Restless legs syndrome is one of those conditions that sounds almost trivial until you have lived through it. The irresistible urge to move the legs, usually worse in the evening and at night, can delay sleep onset by an hour or more and fragment whatever rest does come. For the millions of people who manage RLS, the treatment landscape has changed significantly in recent years. Dopamine agonists, once the go-to therapy, are now used with caution because of the risk of augmentation, a paradoxical worsening of symptoms. The current first-line options, alpha-2-delta ligands such as gabapentin and pregabalin, work well for many but not for everyone. This has left clinicians and researchers looking for new pharmacological avenues, and a recent exploratory trial from Spain suggests that a fixed-dose combination of THC and CBD may be worth a closer look.
What they found
The study, led by Laura Lillo Triguero and colleagues at Hospital Universitario de Getafe and Hospital Ruber Internacional in Madrid, enrolled 18 adults with moderate-to-severe RLS. Sixteen of the participants had multiple sclerosis with secondary RLS, while two had idiopathic RLS. At baseline, the group was scoring an average of 22.44 on the International Restless Legs Scale (IRLS), which places them firmly in the severe range. Their sleep, measured by actigraphy, was also compromised: mean sleep efficiency sat at 83.64 percent, sleep latency at 26.71 minutes, and wake-after-sleep-onset (WASO) at just over 40 minutes per night.
All participants received a fixed-dose combination of 2.7 mg delta-9-tetrahydrocannabinol (THC) and 2.5 mg cannabidiol (CBD), with the option to titrate at week four. At the one-month mark, IRLS scores had dropped significantly, and the improvement held at three months (p < 0.001 for both time points). After one year, 12 of the original 18 participants (66.66 percent) remained on treatment, and their IRLS scores showed sustained improvement (p = 0.000). Among the sleep metrics, WASO showed a statistically meaningful reduction (p = 0.015), while sleep latency and overall sleep efficiency did not change significantly. Daytime sleepiness, measured by the Epworth Sleepiness Scale, and quality of life, measured by the EQ-5D, also did not show significant shifts in this small sample.
Why it matters
The rationale for trying cannabinoids in RLS is grounded in neurobiology. Glutamate dysregulation in the striatum is thought to play a role in the condition, and cannabinoids are known to inhibit glutamate release in that region. This mechanism offers a different route of action than either dopamine agonists or alpha-2-delta ligands, which is important because RLS patients often cycle through multiple treatments over a lifetime. Having another class of drugs with a distinct mechanism could provide options for those who do not respond to existing therapies or who develop tolerance.
The sustained adherence rate is also worth noting. A two-thirds continuation rate at one year in an open-label setting (where patients know exactly what they are taking) suggests that the combination was well tolerated enough for most participants to stay on it. That is a meaningful signal, even if it is not the same as a definitive efficacy readout.
Limits
This is an exploratory, open-label trial with no placebo control, which means placebo effects cannot be ruled out. The sample is small at 18 participants, and the majority had RLS secondary to multiple sclerosis rather than primary idiopathic RLS, so the results may not generalize to all RLS populations. The authors disclose industry relationships with several pharmaceutical companies, which is standard for investigator-initiated work in this space but worth noting. Without a randomized, placebo-controlled phase, the efficacy signal remains suggestive rather than conclusive. Larger, controlled trials in idiopathic RLS patients would be needed before any clinical recommendations could be made.
Bottom line
THC/CBD (2.7 mg / 2.5 mg) produced significant and sustained improvements in RLS severity over 12 weeks and one year in a small, open-label study, with two-thirds of patients still on treatment at the one-year follow-up. Wake-after-sleep-onset also improved. These results are encouraging enough to warrant a properly powered, placebo-controlled trial, but they do not yet support routine clinical use. For RLS patients and their clinicians, this study adds cannabinoids to the list of mechanisms worth watching. Not yet a treatment option, but a genuine signal in a field that needs more of them.
Source
Lillo Triguero L, Pilo de la Fuente B, Diaz Diaz J, Lopez Riolobos C, Aladro Benito Y. Tetrahydrocannabinol/cannabidiol in the treatment of restless legs syndrome. J Neurol. 2026;273(7):440. DOI: 10.1007/s00415-026-13975-y. PMID: 42387200.