Hajak & Zisapel2020. Hajak G, Lemme K, Zisapel N. Lasting treatment effects in a postmarketing surveillance study of prolonged-release melatonin. Int Clin Psychopharmacol. 2015 Jan;30(1):36-42. https://doi.org/10.1097/YIC.0000000000000046
https://doi.org/10.1097/YIC.000000000000...
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Prospective cohort study |
597 patients (210 men and 387 women) |
To investigate the effects of interruption, withdrawal and rebound from Circadin®. |
2 mg 2 hours before sleep for 3 weeks |
Sleep quality was classified as 1 = very good, 2 = good, 3 = regular, 4 = poor and 5 = very poor. Morning alertness was classified as 1 = fully alert, 2 = alert, 3 = regular, 4 = tired and 5 = very tired. Improvement or worsening of sleep quality or morning alertness was defined as a change (decrease) of at least one point from the baseline. |
75% of patients reported that sleep quality and morning alertness had improved to at least regular to good or very good. No serious adverse effects have been reported. |
Culpepper & Wingertzahn2121. Culpepper L, Wingertzahn MA. Over-the-counter agents for the treatment of occasional disturbed sleep or transient insomnia: a systematic review of efficacy and safety. Prim Care Companion CNS Disord. 2015 Dec 31;17(6):10. https://doi.org/10.4088/PCC.15r01798
https://doi.org/10.4088/PCC.15r01798...
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Systematic review |
1344 patients aged ≥ 55 years old |
To investigate the level of evidence that supports the use of over-the-counter agents: diphenhydramine, doxylamine, melatonin and valerian for occasional sleep disorders or insomnia. |
5 mg daily for 8 weeks 2 mg daily for 3 weeks |
Primary: sleep latency actigraphy, sleep time, awakenings, sleep efficiency Secondary: sleep diary, awakenings, alertness. |
It appears to be effective for symptoms associated with onset of sleep and shows a favorable tolerability profile, but the effects may be limited to individuals over 55 years old with insomnia. |
Wright et al. 2222. Wright A, Diebold J, Otal J, Stoneman C, Wong J, Wallace C, et al. The effect of melatonin on benzodiazepine discontinuation and sleep quality in adults attempting to discontinue benzodiazepines: a systematic review and meta-analysis. Drugs Aging. 2015 Dec;32(12): 1009-18. https://doi.org/10.1007/s40266-015-0322-5
https://doi.org/10.1007/s40266-015-0322-...
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Systematic review and meta-analysis |
322 patients with a mean age of 64 years old |
To determine the effect of melatonin compared to placebo on discontinuation of benzodiazepines, in addition to determining the effect of melatonin on sleep quality in this population. |
2 to 5 mg once a day before bed 4 -18 weeks |
Pittsburgh sleep quality score. |
The effect of melatonin on sleep quality was inconsistent. |
Foley & Steel2323. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: a critical systematic review of clinical evidence. Complement Ther Med. 2019 Feb;42:65-81. https://doi.org/10.1016/j.ctim.2018.11.003
https://doi.org/10.1016/j.ctim.2018.11.0...
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Systematic review |
Patients from 1 to 8 years old; 50 to 85 years old with Alzheimer’s, 16-25 years old with chronic sleep problems, 3 to 16 years old with autism and sleep disorders |
To explore the available clinical evidence on the safety of oral use of melatonin. |
2 to 10 mg Period: 3 to 5 years old |
Questionnaire applied weekly. Hematology, electrolytes, urinalysis, physical examination. Holter monitoring 24 hours by electrocardiogram. Selection of cognitive, psychomotor, dexterity and memory recall tasks. Simulated driving task, sedation scale and radioimmunoassay. |
Supplementation appears to be relatively safe. Adverse events are generally minor. |
Williams et al.2424. Williams WPT, McLin DE, Dressman MA, Neubauer DN. Comparative review of approved melatonin agonists for the treatment of circadian rhythm sleep-wake disorders. Pharmacotherapy. 2016 Sep;36(9):1028-41. https://doi.org/10.1002/phar.1822
https://doi.org/10.1002/phar.1822...
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Review |
Patients older than 55 years old |
To compare the pharmacokinetic and pharmacodynamic properties of agomelatine, prolonged release melatonin and ramelteon, to examine the impact of pharmacological properties on clinical efficacy. |
2 mg day, 1 - 2 hours before bed for up to 13 weeks |
Sleep latency, sleep onset time, number and duration of naps. |
Adverse reactions: headache, nasopharyngitis, back pain, arthralgia, and potential for hepatic metabolism interaction with other drugs Pharmacokinetic parameters: Absolute bioavailability 15%, T 1/2, average 3.5-4.0 hours, T max, interval, hours 0.75-3.0. In vitro protein binding: ~ 60%, mainly for albumin, α 1- acid glycoprotein and high-density lipoprotein. |
Mccleery & Sharpley2525. McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in dementia. Cochrane Database Syst Rev. 2016 Nov 16;11(11):CD009178. https://doi.org/10.1002/14651858.CD009178.pub3
https://doi.org/10.1002/14651858.CD00917...
