Author s : James E. Jan , Michael B.
Wasdell , Russel J. Reiter , Margaret D. Weiss , Kyle P. Johnson , Anna Ivanenko , Roger D. DOI : Chronic sleep difficulties commonly coexist with neurodevelopmental and psychiatric problems. Children with special needs may have a variety of sleep disturbances and of these circadian rhythm sleep disorders appear to be the most common. Melatonin supplementation for some circadian rhythm sleep disorders is often an effective treatment because it corrects the associated abnormal melatonin secretion. Melatonin has a benign safety profile and significant potential health benefits.
Melatonin has many functions including sleep promoting and chronobiotic properties. Based on the high quality and favorable results reported, the SMEs concluded that in a jet lagged population, further research may have an impact on the confidence in the estimate of the effect, and as such, provide a weak recommendation in favor of melatonin use for rebalancing the sleep-wake cycle in people with jet lag.
Despite the trend in small sample sizes and lack of effect size reporting, all four studies were high quality, showing positive effects and infrequent, non-serious adverse events; as a result, the SMEs give a weak recommendation in favor of melatonin when used to promote sleep in persons with insomnia, with the understanding that the introduction of more large, high quality studies may have an important impact on this recommendation, and potentially change the confidence in the estimate of the effect size. Fifteen [ 28 , 49 — 61 , 63 ] RCTs with a total of participants described melatonin use for promoting sleep in healthy volunteers.
Two [ 54 , 61 ]of the poor quality studies favored melatonin, whereas the third [ 60 ] favored neither melatonin nor control. The remaining four [ 50 , 55 , 59 , 63 ] high quality studies showed no beneficial effects for either melatonin or control groups. Results for each group are described below. All except one [ 54 ] of the seven studies investigating the effect of melatonin on initiation of sleep or sleep efficacy were scored high quality, and five [ 49 , 51 — 54 ] of them showed results in favor of melatonin.
Because only one [ 52 ] study in this group reported on adverse events, citing a problem with the rectal probe, safety is not well understood. Similarly, effect sizes were not reported. Despite the lack of safety and effect size reporting and small sample sizes, however, most of the studies were high quality, reporting favorable results for melatonin use.
Subsequently, the SMEs provide a weak recommendation in favor of melatonin use in a healthy population for promoting sleep. All five studies investigating daytime sleepiness or somnolence were high quality, and four [ 51 , 56 — 58 ] of the five small studies favored melatonin over the control. Because no information was reported on the frequency or severity of adverse events in any of these studies, safety is not well understood. Although this group of studies suffered from small sample sizes, methodological quality was high.
As a result, the SMEs provided a weak recommendation in favor of melatonin use to improve daytime sleepiness in healthy people. Two [ 60 , 61 ] of the five studies were low quality due to methodological flaws in reporting of randomization, concealment, and dropout rates.
The remaining three [ 59 , 62 , 63 ] studies were high quality; however, the sample sizes for all five studies were fairly low. Because neither adverse events nor effect sizes were reported in any of the studies, this information remains unknown. Given this lack of information, the SMEs could not provide any recommendation for the use of melatonin to improve hormonal phase shift changes in healthy people.
None of the studies in shift workers or jet lagged populations reported information on baseline diet exposures, but two [ 46 , 47 ] studies on insomnia and two [ 52 , 62 ]in healthy populations reported this information.
Melatonin in the Promotion of Health
Four [ 38 — 40 , 43 ] jet lag studies controlled for background diets during the study, compared to nine [ 49 , 51 , 53 , 57 — 59 , 61 — 63 ] studies in healthy volunteers, none in insomnia, and three [ 29 , 33 , 35 ] studies in shift workers. Several studies reported that they did not control for background diets: one jet lag [ 42 ]; one insomnia [ 46 ]; one shift worker [ 34 ], and two [ 52 , 55 ] healthy volunteer studies; the remaining did not report on this information. In four [ 29 , 40 , 53 , 57 ] studies, subjects abstained from caffeine and three [ 43 , 58 , 62 ] studies allowed, but limited caffeine use.
Melatonin supplement purity was analyzed in one [ 33 ] shift worker, two [ 38 , 40 ] jet lag, no insomnia, and three [ 50 , 53 , 60 ] healthy volunteer studies. Finally, analysis of proper absorption of melatonin was conducted in one [ 35 ] shift worker, one [ 37 ] jet lag, two [ 45 , 46 ] insomnia, and nine [ 45 , 49 , 52 , 53 , 55 , 58 — 60 , 63 ] healthy volunteer studies.
Although three of the 12 objective measures were of great interest, they were not relevant outcomes of interest in this review - melatonin measurements in saliva, blood, and urine. Thirteen studies [ 32 , 35 , 36 , 40 , 42 , 45 , 48 , 49 , 53 , 54 , 58 , 59 , 62 ] used a combination of both subjective and objective assessment tools to evaluate outcomes and The amount of melatonin provided, and frequency of administration reported in the included studies varied greatly. Oral preparations were used in amounts ranging from 0. Two [ 33 , 43 ] studies utilized fast-release preparations in amounts ranging from 3.
