{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:06:33Z","timestamp":1785391593928,"version":"3.55.0"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T00:00:00Z","timestamp":1721779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system. More than 90,000 Canadians are affected; a cure is yet to be found. Available treatments to manage the disease course are only partially effective. For many years, persons with MS (PwMS) have used cannabis to relax, to reduce pain and spasticity, or to improve sleep and daily functioning, despite the lack of scientific evidence on the efficacy of specific cannabinoids [i.e., tetrahydrocannabinol (THC) and cannabidiol (CBD)] on these MS symptoms. The purpose of this clinical trial is to assess the effectiveness of different doses of these cannabinoids, alone or combined, on spasticity relief, compared to placebo. Moreover, we aim to determine which treatment is best effective to address other key MS conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A double-blinded, randomized, factorial, placebo-controlled trial will be performed. We intend to include up to 250 PwMS aged over 21 recruited from the Centre hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al MS Clinic. PwMS will be randomly assigned on a 1:1:1:1 ratio to one of the trial arms: THC alone, CBD alone, THC\/CBD combination, or placebo, using stratified blocked randomization, with random blocks within each stratum. The primary outcome is a self-assessment of spasticity using the mean Numeric Rating Scale score over 7\u2009days. The main outcome will be the difference in this score at 4\u2009weeks compared to baseline. Secondary outcomes include assessments of spasticity as measured by a clinician, pain, fatigue, sleep, bowel, bladder, and sexual dysfunction, restless legs syndrome, mental health, quality of life, mobility, cognitive functioning, and adverse events. Treatment responders are eligible for a 12-week extension phase, using the same treatment allocation and assessments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Previous clinical studies examined the efficacy of cannabis-based medicines in PwMS, mostly using products with 1:1 THC\/CBD ratio. The major barrier to effectively use cannabis in real-world clinical settings is the lack of evidence on benefits of specific cannabinoids and information on possible related risks. The CANSEP study will contribute to overcome these limitations and identify the risks and benefits of cannabis-based treatments in PwMS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical trial registration<\/jats:title><jats:p><jats:ext-link>ClinicalTrials.Gov<\/jats:ext-link>, NCT05092191.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2024.1440678","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T04:45:47Z","timestamp":1721796347000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy of cannabinoids compared to the current standard treatments on symptom relief in persons with multiple sclerosis (CANSEP trial): study protocol for a randomized clinical trial"],"prefix":"10.3389","volume":"15","author":[{"given":"Amel","family":"Zertal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanza","family":"Alami Marrouni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Arbour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Jutras-Aswad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Pascale","family":"Pomey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Rouleau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Prat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Larochelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Beaulieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laury","family":"Chamelian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Pierre","family":"Sylvestre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Morin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Sylvain","family":"Ouellette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Fr\u00e9jeau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Duquette","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,24]]},"reference":[{"key":"ref1","year":"2020"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.jns.2012.10.021","article-title":"Environmental factors and their regulation of immunity in multiple sclerosis","volume":"324","author":"Koch","year":"2013","journal-title":"J Neurol Sci"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1191\/1352458504ms1085oa","article-title":"Prevalence and treatment of Spasticity reported by multiple sclerosis patients","volume":"10","author":"Rizzo","year":"2004","journal-title":"Mult Scler"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s11916-019-0800-2","article-title":"Advances in the understanding and Management of Chronic Pain in multiple sclerosis: a comprehensive review","volume":"23","author":"Urits","year":"2019","journal-title":"Curr