Table 1. Chronobiotic effect of exogenous melatonin.
| Author, Year |
Study
Design |
Aim | DX | Subjects | Variables | Dose | Timing | Duration | General Results |
|---|---|---|---|---|---|---|---|---|---|
| Wright et al., 1986 [153] | Double-blind placebo-controlled crossover | To investigate the effects of small doses of MEL administered to normal adults daily at 17:00 | HS | n=12 males 10 age range 22-46 |
MEL onset, cortisol, GH, PRL, T4, LH, and testosterone. Mood and Fatigue (VAS) | 2 mg | 17:00 | 4 weeks | ↑ Tiredness/fatigue, ← MEL onset-offset advanced in 1-3 h in 5/12 subjects (but not significant) |
| Mallo et al., 1988 [159] | Case series | To evaluate the effect of a semi-chronic treatment (with exo-MEL) on the endocrine rhythms | HS | n = 6 males 6 age range 22-26 |
MEL, cortisol, and PRL profiles | 8 mg | 22:00 | 4 days | Third day after exo-MEL withdrawal: ← MEL phase, ↑ PRL between 19:00 and 21:00 h |
| Terzolo et al., 1990 [158] | Case series | To investigate the effects of long-term exo-MEL administration on several hormones characterized by overt daily patterns of secretion | HS | n = 6 males 6 age range 23-32 |
MEL, PRL, cortisol, and testosterone phase. Hormonal levels (LH, FSH, PRL, TSH, Gn-RH, TRH, ACTH, HCG), blood pressure, heart rate | 2 mg | 18:00 | 8 weeks | ← MEL phase, morning acrophase of cortisol and testosterone |
| Lewy et al., 1992 [44] | Placebo-controlled crossover | to determine the DLMO phase in sighted individuals before and after a physiological dose of exo-MEL | HS | n=8 age range 20-48 |
DLMO | 0.5 mg | Trial 1:17/19 Trial 2:13/15, 14/16, 15/17, 16/18, 18/21. Trial 3: 12/14, 20/22, 22/24. |
1 week | ← DLMO exo-MEL CT6-CT12 (clock time: 13:00 to 19:00 h) → DLMO exo-MEL CT20-CT5 (clock time: 03:00 to 12:00) |
| Zaidan et al., 1994 [148] * |
Not specified | To evaluate the phase shift effect of exo-MEL when administered in a physiological rhythm (iv infusion) | HS | n=7 males 7 age range 25-32 |
MEL and cortisol profile (onset, offset, acrophase) | 20 µg (iv) | infusion began at 04:00 or 12:00 or 16:00 or 20:00, administered for 3 h | Single-dose for each protocol | ← MEL acrophase when exo-MEL was given at 16-19 (45±67.7min) and at 20-23 (72.8±66.7min) → MEL acrophase when exo-MEL was given between 4-7 h (23.6±38.6 min) and at 12-15 (40.7±46 min) No changes in cortisol |
| Deacon et al., 1994[147]* | Double-blind placebo-controlled crossover randomized | To describe the effects of an acute administration of exo-MEL on the phase shift of endogenous MEL and CBT | HS | n=8 males 8 age range (23-28) |
MEL onset (acute and delayed), Alertness (VAS), CBT (acute and delayed), SQ | 5 mg | 17:00 | single dose | ← CBT Acrophase ← MEL onset (1.14±0.49h), ↓ alertness, CBT (acute), ↑ SQ |
| Deacon & Arendt, 1995 [134] * | Double-blind, placebo-controlled crossover | To evaluate the dose-dependence effect of exo-MEL on temperature and endogenous MEL secretion | HS | n=6 males 3 age 27.2±3.7 |
CBT (acute and delayed), sleep log (SOT, SOFFT, n° and duration of awakenings), sleep quality (VAS), MEL plasma levels onset, alertness | 0.05, 0.5 or 5 mg | 17:00 | single dose | ↓ CBT (acute), alertness, ← sleep phase and MEL onset (0.36±0.13 h, 0.69± 0.15 h and 1.43± 0.16 h for 0.05 mg, 0.5 mg and 5 mg respectively) ← nadir of CBT, ↑QS |
| Attenburrow et al., 1995 [155]* | Double-Blind, placebo-controlled crossover | To evaluate if MEL administered to HS at 17:00 advances circadian rhythms as determined by a shift in time of onset of endogenous MEL secretion | HS | n=12 males 12 age 30 (range 21-37) |
MEL onset | 0.5 mg | 17:00 | single dose (acute), seven days (subacute) |
← MEL onset (subacute administration induced a MEL onset 50 min earlier than in placebo or acute condition) |
| Kräuchi et al., 1997 [149]* | Double-blind placebo-controlled crossover | To evaluate the phase-shifting and thermoregulatory effects of a single admin of exo-MEL or S-20098 | HS | n=8 males 8 age 27±4 range 23-32 |
DLMO, CBT, Heart rate, distal and proximal skin temperature | 5 mg | 18:00 | Single dose |
← DLMO (49 min), earlier increase in distal skin temperature, earlier decrease in CBT, heart rate, and proximal skin temperature (the day after treatment) |
| Cajochen et al., 1997 [152] | Double-blind placebo-controlled | To distinguish between circadian and non-circadian effects of exo-MEL and its repercussions on sleep architecture and EEG power density. | HS | n=8 males 8 age 27±4 range 23-32 |
Sleepiness and mood self-rating (VAS), CBT, 5-min waking EEG, all night EEG (TST, SE, SL, REM_L, S2, SWS, REM, Arousal) | 5 mg | 18:00 | Single dose | ← CBT ↑ Wakefulness in the latter one-half of the sleep episode on the posttreatment night (earlier termination of sleep period) ↑ REM (longest first REM episode) ↑ theta/alpha in the waking EEG ↑ self-reported sleepiness, |
| Middleton et al., 1997 [154] |
Double-blind placebo-controlled crossover | To investigate the effects of daily exo-MEL administration on sighted individuals kept in continuous very dim light. | HS | n=10 males 10 age 23.9±0.75 |
aMT6s, CBT, actigraphy (SOT, SOFFT) and sleep log (BT, latency, number and duration of night awakenings, wake-up time, SQ). |
5 mg | 20:00 |
(Leg 1): MEL days 1-15 (1st), PLA days 16-30 (2nd) Leg 2: crossover |
MEL1st: stabilization of sleep-wake cycle in 8/10 subjects, PLA1st: 9/10 subjects free-running MEL 2nd: ← sleep-wake cycle in 5/9, → sleep-wake cycle in 2/9 and stabilization in 2/9 subjects. Subsequent synchronization to 24h in 7/9 subjects, CBT continued to run in 4/9 subjects. aMT6s free ran in all subjects with PLA1st, and in 5/9 of MEL 1st. |
| Yang et al., 2001 [150]* | Double-blind placebo-controlled counterbalanced | To test whether a delayed weekend sleep pattern may lead to a phase delay of the endogenous circadian rhythm and whether exo-MEL may counteract the phase delay | HS | n=10 males 2 age 22.1 |
DLMO, PSG (TST, SE, WASO, S1, S2, S3, S4, SWS, NREM, REM, SOL, S2_L, SWS_L, REM_L), sleepiness (SSS), cognition, mood (VAMS) | 6 mg | 5.5 h before habitual BT (mean: 18:04) | Single dose | ← DLMO ↓ SOL and S2_L Improvement in VAMS scores (items: “sleepy”, “overall feeling better” and “alert”, “effort to do anything”) |
| Wirz-Justice et al., 2002 [151] |
Double-blind placebo-controlled randomized | To investigate the phase-shifting potential of MEL on the most probable timing for a delay in the circadian rhythms. | HS | n=9 males 9 age 23.6±2.8 |
CBT, Heart rate, DLMO | 5 mg | 07:00 | Single dose | No changes on circadian markers |
| Rajaratnam et al., 2003 [160] |
Double-blind placebo-controlled crossover | To evaluate whether an artificially prolonged MEL profile influence its own secretion and that of other endocrine parameters | HS | n=8 males 8 age 24.4±4.4 |
MEL plasma onset, cortisol peak, actigraphy (mean activity levels), sleepiness, mood, pituitary and gonadal hormones | 1.5 mg (PR) | 16:00 | 8 days | ← MEL onset and cortisol peak (difference between PLA and exo-MEL advance= 2.9 h) ↓ activity mean during the first sleep interval of an extended sleep opportunity of 16 h |
| Rajaratnam et al., 2004 [161] |
Double-blind placebo-controlled repeated-measures |
To establish whether MEL could advance the sleep timing at a time normally associated with the wake maintenance zone | HS | n=8 males 8 age 24.4±4.4 |
PSG (TST, SE, SOL, sleep timing, duration and percentage of S1,S2,S3,S4,REM, REM:NREM, S1_L, S2_L, REM_L, duration of first REM), Spectral power | 1.5 mg (PR) | 16:00 | 8 days | . ← sleep phase after exo-MEL compared to PLA. During MEL administration, S1, S2, REM longer in the first interval of sleep and shorter in the second interval. SE and TST higher in the first sleep interval and lower in the second interval compared to PLA |
| Burgess et al., 2008 [157] * | Double-blind placebo-controlled counterbalanced | To generate a new PRC to exo-MEL and to determine if any phase shift will occur when EXO-MEL taken close to habitual BT | HS | n=27 males 14 age 28.8±6.9 |
DLMO | 3 mg (FR) | Multiple | Single-dose for 3 consecutive days | ← DLMO 1.8 h (peak when exo-MEL taken 5h before DLMO), → DLMO 1.3 h (peak when exo-MEL taken 11 h after DLMO) |
| Burgess et al., 2010 [156] * | Double-blind placebo-controlled counterbalanced | To generate a PCR to 0.5 mg oral MEL and to compare it to the previously published 3.0 mg PCR using the same protocol | HS | n=34 males16 age 25.3±4.8 |
DLMO | 0.5 mg | Multiple | Single-dose for 3 consecutive days | ← DLMO maximum advance at timing 2-4 h before DLMO or 9-11 h before sleep midpoint, maximum advance of 1.5 h → DLMO maximum delay at timing 12-15 h after the DLMO (13.6 h after the DLMO or within 4 h after wake time, maximum delay of 1.3 h |
| Arendt et al., 1988 [162] | Single-blind placebo-controlled | To evaluate the efficacy of an exo-MEL treatment in a free-running blind patient | BFR | n=1 59-year-old man |
Sleep log (Lights-off, SOL, SOFFT, SOT, AW), SQ, aMT6S (Acrophase). | 5 mg | 21:00-24:00 | 4 weeks | ↓ day sleeps, “some modification of the endogenous rhythm”: aMT6S acrophase delay with respect to the acrophase predicted the end of the treatment, enhanced well-being. |
| Folkard et al., 1990 [163] | Single-blind placebo-controlled | To evaluate the effects of exo-MEL on sleep and circadian rhythms of cortisol, temperature, and MEL in a free-running blind patient | BFR | n=1 60-year-old man |
Rectal temperature, alertness, calmness, elation, sleep log, cortisol, and aMT6S profiles | 5 mg | 23:30 | 4 weeks | ↑ TST and MOOD ↓ naps and variability in sleep onset. No changes in temperature. MEL and cortisol free-run rhythms. |
| Sarrafzadeh et al., 1990 [164] |
Case report | To evaluate the effects of exo-MEL on sleep in a blind patient with delayed cortisol and melatonin rhythms | BFR | n=1 76-year-old man |
Sleep log (lights-off, SOL, SOT, SOFFT, AW), SQ, aMT6S and cortisol acrophase, Mood and fatigue (VAS) | 5-6 mg | 23:30 and 20:00 | 4 and 2 weeks respectively | ← SOT and SOFF ↓ SL, AW, naps, ↑ SQ and mood No changes in MEL and cortisol profiles |
