Study register / Neurology / Restless Legs Syndrome

Restless Legs Syndrome

3 curated studies · 3 key studies · mechoulam.de

The evidence on restless legs syndrome is so far limited to individual cases and preliminary indications. A small controlled trial showed no clear benefit of cannabidiol.

Rating scheme

The letter rates the quality of a study, independently of its type. Every study type can receive any grade: a review can be B or C when it is small or weak, and an RCT can be S. The grade is a synthesis of study design, journal authority and clinical bindingness:

S
Highest evidence, large, methodologically first-rate studies or S3 guidelines
A
Strong evidence, solid, meaningful studies with a clear result
B
Moderate evidence, smaller or methodologically limited studies
C
Weak evidence, preliminary, indirect or contradictory findings
D
Lowest evidence, exploratory hints, single cases or expert opinion

Quality profile per study

To the left of each study there is a profile of four features, it shows the differences within a letter class.

Sample size ★
Number of participants (RCT) or included studies (review).
Blinding
Double-blind, single-blind or open-label.
Effect size
Clear benefit, mixed, no benefit or harm.
Citations / year ★
Age-adjusted citation frequency.

Key studies

3
  1. 01
    A
    Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies
    Suraev et al. ·2020 ·Sleep Medicine Reviews
    Read
  2. 02
    C
    The Effect of Cannabidiol for Restless Legs Syndrome/Willis-Ekbom Disease in Parkinson's Disease Patients with REM Sleep Behavior Disorder: A Post Hoc Exploratory Analysis of Phase 2/3 Clinical Trial.
    de Almeida et al. ·2023 ·Cannabis and cannabinoid research
    Read
  3. 03
    D
    Palmitoylethanolamide (PEA) in the treatment of restless legs syndrome: Rationale and case report.
    Bugnicourt et al. ·2026 ·Neurological sciences
    Read

Systematic Reviews and Meta-Analyses

Syntheses of RCT evidence following Cochrane and PRISMA standards.

1
A
Sample size ★★★★★
Blinding —
Effect size No benefit
Citations / year ★★★★★
● Key study
Suraev et al. ·2020 ·Sleep Medicine Reviews
163 citations

Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies

Design
Systematic Review
Sample
k = 26 Studien
Key finding

Insufficient evidence for routine clinical use of cannabinoid therapies for sleep disorders due to lack of research and moderate to high risk of bias.

Summary

Systematic review on cannabinoid therapies for sleep disorders; k=26 studies (14 preclinical, 12 clinical). For RLS, preliminary, promising evidence is reported that justifies further RCTs. Currently insufficient evidence for routine clinical use due to moderate to high risk of bias in the included studies. The review emphasizes the need for research on THC/CBD in RLS, sleep apnea, insomnia, PTSD nightmares, RBD and narcolepsy.

DOI 10.1016/j.smrv.2020.101339 ↗

Randomised Controlled Trials

Efficacy and safety evidence from controlled interventional trials.

1
C
Sample size ★★★★★
Blinding Double-blind
Effect size No benefit
Citations / year ★★★★★
● Key study
de Almeida et al. ·2023 ·Cannabis and cannabinoid research
12 citations

The Effect of Cannabidiol for Restless Legs Syndrome/Willis-Ekbom Disease in Parkinson's Disease Patients with REM Sleep Behavior Disorder: A Post Hoc Exploratory Analysis of Phase 2/3 Clinical Trial.

Design
RCT
Sample
n = 18 Pat.
Key finding

CBD showed no difference from placebo in reducing RLS/WED severity in patients with Parkinson's and RBD.

Summary

Post-hoc analysis of a phase II/III RCT in n=18 patients with RLS/WED and Parkinson's plus RBD; CBD 75–300 mg (n=6) vs. placebo (n=12) over 14 weeks. CBD showed no significant reduction in RLS severity (IRLSSG scale) compared to placebo. Negative finding, clinically informative but methodologically limited by small sample size and post-hoc nature.

DOI 10.1089/can.2021.0158 ↗

Real-World Evidence and Observational Studies

Data from routine clinical care, registries and mandatory reporting.

1
D
Sample size ★★★★★
Blinding —
Effect size Mixed
Citations / year ★★★★★
● Key study
Bugnicourt et al. ·2026 ·Neurological sciences
0 citations

Palmitoylethanolamide (PEA) in the treatment of restless legs syndrome: Rationale and case report.

Design
Fallserie
Sample
n = 1 Pat.
Key finding

In a case series with one gabapentin-treated patient, reduced painful RLS symptoms were shown after PEA supplementation, with no adverse events reported; the exact duration and magnitude of the effect remain unclear.

Summary

Case report of a gabapentin-treated RLS patient (n=1), in whom oral PEA supplementation (palmitoylethanolamide, an endocannabinoid lipid mediator) led to a subjective decrease in pain symptoms. No adverse events reported. Anecdotal evidence, no controlled intervention.

DOI 10.1007/s10072-025-08677-8 ↗

Ongoing and upcoming studies

Ongoing studies are still in the trial phase and are not evidence of efficacy or safety. The information serves educational purposes only.

1
  • NCT06863740 ClinicalTrials.gov Using Cannabis to Treat Restless Legs Syndrome Recruiting Start: 2025-07