Effect of Cannabinoids use on Symptoms of Restless Leg Syndrome among Adults: A Scoping Review

Abstract

Background and Objectives:

Restless leg syndrome (RLS) is a neurological disorder characterized by an irresistible urge to move the legs, often accompanied by unpleasant sensations such as tingling, crawling, or aching. Symptoms typically worsen during periods of rest or inactivity, particularly in the evening or at night. This scoping review aimed to synthesize the existing literature on the efficacy of cannabis and cannabinoids in alleviating symptoms associated with RLS.

Methods:

A comprehensive search of electronic databases—including PubMed, Embase, Scopus, Cochrane Library, Google Scholar, ClinicalKey, and ClinicalTrials.gov—was conducted from database inception to April 30, 2025. Various keywords related to cannabis, cannabinoids, and RLS were used to identify relevant clinical studies.

Results:

A total of 5,370 records were identified, of which seven studies met the inclusion criteria for final review. The evidence suggests that cannabis or cannabidiol may improve or prevent RLS symptoms.

Conclusions:

Current evidence indicates that cannabis, in various forms, may alleviate or prevent symptoms of RLS through multiple mechanisms. However, the existing literature is limited to case reports, cross-sectional surveys, and post hoc analyses. In the absence of high-quality randomized controlled trials, the evidence is insufficient to support clinical recommendations at this time.

Introduction

Restless leg syndrome (RLS), also known as Willis–Ekbom disease (WED), affects approximately 5–10% of the global population, with 1–3% of the population being afflicted with moderate-to-severe symptoms.[1] Differences in the prevalence have been observed across geographical areas, with lower prevalence in Asian countries.[1] It is characterized by an irresistible urge to move the legs, often accompanied by unpleasant sensations such as tingling, crawling, or aching, typically worsening during periods of rest or inactivity, particularly in the evening or night.[1] For a good number of patients, RLS causes sleep onset insomnia, depression, and increased risk of suicide.[1,2,3,4]

Although the exact etiology of RLS remains unclear, dysfunctions in dopaminergic pathways, iron metabolism, and genetic and environmental factors are implicated in its pathophysiology.[5] Few studies have also illustrated the roles of other neurotransmitters such as gamma-aminobutyric acid (GABA) and endogenous opioids.[5,6]

The available treatment modalities include dopamine agonists, alpha-2-delta calcium channel ligands, opioids, and iron supplementation, which have been reported to provide relief.[7] However, available therapeutic options are not without adverse effects of their own and may not provide an equal amount of relief to all patients.[8,9] Most disabling adverse effects with dopaminergic agonists include impulsivity and augmentation.[7,9] Similarly, alpha-2-delta ligands increase the risk of ataxia, sleepiness, depression, and weight gain.[7,9] Opioid agonists, on the other hand, are generally reserved for treatment-refractory cases in view of their abuse potential, chemical dependence, and overdose.[7,8,9] These limitations underscore the need for alternative treatment options, both in terms of pharmacological and non-pharmacological therapies. A few studies have reported cannabis and its analogs to be effective in the management of RLS.[8]

Cannabis and its components have been reported in several studies as candidate molecules for a host of psychiatric and neurological conditions.[10] Cannabis exerts its effects on the human brain and body through a complex signaling system known as the endocannabinoid system (ECS).[10] The ECS consists of ligand-gated receptors (CB1 and CB2) and endogenous lipid ligands.[10] It modulates various physiological processes like mood regulation, pain perception, memory, appetite, and motor control.[10] Endocannabinoids are lipid-based neurotransmitters modulating the ECS through cannabinoid receptors. Among all endocannabinoids, anandamide and 2-arachidonoylglycerol are the most extensively studied endocannabinoids.[11]

Despite growing interest, literature that has investigated the role of cannabinoids in RLS has not been systematically reviewed.[8] Case reports, case series, and a few original studies have looked into the usage of cannabidiol (CBD), medical cannabis, and other analogs of cannabis in patients with RLS.[12,13,14,15] Literature regarding the possible application of cannabinoids as a pharmacological agent has been scarce and has been plagued with methodological inconsistencies, such as variations in cannabis dosage, formulation, and administration routes, which complicate the interpretation of such studies.[16] Therefore, a comprehensive review of the current literature is warranted to better understand the association between cannabis and RLS and its effect on individual parameters of the disorder. Multiple databases (Cochrane, Google Scholar, PubMed, EMBASE, and SCOPUS) were searched to determine whether a similar review had been conducted to address the above question as of January 2025. Based on the lack of related literature, we planned the present study.

This study aimed to assess the available evidence regarding the effectiveness of cannabinoids in improving symptoms of RLS in adults, compared with placebo or no treatment. By synthesizing findings from clinical and observational studies, this paper aims to provide a clearer understanding of the role of CBD in the management of RLS and to identify avenues for future research.

Methods

This study was planned to answer the question: Whether cannabis or medical cannabis (intervention) improves symptoms of RLS (outcome) compared to no treatment or placebo (comparator) among adult patients with RLS (population). The study adhered to Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA ScR) guidelines [Supplementary Table 1].