| Sack et al., 1991 [166] | Double-blind placebo-controlled | To test the phase-shifting and entraining effects of MEL in human subjects. | BFR | n=5 males 5 age range 30-41 |
Plasma MEL and cortisol | 0.5 mg 5 mg | 22:00 | 21 days | ← MEL and cortisol rhythms |
| McArthur et al., 1996 [171] |
Case report | To report a Non-24h patient with a baseline circadian period of 25.1 hours whose free-running sleep-wake cycle was treated with exo-MEL | BFR | n=1 41-year-old man |
DLMO, PSG (TST and sleep stages) Actigraphy (TST, SE), sleep log | 0.5 mg | 21:00 (initiated when DLMO near to 21:00) | 4 weeks | Regularization to a circadian period of 24.1 hours, the morning awakening become uniform and was locked to the DLMO. |
| Masaaki et al., 1997 [174] | Case report | To describe a MEL treatment in two patients with non-24 h syndrome | FR | Patient 1: female 34-year-old Patient 2: male 23-year-old |
Subjective difficulty in falling asleep, sleep-wake patterns | 2-10 mg 1-5 mg |
24:00-22:00 23:00 |
-- | Patient 1: Difficult to fall asleep and waking, without changes in sleep-wake patterns. Patient 2: sleep-wake patterns change from free-running to DSPD (transiently) |
| Siebler et al., 1998 [173] | Case report | Clinical case description | FR | n=1 female 23-years-old |
sleep-wake patterns | 5 mg | 21:00-22:00 | 6 years | Stabilization of sleep-wake patterns |
| Lockley et al., 2000 [167] | Single-blind placebo-controlled | To assess the ability of exo-MEL to entrain the circadian system of free-running blind subjects. | BFR | n=7 males 7 age range 33-60 |
Cortisol, aMT6s, CBT | 5 mg | 21:00 | 31-71 days | Entrainment of circadian rhythms to a 24.0 period in 4/7 patients, |
| Sack et al., 2000 [168] | Single-blind placebo-controlled crossover | To investigate whether a daily dose of MEL could entrain the circadian rhythms to a normal 24 hour cycle | BFR | n=7 males 7 age range 42-57 |
MEL profile, PSG (TST, SL, SE, WASO) | 10 mg | 1 h before BT | 3-9 weeks | MEL rhythm entrained to a 24h cycle in 6 of 7 patients, ↓ WASO, ↑ SE |
| Lewy et al., 2001 [170] | Case series | To evaluate if exo-MEL can a de novo (starting) dose of 0.5 mg initially capture free-running rhythms | BFR | n=3 males 1 age range 42-47 |
MEL profiles | 0.5 mg | 1 or 2 h before BT | -- | All three subjects entrained circadian rhythms of MEL onset to the de novo 0.5 mg dose. |
| Lewy et al., 2002 [165] | Case report | To evaluate whether exo-MEL at 20 mg may entrain the circadian rhythm of a free-running blind patient with a long circadian period (24.9h) | BFR | n=1 male 46-year-old |
MEL profiles | 20 mg and 0.5 mg | 1 h before BT | 47 days | Entrained circadian rhythms to a 24h with 05mg treatment |
| Hack et al., 2003 [169] | Single-blind placebo-controlled | To assess further the entraining effects of exo-MEL on the cortisol rhythm and its acute effects on subjective sleep in blind subjects with free-running aMT6s rhythms | BFR | n=10 males 9 age range 32-65 |
Sleep log (SL, SOT, AW, SOFFTT, TST, N of naps), SQ, aMT6S at baseline and cortisol acrophase. | 0.5 mg | 21:00 | 26-81 days | 7/10 subjects treated with exo-MEL at individual CT10 to CT 16: entrainment or shortened of cortisol period, 2/10 subjects treated with exo-MEL at CT22, CT3: continued to free-run. ↑ TST, ↓ naps and AW, → SOFFT |
| Lewy et al., 2004 [172] | Double-blind placebo-controlled | To describe the response to a treatment with low doses of exo-MEL, initiated in the phase delay zone of the PCR. | BFR | n=7 males 4 age range (21-67) |
DLMO | 0.05 to 0.5 mg | 1 h before preferred BT (predicted to be locked with the “delay zone” of the MEL PCR). | Range 54-367 days) | Eventually all subjects entrained their circadian rhythm, reduction in circadian period (from 24.51h to 23.99h). Treatment takes between 37 to 52 days until entrainment |
| Dahlitz et al., 1991 [175] | Double-blind placebo-controlled randomized | To report the action of exo-MEL on sleep-wake cycle in 8 subjects with DSPD | DSPD | n=8 males 8 age range 14-61 |
PSG (REM_L, NREM SL), Sleep Log (BT, SOT, SOFFT, TST), Alertness (self-rating), motor activity, plasma MEL and urinary aMT6s at baseline | 5 mg | 22:00 (5 h before SOT determined by pretrial sleep log) | 4 weeks | ← SOT and SOFFT ↓ SL ↓ TST (slight) |
| Tzischinsky et al., 1992 [184] |
Case report | To evaluate the influence of the exo-MEL timing in the treatment of sleep disturbances in a blind young man. | DSPD Blind | n=1 18-year-old man |
Oral temperature, actigraphy (SOT, TST, SE), subjective alertness | 5 mg | 20:00 | 3 weeks | ← Temperature acrophase (3h) ← SOT (1h) ↑ TST ↑ daytime alertness |
| Alvarez et al., 1992 [176] | Placebo-controlled | To report a series of 14 subjects with a DSPS seen over five-year period in a sleep disorders clinic, presenting with primary complaint of insomnia | DSPD | N=14 (MEL=8) |
Sleep-log (SOT, SOFFT), alertness self-rating scales plasma MEL, aMT6s | 5 mg | 22:00 (Aprox 5h before SOT= 03:11 ± 0:50) | 4 weeks | ←SOT (82 min) and SOFFT (117 min) |
| Oldani et al., 1994 [177] | Case series | To objectively evaluate the efficacy of exo-MEL with an optimal and proper scheduling, in advancing the sleep wake rhythm in patients with DSPD | DSPD | n=7 males 4 age range 14-46 |
PSG (SOT, SOFFT, TST, SL, WASO, AW, % S1, S2, S3-4, REM, REM_L, SS (number of stage shifts per hour of sleep), | 5 mg | Between 17:00 and 19:00 (9h prior to the SOT =216±61 min after midnight) | 4 weeks | ←SOT (115 min) and SOFFT (106 min) |
| Laurant., 1997 [188] | Single blind placebo-controlled crossover randomized | To investigate the influence of 5 mg MLT on vigilance and cognitive processing speed in DSPS | DSPD | n=24 | Cognition | 5 mg | Not specified | 2 weeks | ↑ Cognitive performance |
| Nagtegaal et al., 1998 [180] |
Double-blind placebo-controlled crossover | To establish the effectiveness of exo-MEL administered to DSPS patients 5 h before their individual DLMO, in advancing the timing of sleep and the circadian rhythms | DSPD | n=30 males 14 age 37.3±15.3 |
DLMO, CBT, PSG (SOL, SOT, REM_L, amount of REM sleep, n° and duration of AW, actual sleep time, SWS duration, actigraphy (SOT, SOL), sleep log (SL. SOT, SOFT, WASO, SE, TST) and subjective sleep quality | 5 mg | 5h before individual DLMO (mean DLMO at baseline: 23:17h (mean timing: 18:17). | 2 weeks | ←DLMO (98 ± 69min) ←SOT ↓SL ↑ MOOD |
| Okawa et al., 1998 [185] | Case series | Not reported | DSPD and NON-24 | 9 DSPD, 2 Non24 n=11 males 8 age range 16-46 |
Sleep log, actigraphy, CBT | 1-3 mg | 0.5 to 2 h before BT | not reported | positive effects from exo-MEL treatment in 6/11 patients (variables measured not reported) |
| Dagan et al., 1998 [187] | -- | To examine the efficiency of exo-MEL treatment in DSPD subjects by means of subjective reports | DSPD | n=61 males 37 age 27.38 ±10.67 |
Survey of exo-MEL effectiveness one year after the treatment | 5 mg | 22:00 | 6 weeks | 96.7% of patients report that exo-MEL treatment was helpful. Relapse was reported with variable timing of appearance. Relapse was associated with more delayed baseline patterns |
| Kamei et al., 2000 [186] | Case series | To investigate the effects of exo-MEL on CRSD and the clinical characteristics of MEL responders | DSPD and NON-24 | DSPD n=30, males 22, age 24±7.6 NON-24 n=16 males 11, age 20.05±7.6 |
Sleep log and wrist actigraphy | 0-3-1 mg | 5,3 and 1 h before BT | not reported | 40% of DSPD patients and 31% of Non 24h patients showed positive effects from exo-MEL treatment (variables measured not reported) |
| Kayumov et al., 2001 [178] |
Double-blind placebo-controlled crossover randomized | to investigate the effect of exo-MEL on DSPS | DSPD | n=22 males 15 age 35.6±14 females 7 age 30.8±12.4 |
PSG (SOL, TST, SE, WASO, Arousal, % of S1, S2, S3, S4, REM, REM_L, REM), aMT6s, SSS, Fatigue, alertness, cognition | 5 mg | 19:00 (week1), 19:00-21:00 (week 2-3), timing chosen by the patient (week 4) | 4 weeks | ↓ SOL, SSS, composite fatigue score circadian pattern of MEL secretion was normalized in 3 of 5 patients with an abnormal circadian pattern at baseline |
| Mundey et al., 2005 [181] | Double-blind placebo-controlled parallel Randomized | To assess the effectiveness of exo-MEL (0.3 or 3.0 mg) to advance circadian and sleep phase with timing ranging between 1.5 and 6.5 h prior to DLMO. | DSPD | n=13 (PLA=4, exo-MEL=9) males 8 age range 23--42 |
DLMO, CBT, Actigraphy and sleep log (SO, SOFFT, TST, SE, SL) | 0.3 or 3.0 mg | 1.5 and 6.5 h before DLMO. (1h earlier in weeks 3 and 4) Baseline mean DLMO: 23:46±1.62 | 4 weeks | ← DLMO and CBT (1.75 ± 0.89 hours, and 1.63 ± 1.79 hours, respectively). |
| Rahman et al., 2010 [189] | Double-blind placebo-controlled Crossover randomized | To investigate the role of exo-MEL as a chronobiotic in ameliorating depressive symptomatology in DSPS patients. | DSPD | n=20 With depressive symptoms n=8, males 5, age 31.5±7.2. Without depressive symptoms n=12, males 8, age 36.2±17.7 |
HDRS-17, CES-D, PSG (SOL, TST, SE, WASO, Arousal index, Alpha score, %S1,S2,S3,S4,REM, SWS 1st cycle, SWS 2nd cycle, REM_L, REM episodes), aMT6s (baseline) | 5 mg | 19:00-21:00 h | 4 weeks | ↓ SOL ↓HDRS-17 and CES-D scores |
| Abbas et al., 2010 [183] | Case report | To describe a clinical case of DSPD treated with exo-MEL. | DSPD | n=1 53-year-old man |
aMT6 and sleep patterns | 3 mg | 20:00 | Regularization of sleep pattern and aMT6 excretion | |
| Sletten et al., 2018 [182] | Double-blind placebo-controlled randomized | To test the efficacy of exo-MEL in DSPD using a pragmatic, clinically relevant protocol that included behavioral sleep-wake scheduling (sleeping at desired or required bedtime). | DSPD | n=104 (MEL n=54, males 28, age 29.9±9.63 PLA n=50, males 25, age 28.8±10.46 |
DLMO, actigraphy and sleep log (TST, SE, WASO, SOT, SOFFT), CGI-S, PSQI, ESS, MEQ, ISI, BDI-II, BAI | 0.5 mg (FR) | 1 hour before DBT | 28 days | ←SOT, ←SOFFT ↑ SE ↑ GCI ↓ Sleep disturbance (PSQI) ↓ ISI, ↓ SOL No significant differences in DLMO between exo-MEL and PLA (exo-MEL: DLMO ← 0.73 ± 1.21 h. PLA: DLMO ← 0.24 ± 1.11 h [difference:0.49 min]) |
Conventions: ← advance, → delay, ↑ increase, ↓ decrease, * plotted in Fig. (3a).