Beneficial Effects of Melatonin Essay
Beneficial Effects of Melatonin Essay
An attempt to make the world a better place begins with being informed on a particular issue.
The issue about smoking is seriously considering it does not only affect those consuming the product but also the people around them who inhale the smoke. The people around a smoker and who inhale the smoke can be referred to as second-hand smoke, passive smoke, or involuntary smoke. Involuntary smoking involves two processes. The first is called the sidestream smoke that is the smoke produced by a burning cigarette, and the other is known as mainstream smoke that is the smoke exhaled by the smoker. The increased portion of smokers around the world has led to a significant increase in the chance of an individual being exposed to the dangerous chemical contained in the smoke. One can be exposed to cars, homes, elevators, and recreational places such as bars and restaurants. The amount of harmful tobacco smoke produced by a burning cigarette depends on the amount of pure tobacco content available in the cigarette. Beneficial Effects of Melatonin Essay.
It is crucial to measure the rate of exposure to the harmful contents of cigarette smoke. One of the methods that can be used is in determining the concentration of nicotine in the indoor air. Relating the amount of nicotine in the air can estimate the exposure as the composition of other chemicals can be estimated. The other method that can be used is by measuring the level of cotinine in an individual suspected to be exposed to tobacco smoke. Cotinine is a byproduct of the breakdown of nicotine while it gets into the body. It can be obtained by measuring its content in urine, blood or saliva.
The majority of individuals around the world tend to think that second-hand smoke is minute to be harmful to an individual. Contrary to the thoughts, second-hand smoke can cause harmful effects to an individual almost the same rate as a smoker.
A systematic review was conducted using Samueli Institute’s Rapid Evidence Assessment of the Literature (REAL©) process to determine the evidence base for melatonin as an agent to optimize sleep or improve sleep quality, and generalize the results to a military, civilian, or other healthy, active, adult population. Multiple databases were searched yielding 35 randomized controlled trials (RCTs) meeting the review’s inclusion criteria, which were assessed for methodological quality as well as for melatonin effectiveness. The majority of included studies were high quality (83.0%). Overall, according to Grading Recommendations, Assessment Development and Evaluation (GRADE) methodology, weak recommendations were made for preventing phase shifts from jet lag, for improving insomnia in both healthy volunteers and individuals with a history of insomnia, and for initiating sleep and/or improving sleep efficacy. Beneficial Effects of Melatonin Essay. Based on the literature to date, no recommendations for use in shift workers or to improve hormonal phase shift changes in healthy people can be made at this time. Larger and longer-duration RCTs utilizing well characterized products are needed to warrant melatonin recommendations in young, healthy adults.
Sleep quality is a problem in the civilian population, where 17.4% of respondents to the 2002 Alternative Health/Complementary and Alternative Medicine supplement to the National Health Interview Survey (NHIS) reported insomnia or trouble sleeping in the past 12 months [1]. Likewise, sleep quality is a concern within the military. Data are just beginning to be published regarding sleep habits and behaviors in the military. A cross-sectional study of 156 deployed US Air Force Airmen found that 40.0% of respondents suffered from at least one sleep disturbance and 75.0% reported diminished sleep quality while deployed, as compared to sleep quality at home [2]. A 2010 paper on the Millennium Cohort – 41,225 active duty and retired Service Members – demonstrated that deployment significantly compromised sleep quality and quantity [3]. Finally, in 2013, Lentino et al. [4] noted that over 25% of 14,148 Army Active, Reserve, and National Guard members reported to be “poor” sleepers, with only 32.9% self-reporting as “good” sleepers. Clearly, obtaining adequate and good quality sleep are continual challenges for active duty Service Members during training and during periods of deployment. Although sleep promoting medications, such as zolpidem, are available and widely used by military personnel for both sleep problems and fatigue management [5], they have been associated with various adverse effects, including cognitive impairments [6, 7] and in some cases “somnambulism-like state with sleep-related complex behavior.” Thus, more natural solutions to the military “sleep problem” must be sought. Beneficial Effects of Melatonin Essay. The dietary supplement, melatonin, may be one natural solution.
Exogenous melatonin, as both prescription and over the counter pills/tablets, has become one of the most frequently requested non-prescription sleep aids due to its regulator role in the internal timing of biological rhythms, including promotion/regulation of sleep [8]. Melatonin is marketed to help promote total sleep time, aid with fatigue from jet lag, or balance circadian rhythms from jet lag and rotating shift work. Evidence suggests melatonin may reduce the time it takes for people with delayed sleep phase syndrome (i.e., sleep is delayed by two or more hours beyond the conventional bedtime, causing difficulty in waking at a desired time) to fall asleep [9]; melatonin may also help re-set the body’s sleep-wake cycle [10]. Importantly, melatonin has been shown to serve as a mediator between the thermoregulatory and arousal system in humans, such that exogenous administration of melatonin during the day can result in sleepiness in association with reduced core temperature [11, 12].
Of interest, approximately 5.2% of the NHIS survey respondents reported using melatonin and 27.5% of those users reported insomnia as a reason for taking the supplement [1]. Some studies have shown that supplemental melatonin can increase sleep propensity, although it may not be as effective as prescription sleep medications [13]. If melatonin were found to be effective for promoting healthy sleep, it could be a useful and suitable sleep aid for military as well as other populations, where sleep problems are a serious concern.
