Multiple Sclerosis

Spanish MS spasticity guideline (2013), developed using the Metaplan method and SIGN classification by ~250 neurologists; recommends the Numerical Rating Scale (0–10) as the best-practice tool for measuring spasticity (ranked higher than the Spasm Frequency Scale and modified Ashworth).

Nabiximols probably reduces spasticity in the short term (moderate evidence), but shows a possible increase in adverse effects (nervous system and psychiatric disorders) as well as unresolved effects on neuropathic pain and quality of life.

Cochrane systematic review on cannabinoids for MS symptoms (spasticity, chronic neuropathic pain); search period up to December 2021. Evaluated ≥30% reduction on spasticity NRS and ≥50% pain relief as primary outcomes. Included RCTs with synthetic, plant-based and herbal cannabis preparations; evidence assessment conducted according to GRADE.

Cannabinoids showed limited efficacy against spasticity, pain, and bladder dysfunction compared to placebo, but increased risk of adverse events and study discontinuations.

Comprehensive SR+MA of k=17 RCTs (n=3.161) on medical cannabinoids for MS symptoms. Significant efficacy vs. placebo: spasticity (subjective assessment) SMD=-0.25 SD (95% CI -0.38 to -0.13), pain SMD=-0.17 SD (95% CI -0.31 to -0.03), bladder dysfunction SMD=-0.11 SD (95% CI -0.22 to -0.0008). Tolerability: increased adverse events RR=1.72 patient-years (95% CI 1.46–2.02). PRISMA-compliant analysis.

Medical cannabis shows efficacy for MS spasticity (oral cannabis extract), probable efficacy for pain, but probable ineffectiveness for tremor and unclear evidence for epilepsy and other neurological diseases.

AAN guideline based on systematic review of k=34 studies (8 Class I) on medical cannabis in MS. Spasticity: oral cannabis extract (OCE) effective, nabiximols and THC probably effective for patient-centered measures. Central pain/painful spasms: OCE effective, THC and nabiximols probably effective. Bladder dysfunction: nabiximols probably effective (reduction in bladder voids/day), THC and OCE probably ineffective. Tremor: THC and OCE probably ineffective. Risk of serious psychopathological adverse effects <1%.

Cannabinoids show possible benefit for spasticity and pain (Level B), but are probably ineffective for objective spasticity and tremor; other CAM interventions show predominantly little or no efficacy.

Evidence-based guideline of the American Academy of Neurology on complementary/alternative therapies in MS (literature 1970–2013). Oral cannabis extract: Level A for spasticity symptoms and pain (except central neuropathic pain); THC: Level B for spasticity symptoms/pain; nabiximols (Sativex): Level B for spasticity symptoms, pain, urinary frequency. Cannabinoids probably ineffective for objective spasticity (short-term)/tremor (Level B), probably ineffective for urinary incontinence (Level B). Warning regarding adverse effects and quality control for non-standardized extracts.

Cannabinoids may show modest effects on pain and/or spasticity in MS, while evidence for other symptoms is limited.

Umbrella review of k=11 systematic reviews on cannabinoids for MS symptoms (data from 32 studies, including 10 moderate to high-quality RCTs). Five reviews concluded sufficient evidence for efficacy for pain and/or spasticity. Conclusion: cannabinoids may have moderate effects on MS-associated pain or spasticity; evidence for other symptoms (disability progression, tremor/ataxia, bladder function, quality of life) insufficient.

Cannabis and cannabinoids show mixed effects: cannabidiol effective in epilepsy, cannabis-based medicines effective in MS and chronic pain but with substantial adverse effects; cannabis worsens psychotic symptoms in the general population and causes harm in pregnancy and driving.

Umbrella review of k=101 meta-analyses (50 observational, 51 RCTs) on cannabis/cannabinoids. For MS spasticity: cannabis-based medicines improved spasticity (GRADE=moderate), but increased psychiatric and gastrointestinal adverse effects as well as somnolence. CNS adverse effects: OR=2,84 (95% CI 2,16–3,73), psychiatric effects: OR=3,07 (1,79–5,26), visual disturbances: OR=3,00 (1,79–5,03) (GRADE=high).

Moderate evidence for chronic pain and spasticity, low evidence for nausea/vomiting, weight gain and sleep disorders; increased risk of side effects.

Comprehensive SR across 79 RCTs (n=6.462) on medical cannabis; moderate evidence for MS spasticity (nabiximols reduces spasticity NRS by -0,12 points vs. placebo, CI -0,24 to 0,01), based on several phase III studies.

Cannabinoids and botulinum toxin showed better efficacy than placebo for spasticity due to multiple sclerosis, but cannabinoids and tizanidine caused significantly more mild adverse effects than placebo.

Systematic review + network meta-analysis on spasticity therapies in MS; k=23 RCTs, n=2.720. Cannabinoids and botulinum toxin significantly better improvement rate than placebo. Botulinum toxin also significantly better than tizanidine/baclofen. Cannabinoids, tizanidine, diazepam more frequent mild adverse effects than placebo. SUCRA: botulinum toxin optimal intervention, cannabinoids and transcutaneous electrical stimulation (TENS) also worth considering.

Cannabinoids showed no statistically significant benefit for spasticity or spasm frequency, but markedly increased side effects such as dizziness, somnolence and nausea.

SR+MA of k=16 RCTs (n=2.597) on cannabinoids for MS spasticity or paraplegia spasticity. Moderate evidence for NON-significant spasticity reduction (SMD 0.36, 95% CI -0.17 to 0.88, p=0.18, I²=88%); increased adverse effects: dizziness (RR 3.45, 95% CI 2.71–4.4), somnolence (RR 2.9, 95% CI 1.98–4.23), nausea (RR 2.25, 95% CI 1.62–3.13).

No significant association between cannabis/cannabinoids and HRQoL demonstrated; some patient groups (pain, MS, IBD) report small improvements, HIV patients partially report deteriorations.

Systematic review and meta-analysis on cannabis/cannabinoids and health-related quality of life (HRQoL) in medical indications; k=11 RCTs (n=2.322 from RCTs, 20 studies total); no significant overall association between cannabis/cannabinoids and HRQoL; small improvements in HRQoL were reported in MS patients (alongside pain and inflammatory bowel disease); HIV patients reported reduced HRQoL.