Supplementary Table 1.

PRISMA-ScR checklist

Section		Item		PRISMA-ScR checklist item		Reported on page #
Title
Title		1		Identify the report as a scoping review.		1
Abstract
Structured summary		2		Provide a structured summary that includes (as applicable): background, objectives, eligibility criteria, sources of evidence, charting methods, results, and conclusions that relate to the review questions and objectives.		1
Introduction
Rationale		3		Describe the rationale for the review in the context of what is already known. Explain why the review questions/objectives lend themselves to a scoping review approach.		3
Objectives		4		Provide an explicit statement of the questions and objectives being addressed with reference to their key elements (e.g., population or participants, concepts, and context) or other relevant key elements used to conceptualize the review questions and/or objectives.		4
Methods
Protocol and registration		5		Indicate whether a review protocol exists; state if and where it can be accessed (e.g., a Web address); and if available, provide registration information, including the registration number.		Not Registered
Eligibility criteria		6		Specify characteristics of the sources of evidence used as eligibility criteria (e.g., years considered, language, and publication status), and provide a rationale.		4
Information sources*		7		Describe all information sources in the search (e.g., databases with dates of coverage and contact with authors to identify additional sources), as well as the date the most recent search was executed.		4
Search		8		Present the full electronic search strategy for at least 1 database, including any limits used, such that it could be repeated.		5
Selection of sources of evidence†		9		State the process for selecting sources of evidence (i.e., screening and eligibility) included in the scoping review.		4
Data charting process‡		10		Describe the methods of charting data from the included sources of evidence (e.g., calibrated forms or forms that have been tested by the team before their use, and whether data charting was done independently or in duplicate) and any processes for obtaining and confirming data from investigators.		5
Data items		11		List and define all variables for which data were sought and any assumptions and simplifications made.		5
Critical appraisal of individual sources of evidence§		12		If done, provide a rationale for conducting a critical appraisal of included sources of evidence; describe the methods used and how this information was used in any data synthesis (if appropriate).		5-6, Supplementary tables 2-5
Synthesis of results		13		Describe the methods of handling and summarizing the data that were charted.		6–10
Results
Selection of sources of evidence		14		Give numbers of sources of evidence screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally using a flow diagram.		6
Characteristics of sources of evidence		15		For each source of evidence, present characteristics for which data were charted and provide the citations.		14–18
Critical appraisal within sources of evidence		16		If done, present data on critical appraisal of included sources of evidence (see item 12).		Supplementary tables 2–5
Results of individual sources of evidence		17		For each included source of evidence, present the relevant data that were charted that relate to the review questions and objectives.		19,20
Synthesis of results		18		Summarize and/or present the charting results as they relate to the review questions and objectives.		19,20
Discussion
Summary of evidence		19		Summarize the main results (including an overview of concepts, themes, and types of evidence available), link to the review questions and objectives, and consider the relevance to key groups.		10–13
Limitations		20		Discuss the limitations of the scoping review process.		13
Conclusions		21		Provide a general interpretation of the results with respect to the review questions and objectives, as well as potential implications and/or next steps.		13–14
Funding
Funding		22		Describe sources of funding for the included sources of evidence, as well as sources of funding for the scoping review. Describe the role of the funders of the scoping review.		Not applicable

Search criteria

Relevant clinical studies were identified by using the electronic databases from inception until April 30, 2025 using the following Boolean expression: ((Cannabis OR Cannabinoid OR marijuana OR cannabidiol OR CBD OR Tetrahydrocannabinol OR THC OR Cannab*) AND (“Restless legs syndrome” OR RLS OR “Willis Ekbom’s syndrome”)). The following databases were searched: PubMed [Supplementary Table 2], Embase, Scopus, Cochrane, Google Scholar, Clinical Key, and Clinicaltrials.gov.

Supplementary Table 2.

Search Details of one database: Pubmed

		Search item		Number of articles
1.		Cannabis AND “RLS”		12
2.		Cannabinoid AND “RLS”		5
3.		Cannabidiol AND “RLS”		4
4.		Marijuana AND RLS		12
5.		Cannabis AND “restless leg syndrome”		3
6.		Cannabidiol AND “restless leg syndrome		1
7.		Cannabinoid AND “restless leg syndrome”		2
8.		Marijuana AND “restless leg syndrome”		3
9.		Marijuana AND “Willis Ekbom syndrome”		0
10.		Cannabis AND “Willis Ekbom Syndrome’		0
11.		Cannabidiol AND “Willis Ekbom Syndrome”		0
12.		Cannabinoid AND “Willis Ekbom Syndrome”		0
13.		After removing duplicates, total studies		34

Inclusion and exclusion criteria

Inclusion criteria included observational studies, randomized controlled trials (RCTs), case series, and case reports that have included patients with RLS, have reported the effect of cannabis/CBD use on the symptoms of RLS, published in peer-reviewed journals in the English language, and with full text available. Unpublished clinical trials were included only if the data were available and accessible. In addition, the bibliography of the full texts was also screened for missing papers. If any relevant research papers were found, they were also accessed and included. However, review articles, animal studies, and unpublished manuscripts were excluded.