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Systematic review |
222 patients |
To evaluate common adverse effects, compared to placebo for sleep disorders in people with dementia. |
Up to 10 mg 8 to 10 weeks |
Total night sleep time, proportion of day sleep to night sleep. |
There is no evidence that it helped with sleep disorders in patients with moderate to severe dementia due to Alzheimer's disease. |
Cardinali et al. 2626. Cardinali DP, Golombek DA, Rosenstein RE, Brusco LI, Vigo DE. Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse. Pharmacol Res. 2016 Jul;109:12-23. https://doi.org/10.1016/j.phrs.2015.08.016
https://doi.org/10.1016/j.phrs.2015.08.0...
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Review |
Patients aged 20 to 90 years old |
To discuss the available data on the effectiveness of melatonin to reduce chronic use of benzodiazepine drugs in patients with insomnia. |
1 mg, 2 mg, 3 mg, 5 mg, 10 mg 1 day - 18 months |
Daily records of sleep and quality of wakefulness filled in by patients, and polysomnography. |
It has a very safe profile, is well tolerated and, in some studies, has been administered to patients in very large doses and for long periods, without any potential for drug abuse. Several studies have found that more than 50% of patients treated with benzodiazepines discontinue use after treatment with melatonin. Melatonin may become the therapy of choice to reduce dependence on benzodiazepine medications. |
Chang et al. 2727. Chang Y-S, Lin M-H, Lee J-H, Lee P-L, Dai Y-S, Chu K-H, et al. Melatonin supplementation for children with atopic dermatitis and sleep disturbance: a randomized clinical trial. JAMA Pediatr. 2016 Jan;170(1):35-42. https://doi.org/10.1001/jamapediatrics.2015.3092
https://doi.org/10.1001/jamapediatrics.2...
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Randomized, double-blind, placebo-controlled clinical trial. |
73 children and adolescents of 1 to 18 years old with attention deficit. |
To evaluate the effectiveness of melatonin supplementation to improve sleep disorders and disease severity in children with Atopic Dermatitis. |
3 mg or placebo daily for 4 weeks |
Actigraphy, subjective change in sleep and dermatitis, sleep variables measured by polysomnography, nocturnal urinary levels of 6-sulfatoxymelatonin and serum immunoglobulin levels. |
Melatonin supplementation is a safe and effective way to improve sleep onset latency and disease severity in children with Atopic Dermatitis. |
Auld et al.1111. Auld F, Maschauer EL, Morrison I, Skene DJ, Riha RL. Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders. Sleep Med Rev. 2017 Aug;34:10-22. https://doi.org/10.1016/j.smrv.2016.06.005
https://doi.org/10.1016/j.smrv.2016.06.0...
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Systematic review and meta-analysis |
1500 patients of 18 and 80 years old |
To assess the evidence base for the therapeutic effects of exogenous melatonin in treating primary sleep disorders |
0.1 a 10mg for five weeks |
Sleep parameters: primary insomnia, delayed sleep phase syndrome, non 24 hours sleep wake syndrome in blind patients and REM-behaviour disorder |
Reduction in the time to fall asleep between the effect on sleep onset latency for melatonin in patients with primary insomnia. Treating delayed sleep phase syndrome demonstrated an overall significant improvement in sleep onset latency compared with placebo. |
Madsen et al.3030. Madsen MT, Isbrand A, Andersen UO, Andersen LJ, Taskiran M, Simonsen E, et al. The effect of MElatonin on Depressive symptoms, Anxiety, CIrcadian and Sleep disturbances in patients after acute coronary syndrome (MEDACIS): study protocol for a randomized controlled trial. Trials. 2017 Feb 23;18(1):81. https://doi.org/10.1186/s13063-017-1806-x
https://doi.org/10.1186/s13063-017-1806-...
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Randomized, double-blind, placebo-controlled clinical trial. |
240 patients |
To investigate whether prophylactic treatment with melatonin has a preventive effect on depression, depressive and anxiety symptoms, sleep and circadian disorders after Acute Coronary Syndrome. |
25 mg for 12 weeks. |
Actigraphy, Pittsburgh sleep diary, pain, anxiety, fatigue and general well-being measured by visual scales. |
It may have advantages due to its low toxicity, as well as its proven anxiolytic and hypnotic effects. |
Riemann et al.99. Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Groselj LD, Ellis JG, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017 Dec;26(6):675-700. https://doi.org/10.1111/jsr.12594
https://doi.org/10.1111/jsr.12594...
