Efficacy and safety of cannabinoids in the treatment of spasticity in multiple sclerosis

Efficacy and safety of cannabinoids in the treatment of spasticity in multiple sclerosis: A systematic review of randomized clinical trials

Source / Quelle: https://bpspubs.onlinelibrary.wiley.com/doi/10.1002/bcp.70719

Abstract

Aims

This work aimed to evaluate the efficacy and safety of cannabinoids for the treatment of MS-related spasticity.

Methods

Systematic searches were conducted in PubMed, EMBASE, and LILACS on 2 December 2025. Randomized controlled trials evaluating natural or synthetic cannabinoids for MS-related spasticity were included. Studies published in non-Roman characters and those assessing recreational cannabis use were excluded. Two reviewers independently performed study selection, data extraction, and risk of bias assessment using the RoB 2 tool. Qualitative synthesis, pairwise random-effects meta-analyses, and Bayesian network meta-analysis were conducted. Certainty of evidence was assessed using GRADE and CINeMA.

Results

Twenty-seven studies (>3000 participants) were included. Interventions comprised tetrahydrocannabinol:cannabidiol (THC:CBD) extracts, other cannabis extracts, isolated cannabinoids (natural or synthetic), and smoked cannabis. In pairwise meta-analysis (7 studies), THC:CBD extracts reduced patient-reported spasticity versus placebo (MD −0.82; 95% CI −1.24 to −0.40; I2 = 53%). Network meta-analysis confirmed superiority of THC:CBD (MD −0.80; 95% CrI −1.61 to −0.32). Adverse events were frequent but mostly mild to moderate, while serious events were rare. Certainty of evidence was low, and substantial clinical and methodological heterogeneity was observed.

Conclusions

Cannabinoids provide modest improvements in patient-reported spasticity in MS, with more consistent effects for THC:CBD extracts. Given the low certainty of evidence and limited objective benefits, cannabinoids should be considered cautiously as adjunctive therapy with appropriate safety monitoring.

1 INTRODUCTION

Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone), with exaggerated tendon spasms, resulting from hyperexcitability of the stretch reflex—a component of the upper motor neuron syndrome (Lance et al., 1980, cited in Trompetto et al.1). According to the consensus of the Interdisciplinary Movement Disorders Group, it can be defined as ‘involuntary muscle hyperactivity in the presence of central paresis’.2 Among neurological conditions associated with spasticity, multiple sclerosis (MS) stands out due to the high frequency of this symptom. It is estimated that 2.8 million people live with MS worldwide,3 and spasticity occurs in 60%–84% of patients over the course of the disease, being moderate to severe in 40%–60% of them.4 Spasticity contributes to impairment of mobility, dexterity, hygiene, self-care, and the use of orthoses.5

In recent years, cannabinoids have attracted increasing interest as a therapeutic alternative for patients with MS. Published studies indicate that two natural components of the plant, tetrahydrocannabinol (THC) and cannabidiol (CBD), may be used for the treatment of spasticity associated with multiple sclerosis.6-8 The oromucosal spray containing the THC:CBD combination (nabiximols), for example, has been shown to be more effective than optimizing the dose of first-line antispastic medications.7 Nabiximols, composed in a 1:1 ratio of THC and CBD, is already included in European guidelines for the management of spasticity in MS.8-11 In international documents, its use is recommended as a second--line,9, 12, 13 third--line,8, 10, 11 or even fourth-line pharmacological option,14 often before more invasive therapies such as intrathecal baclofen.8, 11, 13 Despite this progressive incorporation into clinical guidelines, there are still relevant uncertainties regarding the practical conduct of therapy, including selection criteria, response monitoring, and optimal treatment duration.15

In light of these uncertainties, this systematic review aimed to evaluate the efficacy and safety of cannabinoids in the treatment of spasticity in patients with multiple sclerosis, in order to critically synthesize the available evidence and provide support for clinical decision-making and future therapeutic recommendations.

2 MATERIALS AND METHODS

This systematic review was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions16 and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020).17 The PRISMA 2020 checklist is provided in Supporting Information. The protocol was registered in PROSPERO (CRD42024557313).

Randomized clinical trials evaluating the efficacy and safety of cannabinoids for the management of spasticity were included. Although the protocol had planned the inclusion of different clinical conditions and nonrandomized and observational studies, this manuscript reports randomized clinical trials conducted in patients with multiple sclerosis, due to the predominance of these studies in this population, allowing for a more homogeneous and concise synthesis.

