Table 2. Sleep-promoting effect of exogenous melatonin.
| Author |
Study
Design |
Aim | DX | Subjects |
Variables
Measured |
Dose | Timing | Duration | General Results |
|---|---|---|---|---|---|---|---|---|---|
| Antón-Tay et al., 1971 [8] |
Case series | To study the effects of exo-Mel administration to humans | HS | n=11 males 5 age 18-25 |
EEG Subjective sleepiness |
0.25 mg/K, 1.25 mg/KG (iv) | Not specified | Single dose | EEG activity slight deactivation, ↑ % and amplitude of alpha rhythm, Sleepiness, wellbeing |
| MORNING ADMINISTRATION | |||||||||
| Vollrath et al., 1981 [5] | Double-blind placebo-controlled crossover | To evaluate the effects of exo-MEL at “low dosages using as form of application nasal spray (ns) | HS | n=10 males 6, females 4 age 28.8 and 26.5 respectively |
Subjective sleepiness | 1.7 mg (ns) | 9:00-10:00 | single dose | ↑ Sleepiness (9/10 subjects fell asleep) |
| Dollins et al., 1993 [196] |
Double-blind placebo-controlled Latin square design |
To determine whether lower acute doses of melatonin than have previously been investigated have sedative-like effects on behavior and if such effects are dose-related. | HS | n=20 males 20 age 25 ± 1.47 (range 19-39) |
MEL levels, oral temperature, cognition, SSS, POMS | 10mg, 20mg, 40mg, or 80mg | 11:45 | single dose | All doses: ↓ Oral temperature, correct responses in auditory vigilance and self-reported vigor, ↑ response latency, self-reported fatigue, confusion, sleepiness |
| Dollins et al., 1994 [89] * | Double-blind placebo-controlled Latin square design |
To evaluate if exo-MEL at physiological doses may induce short-term behavioral effects. | HS | n=20 males 20 age 23.05±4.22 (range 18-24) |
MEL levels, oral temperature, TST SSS, SOL, cognition, POMS, | 0.1mg,0.3mg, 1.0mg, 10 mg | 11:45 | single dose | All doses= ↓ SOL, subjective vigor, ↑ TST, Sleepiness, self-reported fatigue. Doses of 1.0-10 mg= ↓ oral temperature, correct responses in auditory vigilance and reaction time |
| Mishima et al., 1997 [198] * | Single-blind randomized crossover | To study acute hypnotic and hypothermic effects induced by daytime administration of exo-MEL with simultaneous monitoring of serum MEL concentration | HS | n= 6 males 6 age 22.5±19 |
CBT, SL (measured during a MSLT), serum MEL concentration | 3mg or 9mg | 09:30 | single dose | ↓ CBT (3 mg, 9 mg) ↓ SL (9 mg) |
| Hughes & Badia, 1997 [9] * | Double-blind placebo-controlled crossover | To investigate the ability of three different doses of melatonin (1 mg, 10 mg, and 40 mg) to promote sleep in a moderate-duration daytime sleep opportunity. | HS | n=8 males 8 age range 18-30 |
CBT, PSG (SL, SWS_L, REM_L, TST, WASO, % of S1, S2. S3, S4 and REM, ss density, movement time, wake time, AW), pulse rate, blood pressure, cognition | 1 mg, 10 mg 40 mg |
10:00 | Single dose (each treatment) | All dosages: ↓ SL, Stage 3-4, WASO and CBT, ↑ Stage 2, TST. Doses of 10 mg and 40 mg: ↓REM latency, ↑ latency to stage 3-4, TST. |
| Van Den Heuvel et al., 1998 [197] | Double-blind placebo-controlled counterbalanced | To evaluate the effects of daytime melatonin infusion in young adults | HS | n= 24 males 12 age range 19-28 (8 subjects for dose) |
Subjective sleepiness, central and peripheric temperature | Iv 0.04, 0.08, 8.00 μg h-1 kg-1 | 10:00 | Single dose (each treatment) | High dose (supraphysiological): ↑ hand temperature, sleepiness ↓ raising of central temperature |
| Van Den Heuvel et al., 1999 [19] | Double-blind randomized placebo-controlled | To exam the effects of exo-MEL levels on body temperatures and sleepiness when administered with a rapid systemic onset. | HS | n = 8 males 4 age 23.9 ±0.7 |
Subjective sleepiness, central and peripheric temperature | iv 3, 10, and 30 μg | 10:00 | Single dose (each treatment) | All doses (physiological levels): ↑ hand temperature ↓ raising of central temperature |
| Matsumoto, 1999 [10]* | Single-blind crossover | To evaluate the effects of 10mg MEL administered at 10:00 on a diurnal sleep episode (from 11:00 to 19:00 following a full night of sleep. | HS | n=6 males 6 age 23.7±1.3 |
PSG (sleep period time, SL, TST, SE, AW, % and duration of W, S1, S2, S3, S4, REM. Wake time, REM_L, N° REM periods, REM period and cycle length) CBT, Sleepiness | 10 mg | 10:00 | single dose | ↑ TST, SE, Sleepiness, %, and duration of REM and S2. ↓ AW, % and duration of W. No changes in CBT |
| Aeschbach, D.,, 2009 [199] * | Double-blind placebo-controlled and crossover | to test an experimental skin patch designed to deliver melatonin such that plasma levels steadily increase for 6-8 h, and thereby counteract the increasing circadian wake drive and improve daytime sleep. | HS | n=8 males 4 age 27.8±3.6, (range 24-34) |
EEG, (TST, SE, SL, SL_REM, WASO, S1, S2, SWS, REM sleep), EEG spectra, plasma MEL, CBT, sleepiness (KSS) and cognition | 2.1 mg (transdermal) | 08:00 | single dose | ↓ CBT and WASO ↑ REM sleep, SE, TST, S2. Spectral analysis: ↓ density in 2.5-6.5 Hz, ↑ density in 13.25-13.5 HZ. |
| Lieberman et al., 1984 [6] | Double-blind counterbalanced | To examine the ability of oral melatonin, given during the daylight hours in pharmacological quantities, to modify various aspects of behavior | HS | n=14 males 14 age range 18-45 |
POMS, SSS, Cognition | 240 mg (three doses of 80 mg) | Split dose at 12.00, 13.00, 14.00 | single dose | ↑ Fatigue, confusion, Sleepiness, response time ↓ Vigor, number of errors in cognitive tests |
| Dijk et al., 1995 [202] * |
Placebo-controlled crossover | To document the immediate and vigilance state-specific effects of exo-MEL on EEG activity during daytime sleep. | HS | n = 8 males 6 age 22.4 (range 20-26) |
PSG (SL, TST, SE, REM_L, percentage of S1, S2, SWS, REM, and spectral analysis. | 5 mg | 12:30 | Single dose | Spectral analysis: ↑ 13.75-14.0 Hz, ↓ 15.25-16.5 Hz and 2.2.5-5.0 Hz (In the first 2 h). No changes in sleep architecture, SL or SE |
| Nave et al., 1995 [11]* | Double-blind balanced Latin square design | To investigate the effects of exo-MEL on napping during early evening hours (before the nocturnal rise in endogenous melatonin when sleep propensity is low) | HS | n= 20 age 24.6 ± 2.7 |
PSG (SL, TST, S1, S2, S3/S4, REM) | 3mg, 6 mg | 16:00- 17:30 | Single dose by protocol | ↑ TST, S2, SQ ↓ SL |
| Nave et al., 1996 [131] | Double-blind, randomized partially repeated Latin square design. |
To investigate whether 10 mg of flumazenil (BDZ antagonist) can block the hypothermic effects of 3 mg melatonin | HS | n=6 males 6 age 24.5±0.9 |