Nabiximols as add-on therapy leads to significantly higher responder rates in treatment-refractory MS spasticity compared to placebo (OR 2,41, 95% CI 1,39-4,18).

Systematic review + meta-analysis of k=7 RCTs (n=1.128) on nabiximols as add-on in treatment-refractory MS spasticity; responder rate NRS significantly higher under nabiximols than under placebo (OR 2,41; 95% CI 1,39–4,18). Secondary endpoints consistent with primary result.

Nabiximols showed a statistically significant reduction in spasticity versus placebo with a difference of -0,32 points on the numeric rating scale (p=0,026) and a higher responder rate (OR 1,62, p=0,0073).

Meta-analysis of k=3 randomised, placebo-controlled double-blind trials (n=666) on nabiximols (Sativex) for MS spasticity; NRS difference versus placebo -0,32 (95% CI -0,61 to -0,04; p=0,026); responder rate (≥30% improvement) OR=1,62 (95% CI 1,15–2,28; p=0,0073). Nabiximols well tolerated, adverse effects predominantly mild to moderate.

Anticonvulsants showed a moderate effect (pooled effect size -1.88), while cannabinoids showed no significant effect (pooled effect size 0.08); overall insufficient evidence for specific treatment recommendations.

Systematic review (k=15 studies) on pharmacological pain therapy in MS patients (excluding spasticity and trigeminal neuralgia pain). Cannabinoid subgroup: k=3 RCTs, n=565; pooled effect size ES=0,08 (95% CI: −0,74 to 0,89) — no significant effect versus comparator treatment. Anticonvulsant subgroup (k=4, n=78) showed ES=−1,88 (95% CI: −3,13 to −0,64). Overall only 4 studies with evidence class I; the small number of studies does not allow specific treatment recommendations.

Moderate efficacy of cannabinoid-based medications in chronic pain and comorbidities such as sleep problems, anxiety and selected chronic conditions.

Clinical practice guideline for cannabis-based medicine in chronic pain and comorbidities. Systematic review (PROSPERO 135886) included k=70 articles (19 SR, 51 original studies). GRADE-based recommendations: moderate benefit of CBM in chronic pain; evidence for efficacy in sleep disorders, anxiety, appetite suppression and symptoms in HIV, MS, fibromyalgia, arthritis. Collaborative dose titration and education about risks recommended.

Cannabinoids show modest efficacy for spasticity in adults with multiple sclerosis, but limited evidence in other conditions and insufficient evidence in pediatric populations.

Systematic review on cannabinoids for spasticity; k=32 studies (adults + pediatric populations). Evidence from RCTs: cannabinoids more effective than placebo for MS spasticity in adults, predominantly patient-reported (not clinician-reported) outcomes, modest effect size. Narrow therapeutic window. Pediatric studies of low quality, insufficient for practice recommendations.

Nabiximols showed cost-effectiveness for MS spasticity from a European perspective in four of five studies, but was not associated with statistically significant improvements in EQ-5D scores compared to standard therapy.

Systematic review on cost-benefit of prescribed cannabis medicines in chronic diseases; k=10 studies identified, all for MS. Six contained cost-benefit analyses, four quality-of-life data. Nabiximols for MS spasticity potentially cost-effective in five European health systems: ICER per QALY £49.257 (UK), £10.891 (Wales), €11.214 (Germany), €4.968 (Italy), dominant (Spain). EQ-5D scores showed no statistically significant improvement vs. standard care.

Chronic full-spectrum cannabis shows potential cognitive impairments (attention, working memory), while short-term medical cannabinoid preparations do not substantially impair cognitive functions and may possibly even improve them.

Systematic review on cannabis and cognition in MS; k=18 studies included. Chronic whole-plant cannabis use shows potential impairments in attention, working memory, visual/verbal memory and executive functions. Medical cannabinoid preparations show no significant cognitive impairment in the short term and may possibly improve cognitive MS symptoms. Quality of evidence limited by heterogeneous reporting of cannabis use data.

THC:CBD spray showed improvements in spasticity of up to 45% and improved quality of life in MS patients with treatment-resistant spasticity.

Systematic review of THC:CBD spray as add-on therapy for resistant MS spasticity; k=5 studies (2017-2022), spasticity improvement up to 45% on patient-reported scales, average dose 5-7 sprays/day. Discontinuation rate ~40%, adverse effects mild-moderate (~17% incidence).

Botulinum toxin A showed significant effects, but 5-HT3 antagonists, cannabis and levetiracetam had inconsistent or insufficient results; isoniazid showed only minor therapeutic effects.

Systematic review on pharmacological tremor therapy in MS; k=26 studies (13 with low risk of bias). Cannabis-based medicines: inconsistent therapeutic effects, several side effects → use in MS tremor not recommended. 5-HT3 antagonists: inconsistent results. Botulinum toxin A: significant effects, but limited by side effects/application.

Cannabinoids do not reduce spasticity or pain in multiple sclerosis and are likely associated with frequent side effects.

Systematic review on cannabinoids in MS across k=26 RCTs (from 25 SRs); meta-analysis shows NO significant reduction of spasticity or pain; frequent adverse effects likely. GRADE evidence synthesis with negative overall finding.

Sativex showed significant reduction of pain intensity and spasticity as well as modest but significant improvement in disability in MS patients.

Systematic review and meta-analysis across k=20 studies on Sativex® (nabiximols) in multiple sclerosis. Significant reduction in pain intensity (NRS, SMC −0,88; 95% CI −1,20 to −0,57; p<0,0001) and spasticity (SMC −1,29; 95% CI −1,63 to −0,94; p<0,0001); modest but significant improvement in disability (EDSS, SMC −0,17; 95% CI −0,28 to −0,07; p=0,0015). Conclusion: Sativex as an effective treatment option against pain and spasticity in MS.

Cannabis-based therapies showed clinically meaningful improvements in MS-related spasticity, especially over longer periods (MD 75,81 long-term vs. MD 4,53 short-term).

