{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:00:07Z","timestamp":1790312407096,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"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>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>Melatonin may act on immune, oxidative, and circadian pathways relevant to multiple sclerosis (MS), yet its clinical benefits and safety profile remain unclear. This systematic review assessed the efficacy and safety of oral melatonin supplementation in adults with MS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We searched MEDLINE (via PubMed), Scopus, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception through August 15, 2026, and included randomized and prospective non-randomized intervention studies. Two reviewers independently selected studies, extracted data, and assessed risk of bias using RoB 2 or ROBINS-I. Given substantial clinical and methodological heterogeneity, we synthesized findings without meta-analysis, following SWiM guidance, and rated certainty of evidence with GRADE. We registered the protocol in PROSPERO (CRD420251167112).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We included 10 independent studies, reported across 17 publications, covering 435 participants. Nine were randomized trials (two of them crossover designs), and one was a prospective non-randomized intervention study. Melatonin doses spanned 0.5\u2013300\u202fmg\/day, with treatment durations from 2 weeks to 14\u202fmonths. The evidence did not show reductions in relapse activity, disability progression, or new MRI activity. Small studies suggested possible improvements in sleep, fatigue, pain, physical function, cognition, mood, autonomic function, body composition, and inflammatory, metabolic, or oxidative-stress biomarkers, but these results were inconsistent and rarely replicated. Doses of 0.5\u201325\u202fmg\/day were generally well tolerated, though some participants discontinued treatment and adverse-event reporting remained incomplete. At 300\u202fmg\/day, three of four melatonin-treated participants developed hypertransaminasemia, which resolved after withdrawal and recurred on rechallenge in one case. Certainty of evidence was low or very low for every outcome assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Current evidence does not support a disease-modifying effect of melatonin in MS. Any symptomatic or biomarker benefits need confirmation in larger, well-designed trials, and high-dose melatonin may carry meaningful hepatic risk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1889519","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:27:44Z","timestamp":1790310464000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Melatonin supplementation in multiple sclerosis: a systematic review of clinical, imaging, biomarker, and safety outcomes"],"prefix":"10.3389","volume":"17","author":[{"given":"Yehia","family":"Nabil","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Zagazig University","place":["Zagazig, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Ghazou","sequence":"additional","affiliation":[{"name":"Internship, Princess Basma Hospital, Ministry of Health","place":["Irbid, Jordan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Abodabesh","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Mansoura University","place":["Mansoura, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anas","family":"Mansour","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Al-Azhar University","place":["Cairo, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Adel Mohamed","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Zagazig University","place":["Zagazig, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Allam","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Galala University","place":["Suez, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nourhan","family":"Eid","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Zagazig University","place":["Zagazig, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara Ibrahim","family":"Wahba","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Zagazig University","place":["Zagazig, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragda Mamoun MohamedAhmed","family":"Mamoun","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Zagazig University","place":["Zagazig, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Samy","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Zagazig University","place":["Zagazig, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerolos E.","family":"Hanna","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Misr University for Science and Technology (MUST)","place":["Giza, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Noufal","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Ahram Canadian University","place":["Giza, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enas Kamal Abdalaziz","family":"Seyed","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Al-Neelain University","place":["Khartoum, Sudan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa","family":"Meshref","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Al-Azhar University","place":["Cairo, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41583-024-00823-z","article-title":"The neuropathobiology of multiple 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