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Clinical Guideline |
Different populations with insomnia. 4099 patients |
To provide clinical recommendations for the management of adult patients with insomnia. |
0.3 - 40 mg 12 weeks |
Sleep parameters: objective and subjective, number of awakenings, sleep efficiency; sleep onset latency; total sleep time, awakenings after sleep onset. |
Reduces sleep onset latency, improves sleep quality. However, the effects were small from a clinical point of view. It has been regarded as a safe medicine. |
Abdelgadir et al.3131. Abdelgadir IS, Gordon MA, Akobeng AK. Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis. Arch Dis Child. 2018 Dec;103(12):1155-62. https://doi.org/10.1136/archdischild-2017-314181
https://doi.org/10.1136/archdischild-201...
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Systematic review and meta-analysis |
682 children aged <18 years with neurodevelopmental disorders |
To determine the efficacy and safety of melatonin as therapy for sleep problems in children with neurodevelopmental disorders |
0.1 - 12mg 1 a 13 weeks |
Sleep parameters: total sleep time, sleep onset latency, frequency of nocturnal awakening, adverse events and child´s behaviour |
Melatonin improves total sleep time and sleep onset latency in children with neurodevelopmental disorders, with few adverse events related |
Maras et al.3232. Maras A, Schroder CM, Malow BA, Findling RL, Breddy J, Nir T, et al. Long-term efficacy and safety of pediatric prolonged-release melatonin for insomnia in children with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2018 Dec 10;28(10):699-710. https://doi.org/10.1089/cap.2018.0020
https://doi.org/10.1089/cap.2018.0020...
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A prospective double-blind randomized placebo-controlled |
95 patients aged between 2 to 17.5 years old with Autism Spectrum Disorder. |
To describe long-term efficacy and safety of pediatric-appropriate prolonged-release melatonin at the optimal daily dose and impact of the treatment on caregivers’ sleep, daytime sleepiness, and quality of life. |
2.5 a 10mg for 13, 39 and 52 weeks |
Sleep parameters: Sleep and Nap Diary, Composite Sleep Disturbance Index, caregiver’s Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and quality of life |
After 52 weeks of continuous treatment subjects slept 62.08 minutes longer, fell asleep 48.6 minutes faster (p <0.001), had 89.1 minutes longer uninterrupted sleep episodes e less nightly awakenings and better sleep quality compared with baseline and placebo-randomized group. The drug was generally safe; most frequent treatment-related adverse events were fatigue and mood swings. |
Quera - Salva & Claustra3333. Quera-Salva M-A, Claustrat B. Melatonin: physiological and pharmacological aspects related to sleep: the interest of a prolonged-release formulation (Circadin®) in insomnia. Encephale. 2018 Dec;44(6):548-57. https://doi.org/10.1016/j.encep.2018.06.005
https://doi.org/10.1016/j.encep.2018.06....
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Review |
Insomnia patients aged 55 years old or older. |
To provide data on the physiological and pharmacological effects of melatonin related to sleep. |
2 mg for 3 months |
Sleep quality, sleep latency assessed by the falling asleep score, performance the next morning assessed by the behavior score upon awakening and improvement in quality of life. |
Benefits: improvement in sleep quality and latency, alertness the next day, and quality of life. Absence of rebound, abstinence or hangover effect, and without safety concerns in concomitant therapy with antihypertensive, antidiabetic, lipid-lowering or anti-inflammatory drugs. |
Zwat et al.3434. Zwart TC, Smits MG, Egberts TCG, Rademaker CMA, van Geijlswijk IM. Long-term melatonin therapy for adolescents and young adults with chronic sleep onset insomnia and late melatonin onset: evaluation of sleep quality, chronotype, and lifestyle factors compared to age-related randomly selected population cohorts. Healthcare (Basel). 2018 Mar 2;6(1):23. https://doi.org/10.3390/healthcare6010023
https://doi.org/10.3390/healthcare601002...
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Cohort study |
69 children |
To assess the discontinuity of melatonin therapy, the time and the real quality of sleep. To investigate the occurrence of adverse events and the reasons for discontinuing the use of melatonin. |
0.5 - 5 mg Average duration of treatment 7.1 years. |
Pittsburgh Sleep Quality Index, subjective sleep quality, sleep duration, usual sleep efficiency, sleep disorders, use of sleeping medications and daytime dysfunction. Each item is weighted on a scale of 0 to 3. |
Long-term therapy appeared to be safe after an average of 7.1 years of treatment. The results of this study indicate that approximately 75% of children with chronic insomnia in early sleep treated with melatonin will have normal sleep quality without medication ten years later. |
Myers et al.3535. Myers KA, Davey MJ, Ching M, Ellis C, Grinton BE, Roten A, et al. Randomized controlled trial of melatonin for sleep disturbance in dravet syndrome: the DREAMS study. J Clin Sleep Med. 2018 Oct 15;14(10):1697-1704. https://doi.org/10.5664/jcsm.7376
https://doi.org/10.5664/jcsm.7376...
