Key messages
• Treatment with nabiximols likely results in improvement of spasticity and may not increase serious harmful effects compared with placebo
• Compared with placebo, cannabinoids (nabiximols, Cannabis extract, synthetic cannabinoids) likely improve well-being when measured with patient-reported outcomes
• Due to a lack of robust evidence, the benefit of these medicines for treating chronic neuropathic pain is unclear.
What is the issue?
Many people with multiple sclerosis (MS) experience spasticity that causes also pain and impacts on the ability to carry out daily activities. Spasticity is a form of increased muscle tone. Cannabis-based medicines refer to the use of Cannabis, or its ingredients called cannabinoids, as medical therapies to alleviate spasticity, chronic pain and other symptoms in MS. An international survey found that MS was one of the five medical conditions for which Cannabis was most often used. Another survey conducted in the UK found that more than one in five people with MS reported they had used Cannabis to try to manage their symptoms.
What did we want to find out?
We wanted to find out if cannabinoids were better than placebo in adults with MS to improve:
• spasticity;
• chronic neuropathic pain;
• well-being,
We also wanted to find out if cannabinoids were associated with:
• treatment discontinuation due to unwanted effects;
• serious harmful effects;
• nervous system disorders or psychiatric disorders;
• drug tolerance defined as a condition that occurs when the body gets used to a medicine so that more medicine is needed.
What did we do?
We searched for studies that compared cannabinoids against placebo in adult people with MS. We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and certainty of evidence.
What did we find?
We found 25 studies that involved 3763 people with MS, 2290 of whom received cannabinoids. Fifteen studies were very short term or short-term studies (two to 12 weeks), seven were intermediate term (12 to 26 weeks), and two were long term (50 and 156 weeks). One study reported results at three days only. The biggest study was conducted in 657 people and the smallest study involved 14 people. Most studies were done in European countries. Thirteen studies evaluated an oral spray (nabiximols) containing two compounds derived from the Cannabis plant. The other studies compared different cannabinoids with placebo. Pharmaceutical companies funded 15 of the studies.
Main results
Compared with placebo, cannabinoids:
• probably increase the number of people who report an important reduction of perceived severity of spasticity for up to 14 weeks (evidence from five studies in 1143 people);
• may increase the number of people who report an important reduction of perceived severity of chronic neuropathic pain, but the evidence is very uncertain (evidence from one study in 48 people).
We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity:
• probably increase the number of people who perceive their well-being as 'very much' or 'much' improved (evidence from eight studies in 1215 people);
• may increase slightly the number of people who discontinue treatment due to unwanted effects (evidence from 21 studies in 3110 people);
• may result in little to no difference in the number of people who have serious harmful effects (evidence from 20 studies in 3124 people);
• may increase nervous system disorders (evidence from seven studies in 1154 people) or psychiatric disorders (evidence from six studies in 1122 people);
• may have little to no effect on the number of people who have drug tolerance, but the evidence is very uncertain (two studies in 458 people).
What are the limitations of the evidence?
There is no high‐quality evidence.
We are moderately confident that cannabinoids work better versus no cannabinoids to improve severity of spasticity and well-being in adults with MS. We have little confidence in our results for the effect on chronic neuropathic pain because the available evidence is limited.
There is limited evidence to determine the effects of cannabinoids on serious harmful effects, nervous system or psychiatric disorders, and drug tolerance.
How up to date is the evidence?
The evidence is up-to-date to December 2021.
Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies.
Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required.
To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS.
We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews.
We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS.
We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence.
We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female. The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies.
Critical outcomes
• Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I2 = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo.
• Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity.
• Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I² = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people.
Important outcomes
• PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I² = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement.
• HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I2 = 0%; low-certainty evidence);
• SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I² = 0%; low-certainty evidence);
• AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I² = 63%; low-certainty evidence);
• Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I² = 0%; low-certainty evidence);
• Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence).