A groundbreaking clinical trial has demonstrated that inhaled cannabinoids can provide superior pain relief compared to placebo for acute migraine attacks, marking the first randomized controlled study of standardized cannabinoid formulations for this indication. The research, conducted by the University of California at San Diego Health System, found that a combination of 6% tetrahydrocannabinol (THC) and 11% cannabidiol (CBD) delivered via vaporizer achieved significant improvements in pain relief and other key migraine symptoms.
Study Design and Methodology
The randomized, double-blind, placebo-controlled crossover trial enrolled 92 patients who treated up to four acute migraine attacks over a one-year period. Participants received cannabis flower from the National Institute on Drug Abuse drug supply program, delivered through research-grade Storz & Bickel Mighty vaporizers. The study tested four different formulations in randomized order: 6% THC alone, 11% CBD alone, a combination of 6% THC and 11% CBD, and placebo.
Patients were instructed to treat their migraine attacks within four hours of onset, with outcomes measured using a smartphone application. The primary endpoint was pain relief at two hours post-treatment, with secondary endpoints including pain freedom and relief of most bothersome symptoms.
Primary Efficacy Results
The THC-CBD combination demonstrated superior efficacy across multiple endpoints. According to Dr. Nathaniel M. Schuster, headache neurologist and associate clinic director at UC San Diego Center for Pain Medicine, who presented the final results at the 2025 American Headache Society Annual Meeting, "the THC-CBD mix was superior to placebo for pain relief, pain freedom, and most bothersome symptom freedom at 2 hours, with sustained benefits at 24 and 48 hours."
The combination formulation significantly outperformed placebo on the primary endpoint of pain relief at two hours. Additionally, it achieved positive results on co-key secondary endpoints of pain freedom at two hours and most bothersome symptom freedom at two hours, while THC alone showed mixed results and CBD alone was not effective.
Symptom-Specific Outcomes
Beyond pain relief, the study evaluated the treatment's impact on common migraine-associated symptoms. The cannabinoid combination successfully reduced light and sound sensitivity at both two and 24 hours post-treatment. However, researchers noted that the formulation had no significant effect on nausea and vomiting symptoms.
The sustained efficacy was particularly notable, with benefits maintained for 24 to 48 hours after initial treatment, suggesting potential advantages over some traditional acute migraine therapies that may require repeated dosing.
Safety and Tolerability Profile
The study documented expected adverse effects associated with THC administration in both the THC-alone and THC-CBD combination groups. However, a key finding was that adverse effects were reduced when THC was combined with CBD compared to THC alone. As Schuster explained, "CBD is a nonallosteric negative modulator of the CB1 receptor, and so it's been known that it decreases the psychoactive adverse effects that people get from THC."
The researchers emphasized that the THC potencies tested were lower than those typically found in cannabis products available at US dispensaries, making them less likely to cause intoxication while still providing medicinal benefit.
Functional Outcomes and Patient Activity
Post hoc analyses addressed concerns about whether patients might report symptom improvement while remaining functionally impaired. The results were reassuring: return to usual activity rates exceeded 60% for both the THC-CBD combination and THC alone at two hours, compared to slightly below 60% for placebo. Only 12-13% of patients across all groups were sleeping at the two-hour mark, and approximately 20% were lying in bed, indicating that most patients were able to resume normal activities.
Subgroup Analysis Findings
The trial included comprehensive subgroup analyses that revealed important clinical insights. Patients with allodynia, a condition involving scalp sensitivity that typically makes migraine treatment more challenging, still showed reasonable response rates to the cannabinoid combination, though overall treatment responses were lower in this population.
Particularly significant was the inclusion of chronic migraine patients, defined as those with more than 15 headache days and more than 8 migraine days per month. Schuster noted that "these are patients who historically have not been included in acute migraine research studies by industry, with the concern that including more refractory patients might lead to negative studies." The results showed that two-hour pain freedom and most bothersome symptom freedom responses were very similar whether patients had episodic or chronic migraine.
Treatment Timing Considerations
Analysis of treatment timing revealed that patients who treated their migraine attacks within 0-2 hours of onset achieved higher response rates compared to those who treated between 2-4 hours after onset. However, reasonable response rates were still observed in the later treatment window. Schuster advised that "it's better to treat early and this is true pretty much across all migraine treatments. However, if you are treating during that 2-4 hour range... there is still a reasonable response rate."
Clinical Context and Unmet Need
The study addresses a significant unmet medical need in migraine management. Migraine affects over one billion people worldwide, including 38 million Americans, and is the second leading cause of years lived with disability globally according to the Global Burden of Disease Study 2019. Many patients report inadequate relief from traditional therapies and often discontinue treatment.
As the researchers noted, "while migraine sufferers often ask healthcare professionals about the potential of cannabinoids in managing migraine, there has been a lack of data to support their use." This study represents the first prospective, randomized clinical trial of standardized cannabinoid potencies for acute migraine treatment.
Research Implications and Future Directions
The study was specifically designed to inform clinical practice rather than support regulatory approval. Schuster emphasized that "we weren't trying to bring something to market. This was not an industry-funded study. This was a study conducted to test what patients are already doing, and we know that many American people with migraine are self-treating with cannabinoids."
The researchers acknowledge that additional studies are needed to evaluate repeated administrations and long-term use of cannabinoids for migraine. The current legal landscape, with cannabis legal for medical use in 38 of 50 US states and for recreational use in 24 states, provides a framework for further research and potential clinical implementation.
This landmark study provides the first rigorous evidence base for healthcare professionals counseling patients about cannabinoid use for acute migraine treatment, potentially opening new therapeutic avenues for this debilitating condition.
