Oral Melatonin in Critically Ill Patients With COVID‐19: A Quasi‐Experimental Pragmatic Trial
et al., Journal of Medical Virology, doi:10.1002/jmv.70807, Jul 2025
Melatonin for COVID-19
12th treatment shown to reduce risk in
December 2020, now with p = 0.0000000099 from 19 studies.
No treatment is 100% effective. Protocols
combine treatments.
6,400+ studies for
210+ treatments. c19early.org
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Quasi-experimental study of 335 critically ill COVID-19 patients showing significantly lower 90-day mortality with high-dose oral melatonin (50-200mg daily). The study used alternating control and treatment periods, with 202 patients receiving melatonin plus standard care versus 133 receiving standard care alone. Mortality was reduced from 36.1% to 20.8% (OR 0.46 [0.28-0.76]), with lower organ dysfunction scores and fewer severe adverse events in the melatonin group. The quasi-experimental design introduces potential confounding, though authors attempted to control for temporal changes in treatment protocols and COVID variants.
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risk of death, 41.9% lower, RR 0.58, p = 0.002, treatment 42 of 202 (20.8%), control 48 of 133 (36.1%), NNT 6.5, adjusted per study, odds ratio converted to relative risk, day 90.
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risk of mechanical ventilation, 54.0% lower, OR 0.46, p = 0.002, treatment 202, control 133, adjusted per study, day 90, RR approximated with OR.
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ICU time, 31.2% lower, relative time 0.69, p = 0.002, treatment mean 11.0 (±68.9) n=202, control mean 16.0 (±76.5) n=133.
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hospitalization time, 21.4% lower, relative time 0.79, p = 0.007, treatment mean 22.0 (±77.0) n=202, control mean 28.0 (±63.3) n=133.
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| Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates |
Sánchez-García et al., 21 Jul 2025, prospective, Spain, peer-reviewed, 23 authors, study period 30 March, 2020 - 27 April, 2021.
Contact: miguel.sanchez@salud.madrid.org.
Oral Melatonin in Critically Ill Patients With COVID‐19: A Quasi‐Experimental Pragmatic Trial
Journal of Medical Virology, doi:10.1002/jmv.70807
Melatonin has demonstrated antioxidant, anti-inflammatory, and potential antiviral properties. Its therapeutic role in critically ill COVID-19 patients admitted to intensive care was underexplored at the start of the pandemic. We conducted a quasiexperimental, pragmatic study over 4 consecutive uninterrupted time periods alternating control groups receiving standard of care (SoC) with treatment groups receiving SoC plus high-dose oral bedtime melatonin (50-200 mg) (OBM). The primary endpoint was 90-day mortality; secondary outcomes included sequential organ failure assessment (SOFA) scores at 4, 7, 14, and 30 days and pre-defined severe adverse events (SAEs). A total of 335 of 339 consecutive patients with a predicted stay > 48 h were enrolled; 202 received OBM with SoC and 133 received SoC alone. OBM was dispensed during the second (n = 162) and fourth (n = 40) study periods after the first (n = 40) and third (n = 93) control group periods, respectively. Melatonin therapy was associated with significantly lower 90-day mortality (20.8% vs. 36.1%, OR 0.46, 95% CI 0.28-0.76). Subjects receiving melatonin had lower SOFA scores on Day 4 and subsequent study visits. SAEs occurred in 84 (41.6%) subjects on OBM and in 80 (60.2%) receiving SoC (risk ratio 0.68, 95% CI 0.54-0.87; p = 0.001). High-dose oral melatonin was safe and associated with improved clinical outcomes. Further evaluation of melatonin and its potential antiviral effects in future epidemics is warranted.
Author Contributions The structure of the electronic case report form and the study variables were generated and approved by all authors, who participated in the design of the database and reviewed the data. M.S.G. created the first draft of the manuscript. A.N.R. performed the statistical analyses. the Departments of Medicine, Pharmacy and Microbiology at Hospital Clínico San Carlos for their help and cooperation.
Ethics Statement The local Ethics Review Board approved the study (20/352-E_COVID) and granted a waiver for informed consent. (Supporting Information S1: Appendix 1).
Consent All authors had access to the database and reviewed and edited the final version of the manuscript and agreed to publish.
Conflicts of Interest The authors declare no conflicts of interest.
Supporting Information Additional supporting information can be found online in the Supporting Information section. Supplemental Material JMedVirol. Supplemental Figures JMedVirol. Supplemental Tables JMedVirol.
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Late treatment
is less effective
is less effective