Although a small number of systematic reviews have investigated melatonin’s effects on specific clinical conditions, to date no systematic reviews have explored melatonin across all aspects of sleep behavior in an otherwise healthy population. Thus, the purpose of this systematic review was to: 1) determine the evidence base for melatonin to optimize sleep (e.g., improve sleep quality, duration, ability to fall asleep); 2) evaluate the safety of melatonin use; 3) assess outcomes and dosing structure most applicable for this research; and 4) generalize results to those (e.g., at risk military populations) who suffer from issues related to sleep disturbances and sleep hygiene [14–21]. This review also discusses strengths, weaknesses, and gaps emerging from the review, as well as recommendations for moving this research field forward, in particular with regard to the usefulness of melatonin for military populations in need of sleep regulation as well as other populations with similar sleep issues. Beneficial Effects of Melatonin Essay.
Methods
A systematic review was conducted using the Rapid Evidence Assessment of the Literature (REAL©) process, a methodology developed by Samueli Institute to provide a “snapshot” of the peer-reviewed literature in a streamlined and efficient fashion. The REAL process differs from traditional systematic reviews in that it does not “exhaustively” search the literature by including grey and non-English language literature, but instead includes only randomized controlled trial (RCT) and systematic review study designs accessible in current English electronic databases. Following REAL methodology, a research question was developed with subject matter experts (SMEs) by using the evidence-based Population, Intervention, Comparison, Outcome (PICO) framework [22] to assess the effectiveness of melatonin on mitigating poor sleep and/or promoting healthy sleep as published and reported in RCTs.
Data sources and search strategy
PubMed/MEDLINE, CINAHL, Embase, PsycInfo, and Agricola databases were searched from database inception until October 2012 for RCTs investigating the relationship between melatonin and healthy sleep behaviors. Authors explored MeSH terminology within MEDLINE and consulted with three subject matter experts (PAD, CVL, RBC) to not only strategize the most powerful search, but to also ensure the correct key terms were being targeted for the research question proposed. The following search strategy was conducted in PubMed, and MeSH was applied where applicable: “(melatonin) and (sleep or fatigue or sleep disorders, circadian rhythm or insomnia).Beneficial Effects of Melatonin Essay. ” Following traditional REAL methodology, which includes the assessment of RCTs involving humans and published in the English language, all searches were conducted using these parameters. Where this was not a limit option in certain databases, citations were screened for these criteria.
Study selection
Articles were included if they met the following criteria: 1) RCT presented in the English language and involving adult human subjects; 2) healthy non-military or military populations, or populations diagnosed with insomnia, as reported by the study’s authors; 3) use of melatonin as the sole intervention; and 4) at least one sleep outcome of interest (e.g., sleep quality, sleep latency, sleep duration).
Articles were excluded if they met at least one of the following criteria: 1) any study design other than a RCT; 2) population with pre-existing conditions or diseases other than insomnia; 3) focus of article was on an intervention other than melatonin; 4) intervention was a combination of melatonin and other supplements or drugs; or 5) article did not have at least one sleep outcome of interest.
Data extraction
In order to streamline the systematic review process in a secure manner and ensure reliability and consistency across reviewer ratings, the authors conducted the review within the web-based systematic review management program Mobius Analytics SRS (Copyright 2003–2009 Mobius Analytics Inc, Ottawa, Ontario). This program reduces errors and post-review data collation, and increases reviewer efficiency by automating article progression and management. Beneficial Effects of Melatonin Essay.
Articles meeting the inclusion criteria were assessed for methodological quality using the Scottish Intercollegiate Guidelines Network (SIGN 50) checklist, a reliable and valid assessment tool widely used in the literature [23] (Table 1). Three trained reviewers (MLO, MLS, CCB) reviewed articles in pairs until a sufficient kappa (>90%) was achieved, at which point they independently reviewed the remaining articles. All work was cross-checked by the review manager (CCC), and disagreements were resolved either through discussion and consensus, or by one of the SMEs.
Table 1
Sign 50 checklist for RCT study design [23]
| Section 1: Internal validity 1 | |
| Item | Criteria |
| 1.1 | The study addresses an appropriate and clearly focused question. |
| 1.2 | The assignment of subjects to treatment groups is randomized. |
| 1.3 | An adequate concealment method is used. |
| 1.4 | Subjects and investigators are kept blind about treatment allocation. |
| 1.5 | The treatment and control groups are similar at the start of the trial. |
| 1.6 | The only difference between groups is the treatment under investigation. |
| 1.7 | All relevant outcomes are measured in a standard, valid and reliable way. |
| 1.8 | What percentage of subjects in each treatment arm dropped out before the study was completed? |
| 1.9 | All subjects are analyzed in the groups to which they were randomly allocated (intention-treat analysis). |
| 1.10 | Where the study is carried out at more than one site, results are comparable for all sites. |
| Section 2. Overall Assessment | |
| Quality Score | Criteria |
| ++ | All or most of the criteria have been fulfilled adequately or well. Where they have not been fulfilled the conclusions of the study are thought very unlikely to alter. An article receives this score if there are 0 criteria scored as poorly addressed. Beneficial Effects of Melatonin Essay. |
| + | Some of the criteria have been fulfilled adequately or well. Those criteria that have not been fulfilled or not adequately described are thought unlikely to alter the conclusions. An article receives this score if 1-3 criteria are scored as poorly addressed. |
| – | Few or no criteria fulfilled adequately or well (3 or more poorly addressed criteria). The conclusions of the study are thought likely or very likely to alter. An article receives this score if more than 3 criteria are scored as poorly addressed. |
1Each item is evaluated as well covered, adequately addressed or poorly addressed. Item 1.10 can also be marked as not applicable.
