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Meta-Analysis
. 2025 Sep 1;53(9):e1714-e1724.
doi: 10.1097/CCM.0000000000006767. Epub 2025 Jul 15.

Melatonin Use in the ICU: A Systematic Review and Meta-Analysis

Brian Hao Yuan Tang  1 , Judith Manalo  2 , Saifur R Chowdhury  3 , J Matthew Aldrich  4 , Gerald L Weinhouse  5 , Makayla Cordoza  6   7   8 , Patricia R Louzon  9 , Michele C Balas  10 , Joanna L Stollings  6   11 , Molly McNett  12 , Karin Dearness  1 , Jose Estrada-Codecido  2 , Dipayan Chaudhuri  1   2   3 , Kallirroi Laiya Carayannopoulos  1   2   3 , Kimberley Lewis  1   2   3
Affiliations
Meta-Analysis

Melatonin Use in the ICU: A Systematic Review and Meta-Analysis

Brian Hao Yuan Tang et al. Crit Care Med. .

Abstract

Objectives: Melatonin has wide-ranging effects on the body, including the regulation of circadian rhythm, and potentiation of cellular immune and antioxidant activities. In critically ill patients, endogenous melatonin has been shown to be markedly deranged and reduced. Therefore, the purpose of this systematic review and meta-analysis was to determine if exogenous supplementation of melatonin improves patient-centered outcomes.

Data sources: We searched five electronic databases.

Study selection: Randomized clinical trials (RCTs) that compared melatonin to no melatonin in adults admitted to the ICU were identified.

Data extraction: We aggregated data as relative risks, mean differences (MDs), and standard mean differences (SMDs) using a random-effects model. Supporting evidence for each effect was evaluated for certainty using the Grading Recommendations, Assessment, Development, and Evaluations approach.

Data synthesis: In total, 32 RCTs ( n = 3895 patients) were included. We found that melatonin may reduce delirium (relative risk [RR] 0.72; 95% CI, 0.58-0.89; low certainty), may slightly reduce ICU length of stay (MD -0.57 d; 95% CI, -0.95 to -0.18 d; low certainty), and may improve reported sleep quality (SMD 0.54; 95% CI, 0.01-1.07; low certainty). Melatonin may result in a slight reduction in the frequency of adverse events (low certainty). Evidence was uncertain with regards to the frequency of sleep awakenings, anxiety level, agitation, and post-traumatic stress disorder incidence (all very low certainty), as well as to ICU mortality and post-ICU functional status (both low certainty).

Conclusions: Our findings suggest that melatonin administration in the critically ill may improve perceived sleep and reduce delirium, without increasing adverse effects. Certainty of evidence was negatively affected by the risk of bias and inconsistency. Future RCTs should focus on identifying optimal dosing, administration timing, improving measurements of sleep outcomes, and target populations.

Keywords: delirium; intensive care unit; melatonin; meta-analysis; ramelteon; sleep.

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Conflict of interest statement

Ms. Manalo’s and Dr. Lewis’ institution received funding from the Society of Critical Care Medicine (SCCM). Ms. Manalo and Dr. Balas received support for article research from the National Institutes of Health. Dr. Weinhouse received funding from SpringerNature. Drs. Louzon and Balas disclosed off-label use of Melatonin. Dr. Balas’ institution received funding from the National Heart, Lung and Blood Institute, the National Institute of Nursing Research, and the National Institute of Child Health and Human Development; she received funding from Ceribell and the American Association of Critical-Care Nurses; she disclosed she was Co-Chair of the SCCM Clinical Practice Guideline for the Prevention and Management of Pain, Anxiety, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption guideline update. Dr. McNett’s institution received funding from Dexcom. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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