Search methodology

The primary literature search was undertaken independently by two authors (SS and RG). All the searches were downloaded to reference management software Zotero. Duplicates were removed. Abstracts of the articles were screened to ensure that the study addressed the research question posed by these authors. If the study did not meet the inclusion criteria, it was excluded. Full texts of the remaining articles were downloaded, and they were again screened for inclusion and exclusion criteria by two authors (SS, RG). Studies meeting any of the exclusion criteria were excluded. Conflicts, if any, were resolved in consultation with the third author (LKS). The bibliographies of the included studies were searched to identify any missing studies during the primary search. The same process was followed for the missing studies.

Data extraction

The following study characteristics were extracted: author(s) and year of publication, type of study, sample size, age and gender distribution of participants, comorbidities, method used for diagnosing RLS, method for assessment of severity of RLS, type of cannabis used or prescribed, comparator if any, duration and dose of cannabis/cannabinoid used or prescribed, and the effect of cannabis on the symptoms of RLS.

Assessment of quality of studies

The quality of the studies was assessed by two authors independently (NK and LKS). Considering the variety of available evidence, JBI’s critical appraisal tools for case reports, case series, analytical cross-sectional studies, and case-control studies were used for the assessment of quality.[17,18] Discrepancy in the assessment, if any, was resolved with the consultation of the third author (RT).

Results

A total of 5,370 records were identified (Cochrane = 5, ClinicalTrials.gov = 9, Scopus = 71, Embase = 152, PubMed = 33, and Google Scholar = 5,100). After assessing for duplicates, 60 articles were removed. After screening for titles and abstracts, 16 articles were identified for full-text reading.[13,14,15,19,20,21,22,23,24,25,26,27,28,29,30,31] Full texts revealed that two were conference abstracts, two did not report data regarding RLS, one was a physician’s survey, one was a clinical trial that had not been started, two showed indirect evidence, and one was a book chapter; hence, they were excluded.[13,15,20,21,23,24,27,30,31] Bibliographies of the remaining seven articles were searched for papers that might have been missed during the preliminary search. However, the bibliography did not show any missing studies. Finally, seven studies were included in the review [Figure 1].

Figure 1.

PRISMA flow diagram showing process of inclusion of studies in the scoping review. PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses

Extraction of data

Extracted data from the included studies are shown in Table 1. Megelin and Ghorayeb[26] described six adult patients who had symptoms of RLS for 5–23 years; symptoms were very severe despite continued therapy (dopamine agonists in two patients; alpha-2-delta ligand antagonists in two patients, and opiates in two patients) and adequate iron stores. All patients spontaneously used cannabis and reported complete relief in their symptoms.[26]

Table 1.