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Randomized, double-blind, placebo-controlled clinical trial. |
13 patients aged between 2 to 50 years old. |
To investigate the efficacy and safety of melatonin in the treatment of sleep disorders in patients with Dravet's Syndrome. |
6 mg 30 minutes before bed for 2 weeks. |
Actigraphy, average sleep latency, average sleep efficiency, frequency of seizures, caregiver's impression of clinical change and adverse events. |
No significant adverse events were reported by caregivers. Although the double-blind study found no significant difference in total sleep time, the overall impression from the parents' report was that melatonin is very beneficial in some patients. |
Sletten et al.3636. Sletten TL, Magee M, Murray JM, Gordon CJ, Lovato N, Kennaway DJ, et al. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: a double-blind, randomised clinical trial. PLoS Med. 2018 Jun 18;15(6):e1002587. https://doi.org/10.1371/journal.pmed.1002587
https://doi.org/10.1371/journal.pmed.100...
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Randomized, double-blind, placebo-controlled clinical trial. |
116 patients with an average age of 29 years old of both genders. |
To test the effectiveness of melatonin in patients with Delayed Sleep-Wake Phase Disorder (DSWPD) |
0.5 mg for 4 weeks. |
Sleep onset time, sleep efficiency. |
Short-term and casual administration is an effective and safe treatment for patients with DSWPD with confirmed circadian misalignment, resulting in improvements in objective and subjective quality of sleep, daytime function, and severity of clinical symptoms. |
Lewis et al.3737. Lewis SR, Pritchard MW, Schofield‐Robinson OJ, Alderson P, Smith AF. Melatonin for the promotion of sleep in adults in the intensive care unit. Cochrane Database Syst Rev. 2018 May 10;5(5):CD012455. https://doi.org//10.1002/14651858.CD012455.pub2
https://doi.org//10.1002/14651858.CD0124...
|
Systematic review |
151 patients, with 16 admitted to the intensive care unit (ICU). |
To assess whether the quantity and quality of sleep can be improved by administering melatonin to adults in the ICU. To assess whether melatonin improves physical and psychological results. |
3 and 10 mg. Orally or enterally for a minimum of two days or until discharge from the ICU. |
Sleep quantity and quality, measured by polysomnography, actigraphy, bispectral index or electroencephalogram. |
Insufficient evidence was found to determine whether administration would improve the quality and quantity of sleep in ICU patients. Sparse data and differences were found in the study methodology, in the ICU sedation protocols, and in the methods used to measure and report sleep. |
Besag et al.3838. Besag FMC, Vasey MJ, Lao KSJ, Wong ICK. Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review. CNS Drugs. 2019 Dec;33(12):1167-86. https://doi.org/10.1007/s40263-019-00680-w
https://doi.org/10.1007/s40263-019-00680...
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Systematic review |
1625 participants between 1 and 93 years old |
To assess the evidence for adverse events associated with short-term and longer-term treatment for sleep disorders |
0.15 - 12 mg/day for 1 to 29 weeks |
To evaluate the occurrence of adverse effects with the use of melatonin in the short and long term. |
There were no serious adverse effects associated with the use of melatonin in the short term, the most frequent adverse effects were daytime sleepiness and headache. There is scarcity of data with long-term use. |
Schroder et al.3939. Schroder CM, Malow BA, Maras A, Melmed RD, Findling RL, Breddy J, et al. Pediatric prolonged-release melatonin for sleep in children with Autism Spectrum Disorder: impact on child behavior and Caregiver’s quality of life. J Autism Dev Disord. 2019 Aug 15;49(8):3218-30. https://doi.org/10.1007/s10803-019-04046-5
https://doi.org/10.1007/s10803-019-04046...
|
Double-blind placebo-controlled clinical trial. |
125 individuals aged 2 to 17.5 years old with Autism Spectrum Disorder or Smith-Magenis syndrome. |
To evaluate the efficacy and safety of prolonged release melatonin mini-pills in improving the duration and onset of sleep in patients with Autism Spectrum Disorder or Smith-Magenis syndrome. |
3-5 mg for 13 weeks. |
World Health Organization Welfare Index, Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. |
The treatment improved externalizing behaviors (hyperactivity-inattention and conduct) in children and adolescents. The prolonged-release formulation was effective in improving sleep initiation and maintenance, as well as being safe. |
Lemoine; Bablon & Silva4040. