Abstract
Previous studies have reported inconsistent results about exogenous melatonin's sleep‐promoting effects. A possible explanation relieson the heterogeneity in administration schedule and dose, which might be accountable for differences in treatment efficacy. In thispaper, we undertook a systematic review and meta‐analysis of double‐blind, randomized controlled trials performed on patients withinsomnia and healthy volunteers, evaluating the effect of melatonin administration on sleep‐related parameters. The standardized meandifference 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‐relatedparameters 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 andincreases total sleep time, peaking at 4 mg/day. Meta‐regression models showed that insomnia status (β = 0.50, p < 0.001) and timebetween treatment administration and the sleep episode (β = −0.16, p = 0.023) were significant predictors of sleep onset latency, whilethe time of day (β = −0.086, p < 0.01) was the only significant predictor of total sleep time. Our results suggest that advancing the timingof administration (3 h before the desired bedtime) and increasing the administered dose (4 mg/day), as compared to the exogenousmelatonin schedule most used in clinical practice (2 mg 30 min before the desired bedtime), might optimize the efficacy of exogenousmelatonin in promoting sleep.