Data extracted from the included studies

Author(s) (year of publication)		Geographical area		Study type		Study sample		Objective(s) of the study		Formulation of cannabis used/dosage		Type of cannabis (medical/ illicit)		Outcomes/ follow-up outcomes		Adverse events, if any		Diagnostic criteria for RLS used
Megelin & Ghoyareb (2017)[26]		France		Case series, observational		Adult Patients (n=6; 4 females, 2 males). All patients had been on other combinations of RLS medications, but inadequate response		Study reporting the spontaneous total remission of RLS symptoms following cannabis use.		Cannabis in Smoking form=5 patients Oral Sublingual Cannabidiol=1 patient		Combination of medical and illicit		All patients total relief of RLS symptoms as well as complete improvement of sleep quality (charts in the study documented 100% improvement)		1 out of 5 switched to smoking cannabis to only periods of exacerbation due to nausea		IRLS RS
Ghoyareb (2019)[14]		France		Case series; Observational		Adult patients (n=12; males=11, females=1) diagnosed with severe to very severe RLS; all patients had been treated with one or more medications for RLS without significant relief		To report the potential benefit of cannabis use in patients with refractory RLS		Cannabis in smoking form in all 12 patients; later 3 patients shifted to over-the-counter sublingual cannabidiol		Illicit (later 3 used medical form)		Out of 12, 11 reported improvements with cannabis, 1 did not report any relief in RLS symptoms 3 patients who shifted to s/l cannabidiol reported stronger efficacy of smoked form of cannabis in symptom relief		Panic attack in 1 subject, rest tolerated well		IRLS RS
Samaha et al.(2020)[25]		Canada		Questionnaire-based survey, cross- sectional study		ESKD adult patients (n=192; males=114, females=78)		To assess the frequency and severity of RLS and pruritus in ESKD population with the current treatment Options and to estimate patient use of cannabinoids for these symptoms		Not mentioned		N/A		86 Participants (45) reported current or previous symptoms of RLS. 14 participants with RLS had used cannabis in the past to treat their symptoms; 7 experienced an improvement in symptom management (At least 50%), 3 had no effect and rest answers not available		Not mentioned		IRLS RS
Yenilmez et. al (2020)[22]		Germany		Nationwide Questionnaire based survey (self-developed)		Parkinson’s Disorder (PD) community (n=1348; males=737, females=609) 113 cannabis users due to PD; 28 used cannabis for RLS		To assess the PD community’s perception of medical cannabis (MC) and patients’ experience with MC.		Cannabis applied in the form of medical liquid/drops (59%), smoking marijuana (24.8%), marijuana taken orally (9%), medical capsules (4%)		Combination of medical and illicit		6 out of 28 (21%) patients with RLS subjectively improved; 6 no improvement; 3 not answered; 13 no improvement in any symptoms of PD		Most common s/e- fatigue, dizziness, ravenous appetite; 9 discontinues cannabis due to s/e (these s/e are from the overall cohort, not specific to subjects suffering from RLS)		Not mentioned
de Almeida et al. (2023)[29]		Brazil		A post hoc exploratory analysis of a Double- blind, placebo-controlled clinical trial, followed up for 14 weeks		Adult (>18years) male patients with Parkinson’s disorder; 18 total, 6 received CBD capsules, rest received placebo		post hoc exploratory analysis to evaluate CBD´s efficacy to improve the severity of RLS symptoms in patients with PD and RBD		Cannabidiol capsules		Medical cannabis) 75-300 mg)		CBD showed no reduction in the severity of RLS/WED manifestation in patients with PD and RBD				IRLS G
Collister et. al (2022)[28]		Canada		Questionnaire based survey		Adult Canadian patients with kidney disease (n=320, males=187, females=125), 160 previous cannabis users. 25/ 160 were using cannabis for RLS symptom relief		Study assessing regarding their views and previous experiences with cannabis, interest in using it to treat individual symptoms		No info for mode of application for cohort with RLS available. Among 160, smoked cannabis=140, cannabis oil=69, edibles=92. Vaping, spray and topical usage were uncommon		Both illicit and medical forms used		Info regarding efficacy of cannabis on RLS not available; 271 patients were interested in trying cannabis as a part of clinical trial for symptom control; 123 patients wanted to try cannabis for RLS symptom relief		Not mentioned		Not mentioned
Kimless et al (2025)[19]				Clinical trial; prospective study (2 weeks)		Adult patients (n=10)		To investigate the benefits of cannabidiolic acid topical cream for the treatment of restless leg syndrome		Cannabidiolic acid cream topical application every night 30-45 minutes before bed for 20 seconds on the affected areas. Reapplication if required		Medical form		Statistically and clinically significant improvement in RLS symptoms (average score 25.0 on RLS rating scale pre-treatment and avg score 8 post- treatment); reduced sleep disturbances and daytime tiredness in all patients		Not mentioned		RLS rating scale and PGIC (patient’s Global Impression of Change)

RLS: Restless leg syndrome, IRLS RS: International Restless Leg Scale Revised, IRLSSG: International Restless Legs Syndrome Study Group (IRLSSG), ESKD: End-stage kidney disease, CBD: Cannabidiol, PD: Parkinson’s disease, WED: Willis–Ekbom Disease, RBD: Rapid eye movement sleep behavior disorder, MC: Medical cannabis, PGIC: Patient’s Global Impression of Change, WED: Willis–Ekbom disease, s/e: Side effect, s/l: Sublingual

Ghorayeb[14] reported the effect of recreational marijuana smoking in patients with severe to very severe RLS, and were concomitantly on medications viz., dopamine agonists (n = 4), pregabalin (n = 1), pramipexole with codeine (n = 1), pramipexole with diazepam (n = 1), opiates (n = 4), and no therapy (n = 1). It was observed that all patients, except one, reported complete or near-complete improvement in symptoms of RLS with marijuana smoking.[14] Hence, three patients were shifted to sublingual CBD, but they reported that smoking marijuana provided greater relief than sublingual CBD.[14]

Samaha et al.[25] reported a study on patients with end-stage renal disease undergoing maintenance dialysis. Among the participants, 45% reported symptoms of moderate-to-severe RLS. Among the participants having RLS, 14 had used cannabis to ameliorate the symptoms of RLS, and half of them reported complete relief.[25] Interestingly, 70% of participants with RLS showed a positive response to participate in further trials of cannabis/cannabinoids for improvement of RLS.[25]

