Effects of exogenous melatonin on sleep: a meta-analysis

Abstract

Exogenous melatonin reportedly induces drowsiness and sleep, and may ameliorate sleep disturbances, including the nocturnal awakenings associated with old age. However, existing studies on the soporific efficacy of melatonin have been highly heterogeneous in regard to inclusion and exclusion criteria, measures to evaluate insomnia, doses of the medication, and routes of administration. We reviewed and analyzed (by meta-analysis) available information on effects of exogenous melatonin on sleep. A MEDLINE search (1980 to December 2003) provided English-language articles, supplemented by personal files maintained by the authors. The analysis used information derived from 17 different studies (involving 284 subjects) that satisfied inclusion criteria. Sleep onset latency, total sleep duration, and sleep efficiency were selected as the outcome measures. The study effect size was taken to be the difference between the response on placebo and the mean response on melatonin for each outcome measured. Melatonin treatment significantly reduced sleep onset latency by 4.0 min (95% CI 2.5, 5.4); increased sleep efficiency by 2.2% (95% CI 0.2, 4.2), and increased total sleep duration by 12.8 min (95% CI 2.9, 22.8). Since 15 of the 17 studies enrolled healthy subjects or people with no relevant medical condition other than insomnia, the analysis was also done including only these 15 studies. The sleep onset results were changed to 3.9 min (95% CI (2.5, 5.4)); sleep efficiency increased to 3.1% (95% CI (0.7, 5.5)); sleep duration increased to 13.7 min (95% CI (3.1, 24.3)).

Introduction

The extensive reporting about melatonin in lay publications has encouraged very many people to consume this hormone, sometimes on a daily basis, often with the goal of improving sleep quality.¹ In humans, the circadian rhythm of melatonin release from the pineal gland is highly synchronized with the habitual hours of sleep, and the daily onset of melatonin secretion is well correlated with the onset of the steepest increase in nocturnal sleepiness (‘sleep gate’).² Serum melatonin levels were reported to be significantly lower (and the time of peak melatonin values was delayed) in elderly subjects with insomnia, compared with age-matched subjects with no insomnia.³

There are also a number of reports that physiological doses of melatonin (i.e. doses which elevate plasma melatonin within its normal nocturnal range), or pharmacologic doses, induce drowsiness and sleep, and may ameliorate sleep disturbances.4., 5. Unfortunately, the studies described in existing publications on melatonin's efficacy have utilized different inclusion and exclusion criteria, different outcome measures to evaluate insomnia, different doses of the hormone, and different routes and timing of its administration. Adding to this complexity, there continues to be considerable controversy over the meaning of the discrepancies that sometimes exist between subjective and objective (polysomnographic) measures of good and bad sleep.⁶ In an attempt to respond to these problems we have therefore integrated information derived from 17 studies*3., 7., 8., 9., 10., *11., 12., *13., 14., *15., 16., *17., *18., 19., *20., *21., 22. which fulfill the criteria described below, using meta-analysis. To our knowledge, while several reviews have examined the effects of melatonin on sleep and insomnia, none has provided a quantitative meta-analysis of these effects, as presented below.