Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis

Mari Carmen Torres-Moreno; Esther Papaseit; Marta Torrens; Magí Farré

doi:10.1001/jamanetworkopen.2018.3485

Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis

Torres-Moreno, Mari Carmen; Papaseit, Esther; Torrens, Marta; Farré, Magí 2018-10-12 00:00:00 Key Points Question Are medicinal cannabinoids IMPORTANCE Cannabinoids have antispastic and analgesic effects; however, their role in the effective and well tolerated in the treatment of multiple sclerosis (MS) symptoms is not well defined. treatment of multiple sclerosis? Findings In this systematic review and OBJECTIVE To conduct a systematic review and meta-analysis to assess the efficacy and tolerability meta-analysis of 17 randomized clinical of medicinal cannabinoids compared with placebo in the symptomatic treatment of patients trials including 3161 patients, with MS. cannabinoids were significantly associated with efficacy for subjective DATA SOURCES MEDLINE and the Cochrane Library Plus up to July 26, 2016. No restrictions were spasticity, pain, and bladder dysfunction applied. The search was completed with information from ClinicalTrials.gov. compared with placebo. Cannabinoids had a higher risk of adverse events and STUDY SELECTION Randomized, double-blind, and placebo-controlled trials evaluating the effect withdrawals due to adverse events, with of medicinal cannabinoids by oral or oromucosal route of administration on the symptoms of no statistically significant differences spasticity, pain, or bladder dysfunction in adult patients with MS. found for serious adverse events. DATA EXTRACTION AND SYNTHESIS The Preferred Reporting Items for Systematic Reviews and Meaning Cannabinoids appear to be Meta-analyses (PRISMA) reporting guidelines were followed. Effect sizes were calculated as safe regarding serious adverse events, standardized mean difference (SMD) for efficacy, and rate ratio (RR) for tolerability. Within each study, but their clinical benefit may be limited. those SMDs evaluating the same outcome were combined before the meta-analysis to obtain a single value per outcome and study. Pooling of the studies was performed on an intention-to-treat basis by Invited Commentary means of random-effect meta-analysis. Supplemental content MAIN OUTCOMES AND MEASURES Spasticity (on the Ashworth and Modified Ashworth scales and Author affiliations and article information are subjective), pain, bladder dysfunction, adverse events, and withdrawals due to adverse events. listed at the end of this article. RESULTS Seventeen selected trials including 3161 patients were analyzed. Significant findings for the efficacy of cannabinoids vs placebo were SMD = −0.25 SD (95% CI, −0.38 to −0.13 SD) for spasticity (subjective patient assessment data), −0.17 SD (95% CI, −0.31 to −0.03 SD) for pain, and −0.11 SD (95% CI, −0.22 to −0.0008 SD) for bladder dysfunction. Results favored cannabinoids. Findings for tolerability were RR = 1.72 patient-years (95% CI, 1.46-2.02 patient-years) in the total adverse events analysis and 2.95 patient-years (95% CI, 2.14-4.07 patient-years) in withdrawals due to adverse events. Results described a higher risk for cannabinoids. The serious adverse events meta- analysis showed no statistical significance. CONCLUSIONS AND RELEVANCE The results suggest a limited efficacy of cannabinoids for the treatment of spasticity, pain, and bladder dysfunction in patients with MS. Therapy using these drugs can be considered as safe. (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 1/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Abstract (continued) TRIAL REGISTRATION PROSPERO Identifier: CRD42014015391 JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 Introduction Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination in the central nervous system caused by inflammatory immune-mediated attacks. In 2013 there were approximately 2.3 million people affected by MS worldwide. Manifestations may occur in an episodic (relapsing-remitting) or progressive (primary or secondary) pattern and vary from benign to severe. Sensory and motor systems are frequently affected and present symptoms of spasticity, pain, and bladder dysfunction. Treatment of MS focuses on preventing new relapses, modifying the course of the disease, and managing symptoms. No treatment to stimulate remyelination and repair nerves is available. Cannabinoids act as neuromodulators of the endocannabinoid system; therefore, their therapeutic potential has aroused considerable interest over the centuries. In some countries a mixture of cannabinoids (nabiximols) has been approved for the symptomatic treatment of MS 4,5 spasticity and neuropathic pain in cases in which previous medication has proved ineffective. Nabiximols are a mixture of δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in an approximate ratio of 1:1. Oral cannabis extract (CE) contains THC and CBD from the Cannabis sativa plant. Other marketed cannabinoids include dronabinol, an oral synthetic THC, and nabilone, an oral synthetic THC analogue. 6-11 Limited literature regarding previous systematic reviews and meta-analysis was found. The results from these studies were relatively incomplete. We aimed to evaluate the therapeutic efficacy and tolerability of medicinal cannabinoids to treat the symptoms of spasticity, pain, and bladder dysfunction in patients with MS by performing a systematic review and meta-analysis of randomized, double-blind, and placebo-controlled trials. Methods Study Protocol A protocol of the study was prepared and recorded in the International Prospective Register of Systematic Reviews (PROSPERO). The review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Study Eligibility Criteria The inclusion criteria were (1) published studies evaluating the effect of medicinal cannabinoids by oral or oromucosal route on the symptoms of spasticity, pain, or bladder dysfunction in adult patients with MS; (2) randomized, placebo-controlled, double-blind, and parallel or crossover designed trials; (3) a minimum length of treatment of 2 weeks; and (4) studies specifying the results by means of estimated effect size or with sufficient information to calculate it. The exclusion criteria were (1) studies investigating other clinical entities and (2) studies duplicated in publication. Search and Selection of Studies Search, study selection, and data collection were jointly conducted by 2 of us (M.C.T.M. and M.F). The summary of the studies was read by these 2 authors; in case of disagreement, the study was again reviewed, and a final decision was reached by consensus. The bibliographic search was carried out up to July 26, 2016, in the electronic databases MEDLINE and the Cochrane Library Plus. No limits regarding publication date, article type, or language were applied. An additional search was performed in ClinicalTrials.gov to obtain JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 2/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis complementary information not provided in the articles. The search strategy used was “(canna* OR tetrahydrocannabinol OR THC OR marijuana OR dronabinol OR nabilone OR levonantradol OR dexanabinol OR sativex OR namisol OR marihuana OR cesamet OR marinol OR nabiximols) AND multiple sclerosis.” The abstracts were reviewed to identify randomized clinical trials (RCTs). The references of the reviews and selected studies were checked to identify other RCTs that had not been located. In parallel, other documents such as books, monographs, and reports were also reviewed. The authors of the identified studies were contacted in the case of controversy to clarify appropriateness for inclusion. Data Extraction All available data were collected to select those that were valid to compare efficacy and tolerability from the published articles found in the electronic databases and complemented with results from ClinicalTrials.gov. The general data selection criteria were (1) information measuring efficacy and tolerability and (2) information about the phases fulfilling the inclusion criteria in the case of studies with different phases. The data selection criteria for efficacy were (1) data convertible to the effect size of standardized mean difference (SMD) and (2) data from the tools measuring the same clinical aspects. For tolerability, the selection criteria were (1) the number of adverse events or, in case of failure, the number of patients presenting an adverse event, appearing in at least 2 of the studies and (2) the number of patients withdrawn from the intervention and/or the study due to adverse events. Assessment of Bias of Studies Estimates of the risk of bias of each of the included studies, and across them, were reached according to the recommendations of the Cochrane Collaboration. Ratings were low risk of bias, high risk of bias, and unclear risk of bias. Each study was reviewed individually. Assessment of publication bias for each meta-analysis was also performed. Assessments were carried out using the software Review Manager (RevMan) (Cochrane). Synthesis In efficacy, high heterogeneity was clearly demonstrated in the format by which results were obtained (eg, F statistic, mean difference between groups, or odds ratio), making a direct comparison nonviable. As a consequence, standardization to the SMD, which is expressed in standard deviation units, was calculated in order to allow comparison. The SMD used was Hedges g and hereafter the SMD referred to in our study is this unless otherwise indicated. The related standard error was also estimated. Effect size can be interpreted in the clinical field following the rule of thumb in which values of 0.2, 0.5, and 0.8 represent small, moderate, and large effect, respectively. Calculations of the SMD were carried out on an intention-to-treat (ITT) basis by extrapolation of the missing 14-22 23 data. Crossover studies were treated as parallel design. With respect to the evaluation of efficacy, it was necessary to modify the direction of some clinical tools to adapt the results, as some were using higher or inverse punctuations for clinical improvement. The primary studies provided multiple data results obtained from different clinical assessment tools (eg, pain measurement with a numerical rating scale, visual analog scale, and the Neuropathic Pain Scale) for the same common outcome. Converted data resulting from these tools within the same study were combined to include as many data as possible and to avoid loss of information. This option also reduces the risk of bias due to the subjective selection of 1 unique clinical measure on our part. After combination, a single SMD value per outcome and study was obtained, ensuring the assumption of independence of effect sizes. Data pooling was carried out by the simple averages of 18,24 the SMDs and their standard errors. For tolerability, data were analyzed in the form of the rate ratio (RR). The meta-analysis was performed with RevMan software using the inverse-of-variance method. The random-effects model was used on an ITT basis. For efficacy, SMDs and their standard errors JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 3/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis were analyzed. For tolerability outcomes, the natural logarithm (ln) of the RRs and its respective standard errors were introduced. The heterogeneity of the results was evaluated by means of the I statistic. Sensitivity Analysis After the systematic review, we conducted a sensitivity analysis of the results obtained to ascertain whether the findings were strong enough to reaffirm the methods used. With this objective, the meta-analyses were repeated, changing the parameters that could be affected by our decisions: (1) use of the fixed-effects model instead of random effects; (2) exclusion of crossover studies; (3) exclusion of studies with a sample size of 50 patients or fewer; (4) exclusion of studies with a length of treatment of 4 weeks or less; and (5) exclusion of studies with a high risk of bias in any of the evaluated domains. Furthermore, to reaffirm our calculations, other parallel secondary estimations for SMDs were performed with data from the studies. Results Study Characteristics 25-43 A total of 17 RCTs (19 articles) from 775 records were included in our study. Another 22 of the 775 records underwent full-text review but were later excluded (eReferences in the Supplement). Regarding the 17 RCTs, 2 had 2 articles each. In the statistical analysis, they are referred to as 26 27 33 34 Zajicek, 2003/Freeman, 2006 and Aragona, 2009/Tomassini, 2014. Two of the studies were 37,39 conducted in 2 phases (A and B). Only phase B was analyzed in 1 of the studies, in which participants were responders after the initial phase A treatment. The initial participants in phase A 39 42 of the other study were included, in that case excluding phase B. One of the selected articles was based on a published RCT (reference e2 in eReferences in the Supplement) that was discarded after reading the full text, owing to lack of data results. Of the 17 RCTs, 5 (6 articles) were crossover 25,28,29,33,34,43 design. The total number of patients analyzed was 3161. The studied experimental 25-27,29,38 30-37,39,40,43 interventions were (1) oral CE ; (2) oromucosal CE (nabiximols) ; (3) oral 25-28,42 41 dronabinol ; and (4) oral nabilone, evaluated as an adjunctive treatment to gabapentin. Two of the studies (3 articles) included 2 experimental groups, using both oral CE and dronabinol in 25-27 comparison with placebo. Each experimental-placebo comparison was included separately. Figure 1 shows selection of included studies. Main characteristics and outcome measures of each study are included in Table 1; eTable 1 in the Supplement shows further detail. Hereafter, all the results of the pooled-effect sizes of the previously mentioned treatments within the respective meta-analyses are referred to as cannabinoids, unless otherwise indicated. Bias of Studies The risk-of-bias summary of each study included in the systematic review is depicted in eFigure 1 in the Supplement. According to the authors’ judgement, high risk of bias was found relative to blinding 37 33,34,41,43 of participants and personnel, blinding of outcome assessment, incomplete outcome 26,27,41,42 25 data, and selective reporting, with the greatest percentage of high risk for bias concerning blinding of outcome assessment and incomplete outcome data (eFigure 2 in the Supplement). The impact on our results was evaluated in the sensitivity analysis. Publication bias analyses for each meta-analysis are shown in eFigure 3 in the Supplement for efficacy outcomes and eFigure 4 in the Supplement for tolerability. Publication bias was detected both for and against cannabinoids. Efficacy A total of 82 results from clinical assessment tools were selected and converted to SMDs, and 17 combinations were carried out among them. A summary of all selected clinical assessment tools can be seen in eTable 2 in the Supplement. Clinical effect in favor of the experimental treatment is denoted by a negative SMD, and a positive value favors the placebo. Statistically significant results JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 4/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis are considered favorable for cannabinoids or placebo whenever the confidence interval of the results does not exceed the value of no effect (0 in case of the SMD). Spasticity was evaluated separately for objective measures scored by an observer on the Ashworth and Modified Ashworth scales (referred to as spasticity [Ashworth]), and for the subjective spasticity measures (patient assessment data). No effects of cannabinoids on the Ashworth and Modified Ashworth scales were observed. Results showed statistically significant differences in favor of the experimental group vs placebo in spasticity (subjective) in CE (SMD, −0.27 SD; 95% CI, −0.44 to −0.09 SD), nabiximols (SMD, −0.29 SD; 95% CI, −0.47 to −0.12 SD), and cannabinoids (SMD, −0.25 SD; 95% CI, −0.38 to −0.13 SD). Figure 2A shows the meta-analysis for spasticity (Ashworth), and Figure 2B for spasticity (subjective). Results in pain presented statistically significant differences in favor of CE (SMD, −0.33 SD; 95% CI, −0.50 to −0.16 SD), nabilone (SMD, −1.40 SD; 95% CI, −2.78 to −0.03 SD), and cannabinoids (SMD, −0.17 SD; 95% CI, −0.31 to −0.03 SD). Figure 3A shows the meta-analysis for pain. Similar results were obtained for bladder dysfunction in CE (SMD, −0.29 SD; 95% CI, −0.50 to −0.09 SD) and cannabinoids (SMD, −0.11 SD; 95% CI, −0.22 to −0.0008 SD) (Figure 3B). One possible concern in clinical trial results is the impact of industry-funded studies. In our 25-27,29,38 28,42 meta-analysis, all the studies concerning CE and dronabinol were funded by 41 30-32,35-37,39,40,43 independent grants. The study of nabilone and all of those concerning nabiximols 33,34 (except 1 ) were funded by pharmaceutical companies (nabilone by Valeant Canada and nabiximols by GW Pharma and Laboratorios Almirall). We performed an additional analysis excluding those industry-funded studies. The additional analysis showed no differences between nabiximols and placebo in all the efficacy outcomes. For spasticity (Ashworth), the values changed from −0.11 SD (95% CI, −0.22 to 0.01 SD) to 0.06 SD (95% CI, −0.60 to 0.71 SD); for subjective spasticity, the values changed from −0.29 SD (95% CI, −0.47 to −0.12 SD) to −0.26 SD (95% CI, −0.92 to 0.39 SD); and for pain and bladder dysfunction, the values changed to not estimable. The same occurred in nabilone, for which the effect on pain could not be estimated. In the analysis for cannabinoids, only results for Figure 1. Study Selection Flowchart 775 Records identified by database search 654 MEDLINE 121 The Cochrane Library Plus 101 Duplicate records removed 1 Full-text article from contact with authors 674 Identified for screening 634 Titles, abstracts, and full-text articles excluded 41 Full-text articles reviewed in depth for eligibility 22 Full-text articles excluded 2 Duplicates 5 Substudies or same cohort of others included 14 Did not fulfill selection criteria 1 Withdrawal study 17 Randomized clinical trials (19 articles) included in the systematic review and meta-analysis 4 Cannabis extract treatment 10 Nabiximols treatment 4 Dronabinol treatment Two studies using both cannabis extract and 1 Nabilone treatment dronabinol as experimental treatments. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 5/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Table 1. Summary of Characteristics of the Included Studies Interventions, Mean (SD) Dose THC/CBD (CE THC (Dronabinol Source Design Patients, No. or Nabiximols) or Nabilone) Placebo Killestein Patients with progressive MS with spasticity, setting not 16 CE: dose = 2-4 caps/d Dronabinol: Dose = 2-4 caps/d et al, 2002 specified, crossover, 20 wk (4-wk intervention, 4-wk washout (5-10 mg THC + Dose = 2-4 caps/d between treatment periods), ITT analysis approximately (5-10 mg THC) 1.25-2.50 mg CBD) 26 b Zajicek et al, Patients with MS with spasticity, multicentric (UK), parallel, 630 CE: 5.42 (2.11) caps/d Dronabinol: 5.47 6.24 (1.71) caps/d 2003 (same 15 wk, ITT analysis (13.56 mg THC + 6.78 mg (2.08) caps/d (13.67 b b study cohort as CBD) mg THC) Freeman et al, 2006) 26 b Freeman Patients recruited to the Zajicek et al, 2003 study, except those 522 (83% of CE: 5.42 (2.11) caps/d Dronabinol: 5.47 6.24 (1.71) caps/d 27 26 et al, 2006 with a permanent catheter Zajicek et al, (13.56 mg THC + 6.78 mg (2.08) caps/d b b (same study 2003 initial CBD) (13.67 mg THC) cohort as data) Zajicek et al, 2003) Svendsen Patients with MS with central neuropathic pain, unicentric 24 NA Dronabinol: Mean Mean (range) dose, et al, 2004 (Denmark), crossover, 9 wk (3-wk intervention, 3-wk washout (range) dose, 3.1 (2.7- 3.3 (2.8-3.6) between treatment periods), ITT analysis 3.6) caps/d (7.75 caps/d (8.25 [7.00- [6.75-9.00] mg THC) 22.50] mg) Vaney et al, Patients with MS with spasticity, unicentric (Switzerland), 57 CE: 7.20 caps/d (17.99 NA Mean dose not 2004 crossover, 4 wk (2-wk CE treatment, 1-wk placebo, 3-d washout [7.63] mg THC + 6.48 specified between and after interventions), ITT and PP analyses [2.75] mg CBD) Wade et al, Patients with MS with spasticity, spasms, bladder problems, 160 Nabiximols: 12.37 (6.05) NA 18.87 (6.17) 2004 tremor, or pain (not musculoskeletal); multicentric (UK); parallel; sprays/d (33.40 mg THC + sprays/d 6 wk; PP analysis 30.93 mg CBD) Rogetal, Patients with MS with central neuropathic pain, unicentric (UK), 66 Nabiximols: 9.6 (6.1) NA 19.1 (12.9) 2005 parallel, 5 wk, ITT analysis sprays/d (wk 4) (25.92 mg sprays/d (wk 4) THC + 24.00 mg CBD) Collin et al, Patients with MS with spasticity, multicentric (UK and Romania), 189 Nabiximols: 9.4 (6.4) NA 14.7 (8.4) sprays/d 2007 parallel, 6 wk, ITT and PP analyses sprays/d (25.38 mg THC + 23.50 mg CBD) Aragona Patients with secondary progressive MS with spasticity, 17 (94% with Nabiximols: 8.20 (3.15) NA 15.16 (4.51) et al, 2009 unicentric (Italy), crossover, 10 wk (3-wk intervention, 2-wk respect to sprays/d (22.14 mg THC + sprays/d (same study washout between and after treatment periods), ITT and PP Tomassini 20.50 mg CBD) cohort as analyses et at, 2014 Tomassini initial data) et al, 2014) Tomassini Patients with secondary progressive MS with spasticity, 18 Nabiximols: median NA Median (range) et at, 2014 unicentric (Italy), crossover, 10 wk (3-wk intervention, 2-wk (range) dose, 7.4 dose, 16.1 (same study washout between and after treatment periods), ITT and PP (2.7-12.5) sprays/d (19.98 (6.7-26.0) sprays/d cohort as analyses mg THC + 18.50 mg CBD) Aragona et al, 2009) Collin et al, Patients with MS with spasticity, multicentric (UK and Czech 337 Nabiximols: mean (range) NA Mean (range) dose, 2010 Republic), parallel, 15 wk, ITT and PP analyses dose, 8.5 (1-22) sprays/d 15.4 (2-23) (22.95 mg THC + sprays/d 21.25 mg CBD) Kavia et al, Patients with MS with overactive bladder, multicentric (UK, 135 Nabiximols: mean NA Mean (median) 2010 Belgium, and Romania), parallel, 10 wk, ITT and PP analyses (median) dose, 8.91 (7.19) dose,17.05 (14.22) sprays/d (24.06 mg THC + sprays/d 22.28 mg CBD) Novotna Patients with MS with spasticity and at least a 20% reduction in 241 Nabiximols: 8.3 (2.43) NA 8.9 (2.31) sprays/d et al, 2011 mean spasticity numerical rating scale score after the previous sprays/d (22.41 mg THC + (phase B) single-blind phase A treatment (responders), multicentric (UK, 20.75 mg CBD) Spain, Poland, Czech Republic, and Italy), parallel, 12 wk, ITT and PP analyses Zajicek et al, Patients with MS with muscle stiffness, multicentric (UK), 277 CE: 7.81 (2.75) caps/d NA 9.60 (1.27) caps/d 2012 parallel, 14 wk, ITT analysis (end of titration period) (end of titration (19.52 mg THC + 9.76 mg period) CBD); 6.81 (2.99) caps/d (24.00 mg); 9.36 (end of study period) (1.51) caps/d (end (17.02 mg THC + 8.51 mg of study period) b b CBD) (23.40 mg) Langford Patients with MS with central neuropathic pain, multicentric (UK, 339 Nabiximols: 8.8 (3.87) NA 11.1 (4.6) sprays/d et al, 2013 Czech Republic, Canada, Spain and France), parallel, 15 wk, ITT sprays/d (23.76 mg THC + (phase A) and PP analyses 22.00 mg CBD) Vachová Patients with MS with spasticity, multicentric (Czech Republic), 121 Nabiximols: 7.6 (3.1) NA 9.5 (2.4/2.6) et al, 2014 parallel, 50 wk, ITT and PP analyses sprays/d (first mo) (20.52 sprays/d (from first mg THC + 19.00 mg CBD); to last 3 mo) 6.4 (3.1) sprays/d (last 3 mo) (17.28 mg THC + 16.00 mg CBD) (continued) JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 6/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Table 1. Summary of Characteristics of the Included Studies (continued) Interventions, Mean (SD) Dose THC/CBD (CE THC (Dronabinol Source Design Patients, No. or Nabiximols) or Nabilone) Placebo Turcotte Patients with relapsing-remitting MS and neuropathic pain 15 NA Nabilone: dose = 1-2 Dose = 1-2 caps/d et al, 2015 receiving a stable dose of gabapentin (≥1800 mg/d), unicentric caps/d (0.5-1 mg (0.5-1 mg/caps) (Canada), parallel, 9 wk, ITT and PP analyses THC/caps) (0.5-2 mg (0.5-2 mg) THC) Ball et al, Patients with progressive MS, multicentric (UK), parallel, 3 y, ITT 493 NA Dronabinol: median Median (IQR) dose, 2015 and PP analyses (IQR) dose, 4 (2-6) 6 (4-8) caps/d caps/d (final y of (final y of follow-up) 14.00 mg follow-up) THC Leocani, Patients with progressive MS with lower limb spasticity, 43 Nabiximols: 7 (3) sprays/d NA 10 (3) sprays/d et al, 2015 unicentric (Italy), crossover, 10 wk (4-wk intervention, 2-wk (18.90 mg THC + 17.50 washout between treatment periods), PP analysis mg CBD) Abbreviations: CBD, cannabidiol; CE, Cannabis sativa plant extract; IQR, interquartile Randomized, placebo-controlled, double-blind study. range; ITT, intention-to-treat; MS, multiple sclerosis; NA, not applicable; PP, b Estimated by the authors of this systematic review from study data. per-protocol; THC, δ-9-tetrahydrocannabinol; UK, United Kingdom. bladder dysfunction changed in terms of statistical significance, becoming nonsignificant. It seems that sponsored studies favored active treatment. Tolerability A total of 5357 adverse events were selected to be analyzed. Serious adverse events (death or threat to a patient's life or functioning) were also calculated, with 325 events included. A total of 260 withdrawals were due to adverse events. Higher risk in the experimental treatment is denoted by an RR greater than 1, while an RR less than 1 is for placebo. Results are considered statistically significant with higher risk in cannabinoids or placebo whenever the confidence interval of the results does not exceed the value of no effect (1 in the case of the RR). In the total adverse events analysis, there was a higher risk of adverse events in active treatments vs placebo in nabiximols (RR, 1.80 patient-years; 95% CI, 1.53-2.12 patient-years), dronabinol (RR, 1.62 patient-years; 95% CI, 1.12-2.34 patient-years), and cannabinoids (RR, 1.72 patient-years; 95% CI, 1.46-2.02 patient-years) and a higher risk of withdrawals due to adverse events in CE (RR, 3.11 patient-years; 95% CI, 1.54-6.28 patient-years), nabiximols (RR, 2.20 patient- years; 95% CI, 1.34-3.59 patient-years), dronabinol (RR, 4.12 patient-years; 95% CI, 2.39-7.11 patient-years), and cannabinoids (RR, 2.95 patient-years; 95% CI, 2.14-4.07 patient-years), but not in nabilone. No statistical significance was found in the meta-analysis of serious adverse events. Additionally, results showed a higher risk in cannabinoids with respect to the adverse events of dizziness or vertigo, dry mouth, fatigue, feeling drunk, impaired balance or ataxia, memory impairment, and somnolence. Table 2 shows the results obtained after analysis of the tolerability data. Sensitivity Analysis In efficacy, 11.3% of the results in the sensitivity analysis (considering all estimated effect sizes of the interventions [CE, nabiximols, dronabinol, nabilone, and cannabinoids] and the 5 sensitivity analyses globally) became statistically significant or not, with respect to the main results. In tolerability, this percentage was 8.4%. A summary of the main and sensitivity analysis results is shown in eTables 3 and 4 in the Supplement, for efficacy and tolerability, respectively. Additionally, in efficacy, the mean (SE) of the overall differences between the main and secondary calculations to SMDs was −0.0019 (0.0014) SD. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 7/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Figure 2. Analysis of Efficacy A Spasticity (Ashworth) Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Cannabinoids Placebo Study or Subgroup SMD SE No. No. Random (95% CI) % Cannabis extract Killestein, 2002 –0.2249 0.4345 16 8 –0.22 (–1.08 to 0.63) 1.1 Vaney, 2004 0.2269 0.1879 57 57 0.23 (–0.14 to 0.60) 6.1 26 27 Zajicek, 2003/Freeman, 2006 –0.0548 0.1187 211 107 –0.05 (–0.29 to 0.18) 15.2 Subtotal 284 172 0.01 (–0.18 to 0.20) 22.4 2 2 2 Heterogeneity τ = 0.00; χ = 1.92, df = 2 (P = .38); I = 0% Test for overall effect: z = 0.13, (P = .90) Nabiximols 33 34 1.9 Aragona, 2009/Tomassini, 2014 0.0563 0.3334 18 18 0.06 (–0.60 to 0.71) Collin, 2007 –0.1864 0.1534 124 65 –0.19 (–0.49 to 0.11) 9.1 Collin, 2010 –0.0192 0.109 167 –0.02 (–0.23 to 0.19) 18.0 Leocani, 2015 –0.2742 0.2167 43 –0.27 (–0.70 to 0.15) 4.6 Novotna, 2011 –0.215 0.1293 124 –0.21 (–0.47 to 0.04) 12.8 Vachová, 2014 –0.2269 0.1825 62 –0.23 (–0.58 to 0.13) 6.4 Wade, 2004 0.0948 0.1582 80 0.09 (–0.22 to 0.40) 8.6 Subtotal 618 –0.11 (–0.22 to 0.01) 61.5 2 2 2 Heterogeneity τ = 0.00; χ = 4.51, df = 6 (P = .61); I = 0% Test for overall effect: z = 1.82, (P = .07) Dronabinol Killestein, 2002 –0.0927 0.4333 16 –0.09 (–0.94 to 0.76) 1.1 26 27 Zajicek, 2003/Freeman, 2006 –0.1598 0.1197 206 –0.16 (–0.39 to 0.07) 15.0 16.1 Subtotal 222 –0.16 (–0.38 to 0.07) 2 2 2 Heterogeneity τ = 0.00; χ = 0.02, df = 1 (P = .88); I = 0% Test for overall effect: z = 1.34, (P = .18) Total 1124 –0.09 (–0.18 to 0.00) 100.0 2 2 2 Heterogeneity τ = 0.00; χ = 7.96, df = 11 (P = .72); I = 0% Test for overall effect: z = 1.90, (P = .06) –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2 2 Test for subgroup differences: χ = 1.51, df = 2 (P = .47); I = 0% SMD IV, Random (95% CI) B Spasticity (Subjective) Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Study or Subgroup SMD SE No. No. Random (95% CI) Cannabinoids Placebo % Cannabis extract 26 27 Zajicek, 2003/Freeman, 2006 –0.342 0.132 211 107 –0.34 (–0.60 to –0.08) 9.2 –0.2012 0.1207 143 134 –0.20 (–0.44 to 0.04) 9.8 Zajicek, 2012 354 241 –0.27 (–0.44 to –0.09) 19.0 Subtotal 2 2 2 Heterogeneity τ = 0.00; χ = 0.62, df = 1 (P = .43); I = 0% Test for overall effect: z = 2.98, (P = .003) Nabiximols 33 34 Aragona, 2009/Tomassini, 2014 –0.2617 0.3349 18 18 –0.26 (–0.92 to 0.39) 2.9 Collin, 2007 –0.3035 0.1539 124 65 –0.30 (–0.61 to 0.00) 8.0 Collin, 2010 –0.0828 0.109 167 –0.08 (–0.30 to 0.13) 10.5 Langford, 2013 –0.0467 0.1087 167 –0.05 (–0.26 to 0.17) 10.5 Leocani, 2015 –0.1088 0.2158 43 –0.11 (–0.53 to 0.31) 5.5 Novotna, 2011 –0.5343 0.1312 124 –0.53 (–0.79 to –0.28) 9.2 Vachová, 2014 –0.7618 0.1981 62 –0.76 (–1.15 to –0.37) 6.1 Wade, 2004 0.3675 0.1595 80 –0.37 (–0.68 to –0.05) 7.8 Subtotal 785 –0.29 (–0.47 to –0.12) 60.6 2 2 2 Heterogeneity τ = 0.04; χ = 18.30, df = 7 (P = .01); I = 62% Test for overall effect: z = 3.27, (P = .001) Dronabinol Ball, 2015 0.025 0.0956 329 0.03 (–0.16 to 0.21) 11.3 26 27 0.1327 206 9.1 Zajicek, 2003/Freeman, 2006 –0.3106 –0.31 (–0.57 to –0.05) 20.4 Subtotal 535 –0.13 (–0.46 to 0.20) 2 2 2 Heterogeneity τ = 0.04; χ = 4.21, df = 1 (P = .04); I = 76% Test for overall effect: z = 0.78, (P = .44) Total 1674 –0.25 (–0.38 to –0.13) 100.0 2 2 2 Heterogeneity τ = 0.03; χ = 26.68, df = 11 (P = .005); I = 59% Test for overall effect: z = 3.97, (P < .0001) –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2 2 Test for subgroup differences: χ = 0.75, df = 2 (P = .69); I = 0% SMD IV, Random (95% CI) The central point of the bars and diamonds indicates the magnitude of the effect size Upper confidence interval value of 0.0027. (Hedges g standardized mean difference [SMD] value), while width indicates the 95% CI. IV indicates inverse of variance. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 8/16 1235 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Figure 3. Analysis of Efficacy A Pain Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Cannabinoids Placebo Study or Subgroup SMD SE No. No. Random (95% CI) % Cannabis extract 26 27 Zajicek, 2003/Freeman, 2006 –0.3715 0.1266 211 107 –0.37 (–0.62 to –0.12) 10.2 Zajicek, 2012 –0.2899 0.1209 143 134 –0.29 (–0.53 to –0.05) 10.5 Subtotal 354 241 –0.33 (–0.50 to –0.16) 20.6 2 2 2 Heterogeneity: τ = 0.00; χ = 0.22, df = 1 (P = .64); I = 0% Test for overall effect: z = 3.76, (P = .0002) Nabiximols Collin, 2010 –0.0328 0.109 167 170 –0.03 (–0.25 to 0.18) 11.1 11.1 Langford, 2013 –0.0438 0.109 167 172 –0.04 (–0.26 to 0.17) Leocani, 2015 0.4138 0.2181 43 0.41 (–0.01 to 0.84) 6.2 Novotna, 2011 –0.2428 0.1294 124 –0.24 (–0.50 to 0.01) 10.0 Rog, 2005 –0.6571 0.2535 34 –0.66 (–1.15 to –0.16) 5.2 Wade, 2004 0.0665 0.1583 80 0.07 (–0.24 to 0.38) 8.6 Subtotal 615 –0.07 (–0.26 to 0.12) 52.3 2 2 2 Heterogeneity: τ = 0.03; χ = 12.98, df = 5 (P = .02); I = 61% Test for overall effect: z = 0.69, (P = .49) Dronabinol Ball, 2015 0.008 0.0956 329 0.01 (–0.18 to 0.20) 11.8 Svendsen, 2004 –0.5003 0.2936 24 24 –0.50 (–1.08 to 0.08) 4.2 26 27 10.1 Zajicek, 2003/Freeman, 2006 –0.3634 0.1277 206 –0.36 (–0.61 to –0.11) Subtotal 559 –0.23 (–0.55 to 0.09) 26.1 2 2 2 Heterogeneity: τ = 0.05; χ = 6.95, df = 2 (P = .03); I = 71% Test for overall effect: z = 1.43, (P = .15) Nabilone 1.0 0.7005 Turcotte, 2015 –1.4032 8 –1.40 (–2.78 to –0.03) 1.0 Subtotal 8 –1.40 (–2.78 to –0.03) Heterogeneity: Not applicable Test for overall effect: z = 2.00 (P = .05) Total 1536 –0.17 (–0.31 to –0.03) 100.0 2 2 2 Heterogeneity τ = 0.03 χ = 29.72, df = 11 (P = .002); I = 63% Test for overall effect: z = 2.44, (P = .01) –3 –2 –1 03 1 2 2 2 SMD IV, Random (95% CI) Test for subgroup differences: χ = 6.81, df = 3 (P = .08); I = 56% B Bladder dysfunction Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Study or Subgroup SMD SE No. No. Random (95% CI) Cannabinoids Placebo Cannabis extract Vaney, 2004 –0.3428 0.1887 57 57 –0.34 (–0.71 to 0.03) 7.2 26 27 Zajicek, 2003/Freeman, 2006 –0.2729 0.1279 211 –0.27 (–0.52 to –0.02) 12.8 268 164 –0.29 (–0.50 to –0.09) Subtotal 20.1 2 2 2 Heterogeneity: τ = 0.00; χ = 0.09, df = 1 (P = .76); I = 0% Test for overall effect: z = 2.79, (P = .005) Nabiximols Collin, 2010 –0.0795 0.109 167 170 –0.08 (–0.29 to 0.13) 15.7 Kavia, 2010 –0.2685 0.1733 68 67 –0.27 (–0.61 to 0.07) 8.3 0.1087 167 0.10 (–0.11 to 0.31) Langford, 2013 0.0985 15.7 Wade, 2004 –0.1731 0.1585 80 –0.17 (–0.48 to 0.14) 9.5 Subtotal 481 –0.07 (–0.22 to 0.08) 49.1 2 2 2 Heterogeneity: τ = 0.01; χ = 4.11, df = 3 (P = .25); I = 27% Test for overall effect: z = 0.91, (P = .36) Dronabinol Ball, 2015 0.0414 0.0956 329 0.04 (–0.15 to 0.23) 18.1 26 27 Zajicek, 2003/Freeman, 2006 –0.1846 0.1289 206 –0.18 (–0.44 to 0.07) 12.7 30.8 Subtotal 535 –0.06 (–0.27 to 0.16 ) 2 2 2 Heterogeneity: τ = 0.01; χ = 1.98, df = 1 (P = .16); I = 50% Test for overall effect: z = 0.49, (P = .62) 1284 –0.11 (–0.22 to 0.00) Total 100.0 2 2 2 Heterogeneity: τ = 0.01; χ = 10.61, df = 7 (P = .16); I = 34% Test for overall effect: z = 1.97, (P = .05) –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2 2 SMD IV, Random (95% CI) Test for subgroup differences: χ = 3.47, df = 2 (P = .18); I = 42.4% The central point of the bars and diamonds indicates the magnitude of the effect size Upper confidence interval value of −0.0008. (Hedges g standardized mean difference [SMD] value), while width indicates the 95% confi- dence interval. IV indicates inverse of variance. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 9/16 924 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 10/16 Table 2. Tolerability Results Interventions Cannabis Extract Nabiximols Dronabinol Nabilone Cannabinoids Statistically RR Studies, Patients, RR Studies, Patients, RR Studies, Patients, RR Studies, Patients, RR Studies, Patients, Significant Outcome (95% CI) No. No. (95% CI) No. No. (95% CI) No. No. (95% CI) No. No. (95% CI) No. No. Higher Risk 25-27,29,38 30-37,39,40,43 25-28,42 Total adverse 1.51 4 733 1.80 10 1710 1.62 4 877 NA NA NA 1.72 16 3320 Nabiximols, events (0.87-2.63) (1.53-2.12) (1.12-2.34) (1.46-2.02) dronabinol, cannabinoids 26,27,38 30,32,35-37,39,40,43 26-28,42 Serious 0.99 2 595 1.43 8 1608 1.21 3 853 NA NA · NA 1.23 12 3056 NS adverse (0.26-3.74) (0.66-3.09) (0.89-1.63) (0.82-1.85) events 26,27,29,38 30-32,35-37,39,40,43 26,27,42 41 Withdrawals 3.11 3 709 2.20 9 1674 4.12 2 805 2.63 1 15 2.95 14 3203 Cannabis due to (1.54-6.28) (1.34-3.59) (2.39-7.11) (0.11-64.44) (2.14-4.07) extract, adverse nabiximols, events dronabinol, cannabinoids 25-27,29,38 30-37,39,40,43 25-28,42 Dizziness or 2.51 4 733 3.33 10 1710 4.00 4 877 NA NA NA 3.40 16 3320 Nabiximols, vertigo (0.84-7.47) (2.55-4.34) (2.43-6.58) (2.55-4.53) dronabinol, cannabinoids 25-27,29,38 30-35,37,39,40 25-28 Dry mouth 3.17 4 733 2.30 8 1489 4.32 3 384 NA NA· NA 2.94 13 2606 Cannabis (1.91-5.25) (1.42-3.73) (2.12-8.81) (2.15-4.03) extract, nabiximols, dronabinol, cannabinoids 38 30-37,39,40 28,42 Fatigue 2.60 1 277 1.64 9 1624 1.09 2 541 NA NA NA 1.61 12 2442 Cannabis (1.22-5.58) (1.17-2.28) (0.74-1.60) (1.18-2.21) extract, nabiximols, cannabinoids 30,31,36 28 Feeling drunk NA NA NA 3.70 3 361 11.00 1 48 NA NA NA 4.85 4 409 Cannabinoids (0.70-19.55) (0.61-198.93) (1.15-20.53) 25 32,36,37,39,40 28,42 Impaired 3.50 1 24 2.93 5 1025 1.28 2 541 NA NA NA 1.40 8 1590 Nabiximols, balance or (0.18-67.77) (1.04-8.27) (0.90-1.81) (1.01-1.95) cannabinoids ataxia 36,39,40 Memory NA NA NA 4.93 3 595 NA NA NA NA NA NA 4.93 3 595 Nabiximols, impairment (1.07-22.70) (1.07-22.70) cannabinoids 25-27,29 30-37,39,40,43 25-27 Somnolence 1.32 3 456 3.47 10 1710 0.55 2 336 NA NA NA 1.87 13 2502 Nabiximols, (0.95-1.83) (2.10-5.73) (0.06-4.74) (1.24-2.81) cannabinoids Abbreviations: NA, not available; NS, nonsignificant; RR, rate ratio. JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Discussion To our knowledge, this is the most complete systematic review and meta-analysis of the effect of cannabinoids on MS. Our results show limited therapeutic efficacy of cannabinoids for the primary outcomes of spasticity, pain, and bladder dysfunction in patients with MS. None of the interventions demonstrated clear efficacy in the treatment of spasticity when evaluated in a more objective form (ie, the Ashworth and Modified Ashworth scales). In the analysis of subjective spasticity, significant differences were observed with respect to the active treatments of CE, nabiximols, and cannabinoids. However, a large allocation-dependent placebo effect can be expected because of possible difficulties in masking and blinding. It is also interesting to note that the single largest (almost 500 patients), longest (up to 3 years), and non–corporate-sponsored study favored placebo with respect to its tested outcomes (spasticity [subjective], pain, and bladder dysfunction). Differences among results might stem from the fact that a minor improvement in such a disabling symptom is reflected by a more positive evaluation from the patient. Efficacy in pain of CE, nabilone, and cannabinoids was also demonstrated, in addition to efficacy in bladder dysfunction for CE and cannabinoids. Most of the therapeutic effects show a small value of SMD, approximately between −0.09 and −0.25 SD, which represents a limited (small) therapeutic effect. Six previous systematic reviews performed meta-analyses to evaluate the efficacy of 6-11 6 cannabinoids in MS symptoms. One study evaluated spasticity (Wade et al ) and another, pain 7 8 9 (Iskedjian et al ) outcomes; 3 analyzed both spasticity and pain (Whiting et al, Meza et al, da Rovare 10 10 11 et al ). One of these studies (da Rovare et al ) and Abo Youssef et al evaluated bladder dysfunction. Three of them did not focus only on patients with MS in the spasticity and pain analyses 7 8 10 (Iskedjian et al, Whiting et al, da Rovare et al ). 6-8 11 Our results are in accordance with the first 3 systematic reviews and with the last one, taking into account differences in treatments and analyzed pathologies. Our findings did not concur 9,10 with the fourth and fifth systematic reviews, probably because of methodological differences. In comparison with placebo, an increased risk of adverse events and of withdrawals due to adverse 8,10 events was observed in our study. Two of the reviews showed an increased risk of adverse events with cannabinoids, with one review specifically describing short-term and serious adverse events. However, these studies did not focus on MS. Clear methodological differences exist among our systematic review and the ones published so far. The standardization conducted in our study allows comparison among different types of results that cannot be reliably compared otherwise. Furthermore, the high heterogeneity among the clinical assessment tools has been overcome by pooling those effect sizes evaluating the same outcome within the same study, avoiding both the exclusion of the studies where no coincidence between the clinical measures existed, as well as the risk of bias due to the inclusion of 1 unique clinical tool for analysis. Additionally, we included a specific tolerability analysis for the treatment of MS symptoms with cannabinoids. Limitations and Strengths Limitations of our study include the small number of studies included; differences in the length of treatment, particularly in tolerability calculations; inclusion of crossover studies as parallel design; calculations made on the basis of an ITT principle by data extrapolation, which may have provoked bias in our results, although ITT analysis is the standard for medication evaluation; and publication bias. Another potential limitation is that blinding procedures can be affected in studies with drugs with such large difficulties in masking and blinding. Consequently, a large allocation-dependent placebo effect can be expected. This is particularly evident in the study with 2 phases in which the responders in the first phase were selected for the second one. In addition, most of the studies included were funded by the pharmaceutical industry, especially for nabiximols. As explained in the Results section, the exclusion of these studies had an impact on the results on subjective spasticity. In JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 11/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis the interpretation of trends favoring experimental or control treatments, difficult decisions arose in some cases owing to the different forms of exposure across the studies. Our study had strengths as well. The sensitivity analysis showed no relevant differences affecting the results obtained. We can thus consider our results to have a high level of certainty. Results in overall secondary calculations sustained the methods used. In addition, differing assessment tools were combined to evaluate a common outcome, considering the existence of procedural differences among tools. Nevertheless, caution was taken in the selection of tools with minimum differences. The combination maintained all the information provided by the studies and avoided a possibly subjective bias when selecting only 1 of the tools. Shortcomings exist with respect to research into the efficacy of cannabinoids in the treatment of MS. The quantity of available studies is limited. However, they can be considered safe drugs, with no serious complications regarding withdrawal syndromes or drug dependence effects. When comparing the efficacy of cannabinoids with other treatments for spasticity, such as baclofen or differing intrathecal doses of corticosteroids, in the Modified Ashworth scale, baclofen 44 45 reduced the scores by a mean difference of 0.58 and corticosteroids by 0.78. Cannabinoids 37 35 (nabiximols) reduced spasticity in the same scale with a mean difference ranging from 0.1 to 3.3. The risks and invasiveness of baclofen and corticosteroids should be considered. In the case of bladder dysfunction, anticholinergic agents are the most common medication for this condition. Solifenacin, 5 mg, and oxybutynin, 15 mg, reduce the number of incontinence episodes per 24 hours by 1.03 and 2.41 vs placebo, respectively, in patients with MS and spinal cord 46 47 injury, whereas injectable onabotulinumtoxinA, 300 U, reduces the same variable by 1.43. Cannabinoids vs placebo reduce the number of daily urge incontinence episodes by 0.21 (CE) and 27 36 0.16 (dronabinol) and reduce daily incontinence episodes by 0.11 (nabiximols). In comparison, cannabinoids show better tolerability than anticholinergics and less invasiveness than onabotulinumtoxinA. As for pain, painful conditions are handled with drugs such as anticonvulsants, nonsteroidal anti-inflammatory agents, and corticosteroids. Nevertheless, management of pain in MS remains controversial and underresearched. Studies do not demonstrate clear efficacy of any treatment 48-50 above others, whereas adverse events should be taken into consideration. There is no evidence of studies that evaluate the efficacy of cannabinoids vs other treatments in MS. Research into the possible combinations of cannabinoids and other therapies, therefore, 51,52 might bring about greater synergy benefits than in an individual form. Conclusions Cannabinoids produce a limited and mild reduction of subjective spasticity, pain, and bladder dysfunction in patients with MS, but no changes in objectively measured spasticity. They can be considered safe drugs, as the analysis of serious adverse events did not show statistical significance, although the total number of adverse events is higher than in placebo for the treatment of symptoms in patients with MS. ARTICLE INFORMATION Accepted for Publication: August 21, 2018. Published: October 12, 2018. doi:10.1001/jamanetworkopen.2018.3485 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Torres-Moreno MC et al. JAMA Network Open. Corresponding Author: Mari Carmen Torres-Moreno, PhD, Universitat Autònoma de Barcelona (UAB), Departament de Farmacologia, Terapèutica i Toxicologia, Campus de la UAB, Facultat de Medicina, Edifici M, Avinguda de Can Domènech, 08193 Cerdanyola del Vallès, Spain (mariacarmen.torres@e-campus.uab.cat). Author Affiliations: Universitat Autònoma de Barcelona, Departament de Farmacologia, Terapèutica i Toxicologia, JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 12/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Cerdanyola del Vallès, Spain (Torres-Moreno, Papaseit, Farré); Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol, Servei de Farmacologia Clínica, Badalona, Spain (Torres-Moreno, Papaseit, Farré); Universitat Autònoma de Barcelona, Departament de Psiquiatria i Medicina Legal, Cerdanyola del Vallès, Spain (Torrens); Hospital del Mar, Institut de Neuropsiquiatria i Addiccions, Programa Addiccions, Barcelona, Spain (Torrens). Author Contributions: Drs Torres-Moreno and Farré had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Torres-Moreno, Farré. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Torres-Moreno, Farré. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Torres-Moreno, Farré. Obtained funding: Torrens, Farré. Supervision: Torrens, Farré. Conflict of Interest Disclosures: None reported. Funding/Support: The study was funded in part by grants from the Ministerio de Sanidad, Servicios Sociales e Igualdad (Plan Nacional sobre Drogas-PNSD, 2015I054); MINECO/Instituto de Salud Carlos III (ISCIII, FIS-FEDER, PI14/00715); and MINECO/ISCIII (Red de Trastornos Adictivos-RTA, RD12/0028/0009, RD16/0017/0003, and RD16/0017/0010). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: José Enrique Martínez, MD, PhD (Hospital del Mar, Barcelona, Spain), provided technical assistance; José Luis Medina, BS (private consultant, Barcelona, Spain), provided support in computer data processing; and Marjorie Handover, BS (private consultant, Singapore), provided editorial assistance with the manuscript. None of these individuals received additional compensation in association with their work on this article. REFERENCES 1. Multiple Sclerosis International Federation. Atlas of MS 2013. London, United Kingdom: Summers Editorial & Design; 2013. 2. Filippi M, Rocca MA, Ciccarelli O, et al; MAGNIMS Study Group. MRI criteria for the diagnosis of multiple sclerosis: MAGNIMS consensus guidelines. Lancet Neurol. 2016;15(3):292-303. doi:10.1016/S1474-4422(15) 00393-2 3. Comi G, Radaelli M, Soelberg Sørensen P. Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet. 2017;389(10076):1347-1356. doi:10.1016/S0140-6736(16)32388-1 4. 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Neurol Res. 2012;34(9):829-841. doi:10. 1179/1743132812Y.0000000082 50. Vollmer TL, Robinson MJ, Risser RC, Malcolm SK. A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis. Pain Pract. 2014;14(8):732-744. doi:10.1111/ papr.12127 51. Motl RW, Pilutti LA. The benefits of exercise training in multiple sclerosis. Nat Rev Neurol. 2012;8(9):487-497. doi:10.1038/nrneurol.2012.136 52. Snook EM, Motl RW. Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis. Neurorehabil Neural Repair. 2009;23(2):108-116. doi:10.1177/1545968308320641 JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 15/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis SUPPLEMENT. eReferences. Full-text Records Excluded From Eligibility eTable 1. Characteristics of the Included Studies eTable 2. Summary of the Selected Clinical Assessment Tools eTable 3. Sensitivity Analysis Results for Efficacy Outcomes eTable 4. Sensitivity Analysis Results for Tolerability Outcomes eFigure 1. Risk of Bias Summary of the Included Studies eFigure 2. Risk of Bias Graph of the Included Studies eFigure 3. Funnel Plots for Efficacy Outcomes eFigure 4. Funnel Plots for Tolerability Outcomes JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 16/16 Supplementary Online Content Torres-Moreno MC, Papaseit E, Torrens M, Farré M. Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: a systematic review and meta-analysis. JAMA Netw Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 eReferences. Full-text Records Excluded From Eligibility eTable 1. Characteristics of the Included Studies eTable 2. Summary of the Selected Clinical Assessment Tools eTable 3. Sensitivity Analysis Results for Efficacy Outcomes eTable 4. Sensitivity Analysis Results for Tolerability Outcomes eFigure 1. Risk of Bias Summary of the Included Studies eFigure 2. Risk of Bias Graph of the Included Studies eFigure 3. Funnel Plots for Efficacy Outcomes eFigure 4. Funnel Plots for Tolerability Outcomes This supplementary material has been provided by the authors to give readers additional information about their work. © 2018 Torres-Moreno MC et al. JAMA Network Open. 1. Supplementary eReferences eReferences 1: Full-text Records Excluded From Eligibility e1. Svendsen KB, Jensen TS, Bach FW. [Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosis—secondary publication]. Ugeskr Laeger. 2005;167(25-31):2772- e2. Zajicek J, Ball S, Wright D, et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. 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Clin Pharmacol Ther. 1994;55(3):324-328. e8. Corey-Bloom J, Wolfson T, Gamst A, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ. 2012;184(10):1143-1150. doi:10.1503/cmaj.110837. e9. Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler. 2012;18(2):219-228. doi:10.1177/1352458511419700. e10. Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005;76(12):1664-1669. doi:10.1136/jnnp.2005.070136. e11. Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol. 2013;260(1):285-295. doi:10.1007/s00415-012-6634-z. e12. Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther. 2007;29(9):2068-2079. doi:10.1016/j.clinthera.2007.09.013. e13. Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler. 2006;12(5):639-645. e14. Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult Scler. 2004;10(4):425-433. e15. Russo M, Calabrò RS, Naro A, et al. Sativex in the management of multiple sclerosis-related spasticity: role of the corticospinal modulation. Neural Plast. 2015;2015:656582. doi:10.1155/2015/656582. e16. Centonze D, Mori F, Koch G, et al. Lack of effect of cannabis-based treatment on clinical and laboratory measures in multiple sclerosis. Neurol Sci. 2009;30(6):531-534. doi:10.1007/s10072-009- 0136-5. e17. Russo M, Naro A, Leo A, et al. Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis. Pain Med. 2016;17(6):1145-1154. doi:10.1093/pm/pnv080. © 2018 Torres-Moreno MC et al. JAMA Network Open. e18. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17(1):21-29. e19. Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studies. Anaesthesia. 2004;59(5):440-452. doi:10.1111/j.1365- 2044.2004.03674.x. e20. Wissel J, Haydn T, Müller J, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial. J Neurol. 2006;253(10):1337-1341. doi:10.1007/s00415-006-0218-8. e21. Fox P, Bain PG, Glickman S, Carroll C, Zajicek J. The effect of cannabis on tremor in patients with multiple sclerosis. Neurology. 2004;62(7):1105-1109. e22. Kurzthaler I, Bodner T, Kemmler G, et al. The effect of nabilone on neuropsychological functions related to driving ability: an extended case series. Hum Psychopharmacol. 2005;20(4):291-293. doi:10.1002/hup.688. © 2018 Torres-Moreno MC et al. JAMA Network Open. 2. Supplementary eTables eTable 1: Characteristics of the included studies Data are mean (SD), N/n (%). Percentages may not add to 100% due to rounding. *Estimated by the authors of this systematic review from study data. †Interpreted by the authors of this systematic review based on study data. ‡ Computed only for the serious adverse events analysis, so not included in the total adverse events or in any other kind of adverse event analyses since only appeared in one of the included studies. DD = duration of disease. CBD = cannabidiol. CE = Cannabis sativa plant extract. IQR = interquartile range. ITT = intention-to-treat. MS = multiple sclerosis. N/n = no. of participants. PP = per-protocol. PPMS = primary progressive MS. PRMS = progressive relapsing MS. RCT = randomized clinical trial. RRMS = relapsing-remitting MS. SD = standard deviation. SPMS = secondary progressive MS. THC = -9-tetrahydrocannabinol. Assessment: 9-HPT = 9-Hole Peg Test. ADL = Activities of Daily Living. AMIPB = Adult Memory and Information Processing Battery. AS = Ashworth Scale. BDI = Beck Depression Inventory. BI = Barthel Index. BPI-SF = Brief Pain Inventory-Short Form. CRS = Category Rating Scale. C-SSRS = Columbia-Suicide Severity Rating Scale. DS of the WAIS-R= Digit Span of the Wechsler Adult Intelligence Scale-Revised. EDSS = Expanded Disability Status Scale. EQ-5D = European Quality of Life-5 Dimensions. FIM = Functional Independence Measure. fMRI = Functional Magnetic Resonance Imaging. FSS = Fatigue Severity Scale. GHQ-28 = General Health Questionnaire-28. GHQ- 30 = General Health Questionnaire-30. GIC = Global Impression of Change. GNDS = Guy's Neurological Disability Scale. GSI = General Symptomatic Index. HADS = Hospital Anxiety and Depression Scale. HR-QoL = Health-Related Quality of Life. MAS = Modified Ashworth Scale. MI = Motricity Index. MRI = Magnetic Resonance Imaging. MSFC = Multiple Sclerosis Functional Composite Scale. MSIS-29 = Multiple Sclerosis Impact Scale-29. MSQoL-54 = Multiple Sclerosis Quality of Life-54. MSSS-88 = Multiple Sclerosis Spasticity Scale-88. MSWS-12 = Multiple Sclerosis Walking Scale-12. NNH = Number Needed to Harm. NNT = Number Needed to Treat. NOS = Not Otherwise Specified. NPS = Neuropathic Pain Scale. NRS = Numerical Rating Scale. PASAT = Paced Auditory Serial Addition Test. PDI = Pain Disability Index. PSQI = Pittsburgh Sleep Quality Index. PSS = Primary Symptom Score. QoL = Quality of Life. RMI = Rivermead Mobility Index. SAS = Self-rating Anxiety Scale. SCL-90-R = Symptom Checklist- 90 Revised. SDMT = Symbol Digit Modalities Test. SF-36 = Short Form-36 Health Survey/Short Form questionnaire-36 items. SF-36 (PH) = Short Form questionnaire-36 items version 2 (physical health subscale). SF-MPQ = Short-Form McGill Pain Questionnaire. SPART = 10/36 Spatial Recall Test. SRT = Selective Reminding Test. TMS = Transcranial Magnetic Stimulation. T10-MW = Timed 10-m walk. T25-FW = Timed 25-foot walk. UIE = Urge incontinence episode. UKNDS = United Kingdom Neurological Disability Scale. VAS = Visual Analog Scale. WLG = Word List Generation. Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Killestein 2002 Design Progressive MS patients with Oral CE caps.: Oral dronabinol caps.: Placebo caps. No reduction of spasticity. spasticity (2.5 mg THC + 20 to 30% CBD 2.5 mg THC/cap. Setting not specified of standardized THC RCT, placebo-controlled content)/cap. Double-blind Dose = 2-4 caps./day Dose = 2-4 caps./day Dose = 2-4 caps./day Crossover (5-10 mg THC + approx. 1.25- (5-10 mg THC) 20 weeks (4-week/intervention, 2.5 mg CBD) 4-week washout between treatment periods) ITT analysis N/ninitial 16 16 16 16 Sex .. .. .. .. Subtype of MS SPMS 10 (63%) .. .. .. PPMS 6 (38%) .. .. .. Mean age (SD) 46.0 (7.90) .. .. .. years Mean DD (SD) 15.0 (10.70) .. .. .. years Mean EDSS (SD) 6.2 (1.20) .. .. .. N/n 16 16 16 16 final Assessment Efficacy: Included in our analysis: AS. Excluded from our analysis: 9-HPT; Concentration VAS; EDSS, and EDSS-Brainstem functional systems domain; Fatigue VAS; HR-QoL Questionnaire, and HR-QoL-Psychological status domain; Micturition VAS; Mood VAS; MSFC; MS-specific FSS; Pain VAS; PASAT; SF-36, and SF-36-Mental health subscale; Spasticity VAS; Subject´s Global Impression VAS; T25-FW; Tremor VAS; Vision VAS; and Walking VAS. Tolerability: Included in our analysis: Ataxia; dizziness; dry mouth; headache; increased spasticity; somnolence; and withdrawals due to adverse events. Excluded from our analysis: Acute psychosis; emotional lability; and others. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 26 27 Zajicek 2003 /Freeman 2006 (2 publications with same cohort of study) (continue) Zajicek 2003 Design MS patients with spasticity Oral CE caps.: Oral dronabinol caps.: Placebo caps. No beneficial effect on Multicentric (UK) (2.5 mg THC + 1.25 mg 2.5 mg THC/cap. spasticity. RCT, placebo-controlled CBD)/cap. Double-blind Dose = 4-10 caps./day Dose = 4-10 caps./day Dose = 4-10 caps./day Parallel (10-25 mg THC + 5-12.5 mg (10-25 mg THC) 15 weeks (13-week treatment, 1- CBD) Body weight based Body weight based week dose withdrawal, 1-week Body weight based off trial medication) Mean dose (SD) = Mean dose (SD) = Mean dose (SD) = ITT analysis 5.42 (2.11) caps./day 5.47 (2.08) caps./day 6.24 (1.71) caps./day* (13.56 mg THC + 6.78 mg (13.67 mg THC)* CBD)* N/ninitial 630 211 206 213 Sex M 217 (34%) 76 (36%) 63 (31%) 78 (37%) F 413 (66%) 135 (64%) 143 (69%) 135 (63%) Subtype of MS RRMS 33 (5%) 6 (3%) 14 (7%) 13 (6%) SPMS 452 (72%) 152 (72%) 149 (72%) 151 (71%) PPMS 145 (23%) 53 (25%) 43 (21%) 49 (23%) Mean age (SD) .. 50.5 (7.60) 50.2 (8.20) 50.9 (7.60) years Mean AS (SD) .. 21.8 (8.70) 22.6 (10.10) 21.4 (8.50) EDSS, number of .. 209 (6.4-7.7)* 203 (6.4-7.7)* 212 (6.3-7.6)* patients (range) N/n 611 (97%) 207 (98%) 197 (96%) 207 (97%) final Assessment Efficacy: Included in our analysis: AS; Bladder symptoms Questionnaire; Pain CRS; Pain Questionnaire; and Spasticity Questionnaire. Excluded from our analysis: BI; Depression CRS; EDSS; Energy (amount of energy) CRS; GHQ-30; Irritability CRS; Muscle spasms CRS; RMI; Shake/tremor (tremor) CRS; Sleep quality CRS; Spasticity (Muscle stiffness) CRS; T10-MW; Tiredness CRS; Tremor Questionnaire; and UKNDS. Tolerability: Included in our analysis: Abdominal pain of unknown cause; active duodenal ulcer and helicobacter pylori; back pain; chest infection/urinary tract infection; collapse of unknown cause; collapse/bradycardia; constipation; death; deep-vein thrombosis; diarrhoea; dizzy or lightheadedness; dry mouth; fall at home; grand mal seizures; infection; minor cerebrovascular event; MS relapse or possible relapse; numbness or paraesthesia; pain; pneumonia; possible transient ischaemic attack/syncope; sleep; tremor or lack coordination; urinary tract infection; urinary tract infection/relapse; viral gastroenteritis; vision; and withdrawals due to adverse events. Excluded from our analysis: Bladder; blocked/insertion of suprapubic catheter‡; cellulitis of leg/diarrhoea and vomiting‡; chronic pleural effusion‡; depression or anxiety; disease progression (not relapse) ‡; dizziness (inappropriate SAE report); emergency hip replacement‡; gastrointestinal tract; improvements in symptoms; increased appetite; miscellaneous; pneumonia and renal stones‡; spasms or stiffness; urinary tract infection/diarrhoea and vomiting‡; and weakness or reduced mobility. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 26 27 Zajicek 2003 /Freeman 2006 (2 publications with same cohort of study) (continued) 27 26 Freeman 2006 (same as Zajicek 2003, unless specified) Design Patients recruited to Zajicek .. .. .. Clinical effect on 2003 (CAMS study), excepting incontinence episodes. of those with a permanent catheter. N/n (% with 522 (83%) 181 (86%) 174 (84%) 167 (78%) initial respect to Zajicek 2003 initial data) N/nfinal (% with 255 (40%) 88 (42%) 86 (42%) 81 (38%) respect to Zajicek 2003 initial data) Assessment Efficacy: Included in our analysis: UIEs Diary. Excluded from our analysis: King’s Health Questionnaire; Pad test (weight); Post-void residual; and Voiding cystometry. Tolerability: Included in our analysis: Urinary tract infections (included in Zajicek 2003 , but not specified as urinary tract infections), and worsening of detrusor-sphincter- dyssynergia (D-S-D) and urinary retention. Excluded from our analysis: None. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Svendsen 2004 Design MS patients with central .. Oral dronabinol caps.: Placebo caps. Clinical effect on neuropathic pain 2.5 mg THC/cap. central pain. Unicentric (Denmark) Dose = 2.5 mg-10 mg THC/day Dose = 2.5 mg-10 mg/day RCT, placebo-controlled (1-4 caps.) Double-blind Mean dose (range) = Mean dose (range) = Crossover 3.1 [2.7-3.6] caps./day 3.3 [2.8-3.6] caps./day 9 weeks (3-week/intervention, 3- (7.75 [6.75-9.00] mg THC) (8.25 [7.00-22.50] mg) week washout between treatment periods) ITT analysis N/ninitial 24 .. 24 24 Sex M 10 (42%) .. .. .. F 14 (58%) .. .. .. Subtype of MS RRMS 9 (38%) .. .. .. SPMS 9 (38%) .. .. .. PPMS 6 (25%) .. .. .. Median age 50 (23-55) .. .. .. (range) Median DD 7.0 (0.3-25.0) .. .. .. (range) Median EDSS 6.0 (2.5-6.5) .. .. .. (range) Median Pain 5.5 (3.0-8.0) .. .. .. intensity NRS (range) N/nfinal 24 .. 24 24 Assessment Efficacy: Included in our analysis: Pain-relief NRS Diary; Radiating pain NRS Diary; SF-36-Bodily pain subscale; and Spontaneous pain intensity NRS Diary. Excluded from our analysis: 50% Pain relief; EDSS; NNT (50% reduction in central pain), Use of scape medication Diary; Quantitative sensory testing; SF-36- General health, SF-36-Mental health, SF-36-Physical functioning, SF-36-Role emotional, SF-36-Role physical, SF-36-Social functioning, and SF-36-Vitality subscales; and Treatment preference. Tolerability: Included in our analysis: Abdominal pain; anorexia; balance difficulty; diplopia; distortion of wrist; dizziness or lightheadedness; euphoria; fatigue; feeling of drunkenness; fever; headache; migraine; mouth dryness; muscle weakness; myalgia; nausea; palpitations; speech disorders; upper airway infection; weight decrease; and withdrawals due to adverse events. Excluded from our analysis: Chills; hot flushes; hyperactivity; limb heaviness; multiple sclerosis aggravated (one patient admitted to the hospital); nervousness; sleep difficulty; tenderness in nose; and tiredness or drowsiness. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Vaney 2004 Design MS patients with spasticity Oral CE caps.: .. Placebo caps. Reduction of spasm Unicentric (Switzerland) (2.5 mg THC + 0.9 mg frequency and increase of RCT, placebo-controlled CBD)/cap. mobility. Double-blind Dose = 6-12 caps./day Dose = 6-12 caps./day Crossover (15-30 mg THC + 5.4-10.8 mg 4 weeks (2-week cannabinoids CBD) treatment, 1-week placebo, 3- Mean dose (SD) = Mean dose not specified day washout between/after (17.99 [7.63] mg THC + 6.48 interventions) [2.75] mg CBD)/day ITT/PP analyses (7.20 caps.)* N/ninitial 57 57 .. 57 Sex M 28 (49%) .. .. .. F 29 (51%) .. .. .. Subtype of MS RRMS 2 (4%) .. .. .. SPMS 26 (46%) .. .. .. PPMS 29 (51%) .. .. .. Mean age (SD) 54.9 (10.00) .. .. .. years Mean DD (SD) 17.0 (8.40) .. .. .. years Median EDSS 7.0 (6.00) .. .. .. (range) Mean AS (SD) 12.5 (6.20) .. .. .. N/n 50 (88%) 50 (88%) .. 50 (88%) final Assessment Efficacy: Included in our analysis: AS; and Micturition problems Questionnaire Diary. Excluded from our analysis: 9-HPT; DS of the WAIS-R; EDSS; Falling asleep fast Diary; FIM; PASAT; RMI; Spasm-frequency Diary; T10-MW; Tremor Questionnaire Diary; and Waking up again Diary. Tolerability: Included in our analysis: Blurred vision; constipation; dizziness; dry mouth; euphoria, "high"; headache; nausea, feeling sick; pain in extremities; palpitations; sleepiness; sleeplessness; tremor or shakes; and withdrawals due to adverse events. Excluded from our analysis: Cannabinoid toxicity Questionnaire Diary-Likert Scale, difficulty concentrating; fall; feeling aggressive; flu-like symptoms; and inadequate laughing. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Wade 2004 Design MS patients with spasticity, Oromucosal CE (nabiximols): .. Placebo spray Reduction of spasms, bladder problems, (2.7 mg THC + 2.5 mg spasticity. Registered in tremor, or pain (not CBD)/spray ClinicalTrials.gov musculoskeletal) (NCT01610700, Dose = 1-48 sprays/day Dose =1-48 sprays/day Multicentric (UK) study results (2.7-129.6 mg THC + 2.5-120 RCT, placebo-controlled posted) mg CBD Double-blind Self-titrated dose Self-titrated dose Parallel Mean dose (SD) = Mean dose (SD) = 6 weeks (6-week treatment) 12.37 (6.05) sprays/day 18.87 (6.17) sprays/day* PP analysis (33.40 mg THC + 30.93 mg CBD)* N/ninitial 160 80 .. 80 Sex M 61 (38%) 33 (41%) .. 28 (35%) F 99 (62%) 47 (59%) .. 52 (65%) Subtype of MS .. .. .. .. Mean age (SD) 50.7 (9.32) 51.0 (9.36) .. 50.4 (9.33) years Mean MAS (SD) .. 5.0 (3.70) .. 4.6 (4.40) N/n 154 (96%) 77 (96%) .. 77 (96%) final Assessment Efficacy: Included in our analysis: Bladder (Bladder Problems) VAS; Bladder Questionnaire (Bladder Control Test); Bladder VAS Diary; MAS; Pain VAS Diary; Pain VAS; Spasticity VAS Diary; and Spasticity VAS. Excluded from our analysis: 9-HPT; AMIPB; BDI-II; BI; Care-giver Strain Index Score; Feeling upon waking VAS; FSS; GHQ-28; GNDS (UKNDS); How much sleep (Sleep Amount) VAS; PSS (Composite Primary Impairment VAS); Quality of sleep (Sleep Quality) VAS; Reading Visual Acuity Test; RMI; Short Orientation-Memory-Concentration Test; Spasm Frequency VAS Diary; Spasm severity VAS Diary; Spasms (Muscle Spasm) VAS; Subject Global Opinion of Effect on Multiple Sclerosis; Summed Symptom Score; T10-MW (Ten-metre Mobility Score); Tremor ADL Scale; Tremor VAS Diary; and Tremor VAS. Tolerability: Included in our analysis: Appendicitis; application site discomfort; application site pain; application site reaction NOS; diarrhoea; disorientation; disturbance in attention; dizziness; dry mouth; euphoric mood; fatigue; feeling drunk; headache; hypoaesthesia; lower respiratory tract infection NOS; mouth ulceration; muscle spasms; muscle weakness NOS; nausea; oral discomfort; oral pain; pain in limb; respiratory distress; sepsis NOS; somnolence; upper respiratory tract infection NOS; urinary tract infection NOS; vertigo; and withdrawals due to adverse events. Excluded from our analysis: Arthritis NOS‡; cough; and Feeling of intoxication VAS Diary. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Rog 2005 Design MS patients with central Oromucosal CE (nabiximols): .. Placebo Reduction of central neuropathic pain (2.7 mg THC + 2.5 mg neuropathic pain and Registered in Unicentric(UK) CBD)/spray sleep disturbance. ClinicalTrials.gov RCT, placebo-controlled (NCT01604265, Dose = 1-48 sprays/day Dose =1-48 sprays/day Double-blind study results (2.7-129.6 mg THC + 2.5-120 Parallel posted) mg CBD) 5 weeks (1-week run in, 4-week Self-titrated dose Self-titrated dose treatment) Mean dose (SD) = Mean dose (SD) = ITT analysis 9.6 (6.1) sprays/day (week 4) 19.1 (12.9) sprays/day (week 4) (25.92 mg THC + 24.00 mg CBD) N/ninitial 66 34 .. 32 Sex M 14 (21%) 6 (18%) .. 8 (25%) F 52 (79%) 28 (82%) .. 24 (75%) Subtype of MS RRMS 23 (35%) .. .. .. SPMS 33 (50%) .. .. .. PPMS 9 (14%) .. .. .. Benign MS 1 (2%) .. .. .. Mean age (SD) 49.2 (8.32) 50.3 (6.70) .. 48.1 (9.73) years Mean DD (SD) 11.6 (7.70) 10.4 (7.30) .. 12.8 (8.10) years Mean EDSS (SD) 5.9 (1.30) 6.0 (1.10) .. 5.8 (1.50) Mean Pain NRS 6.5 (1.60) 6.5 (1.60) .. 6.4 (1.70) (SD) N/n 64 (97%) 32 (94%) .. 32 (100%) final Assessment Efficacy: Included in our analysis: NPS; Pain (central neuropathic pain) NRS; and Sleep disturbance (due to neuropathic pain) NRS. Excluded from our analysis: GNDS (UKNDS); HADS-Anxiety, and HADS-Depression items; MSFC; NNT (50% reduction in central pain); PASAT; Patient´s (Subject) GIC; SDMT; SPART; SRT; and WLG. Tolerability: Included in our analysis: Application site burning; back pain; breast pain; confusion; diarrhoea; diplopia; disorientation; dissociation; disturbance in attention; dizziness; dry mouth; dyspepsia; dyspnea; euphoria; falls; fatigue; feeling abnormal; feeling drunk; gamma-glutamyltransferase increased; glossodynia; hallucination; headache; hypoaesthesia; intoxication (agitation, tachycardia and hypertension)†; ligament sprain; logorrhea; migraine NOS; mouth ulceration; nasopharyngitis; nausea; oral pain; otitis media NOS; paraesthesia; paranoia; paranoid ideation; pharyngitis; rash NOS; sinusitis NOS; skin irritation; somnolence; urinary tract infection NOS; vomiting; weakness; white blood cell count increased; and withdrawals due to adverse events. Excluded from our analysis: Chest discomfort; crying; hoarseness; Intoxication Levels VAS; low mood; NNH; thirst; and throat irritation. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Collin 2007 Design MS patients with spasticity, failed Oromucosal CE (nabiximols): .. Placebo Reduction of to gain adequate relief using (2.7 mg THC + 2.5 mg spasticity. Registered in current therapy CBD)/spray ClinicalTrials.gov Multicentric (UK and Romania) (NCT00711646, Dose = 1-48 sprays/day Dose =1-48 sprays/day RCT, placebo-controlled study results (2.7-129.6 mg THC + 2.5-120 Double-blind posted) mg CBD) Parallel Self-titrated dose Self-titrated dose 6 weeks (6-week treatment) Mean dose (SD) = Mean dose (SD) = ITT/PP analyses 9.4 (6.4) sprays/day 14.7 (8.4) sprays/day (25.38 mg THC + 23.50 mg CBD) N/ninitial 189 124 .. 65 Sex M 75 (40%) 44 (35%) .. 31 (48%) F 114 (60%) 80 (65%), .. 34 (52%) Mean age (SD) 49.1 (9.90) 49.7 (10.20) .. 47.8 (9.50) years Mean DD (SD) 12.6 (SD not specified) 13.6 (8.60) .. 12.2 (7.70) years N/nfinal 174 (92%) 112 (90%) .. 62 (95%) Assessment Efficacy: Included in our analysis: AS; and Spasticity NRS Diary. Excluded from our analysis: MI (arms), and MI (legs) items; Patient´s GIC; Spasm-frequency NRS Diary; Spasticity NRS 30% responder analysis; and Spasticity NRS 50% responder analysis. Tolerability: Included in our analysis: Appendicitis; balance impaired; Bartholin’s abscess; confusion; constipation; depressed mood; diarrhoea; disorientation; disturbance in attention; dizziness; dry mouth; dysgeusia; euphoric mood; fatigue; headache; lower respiratory tract infection NOS; nausea; oral pain; pain in limb; pancreatic carcinoma NOS; pulmonary embolism; somnolence; urinary tract infection; urinary tract infection NOS; vision blurred; vomiting; weakness; and withdrawals due to adverse events. Excluded from our analysis: Mobility decreased‡; Intoxication NRS Diary; and urinary incontinence aggravated‡. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 33 34 Aragona 2009 /Tomassini 2014 (2 publications with same cohort of study) (continue) Aragona 2009 Design SPMS patients with spasticity Oromucosal CE (nabiximols): .. Placebo No psychopathology Unicentric (Italy) (2.7 mg THC + 2.5 mg induction and no RCT, placebo-controlled CBD)/spray cognition impairment. Double-blind Dose (specified in Tomassini Dose (specified in Tomassini Crossover 34 34 2014 ) 2014 ) 10 weeks (3-week/intervention, 2- Mean dose (SD) = Mean dose (SD) = week washout between/after 8.20 (3.15) sprays/day 15.16 (4.51) sprays/day treatment periods) (22.14 mg THC + 20.50 mg ITT/PP analyses CBD) N/n (% with 17 (94%) 17 .. 17 initial respect to Tomassini 2014 initial data) Sex M 6 (35%) .. .. .. F 11 (65%) .. .. .. Subtype of MS SPMS 17 .. .. .. Mean age (SD) 49.8 (6.64) .. .. .. years Mean DD (SD) 20.76 (8.42) .. .. .. years Mean EDSS (SD) 6.1 (0.30) .. .. .. N/nfinal (% with 17 (94%) 17 .. 17 respect to Tomassini 2014 initial data) Assessment Efficacy: Included in our analysis: None. Excluded from our analysis: 9-HPT; FSS; HR-QoL VAS (EQ-5D Health status VAS); MSIS-29 Physical, and MSIS-29 Psychological items; PASAT; SAS; SCL-90- R-Aggressive behaviour, SCL-90-R-Anxiety, SCL-90-R-Depression, SCL-90-R-Obsessive-compulsive features, SCL-90-R-Paranoiac tendencies, SCL-90-R- Phobic anxiety, SCL-90-R-Psychotic symptoms, SCL-90-R-Sensitivity, and SCL-90-R-Somatized anxiety dimensions; SCL-90-R-GSI item; and T25-FW. Plasma measurements. Tolerability: Included in our analysis: Craving†; depression; dizziness and vertigo; drowsiness and/or slower thinking; euphoria; fatigue; headache; intoxication (transient mental confusion with temporal and spatial disorientation, tachycardia, increased blood pressure, and mydriasis)†;lower limb weakness; mouth dryness or burning; nausea and vomiting; secondary depression; tremor; and withdrawals due to adverse events. Excluded from our analysis: None. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 33 34 Aragona 2009 /Tomassini 2014 (2 publications with same cohort of study) (continued) 34 33 Tomassini 2014 (same as Aragona 2009, unless specified) Design .. Dose = 1-48 sprays/day .. Dose = 1-48 sprays/day No significant benefits (2.7-129.6 mg THC + 2.5-120 on spasticity. Registered in mg CBD) No change in fMRI ClinicalTrials.gov Self-titrated dose Self-titrated dose motor-evoked brain (NCT00202423, no activation. No study results Median dose (range) = Median dose (range) = 16.1 difference in posted) 7.4 (2.7-12.5) sprays/day (6.7-26) sprays/day intracortical and spinal (19.98 mg THC + 18.50 mg motor excitability. CBD) N/n 18 18 .. 18 initial Sex M 6 (33%) .. .. .. F 12 (67%) .. .. .. Subtype of MS SPMS 18 .. .. .. Median age 51 (37-59) .. .. .. (range) years Median DD 21.5 (5-35) .. .. .. (range) years Median EDSS 6.0 (6.0-6.5) .. .. .. (range) Median AS 12 (4-22) .. .. .. (range) Median Spasticity 7 (3-9) .. .. .. NRS (range) N/n 18 18 .. 18 final Assessment Efficacy: Included in our analysis: AS; and Spasticity NRS. Excluded from our analysis: AS (upper/lower extremities) 30% responders; and Spasticity NRS 30% responders. Neurophysiological assessment (fMRI, H-reflex, and TMS); and plasma measurements. Tolerability: None. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Collin 2010 Design MS patients with spasticity, not Oromucosal CE (nabiximols): .. Placebo No significant wholly relieved with current (2.7 mg THC + 2.5 mg improvement in Registered in therapy CBD)/spray spasticity NRS. ClinicalTrials.gov Multicentric (UK and Czech Dose = 1-24 sprays/day (NCT01599234, Dose = 1-24 sprays/day Republic) study results (2.7-64.8 mg THC + 2.5-60 mg RCT, placebo-controlled posted) CBD) Double-blind Self-titrated dose Self-titrated dose Parallel Mean dose (range) = Mean dose (range) = 15 weeks (1-week baseline, 14- 8.5 (1-22) sprays/day 15.4 (2-23) sprays/day week treatment) (22.95 mg THC + 21.25 mg ITT/PP analyses CBD) N/ninitial 337 167 .. 170 Sex M 130 (39 %) 61 (37%) .. 69 (41%) F 207 (61%) 106 (63%) .. 101 (59%) Mean age (SD) 47.5 (9.61) 48.0 (10.06) .. 47.1 (9.15) years Mean DD (SD) 15.2 (8.41) 14.4 (8.29) .. 16.0 (8.48) years Mean EDSS (SD) 6.0 (1.53) 6.0 (1.56) .. 6.0 (1.50) N/nfinal 305 (91%) 150 (90%) .. 155 (91%) Assessment Efficacy: Included in our analysis: Bladder symptoms NRS; MAS; Pain NRS; Sleep quality (due to spasticity) NRS; and Spasticity NRS Diary. Excluded from our analysis: BI; Caregiver´s GIC; EQ-5D Health state index, and EQ-5D Health status VAS items; Fatigue NRS; MSQoL-54-Mental health, and MSQoL-54-Physical health composites; Number of subjects with a 50% or greater improvement in mean Spasticity NRS; Spasm severity NRS; Spasticity NRS 30% responder analysis; Spasticity NRS Time to 30% response; T10-MW; and Tremor NRS. Tolerability: Included in our analysis: Anxiety; asthenia; back pain; burns third degree; confusional state; constipation; death; dehydration; depressed mood; depression; diarrhoea; disorientation; dissociation; disturbance in attention; dizziness; drug dependence; dry mouth; dysarthria; dysgeusia; dyspepsia; epilepsy; erysipelas; euphoric mood; fall; fatigue; feeling abnormal; foot fracture; gastrointestinal carcinoma with liver metastases; hallucination; headache; infections and infestations; insomnia; metastatic oesophageal carcinoma; MS relapse; muscle spasms; muscle spasticity; nausea; orchitis; paranoia; peripheral ischaemia; phlebothrombosis; sepsis; sleep attacks; somnolence; suicidal ideation; tetany; urinary tract infection; urinary retention; urinary tract infection NOS; vertigo; vomiting; withdrawal syndrome (aggression, agitation, delusions, irritability, insomnia and muscle spasms)†; and withdrawals due to adverse events. Excluded from our analysis: Apathy; decubitus ulcer‡; haemoptysis‡; malaise; road traffic accident‡; and worsened depression‡. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Kavia 2010 Design MS patients with overactive Oromucosal CE (nabiximols): .. Placebo Non-statistical bladder (OAB), failed to respond (2.7 mg THC + 2.5 mg significance reduction Registered in adequately to first-line therapies CBD)/spray in Number of episodes ClinicalTrials.gov Multicentric (UK, Belgium and of incontinence. Some Dose = 1-48 sprays/day (NCT00678795, Dose = 1-48 sprays/day Romania) significant positive study results (2.7-129.6 mg THC + 2.5-120 RCT, placebo-controlled effects on other posted) mg CBD) Double-blind bladder symptoms. Self-titrated dose Self-titrated dose Parallel Mean dose (median) = Mean dose (median) = 10 weeks (2-week baseline, 8- 8.91 (7.19) sprays/day 17.05 (14.22) sprays/day week treatment) (24.06 mg THC + 22.28 mg ITT/PP analyses CBD) N/ninitial 135 67 .. 68 Sex M 37 (27%) 15 (22%) .. 22 (32%) F 98 (73%) 52 (78%) .. 46 (68%) Mean age (SD) 47.7 (10.31) 48.6 (9.31) .. 46.8 (11.20) years Episodes of .. 1.8 (n = 63) .. 2.1 (n = 66) Incontinence/day (number of patients) Episodes of .. 1.6 (n = 63) .. 1.5 (n = 66) Nocturia/day (number of patients) N/n 118 (87%) 56 (84%) .. 62 (91%) final Assessment Efficacy: Included in our analysis: Bladder symptom severity (Overall Bladder Condition, OBC) NRS; Daily number of incontinence episodes Diary; Incontinence pad weight; Incontinence QoL Questionnaire; Nocturia episodes Diary (per day); Number Daytime voids Diary (per day); Number of incontinence pads used Diary (per day); and Void urgency episodes Diary (per day). Excluded from our analysis: Cystometric capacity (Voiding cystometry); Patient´s GIC; Post-void residual volume; Responder analysis of the frequency of urgency; Total number of voids Diary (per 24 h); and Volume voided (per 24h). Tolerability: Included in our analysis: Abdominal pain upper; anorexia; application site pain; balance impaired; chest pain; confusion; constipation; cystitis; dehydration; diarrhoea; disorientation; dissociation; disturbance in attention; dizziness; fatigue; feeling abnormal; feeling drunk; haemorrhagic cystitis; headache; influenza; intoxication (shaking, coordination problems and severe absence)†; memory impairment; MS relapse; nasopharyngitis; nausea; neck pain; paraesthesia; pharyngitis; pharyngitis viral NOS; pyrexia; somnolence; toothache; urinary tract infection; vertigo; vomiting; weakness; and withdrawals due to adverse events. Excluded from our analysis: Intoxication NRS; and sweating increased. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Novotna 2011 Design (enriched MS patients with spasticity, not Oromucosal CE (nabiximols): .. Placebo Significant reduction in study design) wholly relieved with current (2.7 mg THC + 2.5 mg spasticity. antispasticity medication, and at CBD)/spray Registered in least a 20% reduction in mean ClinicalTrials.gov Dose = 1-12 sprays/day Dose = 1-12 sprays/day Spasticity NRS score after 4 (NCT00681538, (2.7-32.4 mg THC + 2.5-30 mg weeks of the previous single-blind study results CBD) phase A treatment (responders) posted) Self-titrated dose Self-titrated dose Multicentric (UK, Spain, Poland, Mean dose (SD) = Mean dose (SD) = Czech Republic and Italy) 8.3 (2.43) sprays/day 8.9 (2.31) sprays/day RCT, placebo-controlled (22.41 mg THC + 20.75 mg Double-blind (phase B) CBD) Parallel 12 weeks (12-week treatment) ITT/PP analyses N/ninitial 241 124 .. 117 Sex M 96 (40%) 52 (42%) .. 44 (38%) F 145 (60%) 72 (58%) .. 73 (62%) Mean age (SD) 48.6 (9.33) 49.1 (9.09) .. 48.1 (9.59) years Mean DD (SD) 12.6 (7.88) 13.3 (8.29) .. 11.8 (7.38) years Mean EDSS (SD) 6.0 (1.45) 6.5 (1.46) .. 6.0 (1.44) Mean spasticity 3.9 (1.51) 3.9 (1.49) .. 3.9 (1.55) NRS (SD) N/nfinal 224 (93%) 109 (88%) .. 115 (98%) Assessment Efficacy: Included in our analysis: MAS; SF-36-Bodily pain subscale; Sleep Disruption (due to spasticity) NRS; and Spasticity NRS. Excluded from our analysis: BDI-II; BI; Carer GIC; Clinician GIC; EQ-5D Health state index; EQ-5D Health status VAS items; MI (arms), and MI (legs) items; Physician GIC; SF-36-General health, SF-36-Mental health, SF-36-Physical functioning, SF-36-Role emotional, SF-36-Role physical, SF-36-Social functioning, and SF-36-Vitality subscales; Spasm frequency NRS; Spasticity NRS 30% responders; Spasticity NRS 50% responders; Subject´s GIC; and T10-MW. Tolerability: Included in our analysis: Abdominal pain (upper); back pain; balance disorder; bronchopneumonia; diarrhoea; dizziness; dry mouth; euphoric mood; fatigue; headache; infections and infestations; MS relapse; muscle spasms; muscle spasticity; nasopharyngitis; nausea; pain in extremity; septic shock; somnolence; suicidal ideation; urinary tract infection; urosepsis; vertigo; and withdrawals due to adverse events. Excluded from our analysis: Pregnancy‡. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Zajicek 2012 Design MS patients with muscle stiffness Oral CE caps.: .. Placebo caps. Effect in the treatment Multicentric (UK) (2.5 mg THC + 1.25 mg of muscle stiffness. Registered in RCT, placebo-controlled CBD)/caps. ClinicalTrials.gov Double-blind (NCT00552604, no Dose = 2-10 caps./day Dose = 2-10 caps./day Parallel study results (5 mg-25 mg THC + 2.5 mg-12.5 (5 mg-25 mg/day) 14 weeks (2-week screening, 12- posted) mg CBD) week treatment) Self-titrated dose Self-titrated dose ITT analysis Mean dose (SD) = Mean dose (SD) = 7.81 (2.75) caps./day (end of 9.60 (1.27) caps./day (end of titration period) titration period) (19.52 mg THC + 9.76 mg (24.00 mg)* CBD)* Mean dose (SD) = Mean dose (SD) = 9.36 (1.51) caps./day (end of 6.81 (2.99) caps./day (end of study period) study period) (23.40 mg)* (17.02 mg THC + 8.51 mg CBD)* N/n 277 143 .. 134 initial Sex M 102 (37%) 55 (38%) .. 47 (35%) F 175 (63%) 88 (62%) .. 87 (65 %) Subtype of MS RRMS 21 (8%) 13 (9%) .. 8 (6%) SPMS 190 (69%) 96 (67%) .. 94 (70%) PPMS 66 (24%) 34 (24%) .. 32 (24%) Mean age (SD) .. 51.9 (7.70) .. 52.0 (7.90) years Mean DD (SD) .. 14.5 (9.50) .. 15.1 (8.40) years N/nfinal 224 (81%) 109 (76%) .. 115 (86%) Assessment Efficacy: Included in our analysis: Body pain CRS; and MSSS-88-Ability to walk, MSSS-88-ADL/Daily activities, MSSS-88-Body movement, MSSS-88-Feelings, MSSS-88- Muscle spasms, MSSS-88-Muscle stiffness, MSSS-88-Pain and discomfort, and MSSS-88-Social functioning subscales. Excluded from our analysis: EDSS; MSIS-29 Physical impact, and MSIS-29 Psychological impact items; MSWS-12; Muscle spasms CRS; Muscle stiffness CRS; and Sleep quality (Quality of sleep) CRS. Tolerability: Included in our analysis: Asthenia; dizziness; dry mouth; fatigue; headache; urinary tract infection; and withdrawals due to adverse events. Excluded from our analysis: Balance disorder; confusional state; diarrhoea; disorientation; disturbance in attention; fall; feeling abnormal; head injury; interstitial lung; nausea; pain in extremities; and somnolence. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Langford 2013 Design MS patients with central Oromucosal CE (nabiximols): .. Placebo No statistical neuropathic pain (2.7 mg THC + 2.5 mg significant reduction of Registered in Multicentric (UK, Czech Republic, CBD)/spray pain. ClinicalTrials.gov Canada, Spain and France) Dose = 8-12 sprays/day (NCT00391079, Dose = 8-12 sprays/day RCT, placebo-controlled study results (21.6-32.4 mg THC + 20-30 mg Double-blind (phase A) posted) CBD) Parallel Self-titrated dose Self-titrated dose 15 weeks (1-week baseline, 14- Mean dose (SD) = Mean dose (SD) = week treatment) 8.8 (3.87) sprays/day 11.1 (4.6) sprays/day ITT/PP analyses (23.76 mg THC + 22.00 mg CBD) N/ninitial 339 167 .. 172 Sex M 109 (32%) 54 (32 %) .. 55 (32 %) F 230 (68%) 113 (68 %) .. 117 (68 %) Subtype of MS RRMS 157 (46%) 80 (48%) .. 77 (45%) SPMS 136 (40%) 65 (39%) .. 71 (41%) PPMS 40 (12%) 18 (11%) .. 22 (13%) PRMS 6 (2%) 4 (2%) .. 2 (1%) Mean age (SD) 48.97 (10.47) 48.42 (10.43) .. 49.51 (10.50) years Mean DD (SD) 11.99 (8.26) 11.42 (8.00) .. 12.53 (8.50) years Mean Pain NRS 6.58 (1.32) 6.55 (1.35) .. 6.61 (1.29) (SD) N/n 297 (88%) 141 (84%) .. 156 (91%) final Assessment Efficacy: Included in our analysis: Bladder symptoms NRS; BPI-SF; NPS; Pain (due to MS) NRS; PDI; SF-36-Bodily pain subscale; Sleep quality (Sleep Disruption, due to pain) NRS; Spasticity NRS; and Subjec´s GIC for pain. Excluded from our analysis: Breakthrough analgesia; EQ-5D Health state index, and EQ-5D Health status VAS items; Fatigue NRS; Pain NRS 30% responder analysis; Pain NRS 50% responder analysis; SF-36-General health, SF-36-Mental health, SF-36-Physical functioning, SF-36-Role emotional, SF-36-Role physical, SF-36-Social functioning, and SF-36-Vitality subscales; Spasms severity NRS; and Tremor NRS. Tolerability: Included in our analysis: Balance disorder; constipation; depression; diarrhoea; disturbance in attention; dizziness; dry mouth; dysgeusia; fatigue; feeling abnormal; headache; hepatic enzyme increased; infections and infestations; memory impairment; muscular weakness; nausea; neuralgia; orthostatic hypotension; pain; pain in extremity; pharyngolaryngeal pain; somnolence; suicidal ideation; syncope; vertigo; vision blurred; vomiting; and withdrawals due to adverse events. Excluded from our analysis: Motor dysfunction‡; and psychomotor skills impaired. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Vachová 2014 Design MS patients with spasticity, not Oromucosal CE (nabiximols): .. Placebo No association with wholly relieved with current anti- (2.7 mg THC + 2.5 mg cognitive decline or Registered in spasticity therapy CBD)/spray significant changes in ClinicalTrials.gov Multicentric (Czech Republic) mood (long-term (NCT01964547, Dose = 1-12 sprays/day Dose = 1-12 sprays/day RCT, placebo-controlled treatment). No statistical study results (2.7-32.4 mg THC + 2.5-30 mg Double-blind significant difference in posted) CBD) Parallel spasticity. Self-titrated dose Self-titrated dose 50 weeks (48-week treatment, Mean dose (SD) = Mean dose (SD) = 2-week end of treatment follow- 7.6 (3.1) sprays/day (first 9.5 (2.4/2.6).sprays/day (from up period) month) first to last three months) ITT/PP analyses (20.52 mg THC + 19.00 mg CBD) 6.4 (3.1) sprays/day (last three months) (17.28 mg THC + 16.00 mg CBD) N/ninitial 121 62 .. 59 Sex M 45 (37%) 23 (37%) .. 22 (37%) F 76 (63%) 39 (63%) .. 37 (63%) Subtype of MS RRMS 59 (49%) 26 (42%) .. 33 (56%) SPMS 43 (36%) 24 (39%) .. 19 (32%) PPMS 16 (13%) 11 (18%) .. 5 (8%) PRMS 3 (2%) 1 (2%) .. 2 (3%) Mean age (SD) 48.6 (9.64) 49.0 (8.95) .. 48.2 (10.38) years Mean DD (SD) 13.9 (8.55) 13.9 (8.09) .. 13.9 (9.08) years Mean Spasticity 6.7 (1.86) 6.7 (2.04) .. 6.7 (1.67) NRS (SD) N/n 98 (81%) 50 (81%) .. 48 (81%) final Assessment Efficacy: Included in our analysis: MAS; and Subject´s GIC for spasticity. Excluded from our analysis: BDI-II; Caregiver´s GIC; C-SSRS; Number of visits to a healthcare professional; PASAT; Physician´s GIC; and T10-MW. Tolerability: Included in our analysis: Acute myocardial infarction; anxiety disorder due to a general medical condition; application site discomfort; asthenia; back pain; bacterial infection; blood alkaline phosphatase increased; bronchitis; cerebellar ataxia; death; decreased appetite; dermatitis allergic; diarrhoea; disorientation; dizziness; drug withdrawal syndrome; dry mouth; dysarthria; euphoric mood; fatigue; foot fracture; forearm fracture; gingivitis; headache; herpes zoster; joint dislocation; ligament sprain; lower limb fracture; memory impairment; MS relapse; muscle spasms; muscle spasticity; nausea; neuralgia; oral mucosal erythema; oropharyngeal blistering; overdose; pain in extremity; paraesthesia; paraparesis; pneumonia; pyrexia; somnolence; subcutaneous abscess; suicidal ideation; tetany; thermal burn; tonsillitis; tremor; trigeminal neuralgia; upper limb fracture; upper respiratory tract infection; upper respiratory tract infection bacterial; urinary tract infection; vertigo; viral infection; visual impairment; vitamin D decreased; vomiting; weight decreased; and withdrawals due to adverse events. Excluded from our analysis: Cognitive disorder; contusion; drug hypersensitivity; erectile dysfunction; face injury; inguinal hernia‡; lipoma excision; MS; procedural vomiting; radiculopathy; stupor; and tooth extraction. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Turcotte 2015 Design RRMS patients with neuropathic .. Oral nabilone caps.: Placebo caps. Nabilone as an pain, on a non-effective Available 0.5 or 1 mg THC/cap. adjunctive to Registered in treatment with gabapentin at a Dose = 1 (0.5 mg THC/caps.)- Dose = 1 (0.5 mg/caps.)- gabapentin is an ClinicalTrials.gov stabilized dose of 1800 mg/day 2 (1 mg THC/caps.) caps./day 2 (1 mg /caps.) caps./day effective, well- (NCT00480181, no for at least 1 month tolerated combination (0.5-2 mg THC) (0.5-2 mg) study results Unicentric (Canada) for MS-induced posted) Mean dose not specified Mean dose not specified RCT, placebo-controlled neuropathic pain. Double-blind Parallel 9 weeks (9-week treatment) ITT/PP analyses N/n 15 .. 8 7 initial Sex M 2 (13%) .. 1 (13%) 1 (14%) F 13 (87%) .. 7 (88%) 6 (86%) Subtype of MS RRMS 15 .. .. .. Mean age (SD) 45.5 (10.84) .. 42.12 (11.20) 50.0 (8.48) years Median DD (IQR) 6.5 (5-8.75) .. 5.5 (4.5-7.25) 8 (6.25-9) years Mean EDSS (SD) 2.82 (0.77) .. 2.56 (0.77) 3.17 (1.07) Mean Pain 77.00 (14.04) .. 79.00 (13.76) 74.33 (13.99) intensity (SD) Mean Pain impact 59.85 (23.47) .. 63.00 (19.23) 54.8 (30.86) (SD) N/n 14 (93%) .. 7 (88%) 7 (100%) final Assessment Efficacy: Included in our analysis: Impact of pain on daily activities VAS Diary (VAS ); Pain intensity VAS Diary (VAS ); Patient-rated GIC for neuropathic pain. impact pain Excluded from our analysis: EDSS; SF-36; and SF-MPQ. Tolerability: Included in our analysis: Withdrawals due to adverse events. Excluded from our analysis: Dizziness; drowsiness; dry mouth; and headache. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Ball 2015 Design Progressive MS patients .. Oral THC caps. (dronabinol): Placebo caps. No effect in slowing Multicentric (UK) 3.5 mg THC progression of MS. RCT, placebo-controlled Dose = 2-8 caps./day Dose = 2-8 caps./day Double-blind (7-28 mg THC) Parallel Titrated against body weight Titrated against body weight 3 years (3-year treatment) and adverse effects and adverse effects ITT/PP analyses Median dose = 4 (25th–75th Median dose = 6 (25th–75th percentiles 2–6) caps./day (final percentiles 4–8) caps./day (final year of follow-up) year of follow-up) (14.00 mg THC) N/n 493 .. 329 164 initial Sex M 201 (41%) .. 133 (40%) 68 (41%) F 292 (59%) .. 196 (60%) 96 (59%) Subtype of MS SPMS 302 (61%) .. 203 (62%) 99 (60%) PPMS 191 (39%) .. 126 (38%) 65 (40%) Mean age (SD) 52.19 (7.80) .. 52.29 (7.60) 51.97 (8.20) years Mean EDSS (SD) 5.9 (0.69) .. 5.8 (0.69) 5.9 (0.67) N/nfinal 415 (84%) .. 267 (81%) 148 (90%) Assessment Efficacy: (3 years, unless specified) Included in our analysis: Bladder problems CRS; and MSSS-88-Ability to walk/Walking, MSSS-88-ADL/Daily activities, MSSS-88-Body movements, MSSS-88- Feelings, MSSS-88-Muscle spasms, MSSS-88-Muscle stiffness, MSSS-88-Pain and discomfort, and MSSS-88-Social functioning subscales. Excluded from our analysis: 9-HPT (annual change); BDI-II; Co-ordination CRS; Depression CRS; EDSS (number of first progression events per patient-year); EQ-5D five dimensions questionnaire; Fatigue CRS; Forgetfulness CRS; Irritability CRS; MSFC; MSIS-29 Physical and MSIS-29 Psychological items; MSWS- 12; PASAT (annual change); RMI (annual change); Sensory loss or numbness CRS; SF-36, SF-36 (PH) (annual change); T25-FW (annual change); and Tremor CRS. Neurophysiological measures (MRI). Tolerability: Included in our analysis: Death; dissociative and thinking or perception disorders; dizziness and lightheadedness; falls and injuries; fatigue and tiredness; infections (excluding urinary tract); joint disorders; mobility, balance, and coordination problems; mood disorders (depression); muscle disorders (weakness); musculoskeletal pain and aches; urinary tract infections; and withdrawals due to adverse events. Excluded from our analysis: Admission to hospital‡; constipation, diarrhoea, or faecal incontinence; life-threatening or important medical event‡; and muscle disorders (spasticity, stiffness, spasms, or tremor). (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Leocani 2015 Design Progressive MS patients with Oromucosal CE (nabiximols): .. Placebo Clinical benefit in lower limb spasticity, stable drug (2.7 mg THC + 2.5 mg objective lower limb Registered in treatment not able to relieve CBD)/spray spasticity. Lack of ClinicalTrials.gov symptoms as a whole Dose = 1-12 sprays/day corresponding (NCT01538225, no Dose = 1-12 sprays/day Unicentric (Italy) changes in study results (2.7-32.4 mg THC + 2.5-30 mg RCT, placebo-controlled corticospinal posted) CBD) Double-blind Self-titrated dose excitability and on the Self-titrated dose Crossover monosynaptic Mean dose (SD) = Mean dose (SD) = 10 weeks (4-week/intervention, component of the 7 (3) sprays/day 10 (3) sprays/day 2-week washout between stretch reflex. (18.90 mg THC + 17.50 mg treatment periods) CBD) PP analysis N/ninitial 43 43 .. 43 Sex M 23 (53%) .. .. .. F 20 (47%) .. .. .. Subtype of MS Progressive MS 43 .. .. .. .. Mean age (SD) 48 (8.00) .. .. .. years Mean DD (SD) 17.1 (8.40) .. .. .. years Mean EDSS (SD) 5.5 (1.00) .. .. .. Mean MAS (SD), 8.1 (3.90) lower limbs Mean MAS (SD), 9.3 (5.20) .. .. .. total Mean Spasticity 7.0 (1.50) .. .. .. NRS (SD) N/nfinal 34 (79%) 34 (79%) .. 34 (79%) Assessment Efficacy: Included in our analysis: MAS (lower limbs, extreme outliner value retained); Pain NRS; and Spasticity NRS. Excluded from our analysis: 9-HPT (dominant hand), and 9-HPT (non-dominant hand); FSS; MAS (lower limbs, extreme outliner value removed); MAS (upper limbs); MAS 20% responders; Sleep quality NRS (PSQI); Spasm frequency; Spasticity NRS 20% responders; and T10-MW. Neurophysiological assessment (H-reflex, and TMS). Tolerability: Included in our analysis: Dizziness; faringodynia; fever; hypotension; lower limb weakness; somnolence; subjective weakness; vertigo; and withdrawals due to adverse events. Excluded from our analysis: Acute pancreatitis‡; and hypertension. © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 2: Summary of the selected clinical assessment tools †Items, or some of them, composing the tool were included individually in the statistical analysis. CRS = Category Rating Scale. GIC = Global Impression of Change. MS = multiple sclerosis. NRS = Numerical Rating Scale. QoL = quality of life. VAS = Visual Analog Scale. Publication where analyzed Clinical assessment tool Description Evaluated outcomes 25,26,29,32,34 Ashworth scale Scored by an observer. Measures passive resistance to movement Spasticity (Ashworth) during muscle stretching. Bladder (Bladder Problems) VAS Bladder problems. Bladder dysfunction Bladder problems CRS Bladder problems. Bladder dysfunction Bladder questionnaire (Bladder Control Test) Bladder symptoms and control, and effects on the patient’s life. Bladder dysfunction Bladder symptom severity (Overall Bladder Severity of urinary incontinence and general bladder symptoms. Bladder dysfunction Condition, OBC) NRS Bladder symptoms questionnaire Overall effect of medication in bladder function. Bladder dysfunction 35,39 Bladder symptoms NRS Bladder symptoms. Bladder dysfunction Bladder VAS Diary Severity of bladder symptoms. Bladder dysfunction Body pain CRS Pain. Pain Brief Pain Inventory-Short Form (BPI-SF) Rate pain and the degree to which pain interferes with activities. Pain Daily number of incontinence episodes Diary Incontinence episode frequency. Bladder dysfunction Impact of pain on daily activities VAS Diary Impact of pain on daily activities. Pain (VASimpact) Incontinence pad weight Weight of the incontinence pads used. Bladder dysfunction Incontinence QoL Questionnaire Impact of lower urinary tract symptoms on patient´s quality of life. Bladder dysfunction Micturition problems questionnaire Diary Micturition. Bladder dysfunction 30,35,37,40,43 Modified Ashworth scale Modified version of the Ashworth scale adding a 1+ grade for Spasticity (Ashworth) resistance throughout the reminder (less than half) of the range of movement. Multiple Sclerosis Spasticity Scale-88 (MSSS- Self-reported assessment of impact of spasticity in MS patients in 8 .. 88)† areas (ability to walk, activities of daily living, body movement, feelings, muscle spasms, muscle stiffness, pain and discomfort, and social functioning). 38,42 MSSS-88-Ability to walk/Walking subscale Effect of spasticity on walking mobility. Spasticity (subjective) MSSS-88-Activities of daily living/Daily activities Effect of spasticity on daily activities. Spasticity 38,42 subscale (subjective) 38,42 MSSS-88-Body movement subscale Effect of spasticity on body movements. Spasticity (subjective) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 2: Summary of the selected clinical assessment tools (continued) Publication where analyzed Clinical assessment tool Description Evaluated outcomes 38,42 MSSS-88-Feelings subscale Effect of spasticity on feelings. Spasticity (subjective) 38,42 MSSS-88-Muscle spasms subscale Muscle spasms due to spasticity. Spasticity (subjective) 38,42 MSSS-88-Muscle stiffness subscale Muscle stiffness due to spasticity. Spasticity (subjective) 38,42 MSSS-88-Pain and discomfort subscale Pain and discomfort due to spasticity. Pain Spasticity (subjective) 38,42 MSSS-88-Social functioning subscale Effect of spasticity on social functioning. Spasticity (subjective) 31,39 Neuropathic Pain Scale (NPS) Level of neuropathic pain. Pain Nocturia episodes Diary (per day) Instances of nocturia, and the time that each took place. Bladder dysfunction Number Daytime voids Diary (per day) Number of voids. Bladder dysfunction Number of incontinence pads used Diary (per Number of incontinence pads used. Bladder dysfunction day) Pain (central neuropathic pain) NRS Central neuropathic pain. Pain Pain (pain due to MS) NRS Level of pain due to MS. Pain Pain disability index (PDI) Degree to which aspects of patient´s life are disrupted by chronic Pain pain. Pain intensity VAS Diary (VASpain) Pain intensity. Pain Pain questionnaire Overall effect of medication in pain. Pain Pain CRS Pain. Pain 35,43 Pain NRS Pain. Pain Pain-relief NRS Diary Measurement of the level of relief in pain. Pain Pain VAS Pain. Pain (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 2: Summary of the selected clinical assessment tools (continued) Publication where analyzed Clinical assessment tool Description Evaluated outcomes Pain VAS Diary Severity of pain. Pain Patient-rated GIC for neuropathic pain Overall patient-perceived effect of treatment on their pain levels. Pain Radiating pain NRS Diary Pain. Pain Short Form-36 Health Survey/Short Form Self-rated health status questionnaire. Two summary scales (physical .. questionnaire-36 items (SF-36)† component summary and the mental component summary) are generated from 8 subscales (physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role-limitations due to emotional problems, and mental health). 28,37,39 SF-36-Bodily pain subscale Pain level and interference with normal work. Pain Sleep Disruption (due to spasticity) NRS Sleep disruption due to spasticity. Spasticity (subjective) Sleep disturbance (due to neuropathic pain) Sleep disruption due to neuropathic pain. Pain NRS Sleep quality (Sleep Disruption, due to pain) Sleep disruption due to pain. Pain NRS Sleep quality (due to spasticity) NRS Sleep disruption due to spasticity. Spasticity (subjective) Spasticity questionnaire Overall effect of medication in spasticity. Spasticity (subjective) 34,37,39,43 Spasticity NRS Spasticity. Spasticity (subjective) 32,35 Spasticity NRS Diary Spasticity. Spasticity (subjective) Spasticity VAS Spasticity. Spasticity (subjective) Spasticity VAS Diary Spasticity. Spasticity (subjective) Spontaneous pain intensity NRS Diary Pain. Pain Subject´s GIC (SGIC) for pain Status of pain due to multiple sclerosis since entry into the study. Pain Subject´s GIC (SGIC) for spasticity Change in spasticity since immediately before receiving the first dose Spasticity of study treatment. (subjective) Urge Incontinence Episodes Diary Number of incontinence episodes. Bladder dysfunction Void urgency episodes Diary (per day) Instances of urgency, and the time that each took place. Bladder dysfunction © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 3: Sensitivity analysis results for efficacy outcomes Results obtained performing meta-analysis using the inverse of variance method and the random effects model (except SA1, where fixed effects model was used) on an ITT basis. Sensitivity analysis was conducted using the same statistical methods than the main analysis, but modifying the parameter specified in each of the five performed analyses (SA1 to SA5): Main analysis 25–43 25–43 (all studies included ). SA1: Use of the fixed-effects model instead of random effects (all studies included ). SA2: Exclusion of studies with crossover design (5 studies, 6 publications, 25,28,29,33,34,43 25,28,33,34,41,43 excluded ). SA3: Exclusion of studies with a sample size of 50 patients or fewer (5 studies, 6 publications, excluded ). SA4: Exclusion of studies with a length of treatment 25,28,29,31,33,34,43 25–27,33,34,37,41–43 of 4 weeks or less (6 studies, 7 publications, excluded ). SA5: Exclusion of studies with a high risk of bias (7 studies, 9 publications, excluded ). Not estimable: Not available studies in the intervention group. Results with statistical significance shown in bold type. SA = Sensitivity analysis. SMD = Hedges´g standardized mean difference. SMD (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Spasticity Cannabis 0.01 (-0.18 to 0.01 (-0.18 to -0.05 (-0.29 to 0.05 (-0.22 to -0.05 (-0.29 to 0.23 (-0.14 to (Ashworth) extract 0.20) 0.20) 0.18) 0.31) 0.18) 0.60) Nabiximols -0.11 (-0.22 to -0.11 (-0.22 to -0.10 (-0.22 to -0.10 (-0.22 to -0.10 (-0.22 to -0.06 (-0.20 to 0.01) 0.01) 0.02) 0.02) 0.02) 0.08) Dronabinol -0.16 (-0.38 to -0.16 (-0.38 to -0.16 (-0.39 to -0.16 (-0.39 to -0.16 (-0.39 to Not estimable 0.07) 0.07) 0.07) 0.07) 0.07) Cannabinoids -0.09 -0.09 -0.10 -0.08 (-0.17 to -0.10 -0.03 (-0.17 to (-0.18 to 0.0027) (-0.18 to 0.0027) (-0.20 to -0.0035) 0.02) (-0.20 to -0.0035) 0.12) Spasticity Cannabis -0.27 -0.27 -0.27 -0.27 -0.27 -0.20 (-0.44 to (subjective) extract (-0.44 to -0.09) (-0.44 to -0.09) (-0.44 to -0.09) (-0.44 to -0.09) (-0.44 to -0.09) 0.04) Nabiximols -0.29 -0.26 -0.32 -0.32 -0.32 -0.27 (-0.47 to -0.12) (-0.36 to -0.15) (-0.53 to -0.11) (-0.53 to -0.11) (-0.53 to -0.11) (-0.49 to -0.06) Dronabinol -0.13 (-0.46 to -0.09 (-0.24 to -0.13 (-0.46 to -0.13 (-0.46 to -0.13 (-0.46 to Not estimable 0.20) 0.06) 0.20) 0.20) 0.20) Cannabinoids -0.25 -0.22 -0.26 -0.26 -0.26 -0.25 (-0.38 to -0.13) (-0.29 to -0.14) (-0.40 to -0.13) (-0.40 to -0.13) (-0.40 to -0.13) (-0.43 to -0.08) Pain Cannabis -0.33 -0.33 -0.33 -0.33 -0.33 -0.29 extract (-0.50 to -0.16) (-0.50 to -0.16) (-0.50 to -0.16) (-0.50 to -0.16) (-0.50 to -0.16) (-0.53 to -0.05) Nabiximols -0.07 (-0.26 to -0.07 (-0.18 to -0.12 (-0.29 to -0.12 (-0.29 to -0.07 (-0.19 to -0.09 (-0.29 to 0.12) 0.05) 0.05) 0.05) 0.05) 0.11) Dronabinol -0.23 (-0.55 to -0.15 -0.17 (-0.53 to -0.17 (-0.53 to -0.17 (-0.53 to -0.50 (-1.08 to 0.09) (-0.29 to -0.0041) 0.20) 0.20) 0.20) 0.08) Nabilone -1.40 -1.40 -1.40 Not estimable -1.40 Not estimable (-2.78 to -0.03) (-2.78 to -0.03) (-2.78 to -0.03) (-2.78 to -0.03) Cannabinoids -0.17 -0.15 -0.19 -0.18 -0.17 -0.17 (-0.34 to (-0.31 to -0.03) (-0.23 to -0.07) (-0.33 to -0.06) (-0.31 to -0.05) (-0.29 to -0.04) 0.01) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 3: Sensitivity analysis results for efficacy outcomes (continued) SMD (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Bladder Cannabis -0.29 -0.29 -0.27 -0.29 -0.27 -0.34 (-0.71 to dysfunction extract (-0.50 to -0.09) (-0.50 to -0.09) (-0.52 to -0.02) (-0.50 to -0.09) (-0.52 to -0.02) 0.03) Nabiximols -0.07 (-0.22 to -0.06 (-0.18 to -0.07 (-0.22 to -0.07 (-0.22 to -0.07 (-0.22 to -0.07 (-0.22 to 0.08) 0.07) 0.08) 0.08) 0.08) 0.08) Dronabinol -0.06 (-0.27 to -0.04 (-0.19 to -0.06 (-0.27 to -0.06 (-0.27 to -0.06 (-0.27 to Not estimable 0.16) 0.11) 0.16) 0.16) 0.16) Cannabinoids -0.11 -0.09 -0.09 (-0.20 to -0.11 -0.09 (-0.20 to -0.11 (-0.26 to (-0.22 to -0.0008) (-0.18 to -0.01) 0.02) (-0.22 to -0.0008) 0.02) 0.04) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 4: Sensitivity analysis results for tolerability outcomes Results obtained performing meta-analysis using the inverse of variance method and the random effects model (except SA1, where fixed effects model was used) on an ITT basis. Sensitivity analysis was conducted 25–43 using the same statistical methods than the main analysis, but modifying the parameter specified in each of the five performed analyses (SA1 to SA5): Main analysis (all studies included ). SA1: Use of fixed- 25–43 25,28,29,33,34,43 effects model instead of random effects (all studies included ). SA2: Exclusion of studies with crossover design (5 studies, 6 publications, excluded ). SA3: Exclusion of studies with a sample size of 25,28,33,34,41,43 25,28,29,31,33,34,43 50 patients or fewer (5 studies, 6 publications, excluded ). SA4: Exclusion of studies with a length of treatment of 4 weeks or less (6 studies, 7 publications, excluded ). SA5: Exclusion of 25–27,33,34,37,41–43 studies with a high risk of bias (7 studies, 9 publications, excluded ). Not estimable: Not available studies in the intervention group. Results with statistical significance shown in bold type. SA = Sensitivity analysis. RR = rate ratio. RR (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Total adverse Cannabis 1.51 (0.87 to 2.63) 1.74 (1.53 to 1.99) 2.09 (1.28 to 3.42) 1.41 (0.74 to 2.66) 2.09 (1.28 to 3.42) 1.24 (0.26 to 5.93) events extract Nabiximols 1.80 (1.53 to 2.12) 1.85 (1.68 to 2.03) 1.72 (1.48 to 2.01) 1.72 (1.48 to 2.01) 1.74 (1.47 to 2.06) 1.82 (1.60 to 2.09) Dronabinol 1.62 (1.12 to 2.34) 1.42 (1.29 to 1.56) 1.42 (1.07 to 1.88) 1.42 (1.07 to 1.88) 1.42 (1.07 to 1.88) 3.43 (2.16 to 5.46) Cannabinoids 1.72 (1.46 to 2.02) 1.65 (1.55 to 1.75) 1.70 (1.47 to 1.98) 1.61 (1.37 to 1.89) 1.72 (1.47 to 2.00) 1.80 (1.45 to 2.24) Serious adverse Cannabis 0.99 (0.26 to 3.74) 0.82 (0.40 to 1.70) 0.99 (0.26 to 3.74) 0.99 (0.26 to 3.74) 0.99 (0.26 to 3.74) 2.19 (0.57 to 8.46) events extract Nabiximols 1.43 (0.66 to 3.09) 1.60 (1.002 to 2.56) 1.38 (0.60 to 3.15) 1.38 (0.60 to 3.15) 1.38 (0.60 to 3.15) 1.18 (0.49 to 2.85) Dronabinol 1.21 (0.89 to 1.63) 1.21 (0.89 to 1.63) 1.20 (0.88 to 1.62) 1.20 (0.88 to 1.62) 1.20 (0.88 to 1.62) 3.00 (0.12 to 73.64) Cannabinoids 1.23 (0.82 to 1.85) 1.25 (0.98 to 1.58) 1.20 (0.78 to 1.84) 1.20 (0.78 to 1.84) 1.20 (0.78 to 1.84) 1.35 (0.67 to 2.71) Withdrawals due Cannabis 3.11 (1.54 to 6.28) 3.11 (1.54 to 6.28) 3.09 (1.50 to 6.36) 3.11 (1.54 to 6.28) 3.09 (1.50 to 6.36) 3.14 (1.53 to 6.48) to adverse extract events Nabiximols 2.20 (1.34 to 3.59) 2.20 (1.34 to 3.59) 2.13 (1.29 to 3.50) 2.13 (1.29 to 3.50) 2.11 (1.27 to 3.49) 1.99 (1.20 to 3.31) Dronabinol 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) Not estimable Nabilone 2.63 (0.11 to 64.44) 2.63 (0.11 to 64.44) 2.63 (0.11 to 64.44) Not estimable 2.63 (0.11 to 64.44) Not estimable Cannabinoids 2.95 (2.14 to 4.07) 2.95 (2.14 to 4.07) 2.91 (2.10 to 4.03) 2.92 (2.11 to 4.05) 2.91 (2.10 to 4.04) 2.32 (1.53 to 3.51) Dizziness or Cannabis 2.51 (0.84 to 7.47) 3.28 (2.39 to 4.49) 5.20 (2.23 to 2.62 (0.74 to 9.21) 5.20 (2.23 to 12.12) 2.17 (0.15 to vertigo extract 12.12) 31.20) Nabiximols 3.33 (2.55 to 4.34) 3.33 (2.55 to 4.34) 3.29 (2.50 to 4.33) 3.29 (2.50 to 4.33) 3.29 (2.47 to 4.37) 3.22 (2.45 to 4.25) Dronabinol 4.00 (2.43 to 6.58) 4.10 (3.00 to 5.62) 4.15 (2.97 to 5.80) 4.15 (2.97 to 5.80) 4.15 (2.97 to 5.80) 5.20 (2.00 to 13.54) Cannabinoids 3.40 (2.55 to 4.53) 3.52 (2.97 to 4.18) 3.83 (3.20 to 4.59) 3.42 (2.52 to 4.65) 3.86 (3.17 to 4.69) 3.22 (2.06 to 5.04) (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 4: Sensitivity analysis results for tolerability outcomes (continued) RR (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Dry mouth Cannabis 3.17 (1.91 to 5.25) 3.17 (1.91 to 5.25) 3.18 (1.89 to 5.35) 3.16 (1.89 to 5.28) 3.18 (1.89 to 5.35) 3.15 (1.58 to 6.25) extract Nabiximols 2.30 (1.42 to 3.73) 2.30 (1.42 to 3.73) 2.20 (1.34 to 3.59) 2.20 (1.34 to 3.59) 2.11 (1.28 to 3.48) 2.14 (1.28 to 3.60) Dronabinol 4.32 (2.12 to 8.81) 4.32 (2.12 to 8.81) 4.12 (1.93 to 8.79) 4.12 (1.93 to 8.79) 4.12 (1.93 to 8.79) 7.00 (0.36 to 135.53) Cannabinoids 2.94 (2.15 to 4.03) 2.94 (2.15 to 4.03) 2.84 (2.06 to 3.92) 2.84 (2.06 to 3.91) 2.80 (2.02 to 3.88) 2.49 (1.67 to 3.73) Fatigue Cannabis 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) extract Nabiximols 1.64 (1.17 to 2.28) 1.64 (1.17 to 2.28) 1.70 (1.12 to 2.56) 1.70 (1.12 to 2.56) 1.80 (1.13 to 2.86) 1.60 (1.08 to 2.37) Dronabinol 1.09 (0.74 to 1.60) 1.09 (0.74 to 1.60) 1.06 (0.72 to 1.56) 1.06 (0.72 to 1.56) 1.06 (0.72 to 1.56) 5.00 (0.24 to 104.14) Cannabinoids 1.61 (1.18 to 2.21) 1.46 (1.15 to 1.85) 1.61 (1.14 to 2.30) 1.61 (1.14 to 2.30) 1.67 (1.14 to 2.43) 1.76 (1.25 to 2.47) Feeling drunk Nabiximols 3.70 (0.70 to 19.55) 3.70 (0.70 to 19.55) 3.70 (0.70 to 19.55) 3.70 (0.70 to 8.01 (1.0001 to 3.70 (0.70 to 19.55) 64.14) 19.55) Dronabinol 11.00 (0.61 to 11.00 Not estimable Not estimable Not estimable 11.00 198.93) (0.61 to 198.93) (0.61 to 198.93) Cannabinoids 4.85 (1.15 to 20.53) 4.85 (1.15 to 20.53) 3.70 (0.70 to 19.55) 3.70 (0.70 to 8.01 (1.0001 to 4.85 (1.15 to 19.55) 64.14) 20.53) Impaired Cannabis 3.50 (0.18 to 67.77) 3.50 (0.18 to 67.77) Not estimable Not estimable Not estimable Not estimable balance or extract ataxia Nabiximols 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 3.81 (1.27 to 11.42) Dronabinol 1.28 (0.90 to 1.81) 1.28 (0.90 to 1.81) 1.25 (0.88 to 1.78) 1.25 (0.88 to 1.78) 1.25 (0.88 to 1.78) 5.00 (0.24 to 104.14) Cannabinoids 1.40 (1.01 to 1.95) 1.40 (1.01 to 1.95) 1.37 (0.98 to 1.91) 1.37 (0.98 to 1.91) 1.37 (0.98 to 1.91) 3.93 (1.40 to 11.04) Memory Nabiximols 4.93 (1.07 to 22.70) 4.93 (1.07 to 22.70) 4.93 (1.07 to 4.93 (1.07 to 4.93 (1.07 to 22.70) 4.93 (1.07 to impairment 22.70) 22.70) 22.70) Cannabinoids 4.93 (1.07 to 22.70) 4.93 (1.07 to 22.70) 4.93 (1.07 to 4.93 (1.07 to 4.93 (1.07 to 22.70) 4.93 (1.07 to 22.70) 22.70) 22.70) (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 4: Sensitivity analysis results for tolerability outcomes (continued) RR (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Somnolence Cannabis 1.32 (0.95 to 1.83) 1.32 (0.95 to 1.83) 1.32 (0.94 to 1.85) 1.32 (0.94 to 1.85) 1.32 (0.94 to 1.85) 1.50 (0.06 to extract 36.82) Nabiximols 3.47 (2.10 to 5.73) 3.47 (2.10 to 5.73) 3.50 (2.04 to 6.00) 3.50 (2.04 to 6.00) 3.42 (1.98 to 5.93) 3.48 (1.99 to 6.07) Dronabinol 0.55 (0.06 to 4.74) 1.08 (0.77 to 1.53) 1.12 (0.79 to 1.58) 1.12 (0.79 to 1.58) 1.12 (0.79 to 1.58) Not estimable Cannabinoids 1.87 (1.24 to 2.81) 1.46 (1.18 to 1.81) 1.92 (1.25 to 2.96) 1.88 (1.25 to 2.82) 1.88 (1.22 to 2.90) 3.39 (1.96 to 5.88) © 2018 Torres-Moreno MC et al. JAMA Network Open. 3. Supplementary eFigures eFigure 1: Risk of bias summary of the included studies Review authors' judgements about each risk of bias item for each included study. Low risk of bias Unclear risk of bias High risk of bias © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 2: Risk of bias graph of the included studies 25-43 Review authors' judgements about each risk of bias item presented as percentages across all included studies. © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 3: Funnel plots for efficacy outcomes Panels 3a) Spasticity (Ashworth), 3b) Spasticity (subjective), 3c) Pain, and 3d) Bladder dysfunction Panel 3a) Spasticity (Ashworth) Panel 3b) Spasticity (subjective) Panel 3c) Pain Panel 3d) Bladder dysfunction © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 4: Funnel plots for tolerability outcomes Panels 4a) Total adverse events, 4b) Serious adverse events, 4c) Withdrawals due to adverse events, 4d) Dizziness/vertigo, 4e) Dry mouth, 4f) Fatigue, 4g) Feeling drunk, 4h) Impaired balance/ataxia, 4i) Memory impairment, and 4j) Somnolence Panel 4a) Total adverse events Panel 4b) Serious adverse events Panel 4c) Withdrawals due to adverse Panel 4d) Dizziness or vertigo events Panel 4e) Dry mouth Panel 4f) Fatigue (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 4: Funnel plots for tolerability outcomes (continued) Panels 4a) Total adverse events, 4b) Serious adverse events, 4c) Withdrawals due to adverse events, 4d) Dizziness/vertigo, 4e) Dry mouth, 4f) Fatigue, 4g) Feeling drunk, 4h) Impaired balance/ataxia, 4i) Memory impairment, and 4j) Somnolence Panel 4g) Feeling drunk Panel 4h) Impaired balance or ataxia Panel 4i) Memory impairment Panel 4j) Somnolence © 2018 Torres-Moreno MC et al. JAMA Network Open. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association http://www.deepdyve.com/lp/american-medical-association/assessment-of-efficacy-and-tolerability-of-medicinal-cannabinoids-in-96UQ7bG1wN

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Publisher: American Medical Association
Copyright: Copyright 2018 Torres-Moreno MC et al. JAMA Network Open.