Pain Headache Rep"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"146","DOI":"10.7224\/1537-2073.2012-053","article-title":"Natural history of multiple sclerosis symptoms","volume":"15","author":"Kister","year":"2013","journal-title":"Int J MS Care"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1038\/nrd3248","article-title":"Fingolimod (Fty 720): discovery and development of an Oral drug to treat multiple sclerosis","volume":"9","author":"Brinkmann","year":"2010","journal-title":"Nat Rev Drug Discov"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1016\/j.neuron.2018.01.021","article-title":"Multiple sclerosis: mechanisms and immunotherapy","volume":"97","author":"Baecher-Allan","year":"2018","journal-title":"Neuron"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.ncl.2017.08.015","article-title":"Advanced symptom Management in Multiple Sclerosis","volume":"36","author":"Crabtree-Hartman","year":"2018","journal-title":"Neurol Clin"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1007\/164_2019_315","article-title":"The use of botulinum toxin for treatment of Spasticity","volume":"263","author":"Li","year":"2021","journal-title":"Handb Exp Pharmacol"},{"key":"ref10","doi-asserted-by":"crossref","DOI":"10.51731\/cjht.2021.43","volume-title":"Onabotulinum toxin a (Botox) for Spasticity associated with multiple sclerosis","author":"Hui","year":"2021"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/b978-0-444-52001-2.00023-6","article-title":"Symptomatic treatment and Management of Multiple Sclerosis","volume":"122","author":"Toosy","year":"2014","journal-title":"Handb Clin Neurol"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.ctim.2017.07.002","article-title":"Cannabis use in people with Parkinson's disease and multiple sclerosis: a web-based investigation","volume":"33","author":"Kindred","year":"2017","journal-title":"Complement Ther Med"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.msard.2018.11.022","article-title":"Exploring Cannabis use by patients with multiple sclerosis in a state where Cannabis is legal","volume":"27","author":"Weinkle","year":"2019","journal-title":"Mult Scler Relat Disord"},{"key":"ref14","year":"2018"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"103638","DOI":"10.1016\/j.msard.2022.103638","article-title":"Medical Cannabis use in Canadians with multiple sclerosis","volume":"59","author":"Santarossa","year":"2022","journal-title":"Mult Scler Relat Disord"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.pneurobio.2017.10.007","article-title":"The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: clues for other Neuroinflammatory diseases","volume":"160","author":"Chiurchi\u00f9","year":"2018","journal-title":"Prog Neurobiol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1179573519831997","DOI":"10.1177\/1179573519831997","article-title":"Daily practice managing resistant multiple sclerosis Spasticity with Delta-9-tetrahydrocannabinol: Cannabidiol Oromucosal spray: a systematic review of observational studies","volume":"11","author":"Akg\u00fcn","year":"2019","journal-title":"J Cent Nerv Syst Dis"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"984","DOI":"10.1007\/s00415-012-6739-4","article-title":"A double-blind, randomized, placebo-controlled, parallel-group study of THC\/CBD Oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis","volume":"260","author":"Langford","year":"2013","journal-title":"J Neurol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"CD013444","DOI":"10.1002\/14651858.CD013444.pub2","article-title":"Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis","volume":"5","author":"Filippini","year":"2022","journal-title":"Cochrane Database Syst Rev"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.1212\/wnl.0000000000000250","article-title":"Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development Subcommittee of the American Academy of neurology","volume":"82","author":"Yadav","year":"2014","journal-title":"Neurology"},{"key":"ref21","year":"2021"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1016\/j.clinthera.2008.05.011","article-title":"Validity, reliability, and clinical importance of change in a 0-10 numeric rating scale measure of Spasticity: a post hoc analysis of a randomized, double-blind, placebo-controlled trial","volume":"30","author":"Farrar","year":"2008","journal-title":"Clin Ther"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/s1474-4422(17)30470-2","article-title":"Diagnosis of multiple sclerosis: 2017 revisions of the Mcdonald criteria","volume":"17","author":"Thompson","year":"2018","journal-title":"Lancet Neurol"},{"key":"ref24","year":"2018"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1016\/j.clinthera.2017.01.016","article-title":"Effects on Spasticity and neuropathic pain of an oral formulation of Delta 9-tetrahydrocannabinol in patients with progressive