The following descriptive data were extracted for each of the included studies: population description, sample size, melatonin and control interventions and dosages, all sleep related outcomes and statistics, funding source, author’s main conclusions and whether power calculations, adverse events, and cost analyses were reported. Additional study design elements deemed important for quality control of dietary supplement studies were also extracted from each study, including characterization of the intervention product, baseline exposure or background diet (e.g. use of dietary supplements) of the study participants, and whether or not dietary intake was controlled during the study. Beneficial Effects of Melatonin Essay. Additionally, data regarding melatonin supplement formulation and whether or not it was analyzed for purity and absorption after ingestion were gathered.
Data synthesis and analysis
Once the quality assessment of individual RCT study reports was completed, the SMEs performed a quality assessment of the overall literature pool for each identified population by using a modification of the Grading of Recommendation Assessment, Development and Evaluation (GRADE) [24], an internationally accepted approach to grading the quality of evidence and strength of recommendations across studies. SMEs were trained in this methodology and utilized a grading rulebook developed, tested and agreed upon by the entire team. SMEs examined the outcomes of the individual RCTs for each category of intended use (i.e., shift workers, jet lag, insomnia, healthy volunteers) in order to: 1) examine the confidence in the estimate of the effect; 2) determine the magnitude of the effect size overall; 3) assign a safety grade to the literature; and 4) develop recommendations for the melatonin literature based on the REAL results for the overall literature pool of studies for each category. SMEs performed the GRADE analysis independently before discussing their answers together and coming to consensus with the full team. Due to the heterogeneity of included individual studies, outcome data were not pooled for statistical analysis.
Results
The results of the initial database search yielded 557 references, 39 of which met the inclusion criteria and were subsequently included in the review. Articles were excluded mostly because the intervention was not melatonin or because they did not report on sleep related outcomes. Beneficial Effects of Melatonin Essay. Of these 39 included articles, four [25–28] reported on different outcomes of the same study and were, therefore, combined with their appropriate counterpart. Ultimately, 35 RCTs, with a total of 2,356 subjects, were included in this review (see Figure 1 for the flow chart of included studies).
Flow chart of included studies.
Table 2 describes the characteristics of the individual studies (grouped by shift workers, jet lag, insomnia, and healthy volunteers) and overall SIGN 50 score. Table 3 describes the GRADE analysis results of the overall literature pool, and Table 4 illustrates the key design issues considered important for dietary interventional studies. Table 5 presents the number and types of subjective and/or objective assessment tools utilized in this review. Beneficial Effects of Melatonin Essay.
Table 2
Characteristics and quality score of included studies
| Citation | Population description | Sample entered/completed | Melatonin supplement vs. control | Outcomes | Author’s main conclusions | Qualityf |
|---|---|---|---|---|---|---|
| Shift Workers (n = 8) | ||||||
| Jorgensen et al. [29] | 20 emergency medicine resident and attending physicians (age/gender = ND) at the University of Marylandad | overall (20/20) | 10 mg melatonin pill vs. placebo taken the morning after each night shift (starting day 2)e | Sleep diary, SSS, sleep VAS | Melatonin did not significantly improve night alertness or day sleep in shift workers, although there was a trend toward improved night alertness. | + |
| James et al. [30] | 24 adult emergency medical technicians or paramedics (age/gender = ND) working night shiftsac | overall (24/22) | 6 mg melatonin pill vs. placebo capsule taken 30 min before each day sleep | Sleep diaries, sleep VAS | Melatonin supplements did not improve sleep quality or duration in emergency medical services personnel working rotating night shifts. | + |
| Sadeghniiat-Haghighi et al. [31] | 118 healthy non-smoking non-pregnant shift-worker female nurses (age = ND) with insomniac | overall (118/86) | 5 mg melatonin tablet vs. placebo taken on the first night after shift work, 30 min before habitual nighttime sleepe | Questionnaire | Melatonin significantly decreased sleep onset latency (p = NR) and increased sleep quality as compared with placebo (p < 0.05). | – |
| Bjorvatn et al. [32] | 38 oil rig workers, age/gender NDc | overall (38/17) | 3 mg melatonin capsule vs. placebo taken 1 h before bedtime vs. bright light (10,000 lux) applied for 30 min/day, ranging from midnight (0000) to (0500) during the night shift and from midday (1200) to (1430) during the day shifte | KSS, ATS, sleep diary, 5-min reaction test, actigraph | Melatonin reduced sleepiness at work during the dayshift week (p = 0.016) and subjectively increased sleep by 15-20 min per day (p = 0.05) compared to placebo. Objectives measures indicated that reaction times did not differ between conditions whereas bright light improved sleep to a minor degree (p = 0.04). | – |