eISSN: 2574-3805
DOI: 10.1001/jamanetworkopen.2018.3485
Publisher site: See Article on Publisher Site

Abstract

Key Points Question Are medicinal cannabinoids IMPORTANCE Cannabinoids have antispastic and analgesic effects; however, their role in the effective and well tolerated in the treatment of multiple sclerosis (MS) symptoms is not well defined. treatment of multiple sclerosis? Findings In this systematic review and OBJECTIVE To conduct a systematic review and meta-analysis to assess the efficacy and tolerability meta-analysis of 17 randomized clinical of medicinal cannabinoids compared with placebo in the symptomatic treatment of patients trials including 3161 patients, with MS. cannabinoids were significantly associated with efficacy for subjective DATA SOURCES MEDLINE and the Cochrane Library Plus up to July 26, 2016. No restrictions were spasticity, pain, and bladder dysfunction applied. The search was completed with information from ClinicalTrials.gov. compared with placebo. Cannabinoids had a higher risk of adverse events and STUDY SELECTION Randomized, double-blind, and placebo-controlled trials evaluating the effect withdrawals due to adverse events, with of medicinal cannabinoids by oral or oromucosal route of administration on the symptoms of no statistically significant differences spasticity, pain, or bladder dysfunction in adult patients with MS. found for serious adverse events. DATA EXTRACTION AND SYNTHESIS The Preferred Reporting Items for Systematic Reviews and Meaning Cannabinoids appear to be Meta-analyses (PRISMA) reporting guidelines were followed. Effect sizes were calculated as safe regarding serious adverse events, standardized mean difference (SMD) for efficacy, and rate ratio (RR) for tolerability. Within each study, but their clinical benefit may be limited. those SMDs evaluating the same outcome were combined before the meta-analysis to obtain a single value per outcome and study. Pooling of the studies was performed on an intention-to-treat basis by Invited Commentary means of random-effect meta-analysis. Supplemental content MAIN OUTCOMES AND MEASURES Spasticity (on the Ashworth and Modified Ashworth scales and Author affiliations and article information are subjective), pain, bladder dysfunction, adverse events, and withdrawals due to adverse events. listed at the end of this article. RESULTS Seventeen selected trials including 3161 patients were analyzed. Significant findings for the efficacy of cannabinoids vs placebo were SMD = −0.25 SD (95% CI, −0.38 to −0.13 SD) for spasticity (subjective patient assessment data), −0.17 SD (95% CI, −0.31 to −0.03 SD) for pain, and −0.11 SD (95% CI, −0.22 to −0.0008 SD) for bladder dysfunction. Results favored cannabinoids. Findings for tolerability were RR = 1.72 patient-years (95% CI, 1.46-2.02 patient-years) in the total adverse events analysis and 2.95 patient-years (95% CI, 2.14-4.07 patient-years) in withdrawals due to adverse events. Results described a higher risk for cannabinoids. The serious adverse events meta- analysis showed no statistical significance. CONCLUSIONS AND RELEVANCE The results suggest a limited efficacy of cannabinoids for the treatment of spasticity, pain, and bladder dysfunction in patients with MS. Therapy using these drugs can be considered as safe. (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 1/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Abstract (continued) TRIAL REGISTRATION PROSPERO Identifier: CRD42014015391 JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 Introduction Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination in the central nervous system caused by inflammatory immune-mediated attacks. In 2013 there were approximately 2.3 million people affected by MS worldwide. Manifestations may occur in an episodic (relapsing-remitting) or progressive (primary or secondary) pattern and vary from benign to severe. Sensory and motor systems are frequently affected and present symptoms of spasticity, pain, and bladder dysfunction. Treatment of MS focuses on preventing new relapses, modifying the course of the disease, and managing symptoms. No treatment to stimulate remyelination and repair nerves is available. Cannabinoids act as neuromodulators of the endocannabinoid system; therefore, their therapeutic potential has aroused considerable interest over the centuries. In some countries a mixture of cannabinoids (nabiximols) has been approved for the symptomatic treatment of MS 4,5 spasticity and neuropathic pain in cases in which previous medication has proved ineffective. Nabiximols are a mixture of δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in an approximate ratio of 1:1. Oral cannabis extract (CE) contains THC and CBD from the Cannabis sativa plant. Other marketed cannabinoids include dronabinol, an oral synthetic THC, and nabilone, an oral synthetic THC analogue. 6-11 Limited literature regarding previous systematic reviews and meta-analysis was found. The results from these studies were relatively incomplete. We aimed to evaluate the therapeutic efficacy and tolerability of medicinal cannabinoids to treat the symptoms of spasticity, pain, and bladder dysfunction in patients with MS by performing a systematic review and meta-analysis of randomized, double-blind, and placebo-controlled trials. Methods Study Protocol A protocol of the study was prepared and recorded in the International Prospective Register of Systematic Reviews (PROSPERO). The review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. Study Eligibility Criteria The inclusion criteria were (1) published studies evaluating the effect of medicinal cannabinoids by oral or oromucosal route on the symptoms of spasticity, pain, or bladder dysfunction in adult patients with MS; (2) randomized, placebo-controlled, double-blind, and parallel or crossover designed trials; (3) a minimum length of treatment of 2 weeks; and (4) studies specifying the results by means of estimated effect size or with sufficient information to calculate it. The exclusion criteria were (1) studies investigating other clinical entities and (2) studies duplicated in publication. Search and Selection of Studies Search, study selection, and data collection were jointly conducted by 2 of us (M.C.T.M. and M.F). The summary of the studies was read by these 2 authors; in case of disagreement, the study was again reviewed, and a final decision was reached by consensus. The bibliographic search was carried out up to July 26, 2016, in the electronic databases MEDLINE and the Cochrane Library Plus. No limits regarding publication date, article type, or language were applied. An additional search was performed in ClinicalTrials.gov to obtain JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 2/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis complementary information not provided in the articles. The search strategy used was “(canna* OR tetrahydrocannabinol OR THC OR marijuana OR dronabinol OR nabilone OR levonantradol OR dexanabinol OR sativex OR namisol OR marihuana OR cesamet OR marinol OR nabiximols) AND multiple sclerosis.” The abstracts were reviewed to identify randomized clinical trials (RCTs). The references of the reviews and selected studies were checked to identify other RCTs that had not been located. In parallel, other documents such as books, monographs, and reports were also reviewed. The authors of the identified studies were contacted in the case of controversy to clarify appropriateness for inclusion. Data Extraction All available data were collected to select those that were valid to compare efficacy and tolerability from the published articles found in the electronic databases and complemented with results from ClinicalTrials.gov. The general data selection criteria were (1) information measuring efficacy and tolerability and (2) information about the phases fulfilling the inclusion criteria in the case of studies with different phases. The data selection criteria for efficacy were (1) data convertible to the effect size of standardized mean difference (SMD) and (2) data from the tools measuring the same clinical aspects. For tolerability, the selection criteria were (1) the number of adverse events or, in case of failure, the number of patients presenting an adverse event, appearing in at least 2 of the studies and (2) the number of patients withdrawn from the intervention and/or the study due to adverse events. Assessment of Bias of Studies Estimates of the risk of bias of each of the included studies, and across them, were reached according to the recommendations of the Cochrane Collaboration. Ratings were low risk of bias, high risk of bias, and unclear risk of bias. Each study was reviewed individually. Assessment of publication bias for each meta-analysis was also performed. Assessments were carried out using the software Review Manager (RevMan) (Cochrane). Synthesis In efficacy, high heterogeneity was clearly demonstrated in the format by which results were obtained (eg, F statistic, mean difference between groups, or odds ratio), making a direct comparison nonviable. As a consequence, standardization to the SMD, which is expressed in standard deviation units, was calculated in order to allow comparison. The SMD used was Hedges g and hereafter the SMD referred to in our study is this unless otherwise indicated. The related standard error was also estimated. Effect size can be interpreted in the clinical field following the rule of thumb in which values of 0.2, 0.5, and 0.8 represent small, moderate, and large effect, respectively. Calculations of the SMD were carried out on an intention-to-treat (ITT) basis by extrapolation of the missing 14-22 23 data. Crossover studies were treated as parallel design. With respect to the evaluation of efficacy, it was necessary to modify the direction of some clinical tools to adapt the results, as some were using higher or inverse punctuations for clinical improvement. The primary studies provided multiple data results obtained from different clinical assessment tools (eg, pain measurement with a numerical rating scale, visual analog scale, and the Neuropathic Pain Scale) for the same common outcome. Converted data resulting from these tools within the same study were combined to include as many data as possible and to avoid loss of information. This option also reduces the risk of bias due to the subjective selection of 1 unique clinical measure on our part. After combination, a single SMD value per outcome and study was obtained, ensuring the assumption of independence of effect sizes. Data pooling was carried out by the simple averages of 18,24 the SMDs and their standard errors. For tolerability, data were analyzed in the form of the rate ratio (RR). The meta-analysis was performed with RevMan software using the inverse-of-variance method. The random-effects model was used on an ITT basis. For efficacy, SMDs and their standard errors JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 3/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis were analyzed. For tolerability outcomes, the natural logarithm (ln) of the RRs and its respective standard errors were introduced. The heterogeneity of the results was evaluated by means of the I statistic. Sensitivity Analysis After the systematic review, we conducted a sensitivity analysis of the results obtained to ascertain whether the findings were strong enough to reaffirm the methods used. With this objective, the meta-analyses were repeated, changing the parameters that could be affected by our decisions: (1) use of the fixed-effects model instead of random effects; (2) exclusion of crossover studies; (3) exclusion of studies with a sample size of 50 patients or fewer; (4) exclusion of studies with a length of treatment of 4 weeks or less; and (5) exclusion of studies with a high risk of bias in any of the evaluated domains. Furthermore, to reaffirm our calculations, other parallel secondary estimations for SMDs were performed with data from the studies. Results Study Characteristics 25-43 A total of 17 RCTs (19 articles) from 775 records were included in our study. Another 22 of the 775 records underwent full-text review but were later excluded (eReferences in the Supplement). Regarding the 17 RCTs, 2 had 2 articles each. In the statistical analysis, they are referred to as 26 27 33 34 Zajicek, 2003/Freeman, 2006 and Aragona, 2009/Tomassini, 2014. Two of the studies were 37,39 conducted in 2 phases (A and B). Only phase B was analyzed in 1 of the studies, in which participants were responders after the initial phase A treatment. The initial participants in phase A 39 42 of the other study were included, in that case excluding phase B. One of the selected articles was based on a published RCT (reference e2 in eReferences in the Supplement) that was discarded after reading the full text, owing to lack of data results. Of the 17 RCTs, 5 (6 articles) were crossover 25,28,29,33,34,43 design. The total number of patients analyzed was 3161. The studied experimental 25-27,29,38 30-37,39,40,43 interventions were (1) oral CE ; (2) oromucosal CE (nabiximols) ; (3) oral 25-28,42 41 dronabinol ; and (4) oral nabilone, evaluated as an adjunctive treatment to gabapentin. Two of the studies (3 articles) included 2 experimental groups, using both oral CE and dronabinol in 25-27 comparison with placebo. Each experimental-placebo comparison was included separately. Figure 1 shows selection of included studies. Main characteristics and outcome measures of each study are included in Table 1; eTable 1 in the Supplement shows further detail. Hereafter, all the results of the pooled-effect sizes of the previously mentioned treatments within the respective meta-analyses are referred to as cannabinoids, unless otherwise indicated. Bias of Studies The risk-of-bias summary of each study included in the systematic review is depicted in eFigure 1 in the Supplement. According to the authors’ judgement, high risk of bias was found relative to blinding 37 33,34,41,43 of participants and personnel, blinding of outcome assessment, incomplete outcome 26,27,41,42 25 data, and selective reporting, with the greatest percentage of high risk for bias concerning blinding of outcome assessment and incomplete outcome data (eFigure 2 in the Supplement). The impact on our results was evaluated in the sensitivity analysis. Publication bias analyses for each meta-analysis are shown in eFigure 3 in the Supplement for efficacy outcomes and eFigure 4 in the Supplement for tolerability. Publication bias was detected both for and against cannabinoids. Efficacy A total of 82 results from clinical assessment tools were selected and converted to SMDs, and 17 combinations were carried out among them. A summary of all selected clinical assessment tools can be seen in eTable 2 in the Supplement. Clinical effect in favor of the experimental treatment is denoted by a negative SMD, and a positive value favors the placebo. Statistically significant results JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 4/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis are considered favorable for cannabinoids or placebo whenever the confidence interval of the results does not exceed the value of no effect (0 in case of the SMD). Spasticity was evaluated separately for objective measures scored by an observer on the Ashworth and Modified Ashworth scales (referred to as spasticity [Ashworth]), and for the subjective spasticity measures (patient assessment data). No effects of cannabinoids on the Ashworth and Modified Ashworth scales were observed. Results showed statistically significant differences in favor of the experimental group vs placebo in spasticity (subjective) in CE (SMD, −0.27 SD; 95% CI, −0.44 to −0.09 SD), nabiximols (SMD, −0.29 SD; 95% CI, −0.47 to −0.12 SD), and cannabinoids (SMD, −0.25 SD; 95% CI, −0.38 to −0.13 SD). Figure 2A shows the meta-analysis for spasticity (Ashworth), and Figure 2B for spasticity (subjective). Results in pain presented statistically significant differences in favor of CE (SMD, −0.33 SD; 95% CI, −0.50 to −0.16 SD), nabilone (SMD, −1.40 SD; 95% CI, −2.78 to −0.03 SD), and cannabinoids (SMD, −0.17 SD; 95% CI, −0.31 to −0.03 SD). Figure 3A shows the meta-analysis for pain. Similar results were obtained for bladder dysfunction in CE (SMD, −0.29 SD; 95% CI, −0.50 to −0.09 SD) and cannabinoids (SMD, −0.11 SD; 95% CI, −0.22 to −0.0008 SD) (Figure 3B). One possible concern in clinical trial results is the impact of industry-funded studies. In our 25-27,29,38 28,42 meta-analysis, all the studies concerning CE and dronabinol were funded by 41 30-32,35-37,39,40,43 independent grants. The study of nabilone and all of those concerning nabiximols 33,34 (except 1 ) were funded by pharmaceutical companies (nabilone by Valeant Canada and nabiximols by GW Pharma and Laboratorios Almirall). We performed an additional analysis excluding those industry-funded studies. The additional analysis showed no differences between nabiximols and placebo in all the efficacy outcomes. For spasticity (Ashworth), the values changed from −0.11 SD (95% CI, −0.22 to 0.01 SD) to 0.06 SD (95% CI, −0.60 to 0.71 SD); for subjective spasticity, the values changed from −0.29 SD (95% CI, −0.47 to −0.12 SD) to −0.26 SD (95% CI, −0.92 to 0.39 SD); and for pain and bladder dysfunction, the values changed to not estimable. The same occurred in nabilone, for which the effect on pain could not be estimated. In the analysis for cannabinoids, only results for Figure 1. Study Selection Flowchart 775 Records identified by database search 654 MEDLINE 121 The Cochrane Library Plus 101 Duplicate records removed 1 Full-text article from contact with authors 674 Identified for screening 634 Titles, abstracts, and full-text articles excluded 41 Full-text articles reviewed in depth for eligibility 22 Full-text articles excluded 2 Duplicates 5 Substudies or same cohort of others included 14 Did not fulfill selection criteria 1 Withdrawal study 17 Randomized clinical trials (19 articles) included in the systematic review and meta-analysis 4 Cannabis extract treatment 10 Nabiximols treatment 4 Dronabinol treatment Two studies using both cannabis extract and 1 Nabilone treatment dronabinol as experimental treatments. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 5/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Table 1. Summary of Characteristics of the Included Studies Interventions, Mean (SD) Dose THC/CBD (CE THC (Dronabinol Source Design Patients, No. or Nabiximols) or Nabilone) Placebo Killestein Patients with progressive MS with spasticity, setting not 16 CE: dose = 2-4 caps/d Dronabinol: Dose = 2-4 caps/d et al, 2002 specified, crossover, 20 wk (4-wk intervention, 4-wk washout (5-10 mg THC + Dose = 2-4 caps/d between treatment periods), ITT analysis approximately (5-10 mg THC) 1.25-2.50 mg CBD) 26 b Zajicek et al, Patients with MS with spasticity, multicentric (UK), parallel, 630 CE: 5.42 (2.11) caps/d Dronabinol: 5.47 6.24 (1.71) caps/d 2003 (same 15 wk, ITT analysis (13.56 mg THC + 6.78 mg (2.08) caps/d (13.67 b b study cohort as CBD) mg THC) Freeman et al, 2006) 26 b Freeman Patients recruited to the Zajicek et al, 2003 study, except those 522 (83% of CE: 5.42 (2.11) caps/d Dronabinol: 5.47 6.24 (1.71) caps/d 27 26 et al, 2006 with a permanent catheter Zajicek et al, (13.56 mg THC + 6.78 mg (2.08) caps/d b b (same study 2003 initial CBD) (13.67 mg THC) cohort as data) Zajicek et al, 2003) Svendsen Patients with MS with central neuropathic pain, unicentric 24 NA Dronabinol: Mean Mean (range) dose, et al, 2004 (Denmark), crossover, 9 wk (3-wk intervention, 3-wk washout (range) dose, 3.1 (2.7- 3.3 (2.8-3.6) between treatment periods), ITT analysis 3.6) caps/d (7.75 caps/d (8.25 [7.00- [6.75-9.00] mg THC) 22.50] mg) Vaney et al, Patients with MS with spasticity, unicentric (Switzerland), 57 CE: 7.20 caps/d (17.99 NA Mean dose not 2004 crossover, 4 wk (2-wk CE treatment, 1-wk placebo, 3-d washout [7.63] mg THC + 6.48 specified between and after interventions), ITT and PP analyses [2.75] mg CBD) Wade et al, Patients with MS with spasticity, spasms, bladder problems, 160 Nabiximols: 12.37 (6.05) NA 18.87 (6.17) 2004 tremor, or pain (not musculoskeletal); multicentric (UK); parallel; sprays/d (33.40 mg THC + sprays/d 6 wk; PP analysis 30.93 mg CBD) Rogetal, Patients with MS with central neuropathic pain, unicentric (UK), 66 Nabiximols: 9.6 (6.1) NA 19.1 (12.9) 2005 parallel, 5 wk, ITT analysis sprays/d (wk 4) (25.92 mg sprays/d (wk 4) THC + 24.00 mg CBD) Collin et al, Patients with MS with spasticity, multicentric (UK and Romania), 189 Nabiximols: 9.4 (6.4) NA 14.7 (8.4) sprays/d 2007 parallel, 6 wk, ITT and PP analyses sprays/d (25.38 mg THC + 23.50 mg CBD) Aragona Patients with secondary progressive MS with spasticity, 17 (94% with Nabiximols: 8.20 (3.15) NA 15.16 (4.51) et al, 2009 unicentric (Italy), crossover, 10 wk (3-wk intervention, 2-wk respect to sprays/d (22.14 mg THC + sprays/d (same study washout between and after treatment periods), ITT and PP Tomassini 20.50 mg CBD) cohort as analyses et at, 2014 Tomassini initial data) et al, 2014) Tomassini Patients with secondary progressive MS with spasticity, 18 Nabiximols: median NA Median (range) et at, 2014 unicentric (Italy), crossover, 10 wk (3-wk intervention, 2-wk (range) dose, 7.4 dose, 16.1 (same study washout between and after treatment periods), ITT and PP (2.7-12.5) sprays/d (19.98 (6.7-26.0) sprays/d cohort as analyses mg THC + 18.50 mg CBD) Aragona et al, 2009) Collin et al, Patients with MS with spasticity, multicentric (UK and Czech 337 Nabiximols: mean (range) NA Mean (range) dose, 2010 Republic), parallel, 15 wk, ITT and PP analyses dose, 8.5 (1-22) sprays/d 15.4 (2-23) (22.95 mg THC + sprays/d 21.25 mg CBD) Kavia et al, Patients with MS with overactive bladder, multicentric (UK, 135 Nabiximols: mean NA Mean (median) 2010 Belgium, and Romania), parallel, 10 wk, ITT and PP analyses (median) dose, 8.91 (7.19) dose,17.05 (14.22) sprays/d (24.06 mg THC + sprays/d 22.28 mg CBD) Novotna Patients with MS with spasticity and at least a 20% reduction in 241 Nabiximols: 8.3 (2.43) NA 8.9 (2.31) sprays/d et al, 2011 mean spasticity numerical rating scale score after the previous sprays/d (22.41 mg THC + (phase B) single-blind phase A treatment (responders), multicentric (UK, 20.75 mg CBD) Spain, Poland, Czech Republic, and Italy), parallel, 12 wk, ITT and PP analyses Zajicek et al, Patients with MS with muscle stiffness, multicentric (UK), 277 CE: 7.81 (2.75) caps/d NA 9.60 (1.27) caps/d 2012 parallel, 14 wk, ITT analysis (end of titration period) (end of titration (19.52 mg THC + 9.76 mg period) CBD); 6.81 (2.99) caps/d (24.00 mg); 9.36 (end of study period) (1.51) caps/d (end (17.02 mg THC + 8.51 mg of study period) b b CBD) (23.40 mg) Langford Patients with MS with central neuropathic pain, multicentric (UK, 339 Nabiximols: 8.8 (3.87) NA 11.1 (4.6) sprays/d et al, 2013 Czech Republic, Canada, Spain and France), parallel, 15 wk, ITT sprays/d (23.76 mg THC + (phase A) and PP analyses 22.00 mg CBD) Vachová Patients with MS with spasticity, multicentric (Czech Republic), 121 Nabiximols: 7.6 (3.1) NA 9.5 (2.4/2.6) et al, 2014 parallel, 50 wk, ITT and PP analyses sprays/d (first mo) (20.52 sprays/d (from first mg THC + 19.00 mg CBD); to last 3 mo) 6.4 (3.1) sprays/d (last 3 mo) (17.28 mg THC + 16.00 mg CBD) (continued) JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 6/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Table 1. Summary of Characteristics of the Included Studies (continued) Interventions, Mean (SD) Dose THC/CBD (CE THC (Dronabinol Source Design Patients, No. or Nabiximols) or Nabilone) Placebo Turcotte Patients with relapsing-remitting MS and neuropathic pain 15 NA Nabilone: dose = 1-2 Dose = 1-2 caps/d et al, 2015 receiving a stable dose of gabapentin (≥1800 mg/d), unicentric caps/d (0.5-1 mg (0.5-1 mg/caps) (Canada), parallel, 9 wk, ITT and PP analyses THC/caps) (0.5-2 mg (0.5-2 mg) THC) Ball et al, Patients with progressive MS, multicentric (UK), parallel, 3 y, ITT 493 NA Dronabinol: median Median (IQR) dose, 2015 and PP analyses (IQR) dose, 4 (2-6) 6 (4-8) caps/d caps/d (final y of (final y of follow-up) 14.00 mg follow-up) THC Leocani, Patients with progressive MS with lower limb spasticity, 43 Nabiximols: 7 (3) sprays/d NA 10 (3) sprays/d et al, 2015 unicentric (Italy), crossover, 10 wk (4-wk intervention, 2-wk (18.90 mg THC + 17.50 washout between treatment periods), PP analysis mg CBD) Abbreviations: CBD, cannabidiol; CE, Cannabis sativa plant extract; IQR, interquartile Randomized, placebo-controlled, double-blind study. range; ITT, intention-to-treat; MS, multiple sclerosis; NA, not applicable; PP, b Estimated by the authors of this systematic review from study data. per-protocol; THC, δ-9-tetrahydrocannabinol; UK, United Kingdom. bladder dysfunction changed in terms of statistical significance, becoming nonsignificant. It seems that sponsored studies favored active treatment. Tolerability A total of 5357 adverse events were selected to be analyzed. Serious adverse events (death or threat to a patient's life or functioning) were also calculated, with 325 events included. A total of 260 withdrawals were due to adverse events. Higher risk in the experimental treatment is denoted by an RR greater than 1, while an RR less than 1 is for placebo. Results are considered statistically significant with higher risk in cannabinoids or placebo whenever the confidence interval of the results does not exceed the value of no effect (1 in the case of the RR). In the total adverse events analysis, there was a higher risk of adverse events in active treatments vs placebo in nabiximols (RR, 1.80 patient-years; 95% CI, 1.53-2.12 patient-years), dronabinol (RR, 1.62 patient-years; 95% CI, 1.12-2.34 patient-years), and cannabinoids (RR, 1.72 patient-years; 95% CI, 1.46-2.02 patient-years) and a higher risk of withdrawals due to adverse events in CE (RR, 3.11 patient-years; 95% CI, 1.54-6.28 patient-years), nabiximols (RR, 2.20 patient- years; 95% CI, 1.34-3.59 patient-years), dronabinol (RR, 4.12 patient-years; 95% CI, 2.39-7.11 patient-years), and cannabinoids (RR, 2.95 patient-years; 95% CI, 2.14-4.07 patient-years), but not in nabilone. No statistical significance was found in the meta-analysis of serious adverse events. Additionally, results showed a higher risk in cannabinoids with respect to the adverse events of dizziness or vertigo, dry mouth, fatigue, feeling drunk, impaired balance or ataxia, memory impairment, and somnolence. Table 2 shows the results obtained after analysis of the tolerability data. Sensitivity Analysis In efficacy, 11.3% of the results in the sensitivity analysis (considering all estimated effect sizes of the interventions [CE, nabiximols, dronabinol, nabilone, and cannabinoids] and the 5 sensitivity analyses globally) became statistically significant or not, with respect to the main results. In tolerability, this percentage was 8.4%. A summary of the main and sensitivity analysis results is shown in eTables 3 and 4 in the Supplement, for efficacy and tolerability, respectively. Additionally, in efficacy, the mean (SE) of the overall differences between the main and secondary calculations to SMDs was −0.0019 (0.0014) SD. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 7/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Figure 2. Analysis of Efficacy A Spasticity (Ashworth) Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Cannabinoids Placebo Study or Subgroup SMD SE No. No. Random (95% CI) % Cannabis extract Killestein, 2002 –0.2249 0.4345 16 8 –0.22 (–1.08 to 0.63) 1.1 Vaney, 2004 0.2269 0.1879 57 57 0.23 (–0.14 to 0.60) 6.1 26 27 Zajicek, 2003/Freeman, 2006 –0.0548 0.1187 211 107 –0.05 (–0.29 to 0.18) 15.2 Subtotal 284 172 0.01 (–0.18 to 0.20) 22.4 2 2 2 Heterogeneity τ = 0.00; χ = 1.92, df = 2 (P = .38); I = 0% Test for overall effect: z = 0.13, (P = .90) Nabiximols 33 34 1.9 Aragona, 2009/Tomassini, 2014 0.0563 0.3334 18 18 0.06 (–0.60 to 0.71) Collin, 2007 –0.1864 0.1534 124 65 –0.19 (–0.49 to 0.11) 9.1 Collin, 2010 –0.0192 0.109 167 –0.02 (–0.23 to 0.19) 18.0 Leocani, 2015 –0.2742 0.2167 43 –0.27 (–0.70 to 0.15) 4.6 Novotna, 2011 –0.215 0.1293 124 –0.21 (–0.47 to 0.04) 12.8 Vachová, 2014 –0.2269 0.1825 62 –0.23 (–0.58 to 0.13) 6.4 Wade, 2004 0.0948 0.1582 80 0.09 (–0.22 to 0.40) 8.6 Subtotal 618 –0.11 (–0.22 to 0.01) 61.5 2 2 2 Heterogeneity τ = 0.00; χ = 4.51, df = 6 (P = .61); I = 0% Test for overall effect: z = 1.82, (P = .07) Dronabinol Killestein, 2002 –0.0927 0.4333 16 –0.09 (–0.94 to 0.76) 1.1 26 27 Zajicek, 2003/Freeman, 2006 –0.1598 0.1197 206 –0.16 (–0.39 to 0.07) 15.0 16.1 Subtotal 222 –0.16 (–0.38 to 0.07) 2 2 2 Heterogeneity τ = 0.00; χ = 0.02, df = 1 (P = .88); I = 0% Test for overall effect: z = 1.34, (P = .18) Total 1124 –0.09 (–0.18 to 0.00) 100.0 2 2 2 Heterogeneity τ = 0.00; χ = 7.96, df = 11 (P = .72); I = 0% Test for overall effect: z = 1.90, (P = .06) –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2 2 Test for subgroup differences: χ = 1.51, df = 2 (P = .47); I = 0% SMD IV, Random (95% CI) B Spasticity (Subjective) Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Study or Subgroup SMD SE No. No. Random (95% CI) Cannabinoids Placebo % Cannabis extract 26 27 Zajicek, 2003/Freeman, 2006 –0.342 0.132 211 107 –0.34 (–0.60 to –0.08) 9.2 –0.2012 0.1207 143 134 –0.20 (–0.44 to 0.04) 9.8 Zajicek, 2012 354 241 –0.27 (–0.44 to –0.09) 19.0 Subtotal 2 2 2 Heterogeneity τ = 0.00; χ = 0.62, df = 1 (P = .43); I = 0% Test for overall effect: z = 2.98, (P = .003) Nabiximols 33 34 Aragona, 2009/Tomassini, 2014 –0.2617 0.3349 18 18 –0.26 (–0.92 to 0.39) 2.9 Collin, 2007 –0.3035 0.1539 124 65 –0.30 (–0.61 to 0.00) 8.0 Collin, 2010 –0.0828 0.109 167 –0.08 (–0.30 to 0.13) 10.5 Langford, 2013 –0.0467 0.1087 167 –0.05 (–0.26 to 0.17) 10.5 Leocani, 2015 –0.1088 0.2158 43 –0.11 (–0.53 to 0.31) 5.5 Novotna, 2011 –0.5343 0.1312 124 –0.53 (–0.79 to –0.28) 9.2 Vachová, 2014 –0.7618 0.1981 62 –0.76 (–1.15 to –0.37) 6.1 Wade, 2004 0.3675 0.1595 80 –0.37 (–0.68 to –0.05) 7.8 Subtotal 785 –0.29 (–0.47 to –0.12) 60.6 2 2 2 Heterogeneity τ = 0.04; χ = 18.30, df = 7 (P = .01); I = 62% Test for overall effect: z = 3.27, (P = .001) Dronabinol Ball, 2015 0.025 0.0956 329 0.03 (–0.16 to 0.21) 11.3 26 27 0.1327 206 9.1 Zajicek, 2003/Freeman, 2006 –0.3106 –0.31 (–0.57 to –0.05) 20.4 Subtotal 535 –0.13 (–0.46 to 0.20) 2 2 2 Heterogeneity τ = 0.04; χ = 4.21, df = 1 (P = .04); I = 76% Test for overall effect: z = 0.78, (P = .44) Total 1674 –0.25 (–0.38 to –0.13) 100.0 2 2 2 Heterogeneity τ = 0.03; χ = 26.68, df = 11 (P = .005); I = 59% Test for overall effect: z = 3.97, (P < .0001) –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2 2 Test for subgroup differences: χ = 0.75, df = 2 (P = .69); I = 0% SMD IV, Random (95% CI) The central point of the bars and diamonds indicates the magnitude of the effect size Upper confidence interval value of 0.0027. (Hedges g standardized mean difference [SMD] value), while width indicates the 95% CI. IV indicates inverse of variance. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 8/16 1235 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Figure 3. Analysis of Efficacy A Pain Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Cannabinoids Placebo Study or Subgroup SMD SE No. No. Random (95% CI) % Cannabis extract 26 27 Zajicek, 2003/Freeman, 2006 –0.3715 0.1266 211 107 –0.37 (–0.62 to –0.12) 10.2 Zajicek, 2012 –0.2899 0.1209 143 134 –0.29 (–0.53 to –0.05) 10.5 Subtotal 354 241 –0.33 (–0.50 to –0.16) 20.6 2 2 2 Heterogeneity: τ = 0.00; χ = 0.22, df = 1 (P = .64); I = 0% Test for overall effect: z = 3.76, (P = .0002) Nabiximols Collin, 2010 –0.0328 0.109 167 170 –0.03 (–0.25 to 0.18) 11.1 11.1 Langford, 2013 –0.0438 0.109 167 172 –0.04 (–0.26 to 0.17) Leocani, 2015 0.4138 0.2181 43 0.41 (–0.01 to 0.84) 6.2 Novotna, 2011 –0.2428 0.1294 124 –0.24 (–0.50 to 0.01) 10.0 Rog, 2005 –0.6571 0.2535 34 –0.66 (–1.15 to –0.16) 5.2 Wade, 2004 0.0665 0.1583 80 0.07 (–0.24 to 0.38) 8.6 Subtotal 615 –0.07 (–0.26 to 0.12) 52.3 2 2 2 Heterogeneity: τ = 0.03; χ = 12.98, df = 5 (P = .02); I = 61% Test for overall effect: z = 0.69, (P = .49) Dronabinol Ball, 2015 0.008 0.0956 329 0.01 (–0.18 to 0.20) 11.8 Svendsen, 2004 –0.5003 0.2936 24 24 –0.50 (–1.08 to 0.08) 4.2 26 27 10.1 Zajicek, 2003/Freeman, 2006 –0.3634 0.1277 206 –0.36 (–0.61 to –0.11) Subtotal 559 –0.23 (–0.55 to 0.09) 26.1 2 2 2 Heterogeneity: τ = 0.05; χ = 6.95, df = 2 (P = .03); I = 71% Test for overall effect: z = 1.43, (P = .15) Nabilone 1.0 0.7005 Turcotte, 2015 –1.4032 8 –1.40 (–2.78 to –0.03) 1.0 Subtotal 8 –1.40 (–2.78 to –0.03) Heterogeneity: Not applicable Test for overall effect: z = 2.00 (P = .05) Total 1536 –0.17 (–0.31 to –0.03) 100.0 2 2 2 Heterogeneity τ = 0.03 χ = 29.72, df = 11 (P = .002); I = 63% Test for overall effect: z = 2.44, (P = .01) –3 –2 –1 03 1 2 2 2 SMD IV, Random (95% CI) Test for subgroup differences: χ = 6.81, df = 3 (P = .08); I = 56% B Bladder dysfunction Cannabinoids, Placebo, SMD IV, Favors Favors Weight, Study or Subgroup SMD SE No. No. Random (95% CI) Cannabinoids Placebo Cannabis extract Vaney, 2004 –0.3428 0.1887 57 57 –0.34 (–0.71 to 0.03) 7.2 26 27 Zajicek, 2003/Freeman, 2006 –0.2729 0.1279 211 –0.27 (–0.52 to –0.02) 12.8 268 164 –0.29 (–0.50 to –0.09) Subtotal 20.1 2 2 2 Heterogeneity: τ = 0.00; χ = 0.09, df = 1 (P = .76); I = 0% Test for overall effect: z = 2.79, (P = .005) Nabiximols Collin, 2010 –0.0795 0.109 167 170 –0.08 (–0.29 to 0.13) 15.7 Kavia, 2010 –0.2685 0.1733 68 67 –0.27 (–0.61 to 0.07) 8.3 0.1087 167 0.10 (–0.11 to 0.31) Langford, 2013 0.0985 15.7 Wade, 2004 –0.1731 0.1585 80 –0.17 (–0.48 to 0.14) 9.5 Subtotal 481 –0.07 (–0.22 to 0.08) 49.1 2 2 2 Heterogeneity: τ = 0.01; χ = 4.11, df = 3 (P = .25); I = 27% Test for overall effect: z = 0.91, (P = .36) Dronabinol Ball, 2015 0.0414 0.0956 329 0.04 (–0.15 to 0.23) 18.1 26 27 Zajicek, 2003/Freeman, 2006 –0.1846 0.1289 206 –0.18 (–0.44 to 0.07) 12.7 30.8 Subtotal 535 –0.06 (–0.27 to 0.16 ) 2 2 2 Heterogeneity: τ = 0.01; χ = 1.98, df = 1 (P = .16); I = 50% Test for overall effect: z = 0.49, (P = .62) 1284 –0.11 (–0.22 to 0.00) Total 100.0 2 2 2 Heterogeneity: τ = 0.01; χ = 10.61, df = 7 (P = .16); I = 34% Test for overall effect: z = 1.97, (P = .05) –1.5 –1.0 –0.5 0 0.5 1.0 1.5 2 2 SMD IV, Random (95% CI) Test for subgroup differences: χ = 3.47, df = 2 (P = .18); I = 42.4% The central point of the bars and diamonds indicates the magnitude of the effect size Upper confidence interval value of −0.0008. (Hedges g standardized mean difference [SMD] value), while width indicates the 95% confi- dence interval. IV indicates inverse of variance. JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 9/16 924 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 10/16 Table 2. Tolerability Results Interventions Cannabis Extract Nabiximols Dronabinol Nabilone Cannabinoids Statistically RR Studies, Patients, RR Studies, Patients, RR Studies, Patients, RR Studies, Patients, RR Studies, Patients, Significant Outcome (95% CI) No. No. (95% CI) No. No. (95% CI) No. No. (95% CI) No. No. (95% CI) No. No. Higher Risk 25-27,29,38 30-37,39,40,43 25-28,42 Total adverse 1.51 4 733 1.80 10 1710 1.62 4 877 NA NA NA 1.72 16 3320 Nabiximols, events (0.87-2.63) (1.53-2.12) (1.12-2.34) (1.46-2.02) dronabinol, cannabinoids 26,27,38 30,32,35-37,39,40,43 26-28,42 Serious 0.99 2 595 1.43 8 1608 1.21 3 853 NA NA · NA 1.23 12 3056 NS adverse (0.26-3.74) (0.66-3.09) (0.89-1.63) (0.82-1.85) events 26,27,29,38 30-32,35-37,39,40,43 26,27,42 41 Withdrawals 3.11 3 709 2.20 9 1674 4.12 2 805 2.63 1 15 2.95 14 3203 Cannabis due to (1.54-6.28) (1.34-3.59) (2.39-7.11) (0.11-64.44) (2.14-4.07) extract, adverse nabiximols, events dronabinol, cannabinoids 25-27,29,38 30-37,39,40,43 25-28,42 Dizziness or 2.51 4 733 3.33 10 1710 4.00 4 877 NA NA NA 3.40 16 3320 Nabiximols, vertigo (0.84-7.47) (2.55-4.34) (2.43-6.58) (2.55-4.53) dronabinol, cannabinoids 25-27,29,38 30-35,37,39,40 25-28 Dry mouth 3.17 4 733 2.30 8 1489 4.32 3 384 NA NA· NA 2.94 13 2606 Cannabis (1.91-5.25) (1.42-3.73) (2.12-8.81) (2.15-4.03) extract, nabiximols, dronabinol, cannabinoids 38 30-37,39,40 28,42 Fatigue 2.60 1 277 1.64 9 1624 1.09 2 541 NA NA NA 1.61 12 2442 Cannabis (1.22-5.58) (1.17-2.28) (0.74-1.60) (1.18-2.21) extract, nabiximols, cannabinoids 30,31,36 28 Feeling drunk NA NA NA 3.70 3 361 11.00 1 48 NA NA NA 4.85 4 409 Cannabinoids (0.70-19.55) (0.61-198.93) (1.15-20.53) 25 32,36,37,39,40 28,42 Impaired 3.50 1 24 2.93 5 1025 1.28 2 541 NA NA NA 1.40 8 1590 Nabiximols, balance or (0.18-67.77) (1.04-8.27) (0.90-1.81) (1.01-1.95) cannabinoids ataxia 36,39,40 Memory NA NA NA 4.93 3 595 NA NA NA NA NA NA 4.93 3 595 Nabiximols, impairment (1.07-22.70) (1.07-22.70) cannabinoids 25-27,29 30-37,39,40,43 25-27 Somnolence 1.32 3 456 3.47 10 1710 0.55 2 336 NA NA NA 1.87 13 2502 Nabiximols, (0.95-1.83) (2.10-5.73) (0.06-4.74) (1.24-2.81) cannabinoids Abbreviations: NA, not available; NS, nonsignificant; RR, rate ratio. JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Discussion To our knowledge, this is the most complete systematic review and meta-analysis of the effect of cannabinoids on MS. Our results show limited therapeutic efficacy of cannabinoids for the primary outcomes of spasticity, pain, and bladder dysfunction in patients with MS. None of the interventions demonstrated clear efficacy in the treatment of spasticity when evaluated in a more objective form (ie, the Ashworth and Modified Ashworth scales). In the analysis of subjective spasticity, significant differences were observed with respect to the active treatments of CE, nabiximols, and cannabinoids. However, a large allocation-dependent placebo effect can be expected because of possible difficulties in masking and blinding. It is also interesting to note that the single largest (almost 500 patients), longest (up to 3 years), and non–corporate-sponsored study favored placebo with respect to its tested outcomes (spasticity [subjective], pain, and bladder dysfunction). Differences among results might stem from the fact that a minor improvement in such a disabling symptom is reflected by a more positive evaluation from the patient. Efficacy in pain of CE, nabilone, and cannabinoids was also demonstrated, in addition to efficacy in bladder dysfunction for CE and cannabinoids. Most of the therapeutic effects show a small value of SMD, approximately between −0.09 and −0.25 SD, which represents a limited (small) therapeutic effect. Six previous systematic reviews performed meta-analyses to evaluate the efficacy of 6-11 6 cannabinoids in MS symptoms. One study evaluated spasticity (Wade et al ) and another, pain 7 8 9 (Iskedjian et al ) outcomes; 3 analyzed both spasticity and pain (Whiting et al, Meza et al, da Rovare 10 10 11 et al ). One of these studies (da Rovare et al ) and Abo Youssef et al evaluated bladder dysfunction. Three of them did not focus only on patients with MS in the spasticity and pain analyses 7 8 10 (Iskedjian et al, Whiting et al, da Rovare et al ). 6-8 11 Our results are in accordance with the first 3 systematic reviews and with the last one, taking into account differences in treatments and analyzed pathologies. Our findings did not concur 9,10 with the fourth and fifth systematic reviews, probably because of methodological differences. In comparison with placebo, an increased risk of adverse events and of withdrawals due to adverse 8,10 events was observed in our study. Two of the reviews showed an increased risk of adverse events with cannabinoids, with one review specifically describing short-term and serious adverse events. However, these studies did not focus on MS. Clear methodological differences exist among our systematic review and the ones published so far. The standardization conducted in our study allows comparison among different types of results that cannot be reliably compared otherwise. Furthermore, the high heterogeneity among the clinical assessment tools has been overcome by pooling those effect sizes evaluating the same outcome within the same study, avoiding both the exclusion of the studies where no coincidence between the clinical measures existed, as well as the risk of bias due to the inclusion of 1 unique clinical tool for analysis. Additionally, we included a specific tolerability analysis for the treatment of MS symptoms with cannabinoids. Limitations and Strengths Limitations of our study include the small number of studies included; differences in the length of treatment, particularly in tolerability calculations; inclusion of crossover studies as parallel design; calculations made on the basis of an ITT principle by data extrapolation, which may have provoked bias in our results, although ITT analysis is the standard for medication evaluation; and publication bias. Another potential limitation is that blinding procedures can be affected in studies with drugs with such large difficulties in masking and blinding. Consequently, a large allocation-dependent placebo effect can be expected. This is particularly evident in the study with 2 phases in which the responders in the first phase were selected for the second one. In addition, most of the studies included were funded by the pharmaceutical industry, especially for nabiximols. As explained in the Results section, the exclusion of these studies had an impact on the results on subjective spasticity. In JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 11/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis the interpretation of trends favoring experimental or control treatments, difficult decisions arose in some cases owing to the different forms of exposure across the studies. Our study had strengths as well. The sensitivity analysis showed no relevant differences affecting the results obtained. We can thus consider our results to have a high level of certainty. Results in overall secondary calculations sustained the methods used. In addition, differing assessment tools were combined to evaluate a common outcome, considering the existence of procedural differences among tools. Nevertheless, caution was taken in the selection of tools with minimum differences. The combination maintained all the information provided by the studies and avoided a possibly subjective bias when selecting only 1 of the tools. Shortcomings exist with respect to research into the efficacy of cannabinoids in the treatment of MS. The quantity of available studies is limited. However, they can be considered safe drugs, with no serious complications regarding withdrawal syndromes or drug dependence effects. When comparing the efficacy of cannabinoids with other treatments for spasticity, such as baclofen or differing intrathecal doses of corticosteroids, in the Modified Ashworth scale, baclofen 44 45 reduced the scores by a mean difference of 0.58 and corticosteroids by 0.78. Cannabinoids 37 35 (nabiximols) reduced spasticity in the same scale with a mean difference ranging from 0.1 to 3.3. The risks and invasiveness of baclofen and corticosteroids should be considered. In the case of bladder dysfunction, anticholinergic agents are the most common medication for this condition. Solifenacin, 5 mg, and oxybutynin, 15 mg, reduce the number of incontinence episodes per 24 hours by 1.03 and 2.41 vs placebo, respectively, in patients with MS and spinal cord 46 47 injury, whereas injectable onabotulinumtoxinA, 300 U, reduces the same variable by 1.43. Cannabinoids vs placebo reduce the number of daily urge incontinence episodes by 0.21 (CE) and 27 36 0.16 (dronabinol) and reduce daily incontinence episodes by 0.11 (nabiximols). In comparison, cannabinoids show better tolerability than anticholinergics and less invasiveness than onabotulinumtoxinA. As for pain, painful conditions are handled with drugs such as anticonvulsants, nonsteroidal anti-inflammatory agents, and corticosteroids. Nevertheless, management of pain in MS remains controversial and underresearched. Studies do not demonstrate clear efficacy of any treatment 48-50 above others, whereas adverse events should be taken into consideration. There is no evidence of studies that evaluate the efficacy of cannabinoids vs other treatments in MS. Research into the possible combinations of cannabinoids and other therapies, therefore, 51,52 might bring about greater synergy benefits than in an individual form. Conclusions Cannabinoids produce a limited and mild reduction of subjective spasticity, pain, and bladder dysfunction in patients with MS, but no changes in objectively measured spasticity. They can be considered safe drugs, as the analysis of serious adverse events did not show statistical significance, although the total number of adverse events is higher than in placebo for the treatment of symptoms in patients with MS. ARTICLE INFORMATION Accepted for Publication: August 21, 2018. Published: October 12, 2018. doi:10.1001/jamanetworkopen.2018.3485 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Torres-Moreno MC et al. JAMA Network Open. Corresponding Author: Mari Carmen Torres-Moreno, PhD, Universitat Autònoma de Barcelona (UAB), Departament de Farmacologia, Terapèutica i Toxicologia, Campus de la UAB, Facultat de Medicina, Edifici M, Avinguda de Can Domènech, 08193 Cerdanyola del Vallès, Spain (mariacarmen.torres@e-campus.uab.cat). Author Affiliations: Universitat Autònoma de Barcelona, Departament de Farmacologia, Terapèutica i Toxicologia, JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 12/16 JAMA Network Open | Neurology Assessment of Efficacy and Tolerability of Cannabinoids in Patients With Multiple Sclerosis Cerdanyola del Vallès, Spain (Torres-Moreno, Papaseit, Farré); Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol, Servei de Farmacologia Clínica, Badalona, Spain (Torres-Moreno, Papaseit, Farré); Universitat Autònoma de Barcelona, Departament de Psiquiatria i Medicina Legal, Cerdanyola del Vallès, Spain (Torrens); Hospital del Mar, Institut de Neuropsiquiatria i Addiccions, Programa Addiccions, Barcelona, Spain (Torrens). Author Contributions: Drs Torres-Moreno and Farré had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Torres-Moreno, Farré. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Torres-Moreno, Farré. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Torres-Moreno, Farré. Obtained funding: Torrens, Farré. Supervision: Torrens, Farré. Conflict of Interest Disclosures: None reported. Funding/Support: The study was funded in part by grants from the Ministerio de Sanidad, Servicios Sociales e Igualdad (Plan Nacional sobre Drogas-PNSD, 2015I054); MINECO/Instituto de Salud Carlos III (ISCIII, FIS-FEDER, PI14/00715); and MINECO/ISCIII (Red de Trastornos Adictivos-RTA, RD12/0028/0009, RD16/0017/0003, and RD16/0017/0010). Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 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Summary of the Selected Clinical Assessment Tools eTable 3. Sensitivity Analysis Results for Efficacy Outcomes eTable 4. Sensitivity Analysis Results for Tolerability Outcomes eFigure 1. Risk of Bias Summary of the Included Studies eFigure 2. Risk of Bias Graph of the Included Studies eFigure 3. Funnel Plots for Efficacy Outcomes eFigure 4. Funnel Plots for Tolerability Outcomes JAMA Network Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 October 12, 2018 16/16 Supplementary Online Content Torres-Moreno MC, Papaseit E, Torrens M, Farré M. Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: a systematic review and meta-analysis. JAMA Netw Open. 2018;1(6):e183485. doi:10.1001/jamanetworkopen.2018.3485 eReferences. Full-text Records Excluded From Eligibility eTable 1. Characteristics of the Included Studies eTable 2. Summary of the Selected Clinical Assessment Tools eTable 3. 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Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial. J Neurol. 2006;253(10):1337-1341. doi:10.1007/s00415-006-0218-8. e21. Fox P, Bain PG, Glickman S, Carroll C, Zajicek J. The effect of cannabis on tremor in patients with multiple sclerosis. Neurology. 2004;62(7):1105-1109. e22. Kurzthaler I, Bodner T, Kemmler G, et al. The effect of nabilone on neuropsychological functions related to driving ability: an extended case series. Hum Psychopharmacol. 2005;20(4):291-293. doi:10.1002/hup.688. © 2018 Torres-Moreno MC et al. JAMA Network Open. 2. Supplementary eTables eTable 1: Characteristics of the included studies Data are mean (SD), N/n (%). Percentages may not add to 100% due to rounding. *Estimated by the authors of this systematic review from study data. †Interpreted by the authors of this systematic review based on study data. ‡ Computed only for the serious adverse events analysis, so not included in the total adverse events or in any other kind of adverse event analyses since only appeared in one of the included studies. DD = duration of disease. CBD = cannabidiol. CE = Cannabis sativa plant extract. IQR = interquartile range. ITT = intention-to-treat. MS = multiple sclerosis. N/n = no. of participants. PP = per-protocol. PPMS = primary progressive MS. PRMS = progressive relapsing MS. RCT = randomized clinical trial. RRMS = relapsing-remitting MS. SD = standard deviation. SPMS = secondary progressive MS. THC = -9-tetrahydrocannabinol. Assessment: 9-HPT = 9-Hole Peg Test. ADL = Activities of Daily Living. AMIPB = Adult Memory and Information Processing Battery. AS = Ashworth Scale. BDI = Beck Depression Inventory. BI = Barthel Index. BPI-SF = Brief Pain Inventory-Short Form. CRS = Category Rating Scale. C-SSRS = Columbia-Suicide Severity Rating Scale. DS of the WAIS-R= Digit Span of the Wechsler Adult Intelligence Scale-Revised. EDSS = Expanded Disability Status Scale. EQ-5D = European Quality of Life-5 Dimensions. FIM = Functional Independence Measure. fMRI = Functional Magnetic Resonance Imaging. FSS = Fatigue Severity Scale. GHQ-28 = General Health Questionnaire-28. GHQ- 30 = General Health Questionnaire-30. GIC = Global Impression of Change. GNDS = Guy's Neurological Disability Scale. GSI = General Symptomatic Index. HADS = Hospital Anxiety and Depression Scale. HR-QoL = Health-Related Quality of Life. MAS = Modified Ashworth Scale. MI = Motricity Index. MRI = Magnetic Resonance Imaging. MSFC = Multiple Sclerosis Functional Composite Scale. MSIS-29 = Multiple Sclerosis Impact Scale-29. MSQoL-54 = Multiple Sclerosis Quality of Life-54. MSSS-88 = Multiple Sclerosis Spasticity Scale-88. MSWS-12 = Multiple Sclerosis Walking Scale-12. NNH = Number Needed to Harm. NNT = Number Needed to Treat. NOS = Not Otherwise Specified. NPS = Neuropathic Pain Scale. NRS = Numerical Rating Scale. PASAT = Paced Auditory Serial Addition Test. PDI = Pain Disability Index. PSQI = Pittsburgh Sleep Quality Index. PSS = Primary Symptom Score. QoL = Quality of Life. RMI = Rivermead Mobility Index. SAS = Self-rating Anxiety Scale. SCL-90-R = Symptom Checklist- 90 Revised. SDMT = Symbol Digit Modalities Test. SF-36 = Short Form-36 Health Survey/Short Form questionnaire-36 items. SF-36 (PH) = Short Form questionnaire-36 items version 2 (physical health subscale). SF-MPQ = Short-Form McGill Pain Questionnaire. SPART = 10/36 Spatial Recall Test. SRT = Selective Reminding Test. TMS = Transcranial Magnetic Stimulation. T10-MW = Timed 10-m walk. T25-FW = Timed 25-foot walk. UIE = Urge incontinence episode. UKNDS = United Kingdom Neurological Disability Scale. VAS = Visual Analog Scale. WLG = Word List Generation. Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Killestein 2002 Design Progressive MS patients with Oral CE caps.: Oral dronabinol caps.: Placebo caps. No reduction of spasticity. spasticity (2.5 mg THC + 20 to 30% CBD 2.5 mg THC/cap. Setting not specified of standardized THC RCT, placebo-controlled content)/cap. Double-blind Dose = 2-4 caps./day Dose = 2-4 caps./day Dose = 2-4 caps./day Crossover (5-10 mg THC + approx. 1.25- (5-10 mg THC) 20 weeks (4-week/intervention, 2.5 mg CBD) 4-week washout between treatment periods) ITT analysis N/ninitial 16 16 16 16 Sex .. .. .. .. Subtype of MS SPMS 10 (63%) .. .. .. PPMS 6 (38%) .. .. .. Mean age (SD) 46.0 (7.90) .. .. .. years Mean DD (SD) 15.0 (10.70) .. .. .. years Mean EDSS (SD) 6.2 (1.20) .. .. .. N/n 16 16 16 16 final Assessment Efficacy: Included in our analysis: AS. Excluded from our analysis: 9-HPT; Concentration VAS; EDSS, and EDSS-Brainstem functional systems domain; Fatigue VAS; HR-QoL Questionnaire, and HR-QoL-Psychological status domain; Micturition VAS; Mood VAS; MSFC; MS-specific FSS; Pain VAS; PASAT; SF-36, and SF-36-Mental health subscale; Spasticity VAS; Subject´s Global Impression VAS; T25-FW; Tremor VAS; Vision VAS; and Walking VAS. Tolerability: Included in our analysis: Ataxia; dizziness; dry mouth; headache; increased spasticity; somnolence; and withdrawals due to adverse events. Excluded from our analysis: Acute psychosis; emotional lability; and others. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 26 27 Zajicek 2003 /Freeman 2006 (2 publications with same cohort of study) (continue) Zajicek 2003 Design MS patients with spasticity Oral CE caps.: Oral dronabinol caps.: Placebo caps. No beneficial effect on Multicentric (UK) (2.5 mg THC + 1.25 mg 2.5 mg THC/cap. spasticity. RCT, placebo-controlled CBD)/cap. Double-blind Dose = 4-10 caps./day Dose = 4-10 caps./day Dose = 4-10 caps./day Parallel (10-25 mg THC + 5-12.5 mg (10-25 mg THC) 15 weeks (13-week treatment, 1- CBD) Body weight based Body weight based week dose withdrawal, 1-week Body weight based off trial medication) Mean dose (SD) = Mean dose (SD) = Mean dose (SD) = ITT analysis 5.42 (2.11) caps./day 5.47 (2.08) caps./day 6.24 (1.71) caps./day* (13.56 mg THC + 6.78 mg (13.67 mg THC)* CBD)* N/ninitial 630 211 206 213 Sex M 217 (34%) 76 (36%) 63 (31%) 78 (37%) F 413 (66%) 135 (64%) 143 (69%) 135 (63%) Subtype of MS RRMS 33 (5%) 6 (3%) 14 (7%) 13 (6%) SPMS 452 (72%) 152 (72%) 149 (72%) 151 (71%) PPMS 145 (23%) 53 (25%) 43 (21%) 49 (23%) Mean age (SD) .. 50.5 (7.60) 50.2 (8.20) 50.9 (7.60) years Mean AS (SD) .. 21.8 (8.70) 22.6 (10.10) 21.4 (8.50) EDSS, number of .. 209 (6.4-7.7)* 203 (6.4-7.7)* 212 (6.3-7.6)* patients (range) N/n 611 (97%) 207 (98%) 197 (96%) 207 (97%) final Assessment Efficacy: Included in our analysis: AS; Bladder symptoms Questionnaire; Pain CRS; Pain Questionnaire; and Spasticity Questionnaire. Excluded from our analysis: BI; Depression CRS; EDSS; Energy (amount of energy) CRS; GHQ-30; Irritability CRS; Muscle spasms CRS; RMI; Shake/tremor (tremor) CRS; Sleep quality CRS; Spasticity (Muscle stiffness) CRS; T10-MW; Tiredness CRS; Tremor Questionnaire; and UKNDS. Tolerability: Included in our analysis: Abdominal pain of unknown cause; active duodenal ulcer and helicobacter pylori; back pain; chest infection/urinary tract infection; collapse of unknown cause; collapse/bradycardia; constipation; death; deep-vein thrombosis; diarrhoea; dizzy or lightheadedness; dry mouth; fall at home; grand mal seizures; infection; minor cerebrovascular event; MS relapse or possible relapse; numbness or paraesthesia; pain; pneumonia; possible transient ischaemic attack/syncope; sleep; tremor or lack coordination; urinary tract infection; urinary tract infection/relapse; viral gastroenteritis; vision; and withdrawals due to adverse events. Excluded from our analysis: Bladder; blocked/insertion of suprapubic catheter‡; cellulitis of leg/diarrhoea and vomiting‡; chronic pleural effusion‡; depression or anxiety; disease progression (not relapse) ‡; dizziness (inappropriate SAE report); emergency hip replacement‡; gastrointestinal tract; improvements in symptoms; increased appetite; miscellaneous; pneumonia and renal stones‡; spasms or stiffness; urinary tract infection/diarrhoea and vomiting‡; and weakness or reduced mobility. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 26 27 Zajicek 2003 /Freeman 2006 (2 publications with same cohort of study) (continued) 27 26 Freeman 2006 (same as Zajicek 2003, unless specified) Design Patients recruited to Zajicek .. .. .. Clinical effect on 2003 (CAMS study), excepting incontinence episodes. of those with a permanent catheter. N/n (% with 522 (83%) 181 (86%) 174 (84%) 167 (78%) initial respect to Zajicek 2003 initial data) N/nfinal (% with 255 (40%) 88 (42%) 86 (42%) 81 (38%) respect to Zajicek 2003 initial data) Assessment Efficacy: Included in our analysis: UIEs Diary. Excluded from our analysis: King’s Health Questionnaire; Pad test (weight); Post-void residual; and Voiding cystometry. Tolerability: Included in our analysis: Urinary tract infections (included in Zajicek 2003 , but not specified as urinary tract infections), and worsening of detrusor-sphincter- dyssynergia (D-S-D) and urinary retention. Excluded from our analysis: None. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Svendsen 2004 Design MS patients with central .. Oral dronabinol caps.: Placebo caps. Clinical effect on neuropathic pain 2.5 mg THC/cap. central pain. Unicentric (Denmark) Dose = 2.5 mg-10 mg THC/day Dose = 2.5 mg-10 mg/day RCT, placebo-controlled (1-4 caps.) Double-blind Mean dose (range) = Mean dose (range) = Crossover 3.1 [2.7-3.6] caps./day 3.3 [2.8-3.6] caps./day 9 weeks (3-week/intervention, 3- (7.75 [6.75-9.00] mg THC) (8.25 [7.00-22.50] mg) week washout between treatment periods) ITT analysis N/ninitial 24 .. 24 24 Sex M 10 (42%) .. .. .. F 14 (58%) .. .. .. Subtype of MS RRMS 9 (38%) .. .. .. SPMS 9 (38%) .. .. .. PPMS 6 (25%) .. .. .. Median age 50 (23-55) .. .. .. (range) Median DD 7.0 (0.3-25.0) .. .. .. (range) Median EDSS 6.0 (2.5-6.5) .. .. .. (range) Median Pain 5.5 (3.0-8.0) .. .. .. intensity NRS (range) N/nfinal 24 .. 24 24 Assessment Efficacy: Included in our analysis: Pain-relief NRS Diary; Radiating pain NRS Diary; SF-36-Bodily pain subscale; and Spontaneous pain intensity NRS Diary. Excluded from our analysis: 50% Pain relief; EDSS; NNT (50% reduction in central pain), Use of scape medication Diary; Quantitative sensory testing; SF-36- General health, SF-36-Mental health, SF-36-Physical functioning, SF-36-Role emotional, SF-36-Role physical, SF-36-Social functioning, and SF-36-Vitality subscales; and Treatment preference. Tolerability: Included in our analysis: Abdominal pain; anorexia; balance difficulty; diplopia; distortion of wrist; dizziness or lightheadedness; euphoria; fatigue; feeling of drunkenness; fever; headache; migraine; mouth dryness; muscle weakness; myalgia; nausea; palpitations; speech disorders; upper airway infection; weight decrease; and withdrawals due to adverse events. Excluded from our analysis: Chills; hot flushes; hyperactivity; limb heaviness; multiple sclerosis aggravated (one patient admitted to the hospital); nervousness; sleep difficulty; tenderness in nose; and tiredness or drowsiness. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Vaney 2004 Design MS patients with spasticity Oral CE caps.: .. Placebo caps. Reduction of spasm Unicentric (Switzerland) (2.5 mg THC + 0.9 mg frequency and increase of RCT, placebo-controlled CBD)/cap. mobility. Double-blind Dose = 6-12 caps./day Dose = 6-12 caps./day Crossover (15-30 mg THC + 5.4-10.8 mg 4 weeks (2-week cannabinoids CBD) treatment, 1-week placebo, 3- Mean dose (SD) = Mean dose not specified day washout between/after (17.99 [7.63] mg THC + 6.48 interventions) [2.75] mg CBD)/day ITT/PP analyses (7.20 caps.)* N/ninitial 57 57 .. 57 Sex M 28 (49%) .. .. .. F 29 (51%) .. .. .. Subtype of MS RRMS 2 (4%) .. .. .. SPMS 26 (46%) .. .. .. PPMS 29 (51%) .. .. .. Mean age (SD) 54.9 (10.00) .. .. .. years Mean DD (SD) 17.0 (8.40) .. .. .. years Median EDSS 7.0 (6.00) .. .. .. (range) Mean AS (SD) 12.5 (6.20) .. .. .. N/n 50 (88%) 50 (88%) .. 50 (88%) final Assessment Efficacy: Included in our analysis: AS; and Micturition problems Questionnaire Diary. Excluded from our analysis: 9-HPT; DS of the WAIS-R; EDSS; Falling asleep fast Diary; FIM; PASAT; RMI; Spasm-frequency Diary; T10-MW; Tremor Questionnaire Diary; and Waking up again Diary. Tolerability: Included in our analysis: Blurred vision; constipation; dizziness; dry mouth; euphoria, "high"; headache; nausea, feeling sick; pain in extremities; palpitations; sleepiness; sleeplessness; tremor or shakes; and withdrawals due to adverse events. Excluded from our analysis: Cannabinoid toxicity Questionnaire Diary-Likert Scale, difficulty concentrating; fall; feeling aggressive; flu-like symptoms; and inadequate laughing. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Wade 2004 Design MS patients with spasticity, Oromucosal CE (nabiximols): .. Placebo spray Reduction of spasms, bladder problems, (2.7 mg THC + 2.5 mg spasticity. Registered in tremor, or pain (not CBD)/spray ClinicalTrials.gov musculoskeletal) (NCT01610700, Dose = 1-48 sprays/day Dose =1-48 sprays/day Multicentric (UK) study results (2.7-129.6 mg THC + 2.5-120 RCT, placebo-controlled posted) mg CBD Double-blind Self-titrated dose Self-titrated dose Parallel Mean dose (SD) = Mean dose (SD) = 6 weeks (6-week treatment) 12.37 (6.05) sprays/day 18.87 (6.17) sprays/day* PP analysis (33.40 mg THC + 30.93 mg CBD)* N/ninitial 160 80 .. 80 Sex M 61 (38%) 33 (41%) .. 28 (35%) F 99 (62%) 47 (59%) .. 52 (65%) Subtype of MS .. .. .. .. Mean age (SD) 50.7 (9.32) 51.0 (9.36) .. 50.4 (9.33) years Mean MAS (SD) .. 5.0 (3.70) .. 4.6 (4.40) N/n 154 (96%) 77 (96%) .. 77 (96%) final Assessment Efficacy: Included in our analysis: Bladder (Bladder Problems) VAS; Bladder Questionnaire (Bladder Control Test); Bladder VAS Diary; MAS; Pain VAS Diary; Pain VAS; Spasticity VAS Diary; and Spasticity VAS. Excluded from our analysis: 9-HPT; AMIPB; BDI-II; BI; Care-giver Strain Index Score; Feeling upon waking VAS; FSS; GHQ-28; GNDS (UKNDS); How much sleep (Sleep Amount) VAS; PSS (Composite Primary Impairment VAS); Quality of sleep (Sleep Quality) VAS; Reading Visual Acuity Test; RMI; Short Orientation-Memory-Concentration Test; Spasm Frequency VAS Diary; Spasm severity VAS Diary; Spasms (Muscle Spasm) VAS; Subject Global Opinion of Effect on Multiple Sclerosis; Summed Symptom Score; T10-MW (Ten-metre Mobility Score); Tremor ADL Scale; Tremor VAS Diary; and Tremor VAS. Tolerability: Included in our analysis: Appendicitis; application site discomfort; application site pain; application site reaction NOS; diarrhoea; disorientation; disturbance in attention; dizziness; dry mouth; euphoric mood; fatigue; feeling drunk; headache; hypoaesthesia; lower respiratory tract infection NOS; mouth ulceration; muscle spasms; muscle weakness NOS; nausea; oral discomfort; oral pain; pain in limb; respiratory distress; sepsis NOS; somnolence; upper respiratory tract infection NOS; urinary tract infection NOS; vertigo; and withdrawals due to adverse events. Excluded from our analysis: Arthritis NOS‡; cough; and Feeling of intoxication VAS Diary. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Rog 2005 Design MS patients with central Oromucosal CE (nabiximols): .. Placebo Reduction of central neuropathic pain (2.7 mg THC + 2.5 mg neuropathic pain and Registered in Unicentric(UK) CBD)/spray sleep disturbance. ClinicalTrials.gov RCT, placebo-controlled (NCT01604265, Dose = 1-48 sprays/day Dose =1-48 sprays/day Double-blind study results (2.7-129.6 mg THC + 2.5-120 Parallel posted) mg CBD) 5 weeks (1-week run in, 4-week Self-titrated dose Self-titrated dose treatment) Mean dose (SD) = Mean dose (SD) = ITT analysis 9.6 (6.1) sprays/day (week 4) 19.1 (12.9) sprays/day (week 4) (25.92 mg THC + 24.00 mg CBD) N/ninitial 66 34 .. 32 Sex M 14 (21%) 6 (18%) .. 8 (25%) F 52 (79%) 28 (82%) .. 24 (75%) Subtype of MS RRMS 23 (35%) .. .. .. SPMS 33 (50%) .. .. .. PPMS 9 (14%) .. .. .. Benign MS 1 (2%) .. .. .. Mean age (SD) 49.2 (8.32) 50.3 (6.70) .. 48.1 (9.73) years Mean DD (SD) 11.6 (7.70) 10.4 (7.30) .. 12.8 (8.10) years Mean EDSS (SD) 5.9 (1.30) 6.0 (1.10) .. 5.8 (1.50) Mean Pain NRS 6.5 (1.60) 6.5 (1.60) .. 6.4 (1.70) (SD) N/n 64 (97%) 32 (94%) .. 32 (100%) final Assessment Efficacy: Included in our analysis: NPS; Pain (central neuropathic pain) NRS; and Sleep disturbance (due to neuropathic pain) NRS. Excluded from our analysis: GNDS (UKNDS); HADS-Anxiety, and HADS-Depression items; MSFC; NNT (50% reduction in central pain); PASAT; Patient´s (Subject) GIC; SDMT; SPART; SRT; and WLG. Tolerability: Included in our analysis: Application site burning; back pain; breast pain; confusion; diarrhoea; diplopia; disorientation; dissociation; disturbance in attention; dizziness; dry mouth; dyspepsia; dyspnea; euphoria; falls; fatigue; feeling abnormal; feeling drunk; gamma-glutamyltransferase increased; glossodynia; hallucination; headache; hypoaesthesia; intoxication (agitation, tachycardia and hypertension)†; ligament sprain; logorrhea; migraine NOS; mouth ulceration; nasopharyngitis; nausea; oral pain; otitis media NOS; paraesthesia; paranoia; paranoid ideation; pharyngitis; rash NOS; sinusitis NOS; skin irritation; somnolence; urinary tract infection NOS; vomiting; weakness; white blood cell count increased; and withdrawals due to adverse events. Excluded from our analysis: Chest discomfort; crying; hoarseness; Intoxication Levels VAS; low mood; NNH; thirst; and throat irritation. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Collin 2007 Design MS patients with spasticity, failed Oromucosal CE (nabiximols): .. Placebo Reduction of to gain adequate relief using (2.7 mg THC + 2.5 mg spasticity. Registered in current therapy CBD)/spray ClinicalTrials.gov Multicentric (UK and Romania) (NCT00711646, Dose = 1-48 sprays/day Dose =1-48 sprays/day RCT, placebo-controlled study results (2.7-129.6 mg THC + 2.5-120 Double-blind posted) mg CBD) Parallel Self-titrated dose Self-titrated dose 6 weeks (6-week treatment) Mean dose (SD) = Mean dose (SD) = ITT/PP analyses 9.4 (6.4) sprays/day 14.7 (8.4) sprays/day (25.38 mg THC + 23.50 mg CBD) N/ninitial 189 124 .. 65 Sex M 75 (40%) 44 (35%) .. 31 (48%) F 114 (60%) 80 (65%), .. 34 (52%) Mean age (SD) 49.1 (9.90) 49.7 (10.20) .. 47.8 (9.50) years Mean DD (SD) 12.6 (SD not specified) 13.6 (8.60) .. 12.2 (7.70) years N/nfinal 174 (92%) 112 (90%) .. 62 (95%) Assessment Efficacy: Included in our analysis: AS; and Spasticity NRS Diary. Excluded from our analysis: MI (arms), and MI (legs) items; Patient´s GIC; Spasm-frequency NRS Diary; Spasticity NRS 30% responder analysis; and Spasticity NRS 50% responder analysis. Tolerability: Included in our analysis: Appendicitis; balance impaired; Bartholin’s abscess; confusion; constipation; depressed mood; diarrhoea; disorientation; disturbance in attention; dizziness; dry mouth; dysgeusia; euphoric mood; fatigue; headache; lower respiratory tract infection NOS; nausea; oral pain; pain in limb; pancreatic carcinoma NOS; pulmonary embolism; somnolence; urinary tract infection; urinary tract infection NOS; vision blurred; vomiting; weakness; and withdrawals due to adverse events. Excluded from our analysis: Mobility decreased‡; Intoxication NRS Diary; and urinary incontinence aggravated‡. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 33 34 Aragona 2009 /Tomassini 2014 (2 publications with same cohort of study) (continue) Aragona 2009 Design SPMS patients with spasticity Oromucosal CE (nabiximols): .. Placebo No psychopathology Unicentric (Italy) (2.7 mg THC + 2.5 mg induction and no RCT, placebo-controlled CBD)/spray cognition impairment. Double-blind Dose (specified in Tomassini Dose (specified in Tomassini Crossover 34 34 2014 ) 2014 ) 10 weeks (3-week/intervention, 2- Mean dose (SD) = Mean dose (SD) = week washout between/after 8.20 (3.15) sprays/day 15.16 (4.51) sprays/day treatment periods) (22.14 mg THC + 20.50 mg ITT/PP analyses CBD) N/n (% with 17 (94%) 17 .. 17 initial respect to Tomassini 2014 initial data) Sex M 6 (35%) .. .. .. F 11 (65%) .. .. .. Subtype of MS SPMS 17 .. .. .. Mean age (SD) 49.8 (6.64) .. .. .. years Mean DD (SD) 20.76 (8.42) .. .. .. years Mean EDSS (SD) 6.1 (0.30) .. .. .. N/nfinal (% with 17 (94%) 17 .. 17 respect to Tomassini 2014 initial data) Assessment Efficacy: Included in our analysis: None. Excluded from our analysis: 9-HPT; FSS; HR-QoL VAS (EQ-5D Health status VAS); MSIS-29 Physical, and MSIS-29 Psychological items; PASAT; SAS; SCL-90- R-Aggressive behaviour, SCL-90-R-Anxiety, SCL-90-R-Depression, SCL-90-R-Obsessive-compulsive features, SCL-90-R-Paranoiac tendencies, SCL-90-R- Phobic anxiety, SCL-90-R-Psychotic symptoms, SCL-90-R-Sensitivity, and SCL-90-R-Somatized anxiety dimensions; SCL-90-R-GSI item; and T25-FW. Plasma measurements. Tolerability: Included in our analysis: Craving†; depression; dizziness and vertigo; drowsiness and/or slower thinking; euphoria; fatigue; headache; intoxication (transient mental confusion with temporal and spatial disorientation, tachycardia, increased blood pressure, and mydriasis)†;lower limb weakness; mouth dryness or burning; nausea and vomiting; secondary depression; tremor; and withdrawals due to adverse events. Excluded from our analysis: None. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions 33 34 Aragona 2009 /Tomassini 2014 (2 publications with same cohort of study) (continued) 34 33 Tomassini 2014 (same as Aragona 2009, unless specified) Design .. Dose = 1-48 sprays/day .. Dose = 1-48 sprays/day No significant benefits (2.7-129.6 mg THC + 2.5-120 on spasticity. Registered in mg CBD) No change in fMRI ClinicalTrials.gov Self-titrated dose Self-titrated dose motor-evoked brain (NCT00202423, no activation. No study results Median dose (range) = Median dose (range) = 16.1 difference in posted) 7.4 (2.7-12.5) sprays/day (6.7-26) sprays/day intracortical and spinal (19.98 mg THC + 18.50 mg motor excitability. CBD) N/n 18 18 .. 18 initial Sex M 6 (33%) .. .. .. F 12 (67%) .. .. .. Subtype of MS SPMS 18 .. .. .. Median age 51 (37-59) .. .. .. (range) years Median DD 21.5 (5-35) .. .. .. (range) years Median EDSS 6.0 (6.0-6.5) .. .. .. (range) Median AS 12 (4-22) .. .. .. (range) Median Spasticity 7 (3-9) .. .. .. NRS (range) N/n 18 18 .. 18 final Assessment Efficacy: Included in our analysis: AS; and Spasticity NRS. Excluded from our analysis: AS (upper/lower extremities) 30% responders; and Spasticity NRS 30% responders. Neurophysiological assessment (fMRI, H-reflex, and TMS); and plasma measurements. Tolerability: None. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Collin 2010 Design MS patients with spasticity, not Oromucosal CE (nabiximols): .. Placebo No significant wholly relieved with current (2.7 mg THC + 2.5 mg improvement in Registered in therapy CBD)/spray spasticity NRS. ClinicalTrials.gov Multicentric (UK and Czech Dose = 1-24 sprays/day (NCT01599234, Dose = 1-24 sprays/day Republic) study results (2.7-64.8 mg THC + 2.5-60 mg RCT, placebo-controlled posted) CBD) Double-blind Self-titrated dose Self-titrated dose Parallel Mean dose (range) = Mean dose (range) = 15 weeks (1-week baseline, 14- 8.5 (1-22) sprays/day 15.4 (2-23) sprays/day week treatment) (22.95 mg THC + 21.25 mg ITT/PP analyses CBD) N/ninitial 337 167 .. 170 Sex M 130 (39 %) 61 (37%) .. 69 (41%) F 207 (61%) 106 (63%) .. 101 (59%) Mean age (SD) 47.5 (9.61) 48.0 (10.06) .. 47.1 (9.15) years Mean DD (SD) 15.2 (8.41) 14.4 (8.29) .. 16.0 (8.48) years Mean EDSS (SD) 6.0 (1.53) 6.0 (1.56) .. 6.0 (1.50) N/nfinal 305 (91%) 150 (90%) .. 155 (91%) Assessment Efficacy: Included in our analysis: Bladder symptoms NRS; MAS; Pain NRS; Sleep quality (due to spasticity) NRS; and Spasticity NRS Diary. Excluded from our analysis: BI; Caregiver´s GIC; EQ-5D Health state index, and EQ-5D Health status VAS items; Fatigue NRS; MSQoL-54-Mental health, and MSQoL-54-Physical health composites; Number of subjects with a 50% or greater improvement in mean Spasticity NRS; Spasm severity NRS; Spasticity NRS 30% responder analysis; Spasticity NRS Time to 30% response; T10-MW; and Tremor NRS. Tolerability: Included in our analysis: Anxiety; asthenia; back pain; burns third degree; confusional state; constipation; death; dehydration; depressed mood; depression; diarrhoea; disorientation; dissociation; disturbance in attention; dizziness; drug dependence; dry mouth; dysarthria; dysgeusia; dyspepsia; epilepsy; erysipelas; euphoric mood; fall; fatigue; feeling abnormal; foot fracture; gastrointestinal carcinoma with liver metastases; hallucination; headache; infections and infestations; insomnia; metastatic oesophageal carcinoma; MS relapse; muscle spasms; muscle spasticity; nausea; orchitis; paranoia; peripheral ischaemia; phlebothrombosis; sepsis; sleep attacks; somnolence; suicidal ideation; tetany; urinary tract infection; urinary retention; urinary tract infection NOS; vertigo; vomiting; withdrawal syndrome (aggression, agitation, delusions, irritability, insomnia and muscle spasms)†; and withdrawals due to adverse events. Excluded from our analysis: Apathy; decubitus ulcer‡; haemoptysis‡; malaise; road traffic accident‡; and worsened depression‡. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Kavia 2010 Design MS patients with overactive Oromucosal CE (nabiximols): .. Placebo Non-statistical bladder (OAB), failed to respond (2.7 mg THC + 2.5 mg significance reduction Registered in adequately to first-line therapies CBD)/spray in Number of episodes ClinicalTrials.gov Multicentric (UK, Belgium and of incontinence. Some Dose = 1-48 sprays/day (NCT00678795, Dose = 1-48 sprays/day Romania) significant positive study results (2.7-129.6 mg THC + 2.5-120 RCT, placebo-controlled effects on other posted) mg CBD) Double-blind bladder symptoms. Self-titrated dose Self-titrated dose Parallel Mean dose (median) = Mean dose (median) = 10 weeks (2-week baseline, 8- 8.91 (7.19) sprays/day 17.05 (14.22) sprays/day week treatment) (24.06 mg THC + 22.28 mg ITT/PP analyses CBD) N/ninitial 135 67 .. 68 Sex M 37 (27%) 15 (22%) .. 22 (32%) F 98 (73%) 52 (78%) .. 46 (68%) Mean age (SD) 47.7 (10.31) 48.6 (9.31) .. 46.8 (11.20) years Episodes of .. 1.8 (n = 63) .. 2.1 (n = 66) Incontinence/day (number of patients) Episodes of .. 1.6 (n = 63) .. 1.5 (n = 66) Nocturia/day (number of patients) N/n 118 (87%) 56 (84%) .. 62 (91%) final Assessment Efficacy: Included in our analysis: Bladder symptom severity (Overall Bladder Condition, OBC) NRS; Daily number of incontinence episodes Diary; Incontinence pad weight; Incontinence QoL Questionnaire; Nocturia episodes Diary (per day); Number Daytime voids Diary (per day); Number of incontinence pads used Diary (per day); and Void urgency episodes Diary (per day). Excluded from our analysis: Cystometric capacity (Voiding cystometry); Patient´s GIC; Post-void residual volume; Responder analysis of the frequency of urgency; Total number of voids Diary (per 24 h); and Volume voided (per 24h). Tolerability: Included in our analysis: Abdominal pain upper; anorexia; application site pain; balance impaired; chest pain; confusion; constipation; cystitis; dehydration; diarrhoea; disorientation; dissociation; disturbance in attention; dizziness; fatigue; feeling abnormal; feeling drunk; haemorrhagic cystitis; headache; influenza; intoxication (shaking, coordination problems and severe absence)†; memory impairment; MS relapse; nasopharyngitis; nausea; neck pain; paraesthesia; pharyngitis; pharyngitis viral NOS; pyrexia; somnolence; toothache; urinary tract infection; vertigo; vomiting; weakness; and withdrawals due to adverse events. Excluded from our analysis: Intoxication NRS; and sweating increased. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Novotna 2011 Design (enriched MS patients with spasticity, not Oromucosal CE (nabiximols): .. Placebo Significant reduction in study design) wholly relieved with current (2.7 mg THC + 2.5 mg spasticity. antispasticity medication, and at CBD)/spray Registered in least a 20% reduction in mean ClinicalTrials.gov Dose = 1-12 sprays/day Dose = 1-12 sprays/day Spasticity NRS score after 4 (NCT00681538, (2.7-32.4 mg THC + 2.5-30 mg weeks of the previous single-blind study results CBD) phase A treatment (responders) posted) Self-titrated dose Self-titrated dose Multicentric (UK, Spain, Poland, Mean dose (SD) = Mean dose (SD) = Czech Republic and Italy) 8.3 (2.43) sprays/day 8.9 (2.31) sprays/day RCT, placebo-controlled (22.41 mg THC + 20.75 mg Double-blind (phase B) CBD) Parallel 12 weeks (12-week treatment) ITT/PP analyses N/ninitial 241 124 .. 117 Sex M 96 (40%) 52 (42%) .. 44 (38%) F 145 (60%) 72 (58%) .. 73 (62%) Mean age (SD) 48.6 (9.33) 49.1 (9.09) .. 48.1 (9.59) years Mean DD (SD) 12.6 (7.88) 13.3 (8.29) .. 11.8 (7.38) years Mean EDSS (SD) 6.0 (1.45) 6.5 (1.46) .. 6.0 (1.44) Mean spasticity 3.9 (1.51) 3.9 (1.49) .. 3.9 (1.55) NRS (SD) N/nfinal 224 (93%) 109 (88%) .. 115 (98%) Assessment Efficacy: Included in our analysis: MAS; SF-36-Bodily pain subscale; Sleep Disruption (due to spasticity) NRS; and Spasticity NRS. Excluded from our analysis: BDI-II; BI; Carer GIC; Clinician GIC; EQ-5D Health state index; EQ-5D Health status VAS items; MI (arms), and MI (legs) items; Physician GIC; SF-36-General health, SF-36-Mental health, SF-36-Physical functioning, SF-36-Role emotional, SF-36-Role physical, SF-36-Social functioning, and SF-36-Vitality subscales; Spasm frequency NRS; Spasticity NRS 30% responders; Spasticity NRS 50% responders; Subject´s GIC; and T10-MW. Tolerability: Included in our analysis: Abdominal pain (upper); back pain; balance disorder; bronchopneumonia; diarrhoea; dizziness; dry mouth; euphoric mood; fatigue; headache; infections and infestations; MS relapse; muscle spasms; muscle spasticity; nasopharyngitis; nausea; pain in extremity; septic shock; somnolence; suicidal ideation; urinary tract infection; urosepsis; vertigo; and withdrawals due to adverse events. Excluded from our analysis: Pregnancy‡. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Zajicek 2012 Design MS patients with muscle stiffness Oral CE caps.: .. Placebo caps. Effect in the treatment Multicentric (UK) (2.5 mg THC + 1.25 mg of muscle stiffness. Registered in RCT, placebo-controlled CBD)/caps. ClinicalTrials.gov Double-blind (NCT00552604, no Dose = 2-10 caps./day Dose = 2-10 caps./day Parallel study results (5 mg-25 mg THC + 2.5 mg-12.5 (5 mg-25 mg/day) 14 weeks (2-week screening, 12- posted) mg CBD) week treatment) Self-titrated dose Self-titrated dose ITT analysis Mean dose (SD) = Mean dose (SD) = 7.81 (2.75) caps./day (end of 9.60 (1.27) caps./day (end of titration period) titration period) (19.52 mg THC + 9.76 mg (24.00 mg)* CBD)* Mean dose (SD) = Mean dose (SD) = 9.36 (1.51) caps./day (end of 6.81 (2.99) caps./day (end of study period) study period) (23.40 mg)* (17.02 mg THC + 8.51 mg CBD)* N/n 277 143 .. 134 initial Sex M 102 (37%) 55 (38%) .. 47 (35%) F 175 (63%) 88 (62%) .. 87 (65 %) Subtype of MS RRMS 21 (8%) 13 (9%) .. 8 (6%) SPMS 190 (69%) 96 (67%) .. 94 (70%) PPMS 66 (24%) 34 (24%) .. 32 (24%) Mean age (SD) .. 51.9 (7.70) .. 52.0 (7.90) years Mean DD (SD) .. 14.5 (9.50) .. 15.1 (8.40) years N/nfinal 224 (81%) 109 (76%) .. 115 (86%) Assessment Efficacy: Included in our analysis: Body pain CRS; and MSSS-88-Ability to walk, MSSS-88-ADL/Daily activities, MSSS-88-Body movement, MSSS-88-Feelings, MSSS-88- Muscle spasms, MSSS-88-Muscle stiffness, MSSS-88-Pain and discomfort, and MSSS-88-Social functioning subscales. Excluded from our analysis: EDSS; MSIS-29 Physical impact, and MSIS-29 Psychological impact items; MSWS-12; Muscle spasms CRS; Muscle stiffness CRS; and Sleep quality (Quality of sleep) CRS. Tolerability: Included in our analysis: Asthenia; dizziness; dry mouth; fatigue; headache; urinary tract infection; and withdrawals due to adverse events. Excluded from our analysis: Balance disorder; confusional state; diarrhoea; disorientation; disturbance in attention; fall; feeling abnormal; head injury; interstitial lung; nausea; pain in extremities; and somnolence. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Langford 2013 Design MS patients with central Oromucosal CE (nabiximols): .. Placebo No statistical neuropathic pain (2.7 mg THC + 2.5 mg significant reduction of Registered in Multicentric (UK, Czech Republic, CBD)/spray pain. ClinicalTrials.gov Canada, Spain and France) Dose = 8-12 sprays/day (NCT00391079, Dose = 8-12 sprays/day RCT, placebo-controlled study results (21.6-32.4 mg THC + 20-30 mg Double-blind (phase A) posted) CBD) Parallel Self-titrated dose Self-titrated dose 15 weeks (1-week baseline, 14- Mean dose (SD) = Mean dose (SD) = week treatment) 8.8 (3.87) sprays/day 11.1 (4.6) sprays/day ITT/PP analyses (23.76 mg THC + 22.00 mg CBD) N/ninitial 339 167 .. 172 Sex M 109 (32%) 54 (32 %) .. 55 (32 %) F 230 (68%) 113 (68 %) .. 117 (68 %) Subtype of MS RRMS 157 (46%) 80 (48%) .. 77 (45%) SPMS 136 (40%) 65 (39%) .. 71 (41%) PPMS 40 (12%) 18 (11%) .. 22 (13%) PRMS 6 (2%) 4 (2%) .. 2 (1%) Mean age (SD) 48.97 (10.47) 48.42 (10.43) .. 49.51 (10.50) years Mean DD (SD) 11.99 (8.26) 11.42 (8.00) .. 12.53 (8.50) years Mean Pain NRS 6.58 (1.32) 6.55 (1.35) .. 6.61 (1.29) (SD) N/n 297 (88%) 141 (84%) .. 156 (91%) final Assessment Efficacy: Included in our analysis: Bladder symptoms NRS; BPI-SF; NPS; Pain (due to MS) NRS; PDI; SF-36-Bodily pain subscale; Sleep quality (Sleep Disruption, due to pain) NRS; Spasticity NRS; and Subjec´s GIC for pain. Excluded from our analysis: Breakthrough analgesia; EQ-5D Health state index, and EQ-5D Health status VAS items; Fatigue NRS; Pain NRS 30% responder analysis; Pain NRS 50% responder analysis; SF-36-General health, SF-36-Mental health, SF-36-Physical functioning, SF-36-Role emotional, SF-36-Role physical, SF-36-Social functioning, and SF-36-Vitality subscales; Spasms severity NRS; and Tremor NRS. Tolerability: Included in our analysis: Balance disorder; constipation; depression; diarrhoea; disturbance in attention; dizziness; dry mouth; dysgeusia; fatigue; feeling abnormal; headache; hepatic enzyme increased; infections and infestations; memory impairment; muscular weakness; nausea; neuralgia; orthostatic hypotension; pain; pain in extremity; pharyngolaryngeal pain; somnolence; suicidal ideation; syncope; vertigo; vision blurred; vomiting; and withdrawals due to adverse events. Excluded from our analysis: Motor dysfunction‡; and psychomotor skills impaired. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Vachová 2014 Design MS patients with spasticity, not Oromucosal CE (nabiximols): .. Placebo No association with wholly relieved with current anti- (2.7 mg THC + 2.5 mg cognitive decline or Registered in spasticity therapy CBD)/spray significant changes in ClinicalTrials.gov Multicentric (Czech Republic) mood (long-term (NCT01964547, Dose = 1-12 sprays/day Dose = 1-12 sprays/day RCT, placebo-controlled treatment). No statistical study results (2.7-32.4 mg THC + 2.5-30 mg Double-blind significant difference in posted) CBD) Parallel spasticity. Self-titrated dose Self-titrated dose 50 weeks (48-week treatment, Mean dose (SD) = Mean dose (SD) = 2-week end of treatment follow- 7.6 (3.1) sprays/day (first 9.5 (2.4/2.6).sprays/day (from up period) month) first to last three months) ITT/PP analyses (20.52 mg THC + 19.00 mg CBD) 6.4 (3.1) sprays/day (last three months) (17.28 mg THC + 16.00 mg CBD) N/ninitial 121 62 .. 59 Sex M 45 (37%) 23 (37%) .. 22 (37%) F 76 (63%) 39 (63%) .. 37 (63%) Subtype of MS RRMS 59 (49%) 26 (42%) .. 33 (56%) SPMS 43 (36%) 24 (39%) .. 19 (32%) PPMS 16 (13%) 11 (18%) .. 5 (8%) PRMS 3 (2%) 1 (2%) .. 2 (3%) Mean age (SD) 48.6 (9.64) 49.0 (8.95) .. 48.2 (10.38) years Mean DD (SD) 13.9 (8.55) 13.9 (8.09) .. 13.9 (9.08) years Mean Spasticity 6.7 (1.86) 6.7 (2.04) .. 6.7 (1.67) NRS (SD) N/n 98 (81%) 50 (81%) .. 48 (81%) final Assessment Efficacy: Included in our analysis: MAS; and Subject´s GIC for spasticity. Excluded from our analysis: BDI-II; Caregiver´s GIC; C-SSRS; Number of visits to a healthcare professional; PASAT; Physician´s GIC; and T10-MW. Tolerability: Included in our analysis: Acute myocardial infarction; anxiety disorder due to a general medical condition; application site discomfort; asthenia; back pain; bacterial infection; blood alkaline phosphatase increased; bronchitis; cerebellar ataxia; death; decreased appetite; dermatitis allergic; diarrhoea; disorientation; dizziness; drug withdrawal syndrome; dry mouth; dysarthria; euphoric mood; fatigue; foot fracture; forearm fracture; gingivitis; headache; herpes zoster; joint dislocation; ligament sprain; lower limb fracture; memory impairment; MS relapse; muscle spasms; muscle spasticity; nausea; neuralgia; oral mucosal erythema; oropharyngeal blistering; overdose; pain in extremity; paraesthesia; paraparesis; pneumonia; pyrexia; somnolence; subcutaneous abscess; suicidal ideation; tetany; thermal burn; tonsillitis; tremor; trigeminal neuralgia; upper limb fracture; upper respiratory tract infection; upper respiratory tract infection bacterial; urinary tract infection; vertigo; viral infection; visual impairment; vitamin D decreased; vomiting; weight decreased; and withdrawals due to adverse events. Excluded from our analysis: Cognitive disorder; contusion; drug hypersensitivity; erectile dysfunction; face injury; inguinal hernia‡; lipoma excision; MS; procedural vomiting; radiculopathy; stupor; and tooth extraction. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Turcotte 2015 Design RRMS patients with neuropathic .. Oral nabilone caps.: Placebo caps. Nabilone as an pain, on a non-effective Available 0.5 or 1 mg THC/cap. adjunctive to Registered in treatment with gabapentin at a Dose = 1 (0.5 mg THC/caps.)- Dose = 1 (0.5 mg/caps.)- gabapentin is an ClinicalTrials.gov stabilized dose of 1800 mg/day 2 (1 mg THC/caps.) caps./day 2 (1 mg /caps.) caps./day effective, well- (NCT00480181, no for at least 1 month tolerated combination (0.5-2 mg THC) (0.5-2 mg) study results Unicentric (Canada) for MS-induced posted) Mean dose not specified Mean dose not specified RCT, placebo-controlled neuropathic pain. Double-blind Parallel 9 weeks (9-week treatment) ITT/PP analyses N/n 15 .. 8 7 initial Sex M 2 (13%) .. 1 (13%) 1 (14%) F 13 (87%) .. 7 (88%) 6 (86%) Subtype of MS RRMS 15 .. .. .. Mean age (SD) 45.5 (10.84) .. 42.12 (11.20) 50.0 (8.48) years Median DD (IQR) 6.5 (5-8.75) .. 5.5 (4.5-7.25) 8 (6.25-9) years Mean EDSS (SD) 2.82 (0.77) .. 2.56 (0.77) 3.17 (1.07) Mean Pain 77.00 (14.04) .. 79.00 (13.76) 74.33 (13.99) intensity (SD) Mean Pain impact 59.85 (23.47) .. 63.00 (19.23) 54.8 (30.86) (SD) N/n 14 (93%) .. 7 (88%) 7 (100%) final Assessment Efficacy: Included in our analysis: Impact of pain on daily activities VAS Diary (VAS ); Pain intensity VAS Diary (VAS ); Patient-rated GIC for neuropathic pain. impact pain Excluded from our analysis: EDSS; SF-36; and SF-MPQ. Tolerability: Included in our analysis: Withdrawals due to adverse events. Excluded from our analysis: Dizziness; drowsiness; dry mouth; and headache. (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Ball 2015 Design Progressive MS patients .. Oral THC caps. (dronabinol): Placebo caps. No effect in slowing Multicentric (UK) 3.5 mg THC progression of MS. RCT, placebo-controlled Dose = 2-8 caps./day Dose = 2-8 caps./day Double-blind (7-28 mg THC) Parallel Titrated against body weight Titrated against body weight 3 years (3-year treatment) and adverse effects and adverse effects ITT/PP analyses Median dose = 4 (25th–75th Median dose = 6 (25th–75th percentiles 2–6) caps./day (final percentiles 4–8) caps./day (final year of follow-up) year of follow-up) (14.00 mg THC) N/n 493 .. 329 164 initial Sex M 201 (41%) .. 133 (40%) 68 (41%) F 292 (59%) .. 196 (60%) 96 (59%) Subtype of MS SPMS 302 (61%) .. 203 (62%) 99 (60%) PPMS 191 (39%) .. 126 (38%) 65 (40%) Mean age (SD) 52.19 (7.80) .. 52.29 (7.60) 51.97 (8.20) years Mean EDSS (SD) 5.9 (0.69) .. 5.8 (0.69) 5.9 (0.67) N/nfinal 415 (84%) .. 267 (81%) 148 (90%) Assessment Efficacy: (3 years, unless specified) Included in our analysis: Bladder problems CRS; and MSSS-88-Ability to walk/Walking, MSSS-88-ADL/Daily activities, MSSS-88-Body movements, MSSS-88- Feelings, MSSS-88-Muscle spasms, MSSS-88-Muscle stiffness, MSSS-88-Pain and discomfort, and MSSS-88-Social functioning subscales. Excluded from our analysis: 9-HPT (annual change); BDI-II; Co-ordination CRS; Depression CRS; EDSS (number of first progression events per patient-year); EQ-5D five dimensions questionnaire; Fatigue CRS; Forgetfulness CRS; Irritability CRS; MSFC; MSIS-29 Physical and MSIS-29 Psychological items; MSWS- 12; PASAT (annual change); RMI (annual change); Sensory loss or numbness CRS; SF-36, SF-36 (PH) (annual change); T25-FW (annual change); and Tremor CRS. Neurophysiological measures (MRI). Tolerability: Included in our analysis: Death; dissociative and thinking or perception disorders; dizziness and lightheadedness; falls and injuries; fatigue and tiredness; infections (excluding urinary tract); joint disorders; mobility, balance, and coordination problems; mood disorders (depression); muscle disorders (weakness); musculoskeletal pain and aches; urinary tract infections; and withdrawals due to adverse events. Excluded from our analysis: Admission to hospital‡; constipation, diarrhoea, or faecal incontinence; life-threatening or important medical event‡; and muscle disorders (spasticity, stiffness, spasms, or tremor). (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 1: Characteristics of the included studies (continued) Interventions Study All participants THC/CBD (CE or nabiximols) THC (dronabinol or nabilone) Placebo Conclusions Leocani 2015 Design Progressive MS patients with Oromucosal CE (nabiximols): .. Placebo Clinical benefit in lower limb spasticity, stable drug (2.7 mg THC + 2.5 mg objective lower limb Registered in treatment not able to relieve CBD)/spray spasticity. Lack of ClinicalTrials.gov symptoms as a whole Dose = 1-12 sprays/day corresponding (NCT01538225, no Dose = 1-12 sprays/day Unicentric (Italy) changes in study results (2.7-32.4 mg THC + 2.5-30 mg RCT, placebo-controlled corticospinal posted) CBD) Double-blind Self-titrated dose excitability and on the Self-titrated dose Crossover monosynaptic Mean dose (SD) = Mean dose (SD) = 10 weeks (4-week/intervention, component of the 7 (3) sprays/day 10 (3) sprays/day 2-week washout between stretch reflex. (18.90 mg THC + 17.50 mg treatment periods) CBD) PP analysis N/ninitial 43 43 .. 43 Sex M 23 (53%) .. .. .. F 20 (47%) .. .. .. Subtype of MS Progressive MS 43 .. .. .. .. Mean age (SD) 48 (8.00) .. .. .. years Mean DD (SD) 17.1 (8.40) .. .. .. years Mean EDSS (SD) 5.5 (1.00) .. .. .. Mean MAS (SD), 8.1 (3.90) lower limbs Mean MAS (SD), 9.3 (5.20) .. .. .. total Mean Spasticity 7.0 (1.50) .. .. .. NRS (SD) N/nfinal 34 (79%) 34 (79%) .. 34 (79%) Assessment Efficacy: Included in our analysis: MAS (lower limbs, extreme outliner value retained); Pain NRS; and Spasticity NRS. Excluded from our analysis: 9-HPT (dominant hand), and 9-HPT (non-dominant hand); FSS; MAS (lower limbs, extreme outliner value removed); MAS (upper limbs); MAS 20% responders; Sleep quality NRS (PSQI); Spasm frequency; Spasticity NRS 20% responders; and T10-MW. Neurophysiological assessment (H-reflex, and TMS). Tolerability: Included in our analysis: Dizziness; faringodynia; fever; hypotension; lower limb weakness; somnolence; subjective weakness; vertigo; and withdrawals due to adverse events. Excluded from our analysis: Acute pancreatitis‡; and hypertension. © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 2: Summary of the selected clinical assessment tools †Items, or some of them, composing the tool were included individually in the statistical analysis. CRS = Category Rating Scale. GIC = Global Impression of Change. MS = multiple sclerosis. NRS = Numerical Rating Scale. QoL = quality of life. VAS = Visual Analog Scale. Publication where analyzed Clinical assessment tool Description Evaluated outcomes 25,26,29,32,34 Ashworth scale Scored by an observer. Measures passive resistance to movement Spasticity (Ashworth) during muscle stretching. Bladder (Bladder Problems) VAS Bladder problems. Bladder dysfunction Bladder problems CRS Bladder problems. Bladder dysfunction Bladder questionnaire (Bladder Control Test) Bladder symptoms and control, and effects on the patient’s life. Bladder dysfunction Bladder symptom severity (Overall Bladder Severity of urinary incontinence and general bladder symptoms. Bladder dysfunction Condition, OBC) NRS Bladder symptoms questionnaire Overall effect of medication in bladder function. Bladder dysfunction 35,39 Bladder symptoms NRS Bladder symptoms. Bladder dysfunction Bladder VAS Diary Severity of bladder symptoms. Bladder dysfunction Body pain CRS Pain. Pain Brief Pain Inventory-Short Form (BPI-SF) Rate pain and the degree to which pain interferes with activities. Pain Daily number of incontinence episodes Diary Incontinence episode frequency. Bladder dysfunction Impact of pain on daily activities VAS Diary Impact of pain on daily activities. Pain (VASimpact) Incontinence pad weight Weight of the incontinence pads used. Bladder dysfunction Incontinence QoL Questionnaire Impact of lower urinary tract symptoms on patient´s quality of life. Bladder dysfunction Micturition problems questionnaire Diary Micturition. Bladder dysfunction 30,35,37,40,43 Modified Ashworth scale Modified version of the Ashworth scale adding a 1+ grade for Spasticity (Ashworth) resistance throughout the reminder (less than half) of the range of movement. Multiple Sclerosis Spasticity Scale-88 (MSSS- Self-reported assessment of impact of spasticity in MS patients in 8 .. 88)† areas (ability to walk, activities of daily living, body movement, feelings, muscle spasms, muscle stiffness, pain and discomfort, and social functioning). 38,42 MSSS-88-Ability to walk/Walking subscale Effect of spasticity on walking mobility. Spasticity (subjective) MSSS-88-Activities of daily living/Daily activities Effect of spasticity on daily activities. Spasticity 38,42 subscale (subjective) 38,42 MSSS-88-Body movement subscale Effect of spasticity on body movements. Spasticity (subjective) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 2: Summary of the selected clinical assessment tools (continued) Publication where analyzed Clinical assessment tool Description Evaluated outcomes 38,42 MSSS-88-Feelings subscale Effect of spasticity on feelings. Spasticity (subjective) 38,42 MSSS-88-Muscle spasms subscale Muscle spasms due to spasticity. Spasticity (subjective) 38,42 MSSS-88-Muscle stiffness subscale Muscle stiffness due to spasticity. Spasticity (subjective) 38,42 MSSS-88-Pain and discomfort subscale Pain and discomfort due to spasticity. Pain Spasticity (subjective) 38,42 MSSS-88-Social functioning subscale Effect of spasticity on social functioning. Spasticity (subjective) 31,39 Neuropathic Pain Scale (NPS) Level of neuropathic pain. Pain Nocturia episodes Diary (per day) Instances of nocturia, and the time that each took place. Bladder dysfunction Number Daytime voids Diary (per day) Number of voids. Bladder dysfunction Number of incontinence pads used Diary (per Number of incontinence pads used. Bladder dysfunction day) Pain (central neuropathic pain) NRS Central neuropathic pain. Pain Pain (pain due to MS) NRS Level of pain due to MS. Pain Pain disability index (PDI) Degree to which aspects of patient´s life are disrupted by chronic Pain pain. Pain intensity VAS Diary (VASpain) Pain intensity. Pain Pain questionnaire Overall effect of medication in pain. Pain Pain CRS Pain. Pain 35,43 Pain NRS Pain. Pain Pain-relief NRS Diary Measurement of the level of relief in pain. Pain Pain VAS Pain. Pain (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 2: Summary of the selected clinical assessment tools (continued) Publication where analyzed Clinical assessment tool Description Evaluated outcomes Pain VAS Diary Severity of pain. Pain Patient-rated GIC for neuropathic pain Overall patient-perceived effect of treatment on their pain levels. Pain Radiating pain NRS Diary Pain. Pain Short Form-36 Health Survey/Short Form Self-rated health status questionnaire. Two summary scales (physical .. questionnaire-36 items (SF-36)† component summary and the mental component summary) are generated from 8 subscales (physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role-limitations due to emotional problems, and mental health). 28,37,39 SF-36-Bodily pain subscale Pain level and interference with normal work. Pain Sleep Disruption (due to spasticity) NRS Sleep disruption due to spasticity. Spasticity (subjective) Sleep disturbance (due to neuropathic pain) Sleep disruption due to neuropathic pain. Pain NRS Sleep quality (Sleep Disruption, due to pain) Sleep disruption due to pain. Pain NRS Sleep quality (due to spasticity) NRS Sleep disruption due to spasticity. Spasticity (subjective) Spasticity questionnaire Overall effect of medication in spasticity. Spasticity (subjective) 34,37,39,43 Spasticity NRS Spasticity. Spasticity (subjective) 32,35 Spasticity NRS Diary Spasticity. Spasticity (subjective) Spasticity VAS Spasticity. Spasticity (subjective) Spasticity VAS Diary Spasticity. Spasticity (subjective) Spontaneous pain intensity NRS Diary Pain. Pain Subject´s GIC (SGIC) for pain Status of pain due to multiple sclerosis since entry into the study. Pain Subject´s GIC (SGIC) for spasticity Change in spasticity since immediately before receiving the first dose Spasticity of study treatment. (subjective) Urge Incontinence Episodes Diary Number of incontinence episodes. Bladder dysfunction Void urgency episodes Diary (per day) Instances of urgency, and the time that each took place. Bladder dysfunction © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 3: Sensitivity analysis results for efficacy outcomes Results obtained performing meta-analysis using the inverse of variance method and the random effects model (except SA1, where fixed effects model was used) on an ITT basis. Sensitivity analysis was conducted using the same statistical methods than the main analysis, but modifying the parameter specified in each of the five performed analyses (SA1 to SA5): Main analysis 25–43 25–43 (all studies included ). SA1: Use of the fixed-effects model instead of random effects (all studies included ). SA2: Exclusion of studies with crossover design (5 studies, 6 publications, 25,28,29,33,34,43 25,28,33,34,41,43 excluded ). SA3: Exclusion of studies with a sample size of 50 patients or fewer (5 studies, 6 publications, excluded ). SA4: Exclusion of studies with a length of treatment 25,28,29,31,33,34,43 25–27,33,34,37,41–43 of 4 weeks or less (6 studies, 7 publications, excluded ). SA5: Exclusion of studies with a high risk of bias (7 studies, 9 publications, excluded ). Not estimable: Not available studies in the intervention group. Results with statistical significance shown in bold type. SA = Sensitivity analysis. SMD = Hedges´g standardized mean difference. SMD (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Spasticity Cannabis 0.01 (-0.18 to 0.01 (-0.18 to -0.05 (-0.29 to 0.05 (-0.22 to -0.05 (-0.29 to 0.23 (-0.14 to (Ashworth) extract 0.20) 0.20) 0.18) 0.31) 0.18) 0.60) Nabiximols -0.11 (-0.22 to -0.11 (-0.22 to -0.10 (-0.22 to -0.10 (-0.22 to -0.10 (-0.22 to -0.06 (-0.20 to 0.01) 0.01) 0.02) 0.02) 0.02) 0.08) Dronabinol -0.16 (-0.38 to -0.16 (-0.38 to -0.16 (-0.39 to -0.16 (-0.39 to -0.16 (-0.39 to Not estimable 0.07) 0.07) 0.07) 0.07) 0.07) Cannabinoids -0.09 -0.09 -0.10 -0.08 (-0.17 to -0.10 -0.03 (-0.17 to (-0.18 to 0.0027) (-0.18 to 0.0027) (-0.20 to -0.0035) 0.02) (-0.20 to -0.0035) 0.12) Spasticity Cannabis -0.27 -0.27 -0.27 -0.27 -0.27 -0.20 (-0.44 to (subjective) extract (-0.44 to -0.09) (-0.44 to -0.09) (-0.44 to -0.09) (-0.44 to -0.09) (-0.44 to -0.09) 0.04) Nabiximols -0.29 -0.26 -0.32 -0.32 -0.32 -0.27 (-0.47 to -0.12) (-0.36 to -0.15) (-0.53 to -0.11) (-0.53 to -0.11) (-0.53 to -0.11) (-0.49 to -0.06) Dronabinol -0.13 (-0.46 to -0.09 (-0.24 to -0.13 (-0.46 to -0.13 (-0.46 to -0.13 (-0.46 to Not estimable 0.20) 0.06) 0.20) 0.20) 0.20) Cannabinoids -0.25 -0.22 -0.26 -0.26 -0.26 -0.25 (-0.38 to -0.13) (-0.29 to -0.14) (-0.40 to -0.13) (-0.40 to -0.13) (-0.40 to -0.13) (-0.43 to -0.08) Pain Cannabis -0.33 -0.33 -0.33 -0.33 -0.33 -0.29 extract (-0.50 to -0.16) (-0.50 to -0.16) (-0.50 to -0.16) (-0.50 to -0.16) (-0.50 to -0.16) (-0.53 to -0.05) Nabiximols -0.07 (-0.26 to -0.07 (-0.18 to -0.12 (-0.29 to -0.12 (-0.29 to -0.07 (-0.19 to -0.09 (-0.29 to 0.12) 0.05) 0.05) 0.05) 0.05) 0.11) Dronabinol -0.23 (-0.55 to -0.15 -0.17 (-0.53 to -0.17 (-0.53 to -0.17 (-0.53 to -0.50 (-1.08 to 0.09) (-0.29 to -0.0041) 0.20) 0.20) 0.20) 0.08) Nabilone -1.40 -1.40 -1.40 Not estimable -1.40 Not estimable (-2.78 to -0.03) (-2.78 to -0.03) (-2.78 to -0.03) (-2.78 to -0.03) Cannabinoids -0.17 -0.15 -0.19 -0.18 -0.17 -0.17 (-0.34 to (-0.31 to -0.03) (-0.23 to -0.07) (-0.33 to -0.06) (-0.31 to -0.05) (-0.29 to -0.04) 0.01) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 3: Sensitivity analysis results for efficacy outcomes (continued) SMD (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Bladder Cannabis -0.29 -0.29 -0.27 -0.29 -0.27 -0.34 (-0.71 to dysfunction extract (-0.50 to -0.09) (-0.50 to -0.09) (-0.52 to -0.02) (-0.50 to -0.09) (-0.52 to -0.02) 0.03) Nabiximols -0.07 (-0.22 to -0.06 (-0.18 to -0.07 (-0.22 to -0.07 (-0.22 to -0.07 (-0.22 to -0.07 (-0.22 to 0.08) 0.07) 0.08) 0.08) 0.08) 0.08) Dronabinol -0.06 (-0.27 to -0.04 (-0.19 to -0.06 (-0.27 to -0.06 (-0.27 to -0.06 (-0.27 to Not estimable 0.16) 0.11) 0.16) 0.16) 0.16) Cannabinoids -0.11 -0.09 -0.09 (-0.20 to -0.11 -0.09 (-0.20 to -0.11 (-0.26 to (-0.22 to -0.0008) (-0.18 to -0.01) 0.02) (-0.22 to -0.0008) 0.02) 0.04) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 4: Sensitivity analysis results for tolerability outcomes Results obtained performing meta-analysis using the inverse of variance method and the random effects model (except SA1, where fixed effects model was used) on an ITT basis. Sensitivity analysis was conducted 25–43 using the same statistical methods than the main analysis, but modifying the parameter specified in each of the five performed analyses (SA1 to SA5): Main analysis (all studies included ). SA1: Use of fixed- 25–43 25,28,29,33,34,43 effects model instead of random effects (all studies included ). SA2: Exclusion of studies with crossover design (5 studies, 6 publications, excluded ). SA3: Exclusion of studies with a sample size of 25,28,33,34,41,43 25,28,29,31,33,34,43 50 patients or fewer (5 studies, 6 publications, excluded ). SA4: Exclusion of studies with a length of treatment of 4 weeks or less (6 studies, 7 publications, excluded ). SA5: Exclusion of 25–27,33,34,37,41–43 studies with a high risk of bias (7 studies, 9 publications, excluded ). Not estimable: Not available studies in the intervention group. Results with statistical significance shown in bold type. SA = Sensitivity analysis. RR = rate ratio. RR (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Total adverse Cannabis 1.51 (0.87 to 2.63) 1.74 (1.53 to 1.99) 2.09 (1.28 to 3.42) 1.41 (0.74 to 2.66) 2.09 (1.28 to 3.42) 1.24 (0.26 to 5.93) events extract Nabiximols 1.80 (1.53 to 2.12) 1.85 (1.68 to 2.03) 1.72 (1.48 to 2.01) 1.72 (1.48 to 2.01) 1.74 (1.47 to 2.06) 1.82 (1.60 to 2.09) Dronabinol 1.62 (1.12 to 2.34) 1.42 (1.29 to 1.56) 1.42 (1.07 to 1.88) 1.42 (1.07 to 1.88) 1.42 (1.07 to 1.88) 3.43 (2.16 to 5.46) Cannabinoids 1.72 (1.46 to 2.02) 1.65 (1.55 to 1.75) 1.70 (1.47 to 1.98) 1.61 (1.37 to 1.89) 1.72 (1.47 to 2.00) 1.80 (1.45 to 2.24) Serious adverse Cannabis 0.99 (0.26 to 3.74) 0.82 (0.40 to 1.70) 0.99 (0.26 to 3.74) 0.99 (0.26 to 3.74) 0.99 (0.26 to 3.74) 2.19 (0.57 to 8.46) events extract Nabiximols 1.43 (0.66 to 3.09) 1.60 (1.002 to 2.56) 1.38 (0.60 to 3.15) 1.38 (0.60 to 3.15) 1.38 (0.60 to 3.15) 1.18 (0.49 to 2.85) Dronabinol 1.21 (0.89 to 1.63) 1.21 (0.89 to 1.63) 1.20 (0.88 to 1.62) 1.20 (0.88 to 1.62) 1.20 (0.88 to 1.62) 3.00 (0.12 to 73.64) Cannabinoids 1.23 (0.82 to 1.85) 1.25 (0.98 to 1.58) 1.20 (0.78 to 1.84) 1.20 (0.78 to 1.84) 1.20 (0.78 to 1.84) 1.35 (0.67 to 2.71) Withdrawals due Cannabis 3.11 (1.54 to 6.28) 3.11 (1.54 to 6.28) 3.09 (1.50 to 6.36) 3.11 (1.54 to 6.28) 3.09 (1.50 to 6.36) 3.14 (1.53 to 6.48) to adverse extract events Nabiximols 2.20 (1.34 to 3.59) 2.20 (1.34 to 3.59) 2.13 (1.29 to 3.50) 2.13 (1.29 to 3.50) 2.11 (1.27 to 3.49) 1.99 (1.20 to 3.31) Dronabinol 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) 4.12 (2.39 to 7.11) Not estimable Nabilone 2.63 (0.11 to 64.44) 2.63 (0.11 to 64.44) 2.63 (0.11 to 64.44) Not estimable 2.63 (0.11 to 64.44) Not estimable Cannabinoids 2.95 (2.14 to 4.07) 2.95 (2.14 to 4.07) 2.91 (2.10 to 4.03) 2.92 (2.11 to 4.05) 2.91 (2.10 to 4.04) 2.32 (1.53 to 3.51) Dizziness or Cannabis 2.51 (0.84 to 7.47) 3.28 (2.39 to 4.49) 5.20 (2.23 to 2.62 (0.74 to 9.21) 5.20 (2.23 to 12.12) 2.17 (0.15 to vertigo extract 12.12) 31.20) Nabiximols 3.33 (2.55 to 4.34) 3.33 (2.55 to 4.34) 3.29 (2.50 to 4.33) 3.29 (2.50 to 4.33) 3.29 (2.47 to 4.37) 3.22 (2.45 to 4.25) Dronabinol 4.00 (2.43 to 6.58) 4.10 (3.00 to 5.62) 4.15 (2.97 to 5.80) 4.15 (2.97 to 5.80) 4.15 (2.97 to 5.80) 5.20 (2.00 to 13.54) Cannabinoids 3.40 (2.55 to 4.53) 3.52 (2.97 to 4.18) 3.83 (3.20 to 4.59) 3.42 (2.52 to 4.65) 3.86 (3.17 to 4.69) 3.22 (2.06 to 5.04) (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 4: Sensitivity analysis results for tolerability outcomes (continued) RR (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Dry mouth Cannabis 3.17 (1.91 to 5.25) 3.17 (1.91 to 5.25) 3.18 (1.89 to 5.35) 3.16 (1.89 to 5.28) 3.18 (1.89 to 5.35) 3.15 (1.58 to 6.25) extract Nabiximols 2.30 (1.42 to 3.73) 2.30 (1.42 to 3.73) 2.20 (1.34 to 3.59) 2.20 (1.34 to 3.59) 2.11 (1.28 to 3.48) 2.14 (1.28 to 3.60) Dronabinol 4.32 (2.12 to 8.81) 4.32 (2.12 to 8.81) 4.12 (1.93 to 8.79) 4.12 (1.93 to 8.79) 4.12 (1.93 to 8.79) 7.00 (0.36 to 135.53) Cannabinoids 2.94 (2.15 to 4.03) 2.94 (2.15 to 4.03) 2.84 (2.06 to 3.92) 2.84 (2.06 to 3.91) 2.80 (2.02 to 3.88) 2.49 (1.67 to 3.73) Fatigue Cannabis 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) 2.60 (1.22 to 5.58) extract Nabiximols 1.64 (1.17 to 2.28) 1.64 (1.17 to 2.28) 1.70 (1.12 to 2.56) 1.70 (1.12 to 2.56) 1.80 (1.13 to 2.86) 1.60 (1.08 to 2.37) Dronabinol 1.09 (0.74 to 1.60) 1.09 (0.74 to 1.60) 1.06 (0.72 to 1.56) 1.06 (0.72 to 1.56) 1.06 (0.72 to 1.56) 5.00 (0.24 to 104.14) Cannabinoids 1.61 (1.18 to 2.21) 1.46 (1.15 to 1.85) 1.61 (1.14 to 2.30) 1.61 (1.14 to 2.30) 1.67 (1.14 to 2.43) 1.76 (1.25 to 2.47) Feeling drunk Nabiximols 3.70 (0.70 to 19.55) 3.70 (0.70 to 19.55) 3.70 (0.70 to 19.55) 3.70 (0.70 to 8.01 (1.0001 to 3.70 (0.70 to 19.55) 64.14) 19.55) Dronabinol 11.00 (0.61 to 11.00 Not estimable Not estimable Not estimable 11.00 198.93) (0.61 to 198.93) (0.61 to 198.93) Cannabinoids 4.85 (1.15 to 20.53) 4.85 (1.15 to 20.53) 3.70 (0.70 to 19.55) 3.70 (0.70 to 8.01 (1.0001 to 4.85 (1.15 to 19.55) 64.14) 20.53) Impaired Cannabis 3.50 (0.18 to 67.77) 3.50 (0.18 to 67.77) Not estimable Not estimable Not estimable Not estimable balance or extract ataxia Nabiximols 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 2.93 (1.04 to 8.27) 3.81 (1.27 to 11.42) Dronabinol 1.28 (0.90 to 1.81) 1.28 (0.90 to 1.81) 1.25 (0.88 to 1.78) 1.25 (0.88 to 1.78) 1.25 (0.88 to 1.78) 5.00 (0.24 to 104.14) Cannabinoids 1.40 (1.01 to 1.95) 1.40 (1.01 to 1.95) 1.37 (0.98 to 1.91) 1.37 (0.98 to 1.91) 1.37 (0.98 to 1.91) 3.93 (1.40 to 11.04) Memory Nabiximols 4.93 (1.07 to 22.70) 4.93 (1.07 to 22.70) 4.93 (1.07 to 4.93 (1.07 to 4.93 (1.07 to 22.70) 4.93 (1.07 to impairment 22.70) 22.70) 22.70) Cannabinoids 4.93 (1.07 to 22.70) 4.93 (1.07 to 22.70) 4.93 (1.07 to 4.93 (1.07 to 4.93 (1.07 to 22.70) 4.93 (1.07 to 22.70) 22.70) 22.70) (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eTable 4: Sensitivity analysis results for tolerability outcomes (continued) RR (95% CI) Outcome Intervention Main analysis SA1 SA2 SA3 SA4 SA5 Somnolence Cannabis 1.32 (0.95 to 1.83) 1.32 (0.95 to 1.83) 1.32 (0.94 to 1.85) 1.32 (0.94 to 1.85) 1.32 (0.94 to 1.85) 1.50 (0.06 to extract 36.82) Nabiximols 3.47 (2.10 to 5.73) 3.47 (2.10 to 5.73) 3.50 (2.04 to 6.00) 3.50 (2.04 to 6.00) 3.42 (1.98 to 5.93) 3.48 (1.99 to 6.07) Dronabinol 0.55 (0.06 to 4.74) 1.08 (0.77 to 1.53) 1.12 (0.79 to 1.58) 1.12 (0.79 to 1.58) 1.12 (0.79 to 1.58) Not estimable Cannabinoids 1.87 (1.24 to 2.81) 1.46 (1.18 to 1.81) 1.92 (1.25 to 2.96) 1.88 (1.25 to 2.82) 1.88 (1.22 to 2.90) 3.39 (1.96 to 5.88) © 2018 Torres-Moreno MC et al. JAMA Network Open. 3. Supplementary eFigures eFigure 1: Risk of bias summary of the included studies Review authors' judgements about each risk of bias item for each included study. Low risk of bias Unclear risk of bias High risk of bias © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 2: Risk of bias graph of the included studies 25-43 Review authors' judgements about each risk of bias item presented as percentages across all included studies. © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 3: Funnel plots for efficacy outcomes Panels 3a) Spasticity (Ashworth), 3b) Spasticity (subjective), 3c) Pain, and 3d) Bladder dysfunction Panel 3a) Spasticity (Ashworth) Panel 3b) Spasticity (subjective) Panel 3c) Pain Panel 3d) Bladder dysfunction © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 4: Funnel plots for tolerability outcomes Panels 4a) Total adverse events, 4b) Serious adverse events, 4c) Withdrawals due to adverse events, 4d) Dizziness/vertigo, 4e) Dry mouth, 4f) Fatigue, 4g) Feeling drunk, 4h) Impaired balance/ataxia, 4i) Memory impairment, and 4j) Somnolence Panel 4a) Total adverse events Panel 4b) Serious adverse events Panel 4c) Withdrawals due to adverse Panel 4d) Dizziness or vertigo events Panel 4e) Dry mouth Panel 4f) Fatigue (continue) © 2018 Torres-Moreno MC et al. JAMA Network Open. eFigure 4: Funnel plots for tolerability outcomes (continued) Panels 4a) Total adverse events, 4b) Serious adverse events, 4c) Withdrawals due to adverse events, 4d) Dizziness/vertigo, 4e) Dry mouth, 4f) Fatigue, 4g) Feeling drunk, 4h) Impaired balance/ataxia, 4i) Memory impairment, and 4j) Somnolence Panel 4g) Feeling drunk Panel 4h) Impaired balance or ataxia Panel 4i) Memory impairment Panel 4j) Somnolence © 2018 Torres-Moreno MC et al. JAMA Network Open.

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JAMA Network Open – American Medical Association

Published: Oct 12, 2018

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Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis

Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis

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Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis

Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients With Multiple Sclerosis

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