This review is focused on populations with primary sleep disorders and does not include a review of populations of people with sleep disorders secondary to other disorders (e.g., depression), jet-lag or shift-work disorder. The review is derived from a more comprehensive Evidence Report.35
To our knowledge, there are no other meta-analyses of RCTs of melatonin for primary sleep disorders. Despite its popularity, evidence suggests that melatonin may be of limited clinical use. Our primary analysis showed an average reduction in sleep onset latency of 11.7 minutes. This finding does not support the use of melatonin for the management of primary sleep disorders. However, in our secondary analysis of a subpopulation with delayed sleep phase syndrome, the average reduction in sleep onset latency increased to 38.8 minutes, which is both clinically and statistically significant. This result is based on only 2 studies involving less than 30 participants, necessitating further research to confirm the results.
Despite concerns about the quality of studies of complementary and alternative medicine (CAM) therapies,36,37
the 16 studies included in this review were of moderate to high quality. Moreover, in light of the potential relationship between study results and funding sources, it is somewhat reassuring that the majority of studies that reported funding source used public, rather than industry, funding.38,39
However, it should be noted that half of the studies reviewed did not report funding source.
The basic mechanism by which melatonin induces sleepiness in humans is unclear, although 3 main hypotheses have been proposed. The mechanism may involve a phase-shift of the endogenous circadian pacemaker, a reduction in core body temperature, and/or a direct action on somnogenic structures of the brain. Timing of melatonin administration has been shown to predict its effect on circadian rhythm, such that melatonin delays circadian rhythm following morning administration, and advances circadian rhythm following afternoon or evening administration.40
Our literature review indicated that melatonin reduced sleep onset latency to a greater extent in people with delayed sleep phase syndrome than in people with insomnia. This finding suggests that the effects of melatonin are mediated by a direct resetting of the endogenous circadian pacemaker rather than via a direct action on somnogenic structures of the brain, given that individuals with delayed sleep phase syndrome are distinguished from individuals with insomnia by the presence of a circadian abnormality.
It is noteworthy that the trials that examined the efficacy of melatonin in people with primary sleep disorders are of relatively short trial duration (4 weeks or less), as were the trials examining the safety of melatonin in this population (3 months or less). Therefore, the efficacy and safety of melatonin reported here may reflect only the short-term effects of melatonin on this population. It is necessary that trials of longer duration be conducted in order to determine the long-term effects of melatonin on this population.
There was considerable heterogeneity in study results, and many factors may have contributed to this finding. Like other natural health products, melatonin is subject to variation in product quality. Details of content and quality of melatonin formulations and verification of doses were not adequately described in the published reports. The formulations of melatonin varied from slow to fast release. A wide range of doses was used and the doses were administered for days to up to 4 weeks. The presence, distribution and severity of comorbid conditions in the study population may also contribute to heterogeneity. Although many of the studies reported inclusion/exclusion criteria designed to minimize comorbid conditions in the study population, details of comorbid conditions present in the population were often not clearly described. Heterogeneity may also be explained by the age of the population, duration of melatonin administration or primary diagnosis. Indeed, our analysis suggests that the diagnosis of insomnia versus delayed sleep phase syndrome explains much of the heterogeneity in study results.
Melatonin appears to be safe in the population, doses and timeframe studied. The most commonly reported adverse effects of melatonin were nausea, headache, dizziness, and drowsiness. One must be cautious when interpreting adverse event data—not only are adverse events under reported in clinical trials generally,41–43
there is reason to suspect that adverse reactions related to natural health products may be systematically under reported, when compared with conventional medications.44
Consumers may equate “natural” with “safe” and therefore not recognize or attribute an adverse reaction to a natural health product. The safety of exogenous melatonin when used in the long-term, over months and years, remains unclear.
A limitation of our review is the exclusion of nonEnglish language reports. There is evidence of “reverse” publication bias, in that negative CAM studies are overrepresented in English-language journals and positive CAM studies are overrepresented in nonEnglish language journals.45
We searched a number of electronic databases for nonEnglish language literature on melatonin and sleep disorders. Based on a screen of titles and abstracts resulting from the search, we did not identify any studies that were RCTs of the use of melatonin in people with primary sleep disorders. Thus, it is unlikely that we omitted potentially relevant nonEnglish language reports from the review.
Future studies on the effect of melatonin in the management of primary sleep disorders should clearly define the formulation and pharmacology of the melatonin product under investigation. It remains unclear how the efficacy of melatonin varies by age, dosage, timing, treatment duration, and primary diagnosis. Moreover, the long-term effects of melatonin on people with primary sleep disorders remains to be determined.
Our literature review indicates that there is no evidence that melatonin is effective in the management of most primary sleep disorders with short-term use; however, additional large-scale RCTs are needed before firm conclusions can be drawn. Although some evidence suggests that melatonin may reduce sleep onset latency for persons with delayed sleep phase syndrome, additional research is required to confirm these results. The evidence suggests that short-term use of melatonin is safe; more research is required to determine its long-term safety.