Meta-analysis of k=9 RCTs (2003-2021, n=2.544) on cannabis-based therapies for MS spasticity. Overall effect: standardized mean difference (MD) 39,19 (95% CI: 34,32-44,05) for spasticity scores. Subgroup analysis: Ashworth scale MD=20,36 (95% CI: 20,35-20,37), NRS MD=1,18 (95% CI: 1,16-1,21). Long-term studies show larger effects (MD=75,81, 95% CI: 66,39-85,22) than short-term studies (MD=4,53, 95% CI: -0,06-9,12). Side effects mild (dizziness, dry mouth). High heterogeneity I²=100% (overall/AS), I²=91% (NRS).

Cannabinoids reduced the number of incontinence episodes by an average of 0,35 per 24 hours with good statistical significance.

Systematic review + meta-analysis on cannabinoids for neurogenic bladder dysfunction (NLUTD) due to MS; k=3 studies (2 RCTs + 1 open-label), n=426. Incontinence episodes/24h reduced by mean difference -0.35 (95% CI -0.46 to -0.24). Mild adverse effects common (38-100%), severe adverse effects rare (0.7%).

Fampridine significantly improved walking speed and functional mobility, while cannabinoids mainly reduced spasticity but showed little improvement in mobility outcomes; both drug classes showed considerable side effects.

Systematic review of symptomatic pharmacotherapy and mobility/balance outcomes in MS across k=23 RCTs (all PEDro good-to-excellent). Fampridine (n=13 RCTs) significantly improved walking speed (T25FW), endurance (6MW) and functional mobility (5STS, TUG), with the largest effect on walking speed. Cannabinoids (n=9 RCTs) primarily reduced spasticity; effects on mobility/balance were inconsistent or not significant.

Medicinal Cannabis showed variable cost-effectiveness depending on indication and setting: nabiximols was cost-effective for MS spasticity in European settings, cannabidiol was cost-effective for Dravet syndrome in Canada, but not for Lennox-Gastaut syndrome in the USA.

Systematic review on cost-effectiveness of medical cannabis; k=12 cost-utility analyses (8 MS, 2 pediatric epilepsy, 2 chronic pain). Nabiximols cost-effective for MS spasticity in multiple European settings; ICER range from cost-saving to >451.800 US$ per QALY depending on setting and cannabinoid type. Publications met 70–100% (median 83%) of CHEERS criteria.

High evidence for cannabis benefit in MS spasticity and pain; low evidence for small effect in neuropathic pain; unclear evidence for nausea/vomiting in chemotherapy patients.

Systematic review of k=41 RCTs (n=4.550) on safety and efficacy of cannabis (incl. extracts, tinctures); 15 studies on MS (spasticity/pain control), 12 on chronic neuropathic pain, 14 on chemotherapy-induced nausea. Studies 1975–2015, predominantly Europe. Evidence assessment according to Cochrane and GRADE methodology.

Strong evidence for pain, nausea and MS spasticity, weak to absent evidence for most other therapeutic indications.

Systematic review by the National Academies of Sciences (NASEM report), screening of 10.000 abstracts on therapeutic effects of cannabis. Conclusions for MS: conclusive/substantial evidence for efficacy in spasticity (multiple sclerosis-associated); moderate evidence for secondary sleep disorders. Evidence for other indications limited to absent.

Inconsistent findings on the efficacy of cannabis-based medicines for neuropathic pain and muscle spasms in MS; insufficient evidence for rheumatic diseases and cancer pain.

Umbrella review of k=10 systematic reviews (2009–2017) on cannabis in chronic pain. Inconsistent findings on efficacy for neuropathic pain (4 SRs) and painful spasms in MS (1 SR). Insufficient evidence for rheumatic diseases (3 SRs) and tumor pain (2 SRs). Inconsistent results regarding tolerability and safety. Methodological quality: 4 SRs high, 6 SRs moderate (AMSTAR).

Most studies showed no significant difference between THC:CBD spray and control on cognitive outcomes.

Systematic review on THC:CBD spray and cognition; k=10 studies (7 MS, 1 Huntington's, 2 healthy volunteers), n=510 participants. Despite heterogeneous dosing/duration, the majority of the evidence showed no significant difference between THC:CBD spray and control on cognitive outcomes.

Weak spasmolytic activity without a significant effect in most studies, no dose dependency, and decreasing effect with longer treatment duration.

Systematic review + meta-analysis on cannabinoids for spasticity (k=27 studies, predominantly MS). Weak spasmolytic effect size; non-significant small effect in most studies, large effects only in a few 'enriched' studies (low n). No dose dependency (slope=0.004 for effect size vs. daily dose). Effect decreases with longer treatment duration (3–4 months). Hill criteria analysis shows lack of specific causality; authors conclude that general CNS depression analogous to benzodiazepines is more plausible than direct spasmolysis.

Dronabinol showed no significant effect on progression of progressive multiple sclerosis (HR 0,92; p=0,57).

CUPID trial: multicentre RCT (n=493, of which n=329 dronabinol, n=164 placebo) over 36 months in progressive MS. Primary endpoint EDSS progression: HR 0,92 (95% CI 0,68–1,23; p=0,57) — no significant effect on disease progression. Mean annual MSIS-29-PHYS change 0,62 points (dronabinol) vs. 1,03 points (placebo).

Delta(9)-THC showed a small significant effect on muscle spasticity (Ashworth score reduction 1.82), while cannabis extract (0.10) showed no substantial improvement over placebo (-0.23); indications of effects on some aspects of disability, but overall limited evidence.

CAMS study: n=630 MS patients, 12-month follow-up on oral cannabis extracts (THC/CBD) vs. placebo for spasticity; primary endpoint (Ashworth score) negative, but subjective spasticity improvement (self-report p=0.003), safety data over 12 months robust.

Cannabis extract and THC showed significant reductions in urge incontinence episodes compared to placebo (38% and 33% vs. 18% reduction, respectively), with p-values of 0,005 and 0,039, respectively.

Multicentre RCT (CAMS-LUTS, n=630 MS patients): Cannabis extract reduced urge incontinence episodes by 38 % (vs. 18 % placebo, p=0,005); THC by 33 % (p=0,039). Both cannabinoids showed significant superiority over placebo.

Delta(9)-THC showed no significant effect on EDSS progression or MSIS-29 symptom scale in progressive multiple sclerosis.

