{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:25:58Z","timestamp":1791476758184,"version":"4.3.4"},"reference-count":72,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Previous studies have reported inconsistent results about exogenous melatonin's sleep\u2010promoting effects. A possible explanation relies on the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In this paper, we undertook a systematic review and meta\u2010analysis of double\u2010blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep\u2010related parameters. The standardized mean difference between treatment and placebo groups in terms of sleep onset latency and total sleep time were used as outcomes. Dose\u2212response and meta\u2010regression models were estimated to explore how time of administration, dose, and other treatment\u2010related parameters might affect exogenous melatonin's efficacy. We included 26 randomized controlled trials published between 1987 and 2020, for a total of 1689 observations. Dose\u2212response meta\u2010analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4\u2009mg\/day. Meta\u2010regression models showed that insomnia status (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u20090.50,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001)\u00a0and time between treatment administration and the sleep episode (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u2009\u22120.16,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.023) were significant predictors of sleep onset latency, while the time of day (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2009=\u2009\u22120.086,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3\u2009h before the desired bedtime) and increasing the administered dose (4\u2009mg\/day), as compared to the exogenous melatonin schedule most used in clinical practice (2\u2009mg 30\u2009min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep.\n                  <\/jats:p>","DOI":"10.1111\/jpi.12985","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T06:14:00Z","timestamp":1718691240000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Optimizing the Time and Dose of Melatonin as a Sleep\u2010Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose\u2212Response Meta\u2010Analysis"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5807-6399","authenticated-orcid":false,"given":"Francy","family":"Cruz\u2010Sanabria","sequence":"first","affiliation":[{"name":"Department of Developmental Neuroscience Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Stella Maris  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2523-1924","authenticated-orcid":false,"given":"Simone","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Translational Research and of New Surgical and Medical Technologies University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2254-2420","authenticated-orcid":false,"given":"Alessio","family":"Crippa","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4209-2586","authenticated-orcid":false,"given":"Paolo","family":"Frumento","sequence":"additional","affiliation":[{"name":"Department of Political Sciences University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5087-3182","authenticated-orcid":false,"given":"Marco","family":"Scarselli","sequence":"additional","affiliation":[{"name":"Department of Translational Research and of New Surgical and Medical Technologies University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8202-6180","authenticated-orcid":false,"given":"Debra J.","family":"Skene","sequence":"additional","affiliation":[{"name":"Chronobiology, Faculty of Health and Medical Sciences University of Surrey  Guildford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4814-7218","authenticated-orcid":false,"given":"Ugo","family":"Faraguna","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Stella Maris  Pisa Italy"},{"name":"Department of Translational Research and of New Surgical and Medical Technologies University of Pisa  Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.SLEH.2019.08.008"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6578-6_26"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1378\/CHEST.14-0970"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6578-6_28"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/SLEEP\/30.3.263"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.2010.300014"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.JSMC.2018.03.001"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)60750-2"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2012-000850"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/GPS.3818"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/J.1365-2710.2005.00674.X"},{"issue":"7","key":"e_1_2_9_13_1","first-page":"835","article-title":"Educating Physicians to Reduce Benzodiazepine Use by Elderly Patients: A Randomized Controlled Trial","volume":"168","author":"Pimlott N. 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