multiple sclerosis","volume":"40","author":"van Amerongen","year":"2018","journal-title":"Clin Ther"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1191\/1352458504ms1048oa","article-title":"Efficacy, safety and tolerability of an orally administered Cannabis extract in the treatment of Spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, Crossover Study","volume":"10","author":"Vaney","year":"2004","journal-title":"Mult Scler"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1136\/jnnp-2012-302468","article-title":"Multiple sclerosis and extract of Cannabis: results of the Musec trial","volume":"83","author":"Zajicek","year":"2012","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1159\/000481089","article-title":"Dronabinol is a safe long-term treatment option for neuropathic pain patients","volume":"78","author":"Schimrigk","year":"2017","journal-title":"Eur Neurol"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1136\/bmj.38149.566979.AE","article-title":"Does the cannabinoid Dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial","volume":"329","author":"Svendsen","year":"2004","journal-title":"BMJ"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/s1474-4422(13)70159-5","article-title":"Effect of Dronabinol on progression in progressive multiple sclerosis (Cupid): a randomised Placebo-Controlled Trial","volume":"12","author":"Zajicek","year":"2013","journal-title":"Lancet Neurol"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1111\/pme.12569","article-title":"Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial","volume":"16","author":"Turcotte","year":"2015","journal-title":"Pain Med"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1212\/01.wnl.0000118203.67138.3e","article-title":"The effect of Cannabis on tremor in patients with multiple sclerosis","volume":"62","author":"Fox","year":"2004","journal-title":"Neurology"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1111\/j.1468-1331.2010.03328.x","article-title":"A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of Nabiximols* (Sativex(\u00ae)), as add-on therapy, in subjects with refractory Spasticity caused by multiple sclerosis","volume":"18","author":"Novotna","year":"2011","journal-title":"Eur J Neurol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e0180651","DOI":"10.1371\/journal.pone.0180651","article-title":"Sativex in resistant multiple sclerosis Spasticity: discontinuation study in a large population of Italian patients (Sa.Fe. Study)","volume":"12","author":"Messina","year":"2017","journal-title":"PLoS One"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1111\/bcp.14038","article-title":"A systematic review of Cannabidiol dosing in clinical populations","volume":"85","author":"Millar","year":"2019","journal-title":"Br J Clin Pharmacol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1097\/ADM.0000000000000118","article-title":"Safety and pharmacokinetics of Oral Cannabidiol when administered concomitantly with intravenous fentanyl in humans","volume":"9","author":"Manini","year":"2015","journal-title":"J Addict Med"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.1111\/add.15417","article-title":"Cannabidiol as a treatment for craving and relapse in individuals with cocaine use disorder: a randomized placebo-controlled trial","volume":"116","author":"Mongeau-Perusse","year":"2021","journal-title":"Addiction"},{"key":"ref38","year":"2018"},{"key":"ref39","year":"2022"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1046\/j.1360-0443.1995.9056072.x","article-title":"The severity of dependence scale (Sds): psychometric properties of the Sds in English and Australian samples of heroin, Cocaine and Amphetamine Users Addiction","volume":"90","author":"Gossop","year":"1995","journal-title":"Addiction"},{"key":"ref41","volume-title":"The structured clinical interview for Dsm-5 disorders, research version (Scid-5-Rv)","author":"First","year":"2015"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1093\/ptj\/67.2.206","article-title":"Interrater reliability of a modified Ashworth scale of muscle Spasticity","volume":"67","author":"Bohannon","year":"1987","journal-title":"Phys Ther"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1212\/wnl.