CUPID study: multicentre phase III RCT (n=498, 27 UK centres) of oral Δ9-THC (max. 28mg/day) vs. placebo in progressive MS (PPMS/SPMS, EDSS 4,0-6,5). Randomisation 2:1, 36-42 months follow-up. Primary endpoints: time to EDSS progression and MSIS-29phys score change. MRI substudy, Rasch analyses and health economics conducted. Intention-to-treat analysis according to prespecified plan.

Nabiximols led to significant improvements in spasticity versus placebo across all measured parameters (Spasticity NRS, Spasm Count, MAS) over 12 weeks.

Two enriched-responder RCTs (GWSP0604, SAVANT) with pooled analysis of nabiximols oral spray in MS spasticity; mean NRS improvement versus placebo -0,36 to -0,89 (GWSP0604) and -0,52 to -1,96 (SAVANT); spasm reduction 19–35% vs. placebo; significant MAS improvement with nabiximols, especially in 6 key muscle groups of the lower extremity (-0,16 to -0,37), sustained over 12 weeks.

Primary endpoint in Phase A not met (50% vs. 45% responders, p=0,234), but significant effects in Phase B with improved time to treatment failure and significant improvements in pain and sleep quality scores in favor of THC/CBD.

n=339 MS patients with central neuropathic pain, THC/CBD spray (Sativex) as add-on vs. placebo over 14 weeks; primary endpoint (≥30% responders, week 14) missed (50% THC/CBD vs. 45% placebo, p=0.234), but significant at week 10 (p=0.046). Randomized withdrawal phase: time to treatment failure significantly in favor of THC/CBD (24% vs. 57% placebo, p=0.04); pain reduction (NRS p=0.028) and sleep quality (p=0.015) significantly improved.

ITT analysis showed non-significant improvement; per-protocol population (79%) showed significant superiority of Sativex over placebo for NRS score and responder analyses.

n=337 MS patients with treatment-resistant spasticity; 15-week DBRCT (multicenter), Sativex vs. placebo. Per-protocol population: NRS reduction -1,3 vs. -0,8 points (p=0,035); responder rate (≥30% improvement) 36% vs. 24% (p=0,040). Timed 10-metre walk test significantly improved (p=0,042); Sativex well tolerated, adverse effects predominantly mild to moderate.

Cannabis extract showed almost twice the muscle stiffness relief compared with placebo (29,4% vs. 15,7%; p=0,004).

MUSEC trial: multicentre phase III RCT (n=279, 22 UK centres) of oral cannabis extract vs. placebo in stable MS over 12 weeks (2 weeks titration 5-25 mg THC daily, 10 weeks maintenance). Primary endpoint muscle stiffness: response rate cannabis 29,4% vs. placebo 15,7% (OR=2,26; 95% CI: 1,24-4,13; p=0,004 one-sided) — nearly double the success rate. Comparable effects at 4 and 8 weeks; secondary endpoints (pain, spasms, sleep quality) support the primary finding. Adverse effects consistent with the known cannabinoid profile.

Nabiximols showed a highly significant advantage over placebo in reducing spasticity (primary endpoint NRS, P=0,0002) as well as in all secondary endpoints (responder analysis, spasm frequency, sleep disturbance, global clinical impression).

n=241 MS spasticity patients, nabiximols (Sativex) add-on vs. placebo in multicentre phase 3 RCT with enriched design; ITT analysis: highly significant reduction in spasticity NRS in favour of nabiximols (p=0.0002); secondary endpoints Spasm Frequency Score, Sleep Disturbance NRS and Global Impression of Change all significant in favour of nabiximols.

The cannabis-based medicine showed significant superiority over placebo in the primary endpoint measurement (Numeric Rating Scale for spasticity, P=0,048) and resulted in a 40% responder rate with >30% improvement (P=0,014).

n=184 MS patients with spasticity, oromucosal THC/CBD preparation vs. placebo (6 weeks, double-blind, multicentre); primary endpoint NRS spasticity favouring verum (P=0.048); responder analysis: 40% achieved >30% benefit (P=0.014).

Primary endpoint not met, but significant improvements in nocturia, micturition frequency and overall bladder rating in favour of Sativex.

n=135, MS patients with overactive bladder, Sativex (nabiximols) vs. placebo over 10 weeks; primary endpoint (incontinence episodes) missed significance; 4/7 secondary endpoints significant in favour of Sativex: nocturia episodes (adj. mean difference -0,28; p=0,010), overall bladder condition (-1,16; p=0,001), micturition frequency/day (-0,85; p=0,001), PGIC (p=0,005); daytime micturitions -0,57 (p=0,044).

THC:CBD spray showed significantly better improvement in MS spasticity compared with placebo (77,4% vs. 32,1% clinically relevant responders; p < 0,0001).

SAVANT study: n=106 MS patients with resistant spasticity, randomised to THC:CBD spray (n=53) vs. placebo (n=53) over 12 weeks. Primary endpoint (≥30% NRS improvement): 77,4% vs. 32,1% (p<0.0001). Significant improvement in spasticity NRS (p<0.0001), pain NRS (p=0.0013), Modified Ashworth Scale (p=0.0007).

Dronabinol reduced pain intensity by 1,92 points, placebo by 1,81 points with no significant difference (p = 0,676).

Phase III RCT n=240 MS patients with central neuropathic pain, dronabinol vs. placebo (16 weeks) + 32-week open-label phase (n=100 up to 119 weeks). Primary endpoint: 11-point NRS pain reduction dronabinol −1,92 vs. placebo −1,81 (no significant difference, p=0,676). Higher adverse event rate under dronabinol vs. placebo (50,0% vs. 25,9%), long-term AE rate decreased to 26%. No drug abuse, one possible case of dependency. Safe long-term option for neuropathic MS pain.

Smoked cannabis reduced spasticity (Ashworth scale by 2,74 points more than placebo, p<0,0001) and pain significantly, but impaired cognition (PASAT score worsened by 8,67 points more, p=0,003).

n=30 MS patients with treatment-refractory spasticity, randomised crossover study of smoked cannabis (1x daily for 3 days) vs. placebo. Primary endpoint: Cannabis reduced spasticity (modified Ashworth Scale) by an average of 2,74 points more than placebo (p<0,0001). Secondary: pain reduction (VAS) by 5,28 points more than placebo (p=0,008). Timed Walk with no significant difference (p=0,2). Cognitive function (PASAT) worsened under cannabis by 8,67 points more than under placebo (p=0,003). No serious adverse events.