| Cavallo et al. [33] | 45 second year pediatric residents working two night float periods (16 M/29 F) with a mean age of 28.6 ± 9ac | overall (45/28) | 3 mg melatonin fast release capsule vs. placebo taken every morning after night shift worke | Sleep diary, VAS, POMS | Melatonin treatment did not improve sleep duration, vigor, or fatigue in shift workers. | + |
| Wright et al. [34] | 15 faculty emergency physicians (12 M/3 F) with a mean age of 38.6 ± NDac | overall (15/15) | 2 x 2.5 mg melatonin tablets vs. placebo given 30 min before bedtime | KSS, tiredness VAS, sleep VAS, drug tolerability VAS, questionnaire | Melatonin showed no benefit in a group of emergency physicians after night-shift work. | ++ |
| Sharkey et al. [35] | 21 healthy adults (12 M/9 F) with a mean age of 27.0 ± 5.0c | overall (21/21) | 1.8 mg melatonin sustained-release tablet vs. placebo taken 30 min before 2 daytime sleep episodese | PSG, saliva samples, MSLT, SSS, sleep VAS, sleep diary, actigraph | Melatonin prevented the decrease in sleep time that occurs from sleeping at the ‘wrong’ circadian phase (p < 0.05). Subjects taking melatonin were sleepier at bedtime (p = 0.003) on sleep day 1 compared to placebo. | + |
| Jockovich et al. [36] | 19 volunteer emergency medicine residents (15 M/4 F) with a mean age of 28.2 ± NDac | overall (19/19) | 1 mg melatonin caplet vs. placebo taken 30-60 min prior to anticipated daytime sleep session following a night shifte | SSS, wrist actigraph | Melatonin did not improve daytime sleep for emergency physicians working night shifts. | + |
| Jet Lag (n = 8) | ||||||
| Arendt et al. [37] | 17 healthy volunteers (7 M/10 F) with mean age of 48.5 ± 2.2c | overall (17/17), melatonin (8/8), placebo (9/9) | 5 mg melatonin capsule vs. placebo taken at 1800 h on the day of their transcontinental flight departure for the two preceding days, and between 2200-2400 h on the first four days after their return flight | VAS mood, VAS sleep, VAS jet lag, urine samples | Melatonin is effective in subjectively alleviating jet lag (p < 0.01) following eastward travel over eight time zones. | + |
| Spitzer et al. [38] | 339 Norwegian physicians (203 M/136 F) with a mean age of 44 ± 7ac | overall (339/257) | 5 mg or 0.5 mg melatonin capsules vs. placebo taken daily at bedtime on travel day and post-travel days 1-5 | Columbia jet lag scale | Melatonin did not effectively treat jet lag. | – |
| Claustrat et al. [39] | 37 participants accustomed to intercontinental flights who usually experience subsequent discomfort after an eastward journey (18 M/12 F) with a mean age of 36.3 ± 8.9 in the melatonin group and 35.7 ± 6.4 in the placebo groupd | overall (37/27) | 8 mg melatonin capsule vs. placebo taken on day 1 (2200 h) and days 2-4 at bedtime | Global treatment efficiency VAS, sleepiness and mood VAS, sleep VAS | Melatonin demonstrated an overall efficiency in alleviating jet lag (p < 0.058) in subjects who experienced significant discomfort after an eastward flight, compared to placebo. | + |
| Beaumont et al. [40] | 27 participants from a US Air Force Reserve Unit (18 M/9 F) with a mean age of 35.3 ± 8.1c | overall (27/27), slow-release caffeine (9/9), melatonin (9/9), placebo (9/9) | 5 mg melatonin pill vs. 300 mg slow-release caffeine vs. placebo administered preflight (1700 h) and daily from day 1 (arrival day; 1600 h) – day 5 (2300 h) | PSG, sleep diary, MSLT, piezoelectric accelerometer, sleep VAS | Melatonin decreased sleepiness subjectively (p < 0.05), but not objectively, and improved recovery sleep (p < 0.05), indicating some value for alleviating symptoms related to jet lag combined with sleep deprivation. | + |
| Petrie et al. [41] | 20 volunteers with experience of transcontinental flights through at least 5 time zones (12 M/8 F) with an age range from 28-68c | overall (20/20) | 5 mg melatonin capsule vs. placebo taken once a day on pre-flight days 1-3 (between 1000 h and 1200 h), during flight, and once a day for post-flight days 1-3 (between 2200-2400 h)e | VAS, POMS, hours of sleep, retrospective jet lag ratings | Melatonin use resulted in significantly less overall jet lag compared to placebo (p < 0.01). Subjects taking melatonin reported that they were less tired during the day and required less time to establish a normal sleeping pattern (p < 0.05) and reach their normal level of energy (p < 0.05). | + |