Yenilmez et al.[22] did a nationwide questionnaire-based survey among patients having Parkinson’s disease (PD) to assess the use of cannabis and its benefit on symptoms and perception about medical cannabis. Among the cannabis users (n = 113), RLS was reported by one-fourth (n = 28) participants, and among those, only 21.4% (n = 6) reported improvement in RLS symptoms.[22] Eighty-five percent of these did not report any tolerability issues with cannabis.[22]

de Almeida et al.[29] conducted a post hoc analysis of a 12-week RCT where participants had RLS along with PD and rapid eye movement sleep behavior disorder (RBD). The participants had PD for approximately 10 years with Hoehn–Yahr stages 2 and 3. The average daily levodopa dose was higher in the CBD group (916.67 ± 299.44 mg) compared to the placebo group (637.5 ± 237.72 mg). Symptoms of RLS were present for approximately 5 years.[29] The average International RLS Severity Rating Scale (IRLS) Score reduced from 21 at baseline to 17 in both groups.[29,32] Interestingly, the placebo group had a higher proportion of adverse effects at week 4; however, this difference disappeared by weeks 8 and 12.[29]

Collister et al.[28] did a survey to assess previous exposure to cannabis and explored reasons for the same. Nearly half of the participants reported earlier use of cannabis in various forms.[28] Nearly half of the participants reported earlier use of cannabis in various forms, and almost 25 participants took cannabis to ameliorate symptoms of RLS. The manuscript, however, did not provide any information on the response of cannabis in relieving RLS symptoms, diagnosis and severity of RLS, body iron stores and other relevant medical history.[28]

Kimless et al.[19] reported an improvement in symptoms of RLS (though not explicitly mentioned) in 10 patients after applying topical magnesium-coordinated cannabidiolic acid at night. However, details regarding medical history, body iron stores, and concomitant medications were not provided.[19]

These results indicate that intervention studies in patients with “primary RLS” are currently limited to case reports and case series.[14,19,26] de Almeida et al.[29] also reported the results of an interventional study, but the primary aim was not to assess the efficacy of CBD in primary RLS. Other studies were observational and reported the effect of cannabis on RLS, which was comorbid with other disorders, viz., PD and chronic kidney disease.[22,25,28]

Assessment of quality of the articles

Articles included in this study were heterogeneous in methods used for the diagnosis of RLS and sample size [Supplementary Table 3 a-c]. Many of the included papers had methodological issues. For example, two papers reported cross-sectional observational data, and therefore they did not assess the effect of cannabinoids on RLS prospectively.[22,25] Information regarding iron stores was not available in many studies.[14,22,25] Similarly, information regarding the preparation used or the dose of cannabis was not available in others.[14,25]

Assessment of quality of studies: Supplementary Table 3 A.

Randomized controlled trial		de Almeida et al.[29]
Was true randomization used for assignment of participants to treatment groups?		Unclear
Was allocation to treatment groups concealed?		Yes
Were treatment groups similar at the baseline?		Yes
Were participants blind to treatment assignment?		Yes
Were those delivering treatment blind to treatment assignment?		Yes
Were outcomes assessors blind to treatment assignment?		Unclear
Were treatment groups treated identically other than the intervention of interest?		Unclear
Was follow up complete and if not, were differences between groups in terms of their follow up adequately described and analyzed?		Yes
Were participants analyzed in the groups to which they were randomized?		Unclear
Were outcomes measured in the same way for treatment groups?		Yes
Were outcomes measured in a reliable way?		Yes
Was appropriate statistical analysis used?		Yes
Was the trial design appropriate, and any deviations from the standard RCT design (individual randomization, parallel groups) accounted for in the conduct and analysis of the trial?		Yes
Overall appraisal: Include/Exclude/Seek further info		Include

Assessment of quality of studies: Supplementary Table 3C-Case Series.

		Ghoyareb[14]		Kimless D et al.[19]		Megelin & Ghorayeb[26]
Were there clear criteria for inclusion in the case series?		Unclear		No		Unclear
Was the condition measured in a standard, reliable way for all participants included in the case series?		Yes		Yes		Yes
Were valid methods used for identification of the condition for all participants included in the case series?		No		Yes		No
Did the case series have consecutive inclusion of participants?		No		No		No
Did the case series have complete inclusion of participants?		No		No		No
Was there clear reporting of the demographics of the participants in the study?		Yes		No		Yes
Was there clear reporting of clinical information of the participants?		Yes		No		Yes
Were the outcomes or follow-up results of cases clearly reported?		Unclear		Yes		Unclear
Was there clear reporting of the presenting site(s)/clinic(s) demographic information?		Unclear		No		Unclear
Was statistical analysis appropriate?		NA		Yes		NA
Overall appraisal: Include/Exclude/Seek further info		Include		Include		Include

Assessment of quality of studies: Supplementary Table 3B-Analytical cross-sectional.

		Yenilmez et al.[22]		Samaha et al.[25]		Collister et al.[28]
Were the criteria for inclusion in the sample clearly defined?		No		Yes		Yes
Were the study subjects and the setting described in detail?		Yes		Yes		Yes
Was the exposure measured in a valid and reliable way?		No		Unclear		No
Were objective, standard criteria used for measurement of the condition?		Unclear		Yes		No
Were confounding factors identified?		No		No		No
Were strategies to deal with confounding factors stated?		No		No		No
Were the outcomes measured in a valid and reliable way?		No		No		No
Was appropriate statistical analysis used?		Yes		Yes		Yes
Overall appraisal: Include/Exclude/Seek further info		Include		Include		Include

Excluded articles that contained information about the response in symptoms of RLS

Excluded studies are shown in Supplementary Table 4.[13,15,20,21,23,24,27,30,31]

Supplementary Table 4.