THC:CBD spray showed significantly greater improvement in spasticity compared to placebo across all subgroups, independent of previous failed treatment attempts.

Post-hoc analysis of an enriched-design RCT (n=241 ITT) of THC:CBD spray vs. placebo in MS spasticity. In both subgroups (Group 1: n=162 with ≥1 failed prior therapy; Group 2: n=57 with ≥2 failed prior therapies), response on the NRS 0-10 was significantly greater under THC:CBD than placebo — both for MCID (≥18% improvement vs. baseline) and CID (≥30% improvement). Tolerability was independent of prior therapy history.

Cannabis-based medicine was superior to placebo in reducing pain intensity (p = 0,005) and sleep disturbance (p = 0,003) in MS patients with central neuropathic pain.

n=66 MS patients with central pain (59 dysaesthetic, 7 painful spasms), THC:CBD spray (Sativex) vs. placebo over 4 weeks as add-on; mean pain intensity significantly reduced (CBM -2.7, 95% CI -3.4 to -2.0; placebo -1.4, 95% CI -2.0 to -0.8; p=0.005), sleep disturbance reduced (CBM -2.5, 95% CI -3.4 to -1.7; placebo -0.8, 95% CI -1.5 to -0.1; p=0.003). 97% completion rate (n=64). Well tolerated, most common adverse effects: dizziness, dry mouth, somnolence.

In the per-protocol population, significant improvement in spasm frequency and mobility, but no statistically significant effects in the ITT set.

n=50 MS patients with poorly controlled spasticity (ITT analysis); Cannabis sativa extract vs. placebo; per-protocol (n=37): significant reduction in spasm frequency (p=0,013) and improved mobility (p=0,01); ITT analysis shows only trends. Tolerability good; mild adverse events more frequent during the active phase.

CBD did not significantly reduce spasticity, but significantly improved walking speed (T25-FW) and reduced pain more than placebo.

n=49 MS patients with spasticity-related walking problems, randomized to purified CBD (5–80 mg/day over 4 weeks, n=24) vs. placebo (n=25). Timed 25-Foot Walk (T25-FW): significantly greater reduction in the intervention group (p=0.031); maximum pain significantly more reduced (p=0.033). No significant difference in spasticity severity (Modified Ashworth Scale) between groups at baseline, 4 and 8 weeks.

Pain and spasticity were significantly reduced immediately after administration in the clinic setting, but not in daily self-measurement; other clinical endpoints did not differ significantly from placebo.

n=24 progressive MS with moderate spasticity, oral THC (ECP002A) vs. placebo over 4 weeks; pain reduction significant directly after clinic administration (not in the diary), similar pattern for subjective spasticity. No cognitive deterioration after 2 or 4 weeks vs. placebo.

THC and CBD extracts significantly reduced pain compared to placebo and improved further neurogenic symptoms in a subset of patients.

n=24 (of which n=18 MS patients), cannabis extracts (THC, CBD, THC:CBD 1:1) vs. placebo sublingual (2-week periods); pain relief under THC and CBD significantly superior to placebo; spasticity, bladder symptoms and muscle cramps improved in MS patients. Provided evidence for cannabis efficacy in MS-associated neurological symptoms.

THC/CBD spray significantly increased the nociceptive stimulus threshold (RIII reflex) and reduced the reflex area in MS patients.

n=17 (of 18 randomised) patients with secondary progressive MS, THC/CBD oromucosal spray vs. placebo (crossover); RIII reflex threshold increased and RIII reflex area reduced after cannabinoids (p<0.05); VAS pain score decreased (not significant); H/M ratio unchanged.

Both cannabis extracts significantly reduced urinary incontinence, urgency and frequency as well as pain and spasticity.

n=15 evaluable MS patients (of 21 recruited) with refractory urinary tract symptoms; cannabis extracts THC+CBD (2,5 mg/spray) over 8 weeks; urgency, incontinence episodes, frequency and nocturia significantly reduced (P<0,05, Wilcoxon); patient-rated pain, spasticity and sleep significantly improved (P<0,05). Improvement in pain persisted up to a median of 35 weeks.

THC-CBD spray significantly improved spasticity and pain (MAS, 9HPT, NRS, VAS each p<0.05) with neurophysiological confirmation via prolonged CSP.

n=15 secondary progressive MS patients, THC:CBD spray vs. baseline; significant improvement in Modified Ashworth Scale (p=0.001), 9-Hole Peg Test (p=0.018), NRS spasticity (p=0.001), VAS pain (p=0.005). Neurophysiologically prolonged cutaneous silent period (p=0.001).

At doses above 7,5 mg a significant improvement in patients' spasticity ratings compared to placebo was observed.

n=13 MS patients with spasticity, double-blind crossover RCT; Delta-9-THC 2,5–15 mg oral vs. placebo (5 days each). At doses >7,5 mg significant improvement in patients' spasticity ratings compared to placebo (p<0,05). Findings in a treatment-failure population.

Significant reduction in spasticity (NRS scores from median 6 to 3.5, p<0.001) with inverse correlation to THC/CBD plasma concentrations; no significant effects in motor tests.

Pilot study n=12 MS patients with THC/CBD spray (2 sprays); peak plasma concentrations THC 0,60–13,29 ng/mL, CBD 0,55–11,93 ng/mL. NRS spasticity score decreased median from 6 to 3,5 (p<0,001); significant inverse correlation between NRS and THC plasma concentration (p<0,01) as well as CBD plasma concentration (p<0,002).

THC/CBD showed efficacy without tolerance development: NRS-11 pain score decreased from 3,8 (treatment group at week 5) to 2,9 after ~2 years; 92% of patients reported treatment-related adverse events.

n=63 MS patients with central neuropathic pain, open-label 2-year extension with THC/CBD oromucosal spray (Sativex); NRS-11 pain score in the 28 (44%) long-term completers: mean 2,9 (SD 2,0) after ~2 years vs. 3,8 (THC/CBD group) or 5,0 (placebo group) at the end of the randomised preceding phase; no tolerance development; 92% of patients ≥1 treatment-related adverse event (mostly mild-moderate).