| Suhner et al. [42] | 160 recruited volunteer travelers (age/gender = ND) planning a trip from Switzerland to the American continent through 6 to 9 time zones and staying there at least 1 wk. before returningc | melatonin (ND/35) zolpidem (ND/34) melatonin + zolpidem (ND/29) | 5 mg melatonin capsule vs. placebo vs. 10 mg Zolpidem vs. a combination of 5 mg melatonin + 10 mg Zolpidem taken on the return flight (eastbound) between 1700-2100 h and during 4 consecutive days post-flight at bedtime | Sleep diary, POMS, jet lag VAS, symptom assessments, actigraph | Melatonin reduced jet lag severity to some extent (p < 0.05). However, Zolpidem 10 mg was the most effective treatment in that it significantly improved subjective sleep quality on night flights (p < 0.05), reduced over-all jet lag feelings and alleviated sleep disturbances and confusion associated with jet lag (p < 0.05). | + |
| Suhner et al. [43] | 320 volunteers who had flights over 6-8 time zones (172 M/148 F) with a mean age of 36 ± NDc | overall (320/234) melatonin (ND/174) placebo (ND/60) | 5 mg fast-release (FR), 0.5 mg FR, or 2 mg controlled-release melatonin vs. placebo taken once daily at bedtime during 4 days after an eastward flight | POMS, sleep diary, symptom questionnaire, KSS | Melatonin significantly improved self-rated sleep quality (p < 0.05), shortened sleep latency (p < 0.05), and reduced fatigue (p < 0.05) in subjects with jet lag. Melatonin 5 mg formulation was the most effective dosage to reduce fatigue and sleep disorders associated with jet lag after eastbound flights. | + |
| Petrie et al. [44] | 52 participants from an Air New Zealand cabin crew (26 M/25 F) with a mean age of 34.9 ± 7.7 c | overall (52/44) | 5 mg melatonin capsule vs. placebo taken daily between 0700-0800, 2-3 days prior to return flight, and between 2200-0000 h until 5 days after return homee | VAS, SSS, retrospective jet lag VAS, POMS | Melatonin reduced the subjective effects of jet lag, reduced feelings of jet lag (p < 0.05) and led to a more rapid recovery of sleep and energy levels (p < 0.05). | + |
| Insomnia (n = 4) | ||||||
| Almeida Montes et al. [45] | 10 insomnia patients (6 M/4 F) with a mean age of 50 yrs. ± 12.7c | overall (10/10) | 0.3 mg or 1 mg sustained-release melatonin capsules vs. placebo taken 60 min before bedtime, (bedtime between 2200-2300 h) for 7-day treatment periode | PSG, VAS, sleep diary | Melatonin did not affect sleep quality in patients with primary insomnia. | + |
| Wade et al. [28]Wade et al. [46] | 791 participants (age/gender = ND) with primary insomnia according to the DSM-IV criteriaac | treatment period:overall (791/748), PRM (395/374), placebo (396/374); extension period:overall (711/555), PRM (534/421), placebo (177/134) | 2 mg prolonged-release Circadin pill vs. placebo taken daily 1-2 h before bedtime (bedtime between 2100-2200 h) | National sleep foundation diary, PSQI | Melatonin (Circadin) significantly increased sleep time (p = 0.035) for individuals 18-80 years compared to placebo. | + |
| Garfinkel et al. [47] | 34 patients (9 M/25 F) with a mean age of 68 ± 13 who were willing to discontinue current benzodiazepine therapy at some point during the studyc | overall (34/30), CRM (18/15), placebo (16/15) | 2 mg Circadin pill vs. placebo taken 2 h before bedtime (bedtime between 2100-2300 h) | Subjective sleep quality questionnaire | Melatonin significantly improved sleep quality (p = 0.04) compared to placebo, indicating that controlled-release melatonin may effectively facilitate discontinuation of benzodiazepine therapy while maintaining good sleep quality. | + |
| James et al. [48] | 10 participants (4 M/6 F) with a diagnosis of Disorder in Initiating or Maintaining Sleep with a mean age of 33.4 ± NDd | overall (10/10) | 1 mg or 5 mg melatonin pill vs. placebo taken 15 min before bedtime (2300 h)e | DSQ, VAS, SSS, EEG | Melatonin 1 mg significantly increased REM latency (p < 0.05), and produced a significant delay in REM latency after bedtime administration (p < 0.05). Melatonin 5 mg resulted in less sleep (p = 0.02) and an improvement in overall subjective sleep quality (p = 0.03) compared to 1 mg and placebo. | + |
| Healthy Volunteers (n = 17) | ||||||
| Initiation of Sleep/Sleep Efficacy (n = 7) | ||||||
| Paul et al. [49] Paul et al. [25] | 23 military and civilian volunteers (9 M/ 14 F) with a mean age of 29.9 ± 10.3c | overall (23/ND) | 6 mg time-released Circadin pill vs. placebo vs. 10 mg Zaleplon pill vs. 7.5 mg Zopiclone pill vs. 15 mg Temazepam pill taken at 0945 h on one of 5 experimental dayse | PSG, 7 point Likert drowsiness scale | Melatonin use significantly increased sleep (p < 0.05), decreased sleep latency (p < 0.05), and increased drowsiness (p < 0.0001) immediately after psychomotor testing compared to before testing for all medications. Melatonin increased sleep and reduced sleep latency (p < 0.05) after psychomotor test sessions from 1 3/4h to 4 3/4h post-ingestion. Melatonin significantly prolonged subjective sleepiness (p < 0.001); however, the largest effects on total sleep, sleep latency and drowsiness were attributable to Zopiclone. | + |
| James et al. [50] | 10 participants (7 M/3 F) with a mean age of 29.9 ± NDd | overall (10/10) | 1 mg or 5 mg melatonin pill vs. placebo taken at 2245 h for one of three weeks | PSG | Melatonin 5 mg significantly prolonged REM latency (p < 0.001), suggesting that a larger dosage of melatonin may influence sleep and circadian rhythms. | + |