The PICO strategy comprised the following:

P (participants)—patients with spasticity of any degree;

I (intervention)—natural or synthetic cannabinoids, without restriction regarding formulation, dose, or route of administration;

C (comparator)—placebo, antispastic therapies, usual care, or no exposure;

O (outcomes)—Primary outcomes: change in spasticity; change in complementary examinations assessing spasticity; range of motion; gait analysis; characterization of adverse events and serious adverse events (SAEs). Secondary outcomes: change in functional capacity; change in motor function; assessment of muscle strength; assessment of spasticity-related pain; assessment of quality of life; withdrawals due to adverse events.

Studies published in non-Roman characters, studies on recreational cannabis, and studies comparing different cannabis-based treatments with each other were excluded. This last exclusion criterion had been previously protocolized and did not result in the exclusion of any studies, as no trials with these characteristics were identified. Thus, the body of included studies proved to be adequate for conducting a network meta-analysis, as it presented a connected evidence network anchored in common comparators.

Searches were performed in PubMed, EMBASE, and LILACS on 2 December 2025. The search strategy included descriptors for spasticity and related diseases and cannabis-based treatment, combined using the Boolean operators AND and OR (Supporting Information S1). In addition, a manual search was conducted in the reference lists of included studies and relevant systematic reviews identified.

2.1 Study selection

After duplicate removal, two independent reviewers screened titles and abstracts using the Rayyan platform. Subsequently, full texts of potentially eligible studies were assessed according to predefined criteria by the same two reviewers, independently. Disagreements were resolved by consensus or by a third reviewer.

2.2 Data extraction

Data extraction was performed independently by two reviewers using a standardized form (Microsoft Excel). Data were collected on study design, population, interventions, comparators, trial duration, methods, outcomes, and funding.

When the standard deviation of change was not reported, it was estimated from baseline and final values according to the Cochrane Handbook.16 The required correlation coefficient was empirically derived from the study by Fairhurst et al.18 Standard deviations obtained from 95% confidence intervals, standard errors, or p values were calculated using RevMan Web. Data presented only in graphical format were extracted using WebPlotDigitizer. The specific procedures adopted for each study are described in Supporting Information S2.

2.3 Risk of bias assessment

The risk of bias of randomized clinical trials was assessed by two reviewers using the Risk of Bias in Randomized Trials of Interventions tool (RoB 2.0).19

2.4 Data synthesis

2.4.1 Qualitative synthesis

The characteristics of the populations, interventions, comparators, and main findings were described, highlighting the clinical, conceptual, and methodological heterogeneity.

2.4.2 Pairwise meta-analysis

When two or more studies were clinically comparable, a random-effects meta-analysis was conducted (meta package, R). Mean differences (MD) were calculated for continuous outcomes and risk ratios (RR) for dichotomous outcomes (95% CI). Heterogeneity was assessed using I2 and explored through sensitivity analyses (leave-one-out).

2.4.3 Network meta-analysis

The included studies formed a connected evidence network, enabling a complementary NMA that was not prespecified in the PROSPERO protocol and was conducted without changes to the research question or eligibility criteria. The NMA was conducted in AutoNetBayes using arm-level Bayesian models with noninformative priors. Convergence was assessed using trace plots, density plots, and the Brooks–Gelman–Rubin diagnostic. Results were presented as league tables (RR or MD with 95% CrI), with treatment rankings estimated by SUCRA and consistency evaluated through node-splitting.

2.5 Certainty of the evidence

The certainty of the evidence was assessed using the GRADE system and its updates,20 considering the domains of risk of bias, inconsistency, indirectness, imprecision, and publication bias. For network comparisons, the certainty of network evidence was assessed using the CINeMA framework,21, 22 considering the domains of within-study bias, reporting bias, indirectness, imprecision, heterogeneity, and incoherence. Despite differences in the domains assessed, both systems use the same scale to rate certainty of evidence: high, moderate, low, or very low.

2.6 Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2025/26.23

3 RESULTS

The electronic search identified 3928 records in PubMed, EMBASE, and LILACS. After removal of 574 duplicates, 3354 records were submitted to title and abstract screening. Of these, 79 articles advanced to full-text assessment.

Among the 79 studies assessed for eligibility, 52 were excluded for various reasons. All excluded articles, together with the respective reasons and full citations, are listed in Supporting Information S3.

At the eligibility stage, 25 studies met the pre-established criteria and were included in the qualitative synthesis. In addition, two additional studies were identified through manual searching in other relevant systematic reviews, totalling 27 included studies.

The PRISMA flow diagram illustrating the process of study identification, selection, and inclusion is presented in Figure 1:

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