Nabiximols showed no significant benefit over placebo on the primary endpoint (MAS LLMT-6 change): treatment difference 0,04 (P=0,7152).

Phase III RCT (n=68, crossover, multicenter, double-blind) of nabiximols vs. placebo in MS-associated spasticity; primary endpoint MAS LLMT-6 not met: LS-mean difference 0,04 (p=0,7152). Secondary MAS LLMT-4 values also showed no significant group difference. Safety profile consistent with the known nabiximols profile.

Sativex reduced MS-related neuropathic pain and improved quality of life after 4 weeks.

n=20 MS patients (10 with, 10 without neuropathic pain), Sativex® 4 weeks vs. baseline; significant VAS pain reduction in the pain group, parallel increase in fronto-central γ-band oscillation and pain-motor integration (p<0.05 for neurophysiological parameters).

Cannabis extract showed no significant improvement in objective tremor measurements compared with placebo; finger tapping was faster under placebo.

RCT (crossover, double-blind), n=14 MS patients with arm swing tremor; oral Cannador vs. placebo over 2 weeks. Primary endpoint (tremor index) showed no significant improvement under cannabis extract; finger tapping was faster under placebo (p<0,02). No clinically relevant benefit of cannabis for MS-associated tremor demonstrated.

After one month, 70,5% of patients achieved a ≥20% improvement in spasticity; 28,2% achieved a clinically relevant ≥30% improvement with a mean NRS reduction of 22,6%.

Italian AIFA registry n=1615 MS patients with treatment-resistant spasticity, THC:CBD spray (Sativex). After 1 month: 70,5% achieved ≥20% NRS improvement (Initial Response), 28,2% ≥30% (Clinically Relevant Response); mean NRS reduction 22,6% (7,5→5,8). Multivariate analysis: increased probability of IR with progressive MS (OR=1,4; 95% CI 1,04–1,9; p=0,025) and baseline NRS >8 (OR=1,8; 95% CI 1,3–2,4; p<0,001). 39,5% treatment discontinuations in 6 months (26,2% loss of effect, 18,7% adverse effects).

Sativex showed a known, well-tolerated safety profile in the long-term registry with no new safety signals; 83% of patients reported a clinical benefit.

n=941 MS spasticity patients, 2.213,98 patient-years of exposure with Sativex® (THC:CBD). 83% of patients reported benefit; 60% continued treatment. 32% discontinued therapy (approx. 1/3 due to lack of efficacy, 1/4 due to ADRs). Psychiatric ADRs of clinical significance in 6%; falls requiring medical treatment in 6%; most common treatment-related ADRs: dizziness 2,3%, fatigue 1,7%. No signal for abuse, diversion or dependence.

Nabiximols reduced spasticity NRS in a clinically meaningful way and improved quality of life in the majority of treated MS patients.

n=238 MS spasticity patients (out of 276; Belgian multicentre study), Sativex® after failure of previous anti-spasticity drugs. Spasticity NRS decreased from 8,1 (baseline) to 5,2 (week 4), 4,6 (week 8) and 4,1 (week 12). EQ-VAS increased from 39 to 59 (week 12). 74 % of patients with ≥30 % NRS improvement at week 12 (clinically meaningful response). Treatment discontinuation rate by week 12: 33,7 % (mainly lack of efficacy).

Nabiximols measurably reduced MS-related spasticity (NRS from 7,6 to 5,5), and physiotherapy improved clinically relevant response rate and treatment persistence.

Multicenter real-world study n=290 MS patients with moderate to severe spasticity, nabiximols (THC:CBD spray) + physiotherapy (PT) vs. without PT, 12-week follow-up. Mean NRS reduction: 7,6 (T0) → 5,8 (T1, 4 weeks) → 5,5 (T2, 12 weeks). T1: 77% achieved ≥20% improvement (IR), 22% ≥30% (CRR). PT group: higher probability of CRR (OR=2,6; 95% CI 1,3–5,6; p=0,01). Treatment discontinuation: 10,3% at T1, 24,5% at T2; PT reduced late discontinuations (HR=0,41; 95% CI 0,23–0,69; p=0,001).

NRS improvement of 34,4% after 18 months, but about 50% of patients ended therapy due to loss of effect or side effects.

Prospective multicenter Italian real-world study on THC:CBD oromucosal spray in MS spasticity (n=1845, 32 centers); 81,4% of patients achieved an NRS improvement ≥20% after 4 weeks (26,9% NRS reduction at T1, 34,4% at T5/18 months); 48,3% discontinued treatment within 18 months; higher baseline NRS scores (OR=2,28, 95% CI 1,15-6,36, p<0.01) and greater NRS differences T0-T1 (OR=2,11, 95% CI 1,08-8,26, p<0.05) predicted therapy continuation.

About 60% of patients continued Sativex after 6 weeks, while a poorer early response and low baseline value were predictors of discontinuation.

Registry study (n=1597 MS patients, 30 centres) on Sativex discontinuation rates; 39,5% discontinued therapy (Kaplan-Meier); higher NRS at week 4 increased discontinuation risk (adjHR=2,23; 95%-CI 2,07–2,41; p<0,001), lower baseline NRS protective (adjHR=0,51; 95%-CI 0,46–0,56; p<0,001); first 6 weeks decisive for responder identification.

61,9% of patients achieved sufficient improvement in spasticity (≥20% NRS) after 1 month, 40,2% showed a clinically meaningful ≥30% NRS improvement after 6 months.

AIFA registry Italy (January 2014–February 2015), n=1.534 MS spasticity patients from 30 centres, mean disease duration 17,6±8,6 years, EDSS 6,4±1,2. After 1 month titration: 61,9% achieved ≥20% NRS improvement; after 6 months: 40,2% with ≥30% NRS reduction. Mean dose 6,2–6,7 sprays/day. Adverse effects in 15% (mostly mild-moderate).

THC:CBD spray significantly improved MS-related spasticity and associated symptoms after 3 months with good tolerability.

MOVE-2 EU real-world registry, n=433 MS patients with treatment-resistant spasticity (mean duration 7,4 years, 78,1% used baclofen), prospective observation over 3 months with THC:CBD oromucosal spray as add-on therapy. After 1 month, 349 patients (responders: ≥20% spasticity improvement) continued therapy, after 3 months 281 patients. Mean dosage: 6 sprays/day. Spasticity scores and associated symptoms (spasms, fatigue, pain, sleep quality, bladder function) significantly improved, as well as activities of daily living and quality of life (EQ-5D VAS). Adverse events in 10,4% of patients, none serious.

