Optimizing the Time and Dose of Melatonin as a Sleep‐Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose−Response Meta‐Analysis

Abstract

AbstractPrevious studies have reported inconsistent results about exogenous melatonin's sleep‐promoting 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‐analysis of double‐blind, randomized controlled trials performed on patients with insomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep‐related 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−response and meta‐regression models were estimated to explore how time of administration, dose, and other treatment‐related 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−response meta‐analysis showed that melatonin gradually reduces sleep onset latency and increases total sleep time, peaking at 4 mg/day. Meta‐regression models showed that insomnia status (β = 0.50, p < 0.001) and time between treatment administration and the sleep episode (β = −0.16, p = 0.023) were significant predictors of sleep onset latency, while the time of day (β = −0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timing of administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenous melatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenous melatonin in promoting sleep.