Table 3.

Summary of Safety and Efficacy of Melatonin or Prolonged-Release Melatonin

Study	Participant Characteristics	Outcome Measures	Principal Findings/Outcomes	Secondary Observations and Adverse Events	Interpretation and Limitations	Overall Assessment of the Dataa
Healthy volunteers with or without occasional disturbed sleep
Baskett et al (2003)26 Design: randomized, double-blind, placebo-controlled, cross-over, self-report Arms: melatonin 5 mg/d (fast-release capsule) vs placebo Schedule: 4 wk	Normal vs problem sleepers ≥ 65 y N = 20/group (mean age: 71.1 y, 68% female)	Primary: actigraphy measures of sleep latency, sleep time, no. of awakenings, sleep efficiency Secondary: sleep diary, awakenings, LSEQ, alertness	Melatonin vs placebo: no significant differences in either group on any of the primary outcome measures, except fewer number of awakenings measured by actigraphy (36.4 vs 40.2*) in normal sleepers	Response to melatonin was not dependent on low vs high secretion of endogenous melatonin Very few adverse events were reported	Melatonin demonstrated no significant effects on sleep latency, maintenance, or quality in older individuals (≥ 65 y) Study was sufficiently powered	–
Peck et al (2004)27 Design: randomized, double-blind, placebo-controlled, self-report Arms: melatonin 1 mg/d (Schiff) vs placebo Schedule: 4 wk	Healthy volunteers 64–89 y N = 26 (characteristics not provided)	Primary: 7-item Sleep Interview and 21-item sleep questionnaire VAS (melatonin vs placebo baseline to wk 4) Secondary: various cognitive assessments (conducted at end of study in afternoon)	Melatonin vs placebo: improved morning “restedness” (4.6 vs 3.6* VAS) No other significant effects on sleep-related measures	Melatonin vs placebo: improved CVLT verbal recall at wk 4 (9.3 vs 8.6*) No reported adverse events on exit interview with melatonin	Melatonin improved morning “restedness” and scores on the CVLT interference subtest Limitations: pilot study	U
Diagnosed insomnia
Almeida Montes et al (2003)28 Design: randomized, double-blind, placebo-controlled, cross-over, objective, self-report Arms: sustained-release synthetic melatonin 0.3, 1.0 mg/d (Cronocaps) vs placebo Schedule: 1 wk	DSM-IV primary insomnia N = 10 (mean age: 50 y, 40% female)	Primary: PSG, sleep diary, VAS	No significant differences among treatments on PSG parameters (including sleep architecture) and subjective reports of sleep onset, no. of awakenings, total sleep time, and sleep quality	No differences in reported adverse events among treatments	7-day treatment with melatonin did not produce any sleep benefits in patients with primary insomnia Limitations: small sample size and variable ages (30–72 y)	–
Lemoine et al (2007)29 Design: randomized, double-blind, placebo-controlled, multicenter, self-report Arms: prolonged-release melatonin 2 mg/d (Circadin) vs placebo Schedule: 3 wk	DSM-IV primary insomnia ≥ 55 y N = 170 (mean age: 68.5 y, 66% female)	Primary: change in LSEQ quality and morning alertness (prolonged-release melatonin vs placebo baseline to wk 3) Secondary: sleep diary (quality), rebound and withdrawal effects, adverse events	Prolonged-release melatonin vs placebo: improved LSEQ sleep quality (–22.5 mm vs –16.5 mm*) and morning alertness (–15.7 vs –6.8 mm**)	Prolonged-release melatonin vs placebo: improved sleep quality (diary) (0.89 vs 0.46 unit improvement**) No rebound or withdrawal symptoms Well tolerated, treatment-emergent adverse events (9 subjects in each arm)	Prolonged-release melatonin improved sleep quality and morning alertness suggesting more restorative sleep, with no rebound or withdrawal symptoms after treatment discontinuation	+
Wade et al (2007)30 Design: randomized, double-blind, placebo-controlled, self-report Arms: prolonged-release melatonin 2 mg/d (Circadin) vs placebo Schedule: 3 wk	DSM-IV or ICD-10 diagnosis of primary insomnia 55–80 y N = 334 (mean age: 65.7 y, 60% female)	Primary: responder rate analysis on sleep quality and morning alertness of (baseline to wk 3) ≥ 10 mm on both outcomes Secondary: sleep diaries, PSQI, CGI, WHO-5 QoL, adverse events	Prolonged-release melatonin vs placebo: higher responder rate for change (sleep quality and morning alertness) from baseline to wk 3: (26% vs 15%*)	Prolonged-release melatonin vs placebo: improved sleep quality LSEQ (–8.6 vs –4.2*), next-day alertness LSEQ (–7.0 vs –4.1*), and QoL (1.7 vs 1.1*) scores Well tolerated, adverse events reported by 24% (prolonged-release melatonin) vs 21% (placebo)		+
Diagnosed insomnia
Garzón et al (2009)31 Design: randomized, double-blind, placebo-controlled, cross-over, self-report Arms: melatonin 5 mg/d (Helsinn Chemicals SA) vs placebo Schedule: 8 wk	DSM-IV primary insomnia or transient insomnia ≥ 65 y N = 22 (mean age: 75 y, 68% female)	Primary: sleep quality (38-item NHSMI) (prolonged-release melatonin vs placebo wk 8); ability to discontinue hypnotic drug (benzodiazepine) treatment Secondary: VAS depression (GDS) and anxiety (GAS), adverse events	Melatonin vs placebo: improved sleep quality (1.78 vs 3.44*) and greater benzodiazepine discontinuation rate***	Melatonin vs placebo: reduced depression GDS (5.61 vs 7.06*) and anxiety GAS (0.5 vs 1.5**) scores No adverse events reported for melatonin; no significant changes in clinical laboratory tests	8-wk treatment with melatonin improved sleep quality, reduced depression and anxiety, and facilitated discontinuation of conventional hypnotic drugs in older individuals Limitations: potential interactions with concomitant benzodiazepine treatment	+
Luthringer et al (2009)32 Design: randomized, double-blind, placebo-controlled, objective, self-report Arms: prolonged-release melatonin 2 mg/d (Circadin) vs placebo Schedule: 3 wk	DSM-IV primary insomnia ≥ 55 y N = 40 (mean age: 61 y, 40% female)	Primary: PSG (prolonged-release melatonin vs placebo wk 3); next-day effects (Leeds Psychomotor Test battery) and rebound effects Secondary: LSEQ, adverse events	Prolonged-release melatonin vs placebo: reduced SOL by 9 min (13.7 vs 22.6*) No change in other PSG variables/sleep architecture No next-day psychomotor impairment (prolonged-release melatonin significantly better than placebo) or rebound effects	Improvement on LSEQ sleep quality in prolonged-release melatonin compared with baseline (but not different from placebo) No treatment-related adverse events	Prolonged-release melatonin reduced time to sleep onset without affecting other PSG endpoints, including sleep architecture in insomnia patients aged ≥ 55 y, with no next-day impairment or rebound effects Limited effects on sleep quality	+
Wade et al (2010, 2011)33,34 Design: randomized, double-blind, placebo-controlled, self-report Arms: prolonged-release melatonin 2 mg/d (Circadin) vs placebo Schedule: 3 wk followed by a 26-wk double-blind extension	DSM-IV primary insomnia (sleep latency > 20 min) 18–80 y N = 722 (mean age: 61.7 y, 68.8% female) Low melatonin excretors: n = 172 (mean age: 63.8 y, 74.4% female) Older individuals 65–80 y: n = 281 (mean age: 71.0 y, 64.8% female)	Primary: sSL (prolonged-release melatonin vs placebo change from baseline to wk 3) for low (≤ 8 μg) melatonin excretors and in older individuals (aged 65–80 y) Secondary: sleep diary, PSQI, CGI-I, WHO-5 Index, adverse events, includes 26-wk extension Wade et al (2011)34: sSL by age (18–54 y, 55–80 y)	Prolonged-release melatonin vs placebo: no change in sSL with low endogenous melatonin (–9.0 vs –9.0 min) Prolonged-release melatonin reduced sSL (–19.1 vs placebo –1.7 min**) in subjects 65–80 y regardless of melatonin levels Wade et al (2011)34: prolonged-release melatonin vs placebo: at 3 wk, significant reduction in sSL for 55–80 y (–15.4 vs –5.5 min*) but not for overall (18–80 y) (–14.6 vs –7.9 min) or 18–54 y (–11.0 vs –16.6 min) At 26 wk, significant reduction in sSL for subjects 55–80 y and overall 18–80 y	Some secondary outcomes favored prolonged-release melatonin in older individuals and low excretors over short (3 wk) and long-term (26 wk) Sustained long-term prolonged-release melatonin effects on sSL (65–80 y) Safety profile similar between placebo and prolonged-release melatonin Drug-related adverse events for 3 wk: prolonged-release melatonin (5.36% patients) vs placebo (6.1%); for 26 wk, prolonged-release melatonin (17.3%) vs placebo (12.9%) No withdrawal symptoms after discontinuation of prolonged-release melatonin Wade et al (2011): other secondary measures were significant, favoring prolonged-release melatonin in overall 18–80 y and subgroup 55–80 y at 3 wk and 26 wk	Low melatonin production regardless of age is not useful for predicting response to prolonged-release melatonin Prolonged-release melatonin promoted sleep onset in the older group, but not in low excretors Long-term, sustained effects on subject-reported sleep latency and other secondary measures with prolonged-release melatonin, particularly in insomnia patients aged ≥ 55 y Prolonged-release melatonin was well tolerated and did not cause withdrawal or rebound effects at discontinuation following 3 or 26 wk of treatment Limitations: no objective measures; lack of effect in low excretors may be due to high percentage of younger subjects Fewer number of subjects in study aged 18–54 y vs 55–80 y; study failed to meet statistical power requirements for subgroups	+

^aThe last column provides overall assessment of the data: + = positive study (met primary endpoint and supports use as a sleep aid), – = negative study (did not meet primary endpoint and does not support use as a sleep aid), U = unclear (study interpretation is unclear with regard to use as a sleep aid).

^*P < .05.

^**P < .01.

^***P < .001.

Abbreviations: CGI-I = Clinical Global Impressions–Improvement, CVLT = California Verbal Learning Test (recall after interference), GAS = Goldberg Anxiety Scale, GDS = Geriatric Depression Scale, LSEQ = Leeds Sleep Evaluation Questionnaire (10-cm visual analog scale to rate sleep quality), NHSMI = Northside Hospital Sleep Medicine Institute test, PSG = polysomnography, PSQI = Pittsburgh Sleep Quality Index, QoL = quality of life, SOL = sleep onset latency/latency to persistent sleep via PSG, sSL = sleep latency by participant report, VAS = visual analog scale, WHO-5 = World Health Organization 5-item Well-Being Index.