THC/CBD spray significantly reduced MS spasticity: NRS score decreased by 19,1% (p<0,0001), modified Ashworth score from 2,6 to 2,3 points (p<0,0001), 24,6% of patients showed ≥30% improvement.

MOVE-2 interim analysis Italy: n=322 MS patients with treatment-resistant spasticity under THC:CBD oromucosal spray (Sativex®). Baseline→Month 3: NRS score -19,1% (-1,6 points, p<0,0001), modified Ashworth score 2,6→2,3 (p<0,0001). 24,6% clinically relevant responders (≥30% NRS improvement, p<0,001). Mean dose 5,1±2,6 sprays/day (Month 3). 13,1% reported ≥1 adverse event; most common: dizziness (5,6%), confusion (2,5%), nausea (1,25%).

After 1 month 74,6% of patients reported relief of spasticity; the NRS score decreased on average by 25% after 3 months; 17% reported side effects.

MOVE-2 study, prospective multicenter registry in German routine care, n=276 MS spasticity patients under nabiximols. After 1 month spasticity reduction in 74.6% (physician assessment); mean NRS (0-10) from 6.1±1.8 to 5.2±2.0 (in responders ≥20% improvement: -40%). After 3 months 55.3% still on therapy, NRS reduction -25% vs. baseline. 17% reported side effects.

Nabiximols significantly and durably reduced spasticity and pain in MS patients for up to 48 weeks.

Real-world study (n=144 MS patients, 123 progressive/21 relapsing-remitting) on nabiximols for moderate to severe spasticity (mean sNRS=7,5); 71,7% responders with mean sNRS reduction of 32% (p<0,001), sustained until week 48; concurrent pain reduction (pNRS p<0,001).

Significant reduction in spasticity (NRS score by 2,5 ± 1,2 points, P < 0,0001) as well as improvement in pain and bladder function.

Real-world data n=102 MS patients with THC/CBD spray over 40 weeks; mean daily dose 6,5±1,6 sprays. Spasticity NRS decreased by 2,5±1,2 points (p<0,0001). Additional effects: NRS pain reduction (n=58, p=0,011) and IPSS bladder function improvement (n=46, p=0,001). Adverse events 40,2%, discontinuation rate 36,2%.

Significant reduction in stretch reflex amplitude as well as significant improvements in NRS and MAS scores under THC:CBD spray treatment for MS spasticity.

Prospective observational study (n=57 MS patients with spasticity) on THC:CBD spray. Significant reduction in stretch reflex amplitude as well as significant reduction in NRS and MAS scores. Low concordance between the three measures (stretch reflex, NRS, MAS). Stretch reflex responders used significantly higher puff numbers; no dose differences in NRS/MAS responders. Authors conclude higher sensitivity and specificity of the stretch reflex as an objective measure of spinal excitability.

Significant reduction in spasticity (NRS from 6,0 to 4,5 points after 12 months), good tolerability (84% without side effects).

12-month extension of the MOVE-2 study, n=52 MS spasticity patients on nabiximols in German routine care. Spasticity NRS (0-10) reduced significantly from 6.0±1.8 (baseline) to 4.8±1.9 (1 month) and 4.5±2.0 (12 months); in initial responders (≥20% NRS improvement) from 6.3±1.4 to 4.3±1.9. 84% reported no side effects.

Prolonged cannabis use is associated with significantly worse cognitive performance in several domains in MS patients.

n=50 MS patients (25 cannabis users vs. 25 non-users); cannabis users performed significantly worse in information processing speed, working memory, executive functions and visuospatial perception; twice as likely to be globally cognitively impaired (factor ~2,0) compared to non-users. No group differences in depression/anxiety (HADS).

Pain, spasticity and sleep disturbances decreased significantly; no impairment in degree of disability, ambulation, dexterity or processing speed.

Prospective safety study n=28 MS patients on sublingual cannabis oils (THC-rich, CBD-rich, THC+CBD combined) over 4-week titration. Mean dose THC=4,0 mg, CBD=7,0 mg (once daily in the evening). Pain NRS median 7→4 (p=0,01), spasticity NRS median 6→2,5 (p=0,01), sleep disturbances NRS median 7→3 (p<0,001). Most common side effects: dry mouth, drowsiness, dizziness, nausea (mild-moderate); 2 treatment discontinuations due to excessive dreaming/drowsiness.

Nabiximols worsened postural control in MS patients, especially under dual-task conditions.

n=22 MS patients under nabiximols; after 1–12 months worsened postural control in Continuers (n=11) vs. Quitters (n=11): single task F=3,07, p=0,044; dual task F=4,90, p=0,005. Nabiximols had a negative effect on balance under multi-tasking conditions — relevant negative finding for therapeutic use in MS.

Significant improvements in processing speed and auditory-verbal memory performance within the first 6 months; spasticity improved significantly; mood and anxiety showed no significant changes.

n=20 MS patients on THC:CBD spray (Sativex) over 12 months; significant improvement in processing speed (SDMT: p<0.001) and auditory verbal memory (CVLT: p=0.0001) after 6 months. Spasticity NRS significantly improved (p<0.0001). No significant changes in mood/anxiety.

THC/CBD spray is cost-effective and, when home care costs are taken into account, dominant over standard therapy alone.

Markov model over 30 years: THC/CBD oral spray in addition to standard therapy for moderate to severe MS spasticity in Wales; ICER £10.891/QALY; when including care costs dominant (ICER −£95.423/QALY, incremental savings £33.609/patient), i.e. THC/CBD spray cost-effective.

Descriptive characterization: cannabis users (27% of the sample) were younger and reported higher pain intensity, higher pain interference and higher neuropathic pain scores than non-users; no intervention effect measured.

Baseline cross-sectional analysis from an RCT on chronic pain in MS, n=242. Cannabis prevalence 27% (n=65); most common form of administration: oil/tincture (42%), followed by vaporization (22%) and edibles (17%). Cannabis users significantly younger (median 51 vs. 55 years, p=0,019), higher pain intensity (median 6,0 vs. 5,0, p=0,022), higher pain interference (median 5,9 vs. 5,4, p=0,027) and higher neuropathic pain (median 20,0 vs. 16,0, p=0,001).

