and the diphenhydramine-only group, at two, four, or eight weeks. When looking at responder rates, the investigators also saw no significant differences between groups in the proportion of study participants showing a 50% or greater reduction in migraine days/per week at two, four, and eight weeks.

“That the primary outcome did not achieve statistical significance, even looking over several time periods in the eight-week diary, suggests that the observed effect sizes may not reflect true differences but rather variability inherent in a small sample,” the authors cautioned.

To test blinding integrity – whether the active placebo could mimic psilocybin’s subjective effects – the researchers asked participants, after each dosing session, to rate how confident they were in what drug they believed they had received. These drug confidence ratings suggested that diphenhydramine only partially substituted for psilocybin’s acute effects.

Despite the study’s negative findings, the sample size was small, and the authors say that additional research is necessary. “Further rigorous scientific investigation of psilocybin in migraine is warranted. These studies should include suitable active placebos, measures of expectation and blinding integrity, and be carefully tailored to migraine disease and its particular treatment standards,” they wrote.

Speaking of psychedelics
Despite their promise, psychedelics face obstacles as a potential treatment for migraine and other human health conditions. One issue is that these agents have very complex effects in the brain, and the mechanisms by which they produce those effects remain poorly understood.

To help surmount the hurdles, a recent study provided a “library” of 41 psychedelic compounds. This database includes not only tryptamines, the psychedelic class to which psilocybin belongs, but other classes as well including lysergamides (the class to which LSD belongs), phenethylamines (MDMA, for example), and piperazines.

As reported in an MSC news article, the researchers also described the receptors that the 41 compounds bind to. They discovered that the psychedelics activated many different kinds of G protein-coupled receptors (GPCRs), a class of receptors the researchers paid attention to since previous research showed that psychedelics activate GPCRs in the brain. This “promiscuous” pharmacology shows the complexity of how psychedelics act.

There is still a lot of work to do, and the study provides a resource to move that work forward, study first author Manish Jain told MSC in the news story.

“We need to study a lot more how these psychedelic drugs exert their effects, like studying their downstream effects on signaling pathways and epigenetic changes. And then we also need to study the neurophysiological mechanisms, such as investigating how psychedelics alter neuronal circuitry in the brain. Our study provides a resource for researchers to do this,” he said.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative.

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