PSG (SL, TST S1, S2), spectral analysis, CBT, Sleepiness | 3mg | 12:00 | Single dose | ↑ S1, S2, TST and power density in frequency bands: 1-3Hz and 4-7 Hz, and sleepiness ↓ SL and CBT (BDZ antagonist does not interfere with the MEL effects) |
| Reid et al., 1996 [12]* | Double-blind placebo-controlled, crossover | To explore the relationship between hypothermic and hypnotic effects of melatonin | HS | n=16 males 6 age 20.3±2.4 |
PSG (SOL1, SOL2) CBT | 5 mg | 14:00 | single dose | ↓ CBT, SOL1, SOL2 |
| Cajochen et al., 1996 [201] | Double-blind crossover | To evaluate the acute effect of exo-MEL on EEG power density during waking. | HS | n = 8, males 8 Experiment 1: age 27 ± 4, Experiment 2: age 24.8 ± 3.5 | Sleepiness (VAS, Akerstedt Sleepiness Scale), waking EEG | 5 mg | Exp 1: 18:00, Exp 2: 13:00 | sigle-dose | ↑ Sleepiness and 5.25-9 Hz density. No changes in SWS, sleep spindle and beta band |
| Kräuchi, Cajochen, & Wirz-Justice, 1997 [135] * | Double-blind placebo-controlled crossover | Both MEL and postural changes have thermoregulator sequelae. To evaluate their relationship to subjective sleepiness. | HS | n = 8 males 8 age 25±4 range 21-31 |
Waking EEG, Temperature (superficial and central), sleepiness (VAS), heart rate | 5 mg | 13:00 | single dose | ↑ Subjective Sleepiness, distal temperature, 5.25-9 HZ power density in the waking EEG ↓ central temperature |
| Gilbert et al., 1999 [13]* | Double-blind counterbalanced | compared the thermoregulatory and soporific effects of temazepam with those of melatonin. |
HS | n =20 males 13 females 7 age 23.5 ± 0.4 |
CBT, peripheral temperature, PSG (SL), heart rate | 5 mg | 14:00 | Single session | ↓ SL and CTB (with both exo-MEL and tamazepam). Temporal relationship between minimum SL and the maximum rate of decline in CBT |
| Satomura et al., 2001 [137] * | Single-blind randomized | To assess the hypnotic action by administering exo-MEL during the day | HS | n =7 males 7 age 23.7±1.7 |
EEG (SL, TST, SE, WASO, REM_L, S1, S2), CBT | 1,3,6 mg | 13:30 | single dose | ↑ TST, SE, S2 (1mg, 3mg, 6 mg) ↓ CBT (1mg,3mg) |
| Rogers et al., 2003 [200] | Double-blind randomized crossover | To compare neurobehavioural performance effects following the daytime administration of exo-MEL and temazepam | HS | n= 16 males 6 females 10 age 21.4 ± 0.6 |
Cognition, sleepiness (VAS) | 5 mg | 12:00 | single -dose | ↑ Sleepiness, ↓ performance in unpredictable tracking, spatial memory and vigilance tasks. |
| Cramer et al., 1974 [203] * | Placebo-controlled crossover | To study the effects of MEL in healthy young male volunteers | HS | n=15 males 15 |
PSG (SOL, S3_L, REM_L, NREM_L. TST, % of S1, S2, S3/4, REM, sleep stages), refreshing sleep (MMQ), mental state, 5-HIAA, adenosine 3’,5’monophosphate | 50 mg iv | 21:30 | single dose | ↓SOL |
| James et al., 1987 [18]* |
Double-blind placebo-controlled randomized | To report the findings of the acute effects of orally administered exo-MEL in HS | HS | n=10 males 7 females 3 age 29.9 |
PSG (SOL, SE, REM_L, TST, duration and % of Delta and REM), DSQ, sleepiness (SSS), anxiety, and mood | 1mg, 5mg | 22:45 | Single dose | ↑ REM_L in the 5mg condition compared to 1mg and placebo condition. |
| Waldhauser et al., 1990 [204] | Double-blind placebo-controlled parallel group | To determine the effects of exo-MEL on sleep induction, sleep maintenance, sleep architecture and objective and subjective awakening quality in induced insomnia | HS | n=20 males 10 females 10 age 26.4 ± 4.8 |
PSG (Awake till sleep onset, SL, TSP, TST, SE, AW, WASO, REM_L, stage shifts), sleep quality, awakening quality and somatic complaints, cognition, mood, drowsiness. | 80 mg | 21:00 | Single dose | ↓ SL, N° awakenings, S1. ↑ SE, S2, cognition and alertness (morning after MEL treatment) |
| Ferini-Strambi et al., 1993 [17] * | Single-blind placebo controlled | To compare the effects of exo-MEL with those of a benzodiazepine hypnotic [triazolam (TRI) 0.125 mg] at a low dose in healthy volunteers. |
HS | n=6 males 6 age 25.3 ± 3.6 |
PSG (TST, SL, WASO, AW, SE, Sleep stages %, REM-L, REM periods, stage shifts/hour CAP variables), DSQ, SQ | 100 mg | 22:30 | single dose | No changes in classical PSG variables ↑ sleep quality. MEL, TRI and MEL + TRI = ↓ CAP cycles, MEL in comparison with baseline= longer Phase B (lesser arousal). |
| Zhdanova et al., 1995 [14]* | Double-blind placebo-controlled counterbalanced | To examine the induction of PSG recorded sleep by MEL given later in the evening close to the times of endogenous melatonin release and habitual sleep onset. | HS | n=6 males 6 age 26.5 ± 1.3 |
PSG (SOL, S2_L, REM_L), | 0.3 or 1.0 mg | 18:00, 20:00, 21:00 | 3 sessions by timing | ↓ SOL, S2_L (all doses and all time points). |
| Zhdanova et al., 1996 [15]* | Double-blind placebo-controlled counterbalanced | To characterize the effects of augmented circulating MEL levels within the physiologic nocturnal range on PSG parameters | HS | n=12 males 12 age 28.5±1.8 |
PSG (W, S1, S2, S3, S4, REM, SOL, REM_L, S2_L, WASO, SE, TST), Sleepiness (SSS), cognition and mood (POMS) | 0.3, 1.0 mg | 21:00 (2-4 h before sleep) | 3 sessions | ↓ SOL, S2L ↑ SE No effect on other sleep parameters, no effects on cognition and sleepiness the day after exo-MEL treatment. |
| Attenburrow et al., 1996 [16] * |
Double-blind placebo-controlled crossover | To investigate the effect of exo-MEL on PSG measured sleep in normal, middle-aged volunteers when administered 2 hours before the habitual sleep time | HS | n=15 males 4 age 53.9 range 41-67 |
PSG (TIB, TSP, actual sleep time, SE, SOL, WASO, total movement time, S2_L, SWS_L, S1, S2, SWS, NREM, REM, REM_L), LSEQ | 0.3 mg 1.0 mg | 2 hours before BT | Single dose | 1 mg = ↑ TST, SE, NREM, REM_L |
| Stone et al., 2000 [208] * | Double-blind placebo-controlled crossover | To establish the effect of melatonin upon nocturnal and evening sleep. | HS | Exp1. n= 8 males 8 age 23.4 (range 20-30) Exp 2. n= 6 males 6, age 26.5 (range 21-31) |
EEG (TST, SE, SOL, REM/non-REM ratio, L_SWS, L_REM, REM periods, AW, stage shifts, Awake (min), Duration and % of S1,S2, S3+4, REM, Awake), SQ, ESS, CBT,DLMO (acute effect), Cognition | 0.1mg, 0.5mg, 1.0mg, 5.0mg, 10 mg | 18:30 and 23:30 | single dose | Exo-MEL at 18:00 (all doses) =↑TST, SE, S2, REM periods, stage shifts ↓ WA Exo-MEL at 23:30 = ↓ S3 (5mg), ↓CBT (0.1 mg), ↑ SL |
| Pires et al., 2001 [207]* | Double-blind placebo-controlled | to evaluate the acute effects of single low doses of exo-MEL given to HS in the evening. | HS | n=6 males 6 age range 22-24 |
PSG (TST, SL, SE, WASO, percentage of S1, S2, S3/4, REM, REM_L), SQ, POMS, SSS, Cognition | 0.3 or 1.0 mg | 18:00, 20:00, 21:00 | single dose | ↓ SL, (18:00 and 20:00), ↑ SL (21:00) ↓ S1 (20: 00) ↑REM_L (0.3 mg, 18:00) ↑ SL (0.3mg, 21:00) |
| Ribeiro et al., 2004 [205] * | placebo-controlled | to evaluate SOT in HS taking exo-MEL using 2 different criteria of sleep latency: the Rechtschaffen and Kales and the 10 minutes of uninterrupted sleep | HS | n=45, males 45 age 28 ± 5 (PLA n=10 MEL n=30) |
PSG (SL, SE, sleep architecture, REM_L and density). SL evaluated through the Rechtschaffen and Kales criteria (1.5 minutes of S1) and the 10 minutes of uninterrupted sleep criteria) | 10 mg | 1 h before BT | 28 days | ↓ SL (using the 10 min of uninterrupted sleep criteria) Advance in SOT |
| Arbon et al., 2015 [206] * |
Double-blind, placebo-controlled, randomized crossover | To study the effects of pro-longed-release exo-MEL, temazepam and zolpidem on the spectral composition of the EEG during nocturnal sleep in healthy middle-aged men and women. | HS | N = 16 Males 12 Age 58.8 ± 2.9 |
PSG (SOL, REM_L, duration of S1, S2, S3, S4, NREM, REM, TST, SPT, SE, WASO, AW), spectral analysis Plasma melatonin and aMT6S (acute), SQQ, KSS | 2 mg (PR) | 21:00 (2 h before BT) | Single dose (each treatment) | Exo-MEL = Minor reduction in SWA in the first third of the night. No changes in PSG measures compared to PLA. No effect on SQQ or KSS |
| MULTIPLE TIMING | |||||||||
| Nickelsen et al., 1989 [7] * | Double-blind placebo-controlled | To study the sedative potency of high doses of exo-MEL at different times of the day. | HS | n=25 males 14 age 30.4±6.2 females 11 age 30±7.9 |
Sleepiness (SSS), sedative effect perception, sleep-log (SOL, TST, AW) | 50 mg | 19.00 or 9:00 | Single dose | ↑ Tiredness and sedating perception only in morning administration |
| Tzischinsky & Lavie, 1994 [210] |
Double-blind placebo-controlled crossover | To evaluate the hypnotic effect of exo-MEL using an ultrashort sleep-wake paradigm | HS | n=8 males 8 age 27.06±3.7 |
PSG (sleep propensity[sp]) = averaging total sleep time (sum of stages 1, 2, 3/4 and REM sleep) at each of the 72 trials) spectral analysis, Temperature, Sleepiness (VAS). |
5 mg | 12:00, 17:00, 19:00, 21:00 | Single dose (each treatment) | ↑ SP time-dependent: 12 h = ↑ midafternoon sp (peak at 16 h) and delayed the nocturnal increase in sp from 22 to 24h. 17 h = ↑ sp (peak:19h) 19:00 h = ↑ sp (peak at 21h) 21h = faster ↑ sp (peak at 22h) All trials = ↑ Subjective sleepiness, ↓ T° at 12,17,19 h |
| Wyatt et al., 2006 [209] | Double-blind placebo-controlled parallel-group | To investigate the effects of a physiologic and pharmacologic dose of exo-MEL on SL and SE in sleep episodes initiated across a full range of circadian phases. | HS | n=36 males 21 age range 18-30 |
EEG (SE, TST, Latency to consolidated sleep -LCS-, REM % and SWS%), CBT, Plasma MEL profile. | 0.3 or 5.0 mg | 30 min before 6.67h sleep period during forced desynchrony | 21 days | ↑ SE during the sleep episodes out of endogenous MEL release, no changes in SL, LCS, CBT, % of SWS or REM sleep. |
| INSOMNIA | |||||||||
| James et al., 1990 [33] |
Double-blind placebo-controlled crossover | To report the finding of the acute effects of orally administered exo-MEL at bedtime in patients with persistent complaints of insomnia | Initiating or maintaining sleep Disorder | n=10, males 4 age= 33.4 (range 20-57) | PSG (REM_L, REM period, duration and % of REM, TST, SE, SWS, % of movement time, SOT), subjective sleepiness (SSS), SQ, DSQ, mood-rating scales | 1mg or 5mg | 22:45 | 1 session | ↑REM latency (1 mg), and SQ |