Most respondents reported subjective symptom relief from cannabis, most frequently for spasticity and chronic pain.

n=112 MS patients (53 UK + 59 USA), anonymous questionnaire on cannabis use. 97–30% reported improvement (descending): spasticity (97%), chronic limb pain, acute paroxysms, tremor, emotional dysfunction, anorexia/weight loss. Results served as a basis for planning clinical trials.

79% of cannabis users subjectively report that cannabis is helpful for their MS-related spasticity; however, this is a cross-sectional observation without a control group or objective measurement of spasticity reduction.

Cross-sectional survey among MS patients with spasticity in Oregon: 54% report having ever used cannabis, 36% currently; 79% find cannabis helpful for spasticity, 58% use it at least daily, 79% use multiple forms of administration. 26% combine cannabis with prescribed oral antispastics.

THC/CBD was effective in 80% of patients for improving spasticity in multiple sclerosis.

Retrospective observational study on THC/CBD oromucosal spray in MS spasticity (n=50); 80% of patients showed therapeutic response at a median dose of 5 (2-10) inhalations/day; 16 patients (32%) discontinued treatment (7 due to ineffectiveness, 5 due to side effects); most common side effects: dizziness (n=11), somnolence (n=6), muscle weakness (n=7).

THC/CBD spray significantly reduced OAB symptoms (p=0,001) and post-void residual volume (p=0,016) in MS patients with treatment-resistant overactive bladder.

n=15 MS patients with refractory overactive bladder (OAB); 4 weeks THC/CBD oromucosal spray. Significant reduction in OAB symptoms (OABSS, p=0.001). Urodynamic: significant reduction in residual urine volume (PVR, p=0.016), trend toward increased bladder capacity (CCmax) and bladder volume at first desire to void (BVFD), but not statistically significant.

Sativex is cost-effective with an ICER of €4.968/QALY, clearly below the accepted cost threshold of €30.000/QALY.

Markov model-based cost-effectiveness analysis for Sativex® (THC+CBD oromucosal spray) as add-on in resistant MS spasticity in the Italian healthcare system; ICER over 5 years = €4.968/QALY gained (clearly <€30.000 threshold); robust results in deterministic and probabilistic sensitivity analysis.

Nabiximols showed good tolerability and a safe profile in the treatment of spasticity and chronic pain in everyday clinical practice, with frequent but expected side effects (dizziness, fatigue, somnolence) and a low rate of serious adverse events (3,1% in MS spasticity studies).

Systematic review of nabiximols (THC:CBD spray) in MS spasticity; k=24 studies (20 spasticity, 4 pain), n=4.351 MS spasticity patients. Most common side effects: dizziness, fatigue, somnolence. SAE rate 3,1% (137/4.351), 39 treatment-related SAEs in 32 patients (all resolved). No treatment-related SAEs in pain studies.

THC-CBD oromucosal spray shows efficacy in MS-induced spasticity with predominantly mild to moderate side effects (dizziness, fatigue).

Narrative review on THC-CBD oral spray in MS spasticity (affects >80% of MS patients); summarizes phase III RCTs (n≈1.600 patients or 1.500 patient-years) and real-world studies (>1.000 patients or >1.000 patient-years). Most common side effects: dizziness and fatigue, mostly mild to moderate.

Sativex improved subjective sleep parameters across multiple pain syndromes without development of tolerance over up to four years.

Narrative review on Sativex (THC/CBD 1:1) in multiple sclerosis symptoms; n=2000 patients in phase I-III studies (1000 patient-years). Pronounced subjective improvement of pain and sleep parameters in MS patients; 40-50% achieved good/very good sleep quality; no tolerance phenomenon over up to 4 years of treatment.

Narrative review of Sativex (THC+CBD 1:1) in MS-resistant spasticity; 3 pivotal RCTs summarized: Study 1 (n=189): NRS reduction -1.18 vs. -0.63 (p=0.048); Study 2 (n=337): -1.3 vs. -0.8 (p=0.035); Study 3 (n=572): responder phase (≥20% improvement) 47%, subsequently Sativex vs. placebo NRS difference +0.85 points (p=0.0002). Most common AEs: dizziness, fatigue (mild/transient).

High-quality evidence supports the use of marihuana/cannabinoids for chronic pain, neuropathic pain and spasticity in multiple sclerosis; many other indications are not evidence-supported.

Narrative clinical review on medical cannabis (MEDLINE 1948-March 2015), focus on 28 RCTs on indications outside FDA-approved cannabinoids. High-quality evidence for cannabis in chronic pain, neuropathic pain and MS spasticity: 6 trials (n=325) chronic pain, 6 trials (n=396) neuropathic pain, 12 trials (n=1600) MS spasticity — several positive results for efficacy.

Cannabinoids show probable efficacy for MS-associated spasticity and pain, but are associated with relevant safety risks.

Narrative review on cannabinoid therapy for MS symptoms; two high-quality SRs cited, which as the only strong evidence for cannabinoids in neurological diseases identified patient-reported spasticity reduction and central pain in MS. Nabiximols, oral cannabis extract and synthetic THC are considered 'probably effective' for patient-reported spasticity reduction (20–40 mg THC/day in divided doses); physician-measured spasticity parameters showed no significant improvement.

About one third of patients with treatment-resistant MS spasticity showed clinically relevant and statistically significant improvement with THC:CBD spray versus placebo; effect maintained over 50 weeks, good tolerability, no negative effects on cognition or mood.

Narrative review of THC:CBD oromucosal spray (Sativex) in MS spasticity: In phase III studies, about one third of patients with treatment-resistant MS spasticity achieved clinically relevant and statistically significant improvement vs. placebo. After 50 weeks of treatment, about two thirds of patients, physicians and caregivers reported improvement versus baseline; no significant effects on cognition or mood were demonstrated.

Narrative review on cannabinoids in MS spasticity: growing evidence for positive effects of cannabinoids on MS symptoms including spasticity and pain. Discusses findings from the EAE mouse model (Experimental Allergic Encephalomyelitis) and current clinical studies; long-term studies required to establish a role beyond mere symptom relief.