| Nave et al. [51] | 6 healthy males with a mean age of 24.5 ± 0.9c | overall (6/6) | 3 mg melatonin pill vs. placebo vs. 10 mg Flumazenil + placebo vs. 10 mg Flumazenil + 3 mg melatonin taken at 1200 h for one of four 7 h (1200-1900 h) testing periods | PSG, actigraph | Melatonin significantly decreased latency to the first appearance of sleep (p < 0.05) and increased total sleep time (p < 0.05). | + |
| Middleton et al. [52] | 10 normal healthy male soldiers with a mean age of 23.90 ± 0.75c | overall (10/8) | 5 mg melatonin capsule vs. placebo taken at 2000 h, 1200 or 0400 h for 15 dayse | Sleep diaries, urine samples | Melatonin produced significant differences for sleep onset, sleep offset and activity acrophase (p < 0.001), indicating a sleep phase shift. | + |
| Aeschbach et al. [53] | 8 volunteers (4 M/4 F) with a mean age of 27.8 ± 3.6c | overall (8/8) | 2.1 mg melatonin patch vs. placebo patch given one hour before 8 h daytime sleep opportunity (between 0900-1700 h) on day 2 of a 36 h inpatient visite | PSG, KSS, blood samples | Transdermal melatonin delivered during the daytime elevated plasma melatonin (p < 0.0001) and reduced waking (p < 0.05) after sleep onset by promoting sleep (p < 0.05) in the latter part of an 8 h sleep opportunity. | + |
| Attenburrow et al. [54] | 15 healthy middle aged volunteers (4 M/11 F) with a mean age of 53.9 ± NDc | overall (15/12) | 0.3 mg or 1 mg melatonin pill vs. placebo given 2h before bedtime (bedtime between 2200-2300 h) for 3 separate nightse | PSG, Leeds sleep evaluation questionnaire | Melatonin improved actual sleep time (p < 0.02), sleep efficiency (p < 0.02), non-REM sleep (p < 0.03) and REM sleep latency (p < 0.05) in healthy, middle-aged volunteers sleeping in their home environment. | – |
| Van Den Heuvel et al. [55] | 10 healthy male volunteers with a mean age of 22 ± 1.1c | overall (10/10) | 100 mg atenolol pill + 1 mg melatonin pill vs. placebo pill vs. 100 mg atenolol pill + placebo pill taken at 1900 h, 2200, 0200, or 0400 h during 3 nonconsecutive nights in the sleep laboratorye | MSLT, linear sleepiness rating | Melatonin did not affect sleep onset latencies and subjective sleepiness. | + |
| Daytime Sleepiness (Occurrence Of)/Somnolence (n = 5) | ||||||
| Rose et al. [56] | 68 participants (age/gender = ND) recruited from Santa Clara Universityac | overall (68/53) | 2 x 3 mg melatonin capsules vs. placebo taken 30 min before bedtime for 8 nightse | DSSEQ | Melatonin facilitated an increase in grogginess/ tiredness prior to sleep onset (p = 0.01). Additionally, the expectancy of receiving melatonin resulted in significantly higher mean ratings of grogginess/tiredness (p = 0.02). | + |
| Rogers et al. [57] | 16 young healthy subjects (6 M/10 F) with a mean age of 21.4 ± 6c | overall (16/16) | 5 mg melatonin capsule vs. placebo vs. 10 mg Temazepam capsule taken at 1200 h during 1 of 3 experimental sessions, each lasting from 2200 until 1900 h the following daye | VAS | Melatonin and Temazepam both produced a significant increase in self-reported sleepiness levels (p = 0.02) relative to placebo. However, melatonin use led to a steady increase in self-reported sleepiness levels (p = 0.006) compared to both Temazepam and placebo. | + |
| Krauchi et al. [58] | 8 healthy male students with a mean age of 25 ± 4c | overall (8/8) | 5 mg melatonin capsule vs. placebo taken once at 1300 he | VAS, KSS, waking EEG | Melatonin administration at 1340, 1420, 1510, 1550, and 1620h increased sleepiness (p < 0.05). | + |
| James et al. [50] | 10 participants (7 M/3 F) with a mean age of 29.9 ± NDd | overall (10/10) | 1 mg or 5 mg melatonin pill vs. placebo taken at 2245 h daily for one week | DSQ, VAS, SSS | Melatonin did not produce differences in daily sleep or sleepiness between groups. | + |
| Nave et al. [51] | 6 healthy males with a mean age of 24.5 ± 0.9c | overall (6/6) | 3 mg melatonin pill vs. placebo vs. 10 mg Flumazenil + placebo vs. 10 mg Flumazenil + 3 mg melatonin taken at 1200 h for one of four 7 h (1200-1900 h) testing periods | VAS | Melatonin 3 mg significantly increased sleepiness (p < 0.02) when administered at 1200 h in the placebo + melatonin and flumazenil + melatonin conditions. | + |
| Phase Shift/Hormone Changes (n = 5) | ||||||
| Bonafide et al. [59] | 12 healthy volunteers (age/gender = ND)ac | overall (12/10) | 3 mg melatonin pill + Saline (80 ml/h) IV vs. 3 mg melatonin pill + Remifentanil (0.02-0.04 ug kg) IV vs. placebo + Saline (80 ml/h) IV vs. Remifentanil (0.02-0.04 ug kg) IV + placebo, administered at 2230 he | PSG, sleep diary | Melatonin did not alter normal nocturnal sleep or prevent remifentanil-induced sleep disturbance. | + |
| Luboshitzky et al. [60] | 6 healthy males with a mean age of 23.9 ± 2.4c | overall (6/5) | 6 mg melatonin pill vs. placebo once a day at 1700 h for 1 month | PSG | Neither melatonin nor the control influenced the majority of polysomnographic sleep parameters, however, melatonin did significantly increase REM latency (p < 0.04) and percent REM (p < 0.05) compared to baseline. | – |
