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Link to original content: https://pubmed.ncbi.nlm.nih.gov/35510826
Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis - PubMed Skip to main page content
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Review
. 2022 May 5;5(5):CD013444.
doi: 10.1002/14651858.CD013444.pub2.

Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis

Graziella Filippini  1 , Silvia Minozzi  2 , Francesca Borrelli  3 , Michela Cinquini  4 , Kerry Dwan  5
Affiliations
Review

Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis

Graziella Filippini et al. Cochrane Database Syst Rev. .

Abstract

Background: 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.

Objectives: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS.

Search methods: 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.

Selection criteria: 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.

Data collection and analysis: 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.

Main results: 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).

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

GF: none

SM: none

FB: She received research grants from GW pharmaceuticals (Cambridge, UK) to perform preclinical studies on phytocannabinoids and intestinal diseases, and patents on phytocannabinoids and colorectal cancer or inflammatory bowel diseases

MC: none

KD: She is employed as statistical editor by Cochrane

Figures

1
1
Spasticity and pain scales (NRS); Patient Global Impression of Change (PGIC)
2
2
Search updated to December 27, 2021
3
3
Funnel plot for withdrawn due to AEs
1.1
1.1. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 1: Spasticity: number of participants reporting reduction of 30% in the spasticity NRS (follow up 6‐14 weeks)
1.2
1.2. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 2: Spasticity: NRS as continuous outcome (follow up 2‐14 weeks)
1.3
1.3. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 3: Pain: number of participants reporting pain relief of 50% or greater in the NRS‐PI (follow up 3 weeks)
1.4
1.4. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 4: Pain: NRS‐PI as continuous outcome (follow up 3‐16 weeks)
1.5
1.5. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 5: Withdrawn due to adverse events (follow up 3‐48 weeks)
1.6
1.6. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 6: PGIC: number of participants reporting much or very much improvement in the PGIC (follow up 4‐48 weeks)
1.7
1.7. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 7: Health related quality of life: change score from baseline (follow up  3‐48 weeks)
1.8
1.8. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 8: Health related quality of life:  change score from baseline for each domain of SF‐36 (follow up 12‐14 weeks)
1.9
1.9. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 9: SAEs: number of participants with SAEs (follow up 3‐48 weeks)
1.10
1.10. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 10: Specific AEs: number of participants reporting nervous system disorders (follow up 4‐48 weeks)
1.11
1.11. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 11: Specific AEs: number of participants reporting psychiatric disorders (follow up 4‐48 weeks)
1.12
1.12. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 12: Specific AEs: number of participants reporting drug tolerance (follow up 14‐48 weeks)
1.13
1.13. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 13: Spasticity: Ashworth or Modified Ashworth (follow up 2‐50 weeks)
1.14
1.14. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 14: Fatigue as continuous outcome (follow up 4‐14 weeks)
1.15
1.15. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 15: Sleep quality: NRS as continuous outcome (follow up 4‐14 weeks)
1.16
1.16. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 16: Sleep quality: number of participants reporting an improvement in the NRS sleep (follow up 6‐14 weeks)
1.17
1.17. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 17: Depression: Beck Depression Inventory as continuous outcome
1.18
1.18. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 18: Activities of daily living: Barthel index as continuous outcome
1.19
1.19. Analysis
Comparison 1: Cannabis and cannabinoids versus placebo, Outcome 19: Number of caregivers reporting improvement on the CGIC (follow up 4‐48 weeks)
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References

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Jones 2020 {published data only}
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Lus 2018 {published data only}
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Martínez‐Rodríguez 2008 {published data only}
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NCT03172741 {published data only}
    1. The effects of different medical Marijuana strains on motor and cognitive function in people with multiple sclerosis. clinicaltrials.gov/ct2/show/results/NCT03172741 (first posted June 1, 2017).
Notcutt 2004 {published data only}
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Patti 2020 {published data only}
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Rezapour‐Firouzi 2013 {published data only}
    1. Rezapour-Firouzi S, Arefhosseini SR, Ebrahimi-Mamaghani M, Baradaran B, Sadeghihokmabad E, Mostafaei S, et al.Alteration of delta-6-desaturase (FADS2), secretory phospholipase-A2 (sPLA2) enzymes by hot-nature diet with co-supplemented hemp seed, evening primrose oils intervention in multiple sclerosis patients. Complementary Therapies in Medicine 2015;23(5):652-7. - PubMed
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References to studies awaiting assessment

De Blasiis 2021 {published data only}
    1. De Blasiis P, Siani MF, Fullin A, Sansone M, Melone MA, Sampaolo S, et al.Short and long term effects of Nabiximols on balance and walking assessed by 3D-gait analysis in people with multiple sclerosis and spasticity. Multiple Sclerosis and Related Disorders 2021;51:102805. - PubMed

References to ongoing studies

Hansen 2021 {published data only}
    1. Hansen JS, Hansen RM, Petersen T, Gustavsen S, Oturai AB, Sellebjerg F, et al.The effect of cannabis-based medicine on neuropathic pain and spasticity in patients with multiple sclerosis and spinal cord injury: study protocol of a national multicenter double-blinded, placebo-controlled trial. Brain Sciences 2021;11(9):1212. - PMC - PubMed
NCT03005119 {published data only}
    1. NCT03005119.Evaluation of the safety, tolerability, and efficacy of orally administered PTL201 in MS patients with spasticity-related symptoms. clinicaltrials.gov/ct2/show/results/NCT03005119 (first posted December 29, 2016).
NCT03756974 {published data only}
    1. BX-1 in spasticity due to multiple sclerosis. clinicaltrials.gov/ct2/show/results/NCT03756974 (first posted November 28, 2018).
NCT04203498 {published data only}
    1. NCT04203498.Safety and effectiveness of Nabiximolsoromucosal spray as add-on therapy in participants with spasticity due to multiple sclerosis. clinicaltrials.gov/ct2/show/results/NCT04203498 (first posted December 18, 2019).
NCT04657666 {published data only}
    1. NCT04657666.Trial to evaluate the effect of Nabiximols oromucosal spray on clinical measures of spasticity in patients with multiple sclerosis (RELEASE MSS1). clinicaltrials.gov/ct2/show/results/NCT04657666 (first posted December 8, 2020).
NCT04984278 {published data only}
    1. NCT04984278.A randomized, double-blind, placebo-controlled, 2-way crossover trial to evaluate the effect of nabiximols oromucosal spray on clinical measures of spasticity in patients with multiple sclerosis. clinicaltrials.gov/ct2/show/results/NCT04984278 (first posted: July 30, 2021).
NCT05092191 {published data only}
    1. Cannabis as a complementary treatment in multiple sclerosis (CAN-SEP). clinicaltrials.gov/ct2/show/results/NCT05092191 (first posted: October 25, 2021).
Russo 2017 {published data only}
    1. Russo M, Dattola V, Logiudice AL, Ciurleo R, Sessa E, De Luca R, et al.The role of Sativex in robotic rehabilitation in individuals with multiple sclerosis: rationale, study design, and methodology. Medicine (Baltimore) 2017;96(46):e8826. - PMC - PubMed

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