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Efficacy of treatments for MS is associated with risk of adverse effects, and effective and well-tolerated drugs remain a major unmet need. Cannabis (<jats:italic>Cannabis sativa<\/jats:italic>L., fam. Cannabaceae) and cannabinoids are popular among MS patients to treat spasticity and pain. Cannabinoids are endowed with remarkable immunomodulating properties, and in particular the non-psychotropic cannabinoid cannabidiol (CBD) is increasingly recognized as anti-inflammatory and immunosuppressive, nevertheless with excellent tolerability even at high doses. In this systematic review, we retrieved and critically evaluated available evidence regarding the immune and disease-modifying effects of CBD in experimental autoimmune encephalomyelitis (EAE) and in MS. Evidence in rodent models of EAE strongly supports CBD as effective, while clinical evidence is still limited and usually negative, due to paucity of studies and possibly to the use of suboptimal dosing regimens. Better characterization of targets acted upon by CBD in MS should be obtained in ex vivo<jats:italic>\/<\/jats:italic>in vitro studies in human immune cells, and higher doses should be tested in well-designed clinical trials with clinically relevant efficacy endpoints.<\/jats:p>","DOI":"10.1007\/s11481-021-09982-7","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T06:03:31Z","timestamp":1611554611000},"page":"251-269","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["Immunomodulatory Potential of Cannabidiol in Multiple Sclerosis: a Systematic Review"],"prefix":"10.1007","volume":"16","author":[{"given":"Alessia","family":"Furgiuele","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6978-7775","authenticated-orcid":false,"given":"Marco","family":"Cosentino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franca","family":"Marino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,25]]},"reference":[{"key":"9982_CR1","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.bbi.2019.07.028","volume":"82","author":"ZZ Al-Ghezi","year":"2019","unstructured":"Al-Ghezi ZZ, Busbee PB, Alghetaa H, Prakash S, Nagarkatti PS, Nagarkatti M (2019a) Combination of cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), mitigates experimental autoimmune encephalomyelitis (EAE) by altering the gut microbiome. 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