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Table 2 Characteristics and quality score of included studies

From: The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature

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). +
  1. 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.
  2. 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).
  3. Note. Four [2528] RCTs reported on different outcomes of the same study and were therefore combined; the most recent study was cited in the paper.