| MacFarlane et al., 1991 [211] |
Single Blind placebo-controlled crossover | To determine the effectiveness of consecutive single evening oral doses of exo-MEL in the initiation and maintenance of sleep /chronic insomnia. | Chronic Insomnia | n=13 males 8 age range 25-65 |
Subjective TST, awareness of MEL vs. Placebo, alertness |
75 mg | 22:00 | 1 week | ↑TST and Subjective alertness |
| Haimov et al., 1995 [20] | Double-blind placebo-controlled crossover | To investigate the effects of exo-MEL replacement therapy on MEL-deficient elderly insomniacs. | Chronic Insomnia | Independently living n= 8, males 4, age 73.1±3.9 Institutionalized n= 18, males 6, age 81.1±8.9 |
Actigraphic TST, SE, SL, Mean activity level | 2mg, PR (P-1w) FR (F-1w) |
2 h before the desired bedtime | 1 week-2 month | ↑ SE and ↓Mean level activity in PR-MEL vs. placebo (after 2 months of treatment). ↓ SL and ↑ sleep maintenance in FR-MEL and PR-MEL |
| Ellis et al., 1996 [30] | Double-blind placebo-controlled crossover | To evaluate the hypnotic effect of exo-MEL in subjects with psychophysiological insomnia | psychophysiological Insomnia | n= 15 males 9 age 46±11 range 32-67 |
sleep log (BT, SOT, first wake, final wake, get up time, TST, time wake time in bed, SE), SQ, subjective sleep duration, daytime sleepiness, mood | 5 mg | 20:00 | 1 week | No changes |
| Lushington et al., 1997 [29] | Double-blind placebo-controlled, crossover | to explore the short-term effects of exo-MEL on CBT, SL and subjective vigor and affect in aged women. | Sleep maintenance Insomnia | Insomnia patients n=20 HS n= 10 All females age 65.2±7.4 |
CBT, PSG (focused on SL to S1 and S2), sleepiness and mood (VAS) | 5 mg | 14:00 | single dose | ↓ CBT, SL (stage 1 and 2) in both groups |
| Hughes et al., 1998 [21] | Double-blind placebo-controlled crossover | To assess the sleep-promoting effect of exo-MEL replacement delivery strategies in age-related sleep-maintenance insomnia. | Age-related sleep maintenance insomnia | n=14 males 5 age 70.29±1.8 |
DLMO, CBT, PSG (TST, SE, WASO, SL, TBT, SPT, WT, amount of sleep S1, S2, S3, S4 and REM, REM_L) Actigraphy (TST, SE. WASO, SL), sleep log, SQ, POMS, sleepiness and fatigue (VAS) | 0.5 mg PR and IR |
Early: IR 30m before BT Continuous: PR 30m before BT, Late: IR 4h after BT Placebo: 30m before BT 4h after BT |
Four two- week trials with two weeks of washout | ↓ SOL (PSG) ↓ CBT No changes in TST, WASO, SE, other PSG parameters, nor in subjective measurements or in DLMO profiles |
| Dawson et al., 1998 [31] | Double-blind placebo-controlled crossover | To determine whether nocturnal exo-MEL replacement, using a transbuccal delivery system, would lower core temperature and improve sleep in insomniac patients | Sleep maintenance insomnia ICSD criteria | n=12 age 65.67 ±1.68 |
PSG (TST, SOL, REM_L, EMA, percentage time awake, SE, Stage changes, SOT, WASO), spectral analysis, body temperature, aMT6S | 0.5 mg transbuccal patch | 19:00 | 4 consecutive nights | ↑ aMT.6S ↑ WASO in the first half of the night on night 4 and in whole night on night 3. ↓ Body temperature |
| Zhdanova et al., 2001 [22] | Double-blind placebo-controlled randomized | To examine the ability of similar, physiological exo-MEL doses to restore nighttime MEL levels and SE in insomniac subjects over 50 years old. | Chronic Insomnia | Patients n=15 age >50 HS n=15 age >50 |
PSG (SOL, TST, SE, WASO, AW, duration of S1, S2, S3, S4 and REM, REM_L, SWS_L), CBT, MEL | 0.1 mg, 0.3 mg, 3.0 mg |
30 min before BT | 1 week | ↑ SE (3 doses) only in insomnia patients ↓CBT (3mg) |
| Almeida Montes et al., 2003 [32] | Double-blind placebo-controlled crossover | To assess the hypnotic effect of exo-MEL in primary insomnia. | Primary Insomnia DSM-IV criteria | n=10 males 6 age 50±12.7 range 30-72 |
PSG (duration and latency of S1, S2, S3, REM, AW, TST, average length of NREM-REM cycle and SE), subjective quality and amount of sleep, Sleep log | 0.3mg, 1.0 mg PR | 1h before BT | 1 week for each treatment | No changes |
| Baskett et al., 2003 [213] | Double-blind placebo controlled randomized crossover | To determine whether exo-MEL will improve quality of sleep in healthy older people with age-related sleep maintenance problems. |
HS (normal vs. problem sleepers) |
Normal sleepers= n=20 Problem sleepers n=20 Age 71.7 ± 4.9 range 65-84 |
PSQI, LSEQ, sleep log (diary awakenings, quality scale, alertness scale), actigraphy (TIB, Sleep time, SL, AW, SE) | 5 mg | BT | 4 weeks | No changes in outcomes of interest. ↓ AW in normal sleepers |
| Leger et al., 2004 [37] | Placebo-controlled crossover | To examine the excretion of aMT6s in insomnia patients aged 55 years and its relation with the subsequent response to exo-MEL therapy. | Primary Insomnia DSM-IV criteria | n=396 males 330 age 68 ± 8 range 55-93 |
aMT6s, LSEQ domains: GTS, SQ, AFS, BFW | 2 mg | 21:00-23:00 | 3 weeks | Proportion of response in “Low excretors” response to MEL (58% [65/112] was major than in “normal excretors” 47% [122/260] in SQ and BFW |
| Wade et al., 2007 [23] | Double-blind placebo-controlled randomized parallel |
To evaluate the efficacy and safety of a prolonged-release exo-MEL formulation (PR-melatonin; Circadin 2mg) in insomnia patients aged 55 years and older. | Primary Insomnia based on the Sleep History Questionnaire (SHQ) | n = 334 (MEL= 169, PLA = 165) males 113 age aged: 65.7 ± 6.4 |
LSEQ (GTS, SQ, AFS, BFW), PSQI, subjective quality of day and quality of life, CGI, WHO-5 | 2 mg PR | 2 hours before bedtime | 3 weeks | ↑ SQ, BFW, WHO-5. ↓ SL (24.3 min vs. 12.9 min), measured through the PSQI |
| Lemoine et al., 2007 [24] | multi-center randomized placebo-controlled parallel group | To assess the efficacy and safety of exo-MEL in improving sleep quality and morning alertness in insomnia patients 55 years and older | Primary Insomnia DSM-IV criteria | n=170 males 58 age 55-93 MEL-PR n=82 PLA n=88 |
LSEQ, QON, QOD, BWSQ | 2mg PR | 1-2 h before BT (between 21:00-22.00) | 3 weeks | ↑ SQ, BFW, QON. No withdrawal symptoms |
| Luthringer et al., 2009 [25] | Double-blind, placebo-controlled, parallel group | To investigate the effects of PR exo-MEL 2mg on sleep and subsequent daytime psychomotor performance | Primary Insomnia DSM-IV criteria | n=40 males 24 MEL (n=20) Males 13 (65%) Age 59.6 ± 2.9 PLA (n=20) Males 11 (55%) Age 61.9± 4.8 |
