Cannabis Cuts Migraine in First Placebo-Controlled Trial

MINNEAPOLIS — In the first placebo-controlled trial of vaporized cannabis for acute migraine, patients experienced greater relief from pain and other symptoms than those receiving a placebo.

During a migraine attack, participants who inhaled a combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) reported significant pain reduction and improvement in their most bothersome symptom within 2 hours of treatment.

The findings suggest that a THC-CBD combination may offer a viable treatment option for acute migraine in patients who do not respond to standard therapies, study investigator Nathaniel M. Schuster, MD, pain and headache neurologist and associate professor of anesthesiology at the UC San Diego (UCSD) Health Center for Pain Medicine, told Medscape Medical News.

“This is the first placebo-controlled study in this space. It’s the first real — to me — compelling evidence for the antimigraine effects of cannabis in humans,” he said.

The findings were presented here at the American Headache Society (AHS) Annual Meeting 2025.

Undisclosed Cannabis Use Common

Some patients are likely already using cannabis to self-medicate during migraine attacks, Schuster noted. He pointed to a recent cross-sectional survey showing that 31.0% of individuals with chronic pain reported using cannabis for pain relief. In another cross-sectional study of 1429 medical cannabis users, 61.2% reported they used it specifically to manage chronic pain.

Schuster noted that cannabis use may be even more common among those with migraine. However, patients often don’t disclose cannabis use to their physicians. Uncertain about how their doctors might react, some individuals may choose to self-medicate or combine cannabis with prescribed treatments without informing healthcare providers.

To determine the efficacy of vaporized cannabis for acute migraine, the investigators conducted a randomized, double-blind, placebo-controlled crossover trial. It included 92 patients with a history of migraine with or without aura who received treatment for a moderate-to-severe migraine attack using vaporized cannabis or a placebo between November 2020 and February 2023.

With respect to cannabis use, 37 (40.2%) of study participants reported they had used it within the past year, 21 (22.9%) more than a year ago, and 33 (35.9%) had never used it.

Participants had a median age of 41 years, with the majority being women (82.6%). Participants had a median onset age of 20 years, with a median of 15 headache days and six migraine days per month. In addition, 30.4% had chronic migraine.

For each migraine attack, patients received one of four randomized treatments: 6% THC, 11% CBD, a combination of 6% THC and 11% CBD, or a placebo. All cannabis was provided through the National Institute on Drug Abuse Drug Supply Program.

Instructions for using vaporized cannabis were provided by a research coordinator during the screening visit and reinforced through a custom smartphone app, which also captured real-time data on outcomes and safety events. Patients self-administered the treatment or placebo using the Foltin Uniform Puff Procedure with the vaporizer.

Patients were not permitted to use any migraine treatment before the onset of an attack but were permitted to use standard acute therapy as a rescue medication if needed after 2 hours. They were also prohibited from repeating the cannabis dose before reporting outcomes at the 2-hour mark.

The study’s primary outcome was pain relief at 2 hours. Secondary outcomes included pain freedom and relief from the most bothersome symptom at the same timepoint. Patients also recorded improvements in photophobia, phonophobia, nausea, and vomiting, as well as sustained pain and symptom freedom out to 48 hours.

Overall, 73 patients experienced at least one migraine attack. This included 52 patients with four attacks, six with three attacks, six with two attacks, and nine with a single attack.

Efficacy and Tolerability

A total of 247 migraine attacks were included in the intent-to-treat analysis, with 234 attacks providing 2-hour outcome data for the modified intent-to-treat analysis. Among these 234 treated attacks, patients identified photophobia as the most bothersome symptom in 137 cases (58.5%), nausea in 60 cases (25.6%), and phonophobia in 37 cases (15.8%).

At 2 hours, 68.9% of patients in the THC group, 67.2% in the THC/CBD group, 52.6% in the CBD group, and 46.6% in the placebo group reported pain relief. Both the THC group (odds ratio [OR], 2.846; 95% CI, 1.218-6.652; P = .008) and the THC/CBD group (OR, 2.846; 95% CI, 1.218-6.652; P = .016) showed significantly greater pain relief than the placebo group.

The 2-hour pain freedom was achieved by 34.5% of patients in the THC/CBD group, 27.9% in the THC group, 22.8% in the CBD group, and 15.5% in the placebo group. The THC/CBD group had significantly improved 2-hour pain freedom compared with the placebo group (OR, 3.295; 95% CI, 1.235-8.795; P = .017).

Freedom from the most bothersome symptom at 2 hours was also significantly higher in the THC/CBD group than the placebo group (60.3% vs 34.5%; OR, 3.332; 95% CI, 1.445-7.637; P = .005), but not in the THC (47.5%) or CBD (42.1%) groups.

Compared with the placebo group, the THC/CBD group also had significantly higher rates of sustained pain relief and symptom freedom up to 24 and 48 hours. Improvements were also seen in photophobia (56.9% vs 37.9%) and phonophobia (74.1% vs 51.7%), though there were no significant differences in relief from nausea at 2 hours or vomiting at 48 hours.

Schuster noted initial concern that the observed effect on the most bothersome symptoms might be driven primarily by nausea relief, rather than a broader symptom response.

“That’s certainly not what we found. What we found is that it does have effects on the photophobia and phonophobia, and that’s an important finding,” he said.