| Gorfine et al. [61] | 12 participants (2 M/10 F) with a mean age of 25 ± 4.8c | overall (12/ND) | 2 mg melatonin drink (100 ml of 1% ethanol in water) vs. placebo drink administered every 2-3 h, starting at 1600–1700 he | Bond-Lader questionnaire | Melatonin caused significant increases from predosing scores in self-reported parameters of fatigue (p < 0.001), sleepiness (p < 0.001), dreaminess (p < 0.01) and boredom (p = 0.02) and significant decreases in lucidness (p = 0.03). | – |
| Vandewalle et al. [62] Rajaratnam et al. [26] Rajaratnam et al. [27] | 8 male subjects with a mean age of 24.4 ± 4.4c | overall (8/8) | 1.5 mg surge-sustained-release melatonin pill vs. placebo taken at 1600 h during daily scheduled 16 h sleep opportunities for 8 consecutive dayse | HR/HRV, blood samples, actigraph, KSS, PSG. | Melatonin successfully phase-shifted circadian rhythms (p < 0.045) without indication of deleterious effects on daytime sleepiness/mood on the day following administration. | + |
| Paul et al. [63] | 11 normal healthy male volunteers with a mean age of 38.2 ± 9.7ac | overall (11/11) | 3 mg sustained release melatonin capsule vs. light treatment + 3 mg melatonin capsule vs. placebo capsule vs. light treatment. Capsules were administered at 1600h on day 2, light treatment from 0600-0800h on day 3e | Melatonin assays, saliva samples, actigraph | Melatonin significantly increased phase advances compared to placebo condition (p < 0.0002). | + |
ATS = Accumulated Time with Sleepiness scale, CRM = controlled-release melatonin, DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, DSQ = Daily Sleep Questionnaire, DSSEQ = Daily Subjective Sleep Experiencing Questionnaire, EEG = Electroencephalogram, F = female, h = hour, HR = heart rate, HRV = heart rate variability, KSS = Karolinska Sleepiness Scale, M = male, mg = milligram, MSLT = Multiple sleep latency test, n = number, ND = not described, NR = not reported, POMS = Profile of Mood States, PRM = Prolonged-release circadin, PSG = Polysomnographic recording, PSQI= Pittsburgh Sleep Quality Index, REM = Rapid eye movement, SSS = Stanford Sleepiness Scale, VAS = Visual Analog Scale, wk = week apower achieved, bpower not achieved, cinformed consent obtained, dinformed consent not obtained, ecrossover design.
fSee Table 1: Quality refers to the overall SIGN 50 score, categorized as ++ (well covered; where criteria has not be filled, conclusions of the study are thought very unlikely to alter); +(adequately addressed; criteria that have not been adequately described are thought unlikely to alter conclusions) or – (poorly addressed; conclusions of study are thought likely or very likely to alter). Beneficial Effects of Melatonin Essay.
Note. Four [25–28] RCTs reported on different outcomes of the same study and were therefore combined; the most recent study was cited in the paper.
Table 3
Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis: quality of the overall literature pool assessing melatonin for the promotion of healthy sleep patterns
| Category | Number of participants completed (Number of studies) | Confidence in estimate of Effect GRADE 1 | Magnitude of estimate of Effect GRADE 2 | Safety GRADE3 | Strength of the Recommendation4 |
|---|---|---|---|---|---|
| Shift Workers | 300 (8) | C | ND | +1 | None |
| Jet Lag | 972 (8) | B | ND | +1 | Weak, in favor |
| Insomnia | 845 (4) | B | ND | +1 | Weak, in favor |
| Healthy Volunteers | |||||
| Initiation of Sleep/Sleep Efficacy | 82 (7)* | B | ND | 0 | Weak, in favor |
| Occurrence of Daytime Sleepiness/Somnolence | 108 (5)* | B | ND | 0 | Weak, in favor |
| Phase Shift Changes | 49 (5) | C | ND | 0 | None |
*2 Studies [50, 51] mentioned in both groups.
There are four major domains that comprise the core of the modified GRADE methodology:
1Categorized as A (High; further research is very unlikely to change confidence in the estimate of effect); B (Moderate; further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate); C (Low; further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate)or; D (Very Low; any estimate of effect is very uncertain).
2Categorized as none (<0.2), small (0.2 – 0.5), moderate (0.5 – 0.8), large (>0.8) or not described (ND; authors did not describe or report effect size for this review’s outcomes of interest due to the lack of author reporting).
3Dependent on the frequency and severity of adverse events and interactions; as +2 (appears safe with infrequent adverse events and interactions); +1 (appears relatively safe but with frequent but not serious adverse events and interactions); 0 (safety not well understood or conflicting); −1 (appears to have safety concerns that include infrequent but serious adverse events and/or interactions) or; −2 (has serious safety concerns that include frequent and serious adverse events and/or interactions).Beneficial Effects of Melatonin Essay.
4Strength of the recommendation can be determined using the following categories and criteria: Strong recommendation in favor of or against (very certain that benefits do, or do not, outweigh risks and burdens); No recommendation (no recommendations can be made) or; Weak recommendation in favor of or against (benefits and risks and burdens are finely balanced, or appreciable uncertainty exists about the magnitude of benefits and risks).