Description of excluded studies

Authors		Study type		Sample		Objectives		Findings		Reason for exclusion
Kachechian et al.[13]		Retrospective chart review		41 cannabis/ CBD users		Effect of cannabis/ CBD on RLS		Four patients had used medical cannabis to ameliorate their symptoms of RLS, and two patients reported complete relief in their symptoms		Conference abstract. No details about the method of diagnosis of RLS, the severity of RLS, and the doses of cannabinoids
Ghorayeb I[15]		Book Chapter		NA		NA		NA		Book Chapter
Zarabian et al. (2021)[20]		Case report		71-year-old female		To report a case of chronic neuropathic pain treated with integrative interventions		Multiple medical conditions leading to chronic pain syndrome, tried multiple modalities like acupuncture, medical cannabis, massage, yoga, mind and body program- leading to steady improvement in pain		Effect of cannabis on RLS not mentioned separately
Cahill et al. (2021)[21]		Questionnaire-based survey; 6 weeks follow-up period		214 patients (124 males, 71 females, 19 others)		To collect data on efficacy, safety and cannabis product type Information to capture the potential impact medical cannabis had on patient-reported quality of life (QOL) and several medical conditions over a 6-week period		Over 60% of the medical cannabis cohort self-reported improvements in their medical Conditions (includes RLS); patients who stated anxiety as their main medical condition did not experience significant changes in their anxiety after 6 weeks of cannabis treatment, though there were QOL improvements		Sleep disorders were mentioned as a group which included RLS. But no separate data on the RLS cohort are available. Effect of cannabis on RLS not studied
Motlke and Hindocha (2021)[23]		Online survey, cross- sectional		387 current or past-CBD users		To study the CBD use patterns, reasons for use, and effects on anxiety, sleep, and stress		CBD users took the drug to manage self-perceived anxiety, stress, sleep, and other symptoms, often in low doses, and these patterns vary by demographic characteristics		Effect of cannabis on RLS not a part of the study objectives or findings
Buck and Abraham[24]		Case report		60-year-old female who had severe RLS symptoms for the last 20 years		To report a case of RLS who had low response to baclofen and gabapentin and worsening of symptoms with dopamine agonists but good response to CBD		Good subjective improvement in RLS, sleep, and quality of life with prescription of cannabidiolic acid (CBDA) drops, vaporized tetrahydrocannabinol (THC)/cannabinol (CBN)/cannabigerol (CBG), and oral gummies with 1:1 THC/ CBG		Conference abstract. No details about the method of diagnosis of RLS, the severity of RLS, and the doses of cannabinoids
Collister et al.[27]		Online Survey		348 participants		To elicit Canadian nephrologists’ views regarding the use and study of cannabinoids in patients with kidney disease in an Internet-based survey of Canadian of Society of Nephrology members treating adult patients with kidney disease including dialysis		151 (43.4%) responses from 348 eligible participants. One hundred twenty-four (82%) previously cared for patients using prescribed cannabinoids by other providers; 29 (19%) had previously prescribed cannabinoids themselves. One hundred thirty-seven (91%) had previously cared for patients using nonprescription cannabinoids, used most commonly recreationally (88.3%), for chronic pain (73.7%) or for anxiety (52.6%). Respondents supported the use of cannabinoids (mean score >5) for each symptom in the setting of refractory symptoms.		The online survey did not provide any clear data regarding RLS
Boulus[30]		Randomized Controlled Trial		NA		To compare the effect of medical cannabis compared to placebo in participants having moderate-to-severe RLS		NA		Not yet started
Gupta et al. (2018)[31]		Case series, observational		19 participants with Opioid Use Disorder; 10 reported RLS		To observe the effect of cannabis use on RLS symptoms in opioid withdrawal		Participants with cannabis use disorder did not develop RLS during opioid/opiate withdrawal		Effect of cannabis on RLS in relation to opioid withdrawal

CBD: Cannabidiol, NA: Not applicable, RLS: Restless leg syndrome

Discussion

This scoping review shows that use of illicit or medical cannabis can either prevent or improve symptoms of RLS, including refractory RLS; however, evidence is of low quality because of the absence of RCTs designed to assess the efficacy of CBD in patients with RLS as a primary outcome measure.[14,21,25,26,31] Interestingly, topical application of CBD improved RLS significantly after two weeks, and smoked marijuana had better relief in symptoms of RLS compared to medical cannabis.[14,19] However, results are heterogeneous across studies. Notably, an RCT evaluating oral medical cannabis at doses up to 300 mg/day failed to demonstrate improvement in RLS symptoms or periodic limb movements during sleep.[29] Despite these limitations, existing evidence indicates a potential role for cannabis in the management of RLS, primarily when available therapies do not provide optimal relief, lose efficacy over time, or have some disabling adverse effects.[7,8,9]

From a clinician’s and researcher’s perspective, the findings of this scoping review invite cautious optimism regarding the role of cannabis and cannabinoids in RLS. While preliminary evidence suggests that both illicit and medical cannabis may alleviate symptoms—even in refractory cases—the current body of literature remains limited by low methodological quality and a lack of rigorously designed RCTs. This means that although the signal of benefit is intriguing, it should not yet be interpreted as definitive or practice-changing.

An interesting pattern emerges in the review when considering iron status. Three studies that reported the non-occurrence or complete resolution of RLS symptoms in most study participants also reported adequate iron stores in their bodies.[14,26,31] Reports where data for iron stores were not available showed variable responses ranging from no response to improvement in a small proportion or among all patients after prescription cannabis or illicit cannabis.[19,22,29] Iron plays an important role in the pathophysiology of RLS, and many patients with RLS experience improvement after optimizing their body iron stores.[6,7,9] Iron has been reported to have efficacy similar to that of dopamine agonists, and hence, it has been advised as the first-line treatment for RLS.[33,34] Two findings are worth mentioning here: first, iron therapy is not effective in patients who are not iron-deficient; second, iron deficiency increases the risk of augmentation.[6,35] We could not find any literature suggesting the pattern of response based on iron stores for commonly used medications other than iron therapy itself. However, it might be possible that the response to classical treatment is affected by iron stores, which might hold true for cannabis/cannabinoids as well. These findings thus raise an important clinical question: could iron status be a key modifier of treatment response, not only for conventional therapies but also for cannabinoids? The answer to this question is inconclusive at present, but given the well-established role of iron in RLS pathophysiology and its position as first-line therapy, it becomes essential for clinicians to ensure optimization of iron stores before considering alternative or adjunctive treatments such as cannabis.

Studies included in this scoping review involved patients with both “primary” and “secondary” RLS.[14,19,22,25,26,28,29,31] Poorer response to cannabis was observed only among studies having participants with “secondary” RLS.[22,25,29] It is possible that these patients were taking other medications that may be either accentuating the symptoms or worsening the RLS in addition to an unknown iron status.[22,25,29] These factors could have resulted in a variable response. In addition, the dose and form of the cannabis/cannabinoid also appeared to play a role in the response. Smoking illicit marijuana and topical cannabinoids has shown a superior response compared to medical cannabis.[14,19,29,31] This could be related to several factors, such as variability in the content of CBD and THC, the total dose reaching systemic circulation, and the use of concomitant non-pharmacological methods for the treatment.[36,37] This underscores a critical point that “cannabis” is not a uniform intervention.

Cannabis can improve symptoms of RLS by interacting with several neurotransmitter pathways that are implicated in the pathophysiology of RLS, including dopamine, opioids, norepinephrine, serotonin, GABA, and glutamate [Figure 2].[38,39,40,41,42,43,47,48,49,52] With the striatum having a high expression of Cannabinoid receptor 1 (CB1R), ECS can regulate the synaptic dopamine (DA) either directly through their presence on DA neurons in specific brain areas (e.g., substantia nigra) or indirectly by regulation of GABAergic and glutamatergic neurons that are directly connected to DA neurons.[38,39,40,41,42,43] Proposed mechanisms of cannabinoid-mediated modulation of the opioid system include alterations in concentration of endogenous opioids and their precursors, e.g., prodynorphin, proenkephalin, and pro-opiomelanocortin or regulation of µ opioid receptor density in a time- and region-dependent manner, which takes place through various mechanisms, namely G-protein-mediated signaling through opioid receptors or µ opioid receptor–CB1R complexes or via cannabinoid-induced changes in µ opioid receptor-dependent G-protein activation through Guanosine tri phosphate yS (GTPγS) binding assays.[44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60] Findings from preclinical studies in rodents and rats have suggested the presence of CB1R in locus coeruleus (LC) postsynaptic on noradrenergic (NA) neurons and presynaptic on GABAergic/glutamatergic axon terminals projecting to LC neurons.[11,61,62] Although systemic administration of cannabinoids increases the activity of LC neurons through CB1R, ECS can inhibit the activity of serotonin neurons in the dorsal raphe nuclei through CB1R-dependent GABAergic inhibition and through some yet-to-be-discovered mechanism [Figure 3]. ECS and cannabis can modulate hyperarousal at sleep onset that is common in patients with RLS, through these mechanisms.[63] Moreover, the effects of cannabis/ECS in RLS could be mediated through adenosine receptors that, in turn, regulate dopamine and glutamate activity.[64,65]

Figure 2.

Pathophysiology of restless leg syndrome showing role of various neurotransmitters including endocannabinoids. A1-D1: Adenosine 1-Dopamine 1 receptor heterodimers, BG: Basal ganglia, CNS: Central nervous system, DA: Dopamine, D1-D3: Dopamine receptors 1,2 and 3;, RLS: Restless legs syndrome, SMI: Sensorimotor integration;, SN: Substantia nigra. 1. Reduced dopamine synthesis. 2. Modulation of adenosinergic system. 3. Modulate release of nor-adrenaline and serotonin

Figure 3.

Proposed mechanisms of endocannabinoids and various heterodimers they form with other neurotransmitter receptors and their role in attenuation of symptoms of restless legs syndrome. A2AR: Adenosine 2A receptor, BG: Basal ganglia, CB1R: Cannabinoid 1 receptor, DA: Dopamine, D1R: Dopamine 1 receptor, D2R: Dopamine 2 receptor, Dec.: Decreased, 5-HT: 5-Hydroxytryptamine (Serotonin), HyperDA: Hyperdopaminergic, Inc.: Increased, MOR: Mu opioid receptor, NA: Nor-adrenaline, Red.: Reduced, RLS: Restless legs syndrome

Despite showing preliminary evidence for the efficacy of cannabis/cannabinoids in the management of RLS, the present systematic review has some limitations. First, the available evidence has not been generated through RCTs designed to assess the efficacy of CBD in RLS. Second, the CBD dose, the form of cannabis used, the sample size, and sample characteristics varied across studies. Third, all but one of the included studies were observational and cross-sectional in nature. Fourth, details of RLS (diagnostic criteria, severity of RLS, concomitant medications, comorbidities, iron stores, family history, and duration of symptoms) that can influence treatment response were not available.

Despite these limitations, this study shows the evidence, though preliminary and low quality, of efficacy and adequate tolerability of cannabis/cannabinoids in the management of RLS. The current evidence positions cannabis and cannabinoids as a potential adjunct rather than a replacement for established therapies. They may be worth considering in carefully selected patients—particularly those with refractory symptoms or intolerance to standard treatments—but only with a clear understanding of the uncertainties involved.

Ultimately, this review highlights a familiar yet important gap in clinical research: promising early signals that are unsupported by high-quality evidence. This highlights the necessity of conducting multicentric RCTs, especially among individuals diagnosed with primary RLS, to determine the dose–response relationship of medical cannabis, as well as its efficacy, tolerability, adverse effects, and impact on related factors such as sleep quality, quality of life, and daytime alertness. While cannabis carries a risk for addiction due to the presence of THC, CBD does not have addictive potential; instead, it has the potential to be used in the treatment of addictive disorders. This also calls for measured, individualized decision-making by the clinicians.

Conclusions

In conclusion, while cannabinoids—particularly CBD—may hold therapeutic promise in RLS through multi-system neurobiological effects, the current evidence is insufficient to support routine use mandating the need for further data through rigorous RCTs. Ongoing clinical trials are expected to provide much-needed clarity and may help determine whether this emerging therapy can transition from experimental consideration to evidence-based practice. At present, two clinical trials are ongoing, and their findings are expected to further clarify the therapeutic role of cannabinoids in RLS, thereby strengthening the existing evidence base [Supplementary Table 5].

Supplementary Table 5.

Description of ongoing clinical trials

		Trial		Start date		Expected completion		Type of study		Study detail
1.		Using Cannabis to Treat Restless Legs Syndrome ClinicalTrials.gov ID NCT06863740		July, 2025		May, 2026		Interventional Intervention/Treatment • Drug: Cannabis oil • Drug: Cannabis placebo		The investigators plan to randomize 30 participants with moderate-to-severe RLS to receive either cannabis or placebo for 8 weeks. The investigators will measure patients’ sleep quality and quality of life at baseline and 8-week follow-up. The investigators will also monitor patients for any adverse reactions to the study drug.
2.		Randomized, Double-blind, Placebo-controlled Parallel Study of the Tolerability and Efficacy of High Cannabidiol (CBD) Cannabis Extract for the Treatment of Patients With Idiopathic Restless Legs Syndrome (RLS) ClinicalTrials.gov ID NCT07224932		December, 2025		-		Half of the patients will be randomized to receive placebo orally. It is an oral solution of mono-, di-, and triglycerides Half of the patients will be randomized to receive oral investigational product. BRC-002 is a non-scheduled high cannabidiol cannabis extract (<0.3% THC). The cannabinoids in BRC-002 are naturally biosynthesized within the Cannabis sativa L. plant.		Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) This study plans to learn more about the safety and tolerability of high Cannabidiol (CBD) cannabis extract (BRC-002) for use in Idiopathic Restless Legs Syndrome. Symptoms and side effects experienced while taking the study drug will be tracked to determine if this medication is safe to use.

Author contributions

SS, RG, LKS, RT and NK: involved in conception and design; authors. RG and SS: involved in analyzing and interpreting data; authors. SS, RT and LKS: involved in drafting the article; authors. NK and RG: involved in revising it critically for important intellectual content and approving the final version to be published.

Conflicts of interest

There are no conflicts of interest.

Data availability statement

All data relevant to this study are included in the article and its supplementary materials.

Funding Statement

Nil.