At 1 hour, sleepiness was more common in the THC (41.4%), THC/CBD (44.6%), and CBD (37.5%) groups compared with the placebo group (26.7%). Euphoria was also more frequently reported in the THC (36.2%) and THC/CBD (28.6%) groups compared with the CBD (8.9%) and placebo (7%) groups.

Cognitive impairment followed a similar pattern, with higher rates in the THC (34.5%) and THC/CBD (21.4%) groups than in the CBD (14.3%) and placebo (7%) groups.

By 2 hours, sleepiness increased across all groups, with rates highest in the CBD group (50.9%), followed by the THC (42.6%), placebo (37.9%), and THC/CBD (31.0%) groups.

No Serious Adverse Events

At 2 hours, rates of euphoria were lower than at 1 hour but remained higher in the THC (26.2%) and THC/CBD (12.1%) groups than in the CBD (7.0%) and placebo (5.2%) groups.

Similarly, cognitive impairment was more common in the THC (26.2%) and THC/CBD (12.1%) groups than in the CBD (7.0%) and placebo (5.2%) groups.

The fact that the THC group had a higher rate of euphoria and cognitive impairment than the THC/CBD group was an expected finding. “It’s known that CBD is a noncompetitive, negative allosteric modulator of the CB-1 [cannabinoid receptor 1] receptor that decreases the psychoactive side effects of the THC,” Schuster said.

Patients rated their level of intoxication on a 0-10 scale at 1 and 2 hours post-treatment. At 1 hour, the THC group reported an average intoxication rating of 3.5; the THC/CBD group, 2.4; the CBD group, 1.5; and the placebo group, 0.6. By 2 hours, all groups reported reduced intoxication levels: THC at 2.4, THC/CBD at 1.3, CBD at 0.9, and placebo at 0.4.

Schuster noted that patients can experience therapeutic benefits for migraine without needing to use recreational-level doses.

At 1 hour, adverse events were reported by 31.0% of patients in the THC group, 19.6% in both the THC/CBD and CBD groups, and 5.0% in the placebo group. By 2 hours, rates declined to 18.0% in the THC group, 6.9% in the THC/CBD group, 7.0% in the CBD group, and 5.2% in the placebo group.

The most common side effects — sedation and slowness — were primarily reported in the THC-containing groups.

The researchers reported no serious adverse events, which Schuster noted was a potential concern. However, there were no reports of paranoia, dysphoria, after-hours calls, or emergency room visits in the study, he said.

At 2 hours, 29.3% of patients believed they had received the placebo, 20.7% thought they received the THC/CBD combination, 13.1% guessed THC, and 10.5% guessed CBD. Meanwhile, 49.2% of patients correctly identified they had received THC, and 46.6% correctly identified the THC/CBD combination.

What to Tell Patients

Patients who have never used other acute treatments should start with standard-of-care treatments, such as a triptan or calcitonin gene-related peptide inhibitor, before looking to cannabis as an option, Schuster said.

When counseling patients who ask about cannabis or report cannabis use, neurologists should consider that the THC/CBD arm of the study showed a similar effect to THC alone with fewer side effects. Another consideration is that the study used vaporized cannabis flower, which is seen as a safer option than waxes, oils, and smoking cannabis, he said.

It is also important to not overuse cannabis as an acute migraine treatment, he noted. “A lot of neurologists, myself included, suspect that there could be medication overuse headache with [using] cannabinoids frequently,” he said.

“When I counsel patients now, I say, ‘Look, we were only studying infrequent — four times over the course of a year — administration.’ So, I encourage patients to certainly limit it to under 10 times per month and to optimally be using it really for those migraines that would not respond to standard-of-care therapy,” he added.

More Research Needed

Commenting on the research for Medscape Medical News, Amaal J. Starling, MD, associate professor of neurology at the Mayo Clinic in Phoenix, said that the efficacy and safety of cannabis as a migraine treatment are not well understood.

“Even though THC/CBD use for the treatment of migraine is a popular topic for patients, there is a paucity of robust clinical trials on this topic. However, people are using cannabis to treat migraine and migraine symptoms, like nausea,” she said.

Starling said the blinding analysis was a strength and noted that patients did not appear to be able to guess whether they had received cannabis despite having used it before. While the study found THC and THC/CBD together improved migraine pain compared with a placebo group, there was a high rate of side effects, and it was a single-center study.

“Generalizability of efficacy and consistency of efficacy are still unknown,” she said.

“We need additional studies to replicate this work in larger populations. In addition, we need to know the longer-term implications of cannabis use for the treatment of migraine,” she added.

Schuster reported being a consultant to Averitas Pharma, Inc., Eli Lilly and Company, Lohocla Research Corporation, Salvia Cosmeceuticals Pvt. Ltd., Schedule 1, Syneos Health, Syqe, and Vertex; served on the advisory boards of Lundbeck and Rapport; and held stock in AltaMont. Schuster also reported that his institute received support from the National Institutes of Health, National Institute of Neurological Disorders and Stroke, Migraine Research Foundation, National Center for Complementary and Integrative Health, ShiraTronics, UCSD Academic Senate, and UCSD Department of Anesthesiology RAG. Starling reported no relevant conflicts of interest.