Effect of melatonin versus placebo for the prevention of delirium among medically hospitalised older patients: a double-blinded randomised controlled trial (project RESTORE).
Al Alawi A, Al Busaidi S, et al. • BMJ open • 2026
Melatonin did not significantly reduce the incidence of delirium among medically hospitalised older patients compared to placebo, and the trial was terminated early due to futility.
Key Findings
Results
The overall incidence of delirium by day 5 was very low and did not differ significantly between melatonin and placebo groups.
Overall delirium incidence was 2.75% across all participants
Delirium incidence was 3.64% in the melatonin group versus 1.85% in the placebo group (p=1.000)
Delirium was assessed using the 3-Minute Diagnostic Confusion Assessment Method (3D-CAM)
Assessment was conducted within 5 days of hospitalisation
Both intention-to-treat (ITT) and per-protocol (PP) analyses yielded similar findings
Results
The trial was terminated early due to futility before reaching its planned sample size.
115 participants were recruited at termination, with 109 included in ITT analyses
55 participants were in the melatonin group (5 mg or 8 mg) and 54 in the placebo group
Early termination was driven by lower-than-expected numbers of outcome events
The study's reduced sample size limited its statistical power
The authors note findings 'should be interpreted with caution'
Results
No statistically significant difference in average sleep duration was found between melatonin and placebo groups.
Sleep duration comparison yielded p=0.136
Sleep was assessed as average sleep duration or sleep maintained during hospitalisation
Participants received melatonin (5 mg or 8 mg) or placebo nightly for up to 5 days
Results
28-day mortality did not differ significantly between the melatonin and placebo groups.
28-day mortality was 3.64% in the melatonin group versus 1.85% in the placebo group (p=1.000)
This was a pre-specified secondary outcome
Analyses followed the intention-to-treat principle
Results
28-day hospital readmission rates were similar between the melatonin and placebo groups.
Readmission rate was 21.82% in the melatonin group versus 20.37% in the placebo group (p=0.853)
28-day readmission was a pre-specified secondary outcome
No statistically significant difference was observed
Methods
The study was a single-centre, double-blinded, randomised, placebo-controlled trial conducted in general medical wards of a tertiary hospital in Oman.
Patients aged ≥65 years admitted within 24 hours to general medical wards were screened
Key exclusion criteria included prevalent delirium, vasopressor use, non-invasive ventilation, ICU or high-dependency unit admission, and aphasia
Participants received 5 mg or 8 mg of melatonin or placebo nightly for up to 5 days or until discharge, whichever came first
Analyses followed the intention-to-treat (ITT) principle with per-protocol (PP) analyses for robustness
The trial was registered under NCT06509191
What This Means
This research tested whether melatonin — a hormone the body naturally produces to regulate sleep — could prevent delirium (sudden confusion and disorientation) in hospitalized patients aged 65 and older. Patients admitted to general medical wards in a hospital in Oman were randomly assigned to receive either 5 mg or 8 mg of melatonin or a placebo pill each night for up to 5 days. The study found that melatonin did not reduce the rate of delirium compared to placebo, and there were also no meaningful differences in sleep duration, deaths within 28 days, or hospital readmissions within 28 days between the two groups.
The trial was stopped early because it became clear that not enough patients were developing delirium for the study to detect any meaningful difference between the groups — a situation called 'futility.' Only 109 patients were included in the final analysis instead of the originally planned number, which means the study may not have been large enough to detect a small but real benefit if one exists. The very low rate of delirium observed (under 4%) across both groups was lower than expected.
This research suggests that melatonin, at the doses and duration tested here, does not appear to prevent delirium in older hospitalized patients, but the early stopping of the trial means these results should be interpreted cautiously. The authors call for further, larger studies before any firm recommendations about melatonin use for delirium prevention can be made.
Al Alawi A, Al Busaidi S, Al Rasbi S, Al Farsi R, Al Zeedy K, Al Huraizi A, et al.. (2026). Effect of melatonin versus placebo for the prevention of delirium among medically hospitalised older patients: a double-blinded randomised controlled trial (project RESTORE).. BMJ open. https://doi.org/10.1136/bmjopen-2025-107775