Six [ 35 , 45 , 46 , 49 , 62 , 63 ] studies utilized a sustained-release formulation in amounts ranging from 0. In fact, a number of meta-analyses have been published to evaluate the efficacy and safety of exogenous melatonin for subjects with primary sleep disorders [ 65 , 66 ], and include a range of population groups for the outcomes of sleep onset latency, total sleep duration and sleep efficiency [ 65 ] and for the prevention and treatment of jet lag [ 65 ]. The inclusion and exclusion criteria vary for each of these meta-analyses.
In contrast to earlier meta-analyses, the authors of this review investigated the use of melatonin in military and civilian populations across various sleep behaviors, and divided the included literature into four distinct user groups: shift workers, individuals experiencing jet lag, persons suffering from insomnia, and healthy individuals who want to improve their sleep; although the review focused on healthy populations, the authors chose to include insomnia populations as many military personnel who have been deployed may experience some form of insomnia [ 67 ].
Unfortunately, only two studies in this review were conducted in military populations: one study evaluated melatonin for jet lag in a US Air Force Reserve Unit [ 40 ] and the other assessed melatonin for sleep efficacy in the Canadian military [ 25 ]. Importantly, both were of high quality and utilized both subjective and objective measures.
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The authors encourage more research in this population, but suggest that the way the authors divided the literature into user groups can be useful for making generalizations for the military exposed to disruptions in sleep behavior. Besides the limited amount of studies available in the literature that were directly on military populations exposed to melatonin and were needed to make generalizations for this specific population, another limitation of this review is that, unlike traditional systematic reviews, the REAL process only includes RCT and systematic review study designs accessible in current English electronic databases.
Melatonin: A Sleep-Promoting Hormone | Sleep | Oxford Academic
Overall, results from this review suggest that melatonin shows promise to prevent phase shifts from jet lag and improve insomnia in otherwise healthy adults, but to a limited extent; the use of melatonin in shift workers is inconclusive. More high quality studies with large sample sizes and power are needed to increase the confidence in the estimate of the effect. Although no recommendation that melatonin can improve sleep outcomes in shift workers can be made at this time, the use of melatonin in healthy adults shows potential in preventing phase shifts due to jet lag.
Due to these limitations and the quality of the literature, our confidence in the estimate of the effect is moderate. A weak recommendation in favor of melatonin for use on sleep outcomes in jet lagged populations is noted. Although the purpose of the review was to look at healthy adults, the authors also explored whether melatonin could be a viable treatment option for insomnia because the consequences of insomnia are detrimental and associated with other comorbidities.
All four insomnia studies showed positive effects, despite small sample sizes; thus a weak recommendation with moderate confidence in favor of melatonin is made for individuals with insomnia for improving sleep outcomes. More studies with high quality, large sample sizes are needed to increase the confidence in the estimate of the effect. For the studies with exclusively healthy volunteers, a weak recommendation was made in favor of melatonin use for initiating sleep or sleep efficacy, again, despite sample sizes and low power.
A weak recommendation with moderate confidence was made in favor of melatonin use in healthy populations for daytime sleepiness or somnolence.
Clearly more research will be needed to strengthen this information. Whereas the majority Although most of the assessment tools aligned with good quality studies, their lack of robustness may have been a limiting factor in achieving significant effect sizes for the outcomes.
Finally, although the studies were reviewed by specific indications of use i. For example, the effects of melatonin may benefit military personnel given their training and deployment requirements, and prove to be a safe intervention to promote sleep — in both warfighters and family members with sleep issues; however, the lack of studies including military populations prevents the authors from making definitive conclusions regarding the usage of melatonin in these populations.
Three physiologic effects: 1 promotion of sleep onset; 2 maintenance of sleep; and 3 phase-shifting of circadia rhythms - an indirect action - and the diurnal rhythm in melatonin itself [ 70 ] have been associated with melatonin administration. Melatonin has a distinct daily secretion rhythm that is determined by the sleep-wake and light—dark cycles. Administration of melatonin has an opposite effect in that melatonin can reduce or completely block the phase shift alterations in circadian rhythms induced by bright light.
Very small oral amounts i. Because the clinical administration of melatonin i. As noted above, many different melatonin preparations were used throughout the included studies to include fast [ 33 , 42 ] and long [ 35 , 62 ] acting formulations, a melatonin patch [ 53 ] and a drink intervention [ 61 ]. These diverse preparations may have contributed to the effect size of the outcome measures. Melatonin can be absorbed transdermally, but time to peak blood levels is delayed. However, significant individual differences in peak melatonin levels after a standardized administration have been noted.
In the most recent meta-analysis [ 66 ], the meta-regression technique was used to discern that higher melatonin amounts and longer duration trials were related to significantly greater effect sizes on sleep latency and total sleep time in subjects with primary sleep disorders than lower amounts. Urinary metabolites and saliva measures have also been utilized in clinical studies.
The wide variety of methods reported in the literature for measuring melatonin in humans has increased the difficulty of comparing results across different studies; guidelines for the measurement and reporting of studies utilizing melatonin preparations have been recommended in order to advance the field [ 77 ].
Although no serious adverse events or health risks from melatonin use were noted in this review, potential detrimental health effects associated with using melatonin should be addressed. In healthy subjects, daytime administration of oral melatonin 0.