PSG (SOL, TST, REM, NREM, SE, Number of awakenings, WASO, duration and % of sleep stages REM, NREM, SWS, REM_L, spectral analysis), LSEQ, subjective improvement SQ (VAS), cognition | 2 mg PR | 2 h before BT (between 21:00 and 23:00) |
3 weeks | ↓SOL, ↑ SQ and cognitive performance |
| Garzón et al., 2009 [28] | Prospective, randomized, double-blind, placebo-controlled, crossover |
to evaluate the effect of melatonin administration on sleep and behavioral disorders in the elderly and the facilitation of the discontinuation of regular hypnotic drugs. |
Primary Insomnia DSM-IV criteria or transient sleep disorder | n=22, males 7, age 75.8, females 15 age 74.3 | NHSMI, GDS, GAS | 5 mg | BT (aprox 23:00) | 8 weeks | ↑ SQ, nine out of 14 subjects receiving hypnotic drugs were able to discontinue this treatment during melatonin but not placebo administration. |
| Wade et al., 2010 [26] | Double-blind placebo-controlled randomized parallel group | To investigate whether exo-MEL PR efficacy is related to low endogenous MEL levels or age. And to investigate the maintenance of efficacy and the safety of exo-MEL PR beyond the acute treatment. | Primary Insomnia (DSM-IV criteria) | n=746 MEL=373 Age>65 (143) Low excretors (88) PLA=373 Age>65 (150) Low excretors (90) |
SL, PSQI, CGI, WHO-5 | 2 mg PR | 2 before BT (between 21:00 and 22:00) | Short-term: 3 weeks Long-term: 26 weeks |
↓ SL (in elderly regardless of the endogenous MEL) Low excretors: aged 18-80 years ↓ PSQIc5; ↑WHO5 Age>65 ↓ PSQI_c2, ↑sleep maintenance and PSQI total score. The effects were maintained over the 6 months protocol. |
| Wade et al., 2011 [27] | Double-blind placebo-controlled randomized | To evaluate the age cut-off for response to exo-MEL PR and the long-term maintenance of efficacy and safety in subsets of patients aged 18-54 and 55-80 years. | Primary Insomnia, DSM-IV criteria | n=722 age 18-54 (n=144) age 55-80 (n=578). |
SL, PSQI, CGI, WHO-5 | 2 mg PR | 2 h before bedtime | 3 weeks-24 weeks | ↓SL (sleep diary) (55-80 range), ↓ SL (PSQI_c2), PSQI total score (whole sample) ↑WHO-5, CGI (whole sample) |
| Chung et al., 2016 [214] |
Retrospective | To investigate patients’ satisfaction rate with exo-MEL PR when they took it after their sleep-wake cycle was set. | Primary Insomnia ICSD criteria 2° edition | n=44 males 27 age 65.9 ± 8.6 |
sleep indices extracted from interview (BT, SOT, SOFFT, SL, TIB) at baseline, satisfaction with treatment | 2 mg PR | 2 h before BT | 4 weeks | Satisfaction with MEL-PR use in 66% of patients. reduction of sleeping pill dosage by at least 50% in 44% of patients. Complete discontinuation of previous sleeping pills in 20% of patients. No significant differences in sleep indices between patients satisfied vs. dissatisfied |
| Xu et al., 2020 [212] | Double-blind placebo-controlled randomized parallel |
To determine the efficacy of exo-MEL for sleep disturbances in patients with middle-aged primary insomnia | Primary insomnia, DSM-IV criteria | MEL (n=29) Males 12 (41.38%) Age 57.24 ± 5.59 PLA (n=32) Males 17 (53.13%) Age 56.53± 4.65 |
PSG (SL, REM_L, TST, SE, Micro-arousal index, WASO, Early wake (min), % of NREM S1, S2, S3, REM), PSQI, ISI, ESS, | 3 mg IR | 1 h before BT | 4 weeks | ↓ Early wake time, S2 sleep |
Conventions: ← advance, → delay, ↑ increase, ↓ decrease, * plotted in Fig. (3b).