Table 2.
Characteristics and quality score of included studies
| Citation | Population description | Sample entered/completed | Melatonin supplement vs. control | Outcomes | Author's main conclusions | Quality f |
|---|---|---|---|---|---|---|
| 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).
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.