Table 4
Reporting of dietary supplement design elements
| Jet lag (n = 8) | Insomnia (n = 4) | Healthy volunteers (n = 15) | Shift workers (n = 8) | Total N (%) | |
|---|---|---|---|---|---|
| Assessment of baseline exposure | 0/8 | 2/4 | 2/15 | 0/8 | 4/35 (11%) |
| Control for background diet | 5/8 | 1/4 | 11/15 | 4/8 | 21/35 (58%) |
| Description of Melatonin preparation | 1/8 | 3/4 | 11/15 | 5/8 | 20/35 (57%) |
| Chemical analysis of Melatonin preparation | 2/8 | 0/4 | 3/15 | 1/8 | 6/35 (17%) |
| Absorption analysis of the Melatonin preparation | 1/8 | 2/4 | 9/15 | 1/8 | 13/35 (37%) |
| Total N (%) | 9/40 (22%) | 8/20 (40%) | 16/75 (48%) | 11/40 (27%) |
Table 5
Objective and subjective outcome measures captured in the review
| Outcome name | Shift workers | Jet lag | Insomnia | Initiation of Sleep/Sleep efficacy | Daytime sleepiness (occurrence of)/Somnolence | Phase shift/hormone changes |
|---|---|---|---|---|---|---|
| Objective measures | ||||||
| Polysomnographic recording (PSG)*; Actigraph*; Saliva samples**; Blood samples**; Electroencephalogram (EEG)*; Accelerometers*; Hours of sleep*; Heart rate/Heart rate variability (HR/HRV)*; Melatonin assays*; Multiple sleep latency test(MSLT)*; Urine samples**; 5- min reaction test* | 7 | 6 | 2 | 9 | 1 | 9 |
| Subjective measures | ||||||
| Visual Analog Scale (VAS)*; Sleep diaries; Stanford Sleepiness Scale (SSS)*; Profile of Mood States (POMS)*; Karolinska Sleepiness Scale (KSS)*; Daily Sleep Questionnaire (DSQ); Questionnaire; 7 point Likert Drowsiness Scale; Accumulated Time with Sleepiness Scale (ATS)*; Accumulated Time with Sleepiness Scale (ATS)*; Bond-Lader Questionnaire; Columbia Jet Lag Scale*; Daily Subjective Sleep Experiencing Questionnaire (DSSEQ); Leeds Sleep Evaluation Questionnaire*; Linear Sleepiness Rating; Pittsburgh Sleep Quality Index (PSQI)*; Retrospective ratings; Subjective Sleep Quality Questionnaire; Symptom assessments; Symptom questionnaire | 21 | 24 | 8 | 5 | 6 | 3 |
*Validated Measures.
**Objective measures captured to determine melatonin bioavailability but not relevant outcomes of interest to this review.
Overall quality assessment of individual included studies
The overall methodological quality of the RCTs was evaluated as being of the highest (++) quality, high (+) quality or poor (−) quality, according to the SIGN 50 criteria indicated in Table 1 (see Table 2 for quality scores). The majority (80%) of the 35 included RCTs were high (+) quality, with one study (3%) being of the highest (++) quality [34]. Conversely, 17.0% of studies were scored as poor quality. An appropriate and clearly focused research question was adequately addressed in 80.0% of the trials; the remaining (20.0%) addressed this area well. Over half (51.0%) of the studies had dropout rates less than 10.0% and were, therefore, considered well-covered for this criterion, whereas 31.0% of studies either did not mention dropout rates or reported rates greater than 20.0%. Regarding intention-to-treat analysis, 54.0% of the included studies were classified as poorly addressed because such analyses were not mentioned or described; 3.0% of the studies adequately addressed intention-to-treat analysis; and 43.0% addressed it well. Although the majority (86.0%) of studies poorly described their methods of allocation concealment, all (100%) studies adequately addressed blinding methods regarding treatment allocation. Methods of randomization were described poorly by 48.0% of the studies; 46.0% adequately described this process and only 6.0% did it well. Nearly all (97.0%) and the majority (55.0%) of the trials adequately addressed differences between treatment groups and baseline similarities, respectively. Beneficial Effects of Melatonin Essay.Results indicated that 51.0% of articles adequately covered outcome validity and reliability, whereas 37.0% covered this criterion well. Three studies [28, 29, 62] were multi-site, and one [28] poorly addressed the comparability of results among sites; the remaining two were well covered [29] or adequately addressed [62] in this area.
Adverse events
Of the total 35 studies included in our analysis, 15 [29, 30, 33, 34, 36, 38, 39, 41–47, 52] included information on adverse events. No serious adverse events were reported. One [36] study reported that adverse events occurred, but did not describe them, and two [34, 45] reported no adverse events occurred at all. The most common adverse events were headache [29, 33, 44, 46, 47] and somnolence [33, 41, 44, 48]. Palpitations [42, 43] and abdominal pain [33, 43] were each reported in two studies. The remaining adverse events were reported infrequently, and each occurred in only one of the multiple studies: nasopharyngitis [46], arthralgia [46], tachycardia [39], dizziness [33], nausea [33], vomiting [33], nightmares [33], difficulty swallowing and breathing [38], hypnotic activity [39], heavy head [39], heartburn [43], flatulence [43], swelling of arms/legs [43], sweating/hot flash [43], exanthema [43], sleeping difficulties [44], depression [44], problems with the rectal probe [52], and sleep walking [42].
Effectiveness of melatonin for promoting healthy sleep outcomes
Included studies were categorized according to the intended use of melatonin in 1) shift workers and individuals with jet lag to rebalance the sleep-wake cycle; 2) persons with insomnia to promote sleep; and 3) in healthy volunteers to improve outcomes of sleep efficacy, somnolence, and/or hormonal phase shift changes (see Table 2 for full description of included studies and Table 3 for GRADE Analysis). Beneficial Effects of Melatonin Essay.