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s11910-019-0991-2","article-title":"Assessment and measurement of Spasticity in MS: state of the evidence","volume":"19","author":"Hugos","year":"2019","journal-title":"Curr Neurol Neurosci Rep"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1093\/schbul\/13.2.261","article-title":"The positive and negative syndrome scale (Panss) for schizophrenia","volume":"13","author":"Kay","year":"1987","journal-title":"Schizophr Bull"},{"key":"ref46","volume-title":"The consortium of multiple sclerosis centers health services research subcommittee. Msqli multiple sclerosis quality of life inventory: A User's manual","year":"1997"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1177\/135245859900500410","article-title":"Recent developments in the assessment of quality of life in multiple sclerosis (MS)","volume":"5","author":"Fischer","year":"1999","journal-title":"Mult Scler"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1080\/00926237908403731","article-title":"Assessing sexual behavior in couples","volume":"5","author":"Nowinski","year":"1979","journal-title":"J Sex Marital Ther"},{"key":"ref49","first-page":"99","article-title":"A survey of multiple sclerosis. Part I: perceived cognitive problems and compensatory strategy use. Can","volume":"4","author":"Sullivan","year":"1990","journal-title":"J Rehabil"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/0165-1781(89)90047-4","article-title":"The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research","volume":"28","author":"Buysse","year":"1989","journal-title":"Psychiatry Res"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1093\/sleep\/14.6.540","article-title":"A new method for measuring daytime sleepiness: the Epworth sleepiness scale","volume":"14","author":"Johns","year":"1991","journal-title":"Sleep"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/s1389-9457(02)00193-4","article-title":"Factor analysis of the international restless legs syndrome study Group's scale for restless legs severity","volume":"4","author":"Allen","year":"2003","journal-title":"Sleep Med"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/s1389-9457(02)00258-7","article-title":"Validation of the international restless legs syndrome study group rating scale for restless legs syndrome","volume":"4","author":"Walters","year":"2003","journal-title":"Sleep Med"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/1477-7525-1-29","article-title":"The hospital anxiety and depression scale","volume":"1","author":"Snaith","year":"2003","journal-title":"Health Qual Life Outcomes"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"1518","DOI":"10.1177\/1352458509347150","article-title":"Validation of the hospital anxiety and depression scale for use with multiple sclerosis patients","volume":"15","author":"Honarmand","year":"2009","journal-title":"Mult Scler"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1159\/000092678","article-title":"Cannabis-induced psychosis-like experiences are associated with high Schizotypy","volume":"39","author":"Barkus","year":"2006","journal-title":"Psychopathology"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.schres.2017.01.048","article-title":"Development and validation of the Cannabis experiences questionnaire-intoxication effects checklist (Ceq-I) short form","volume":"189","author":"Quinn","year":"2017","journal-title":"Schizophr Res"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1111\/j.1532-5415.2005.53221.x","article-title":"The Montreal cognitive assessment, Moca: a brief screening tool for mild cognitive impairment","volume":"53","author":"Nasreddine","year":"2005","journal-title":"J Am Geriatr Soc"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1037\/1040-3590.8.2.145","article-title":"Revision of the brief visuospatial memory test: studies of Normal performance, reliability, and validity","volume":"8","author":"Benedict","year":"1996","journal-title":"Psychol Assess"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1207\/s15324826an1304_9","article-title":"Test review: Dean C. Delis, Edith Kaplan & Joel H. Kramer, delis Kaplan executive function system (D-Kefs), the psychological corporation, San Antonio, Tx, 2001. $415.00 (complete kit)","volume":"13","author":"Shunk","year":"2006","journal-title":"Appl Neuropsychol"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1080\/13854049108403297","article-title":"The Hopkins verbal learning test: development of a new memory test with six equivalent forms","volume":"5","author":"Brandt","year":"1991","journal-title":"Clin Neuropsychol"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1037\/1040-3590.7.2.220","article-title":"Effect of physical layout in performance of the trail making test","volume":"7","author":"Arnett","year":"1995","journal-title":"Psychol Assess"},{"key":"ref63","volume-title":"Symbol digit modalities test [manual]","author":"Smith","year":"1973"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1002\/ana.410420318","article-title":"Recommendations from the National Multiple Sclerosis Society clinical outcomes assessment task force","volume":"42","author":"Rudick","year":"1997","journal-title":"Ann Neurol"},{"key":"ref65","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1177\/135245859900500409","article-title":"The multiple sclerosis functional composite measure (Msfc): an integrated approach to MS clinical outcome assessment. National MS Society clinical outcomes assessment task force","volume":"5","author":"Fischer","year":"1999","journal-title":"Mult Scler"},{"key":"ref66","author":"Fischer","year":"2001"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"109761","DOI":"10.1016\/j.jpsychores.2019.109761","article-title":"Emotional outcomes in clinically isolated syndrome and early phase multiple sclerosis: a systematic review and Meta-analysis","volume":"124","author":"Rintala","year":"2019","journal-title":"J Psychosom Res"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"100484","DOI":"10.1016\/j.bbih.2022.100484","article-title":"Prevalence of depression and anxiety in the different clinical forms of multiple sclerosis and associations with disability: a systematic review and Meta-analysis","volume":"24","author":"Peres","year":"2022","journal-title":"Brain Behav Immun Health"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1002\/(SICI)1097-0258(19960715)15:13<1421::AID-SIM266>3.0.CO;2-H","article-title":"An index for assessing blindness in a multi-Centre clinical trial: disulfiram for alcohol cessation--a Va cooperative study","volume":"15","author":"James","year":"1996","journal-title":"Stat Med"},{"key":"ref70","year":"2019"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1471-2288-3-26","article-title":"Design, analysis and presentation of factorial randomised controlled trials","volume":"3","author":"Montgomery","year":"2003","journal-title":"BMC Med Res Methodol"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1111\/j.1468-1331.2006.01639.x","article-title":"Randomized controlled trial of Cannabis-based medicine in Spasticity caused by multiple sclerosis","volume":"14","author":"Collin","year":"2007","journal-title":"Eur J Neurol"},{"key":"ref73","doi-asserted-by":"publisher","first-page":"e0219670","DOI":"10.1371\/journal.pone.0219670","article-title":"The influence of physiotherapy intervention on patients with multiple sclerosis-related Spasticity treated with Nabiximols (THC:CBD Oromucosal spray)","volume":"14","author":"Grimaldi","year":"2019","journal-title":"PLoS One"},{"key":"ref74","doi-asserted-by":"publisher","first-page":"4334","DOI":"10.1002\/sim.2682","article-title":"Change from baseline and analysis of covariance revisited","volume":"25","author":"Senn","year":"2006","journal-title":"Stat Med"},{"key":"ref75","first-page":"195","article-title":"Hormonal factors in susceptibility to multiple sclerosis","volume":"6","author":"Duquette","year":"1993","journal-title":"Curr Opin Neurol Neurosurg"},{"key":"ref76","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1017\/s0317167100014724","article-title":"Multiple sclerosis and pregnancy: a comparison study","volume":"40","author":"Alwan","year":"2013","journal-title":"Can J Neurol Sci"},{"key":"ref77","doi-asserted-by":"publisher","first-page":"797","DOI":"10.2217\/whe.10.69","article-title":"Gender issues in multiple sclerosis: an update","volume":"6","author":"Jobin","year":"2010","journal-title":"Womens Health"},{"key":"ref78","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1177\/0706743718804541","article-title":"Early risk factors for daily Cannabis use in young adults","volume":"64","author":"Dugas","year":"2019","journal-title":"Can J Psychiatr"},{"key":"ref79","volume-title":"Common Terminology Criteria for Adverse Events (Ctcae) Version 5.0: US Department of Health and Human Services","year":"2017"},{"key":"ref80","volume-title":"Evaluating the patient Partnership in Research","author":"Maybee","year":"2016"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1189\/jlb.0205111","article-title":"Reduced endocannabinoid immune modulation by a common cannabinoid 2 (Cb2) receptor gene polymorphism: possible risk for autoimmune disorders","volume":"78","author":"Sipe","year":"2005","journal-title":"J Leukoc Biol"},{"key":"ref82","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1007\/s11136-021-03003-z","article-title":"Perceived benefits and limitations of using patient-reported outcome measures in clinical practice with individual patients: a systematic review of qualitative studies","volume":"31","author":"Campbell","year":"2022","journal-title":"Qual Life Res"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"26","DOI":"10.51731\/cjht.2024.897","article-title":"Efficacy and safety of cannabinoids in treating Spasticity and other symptoms of multiple sclerosis: a double-blind, randomized, placebo-controlled trial protocol","volume":"4","author":"Alami Marrouni","year":"2024","journal-title":"Can J Health Technol"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1440678\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T04:45:55Z","timestamp":1721796355000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1440678\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,24]]},"references-count":83,"alternative-id":["10.3389\/fneur.2024.1440678"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2024.1440678","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,24]]},"article-number":"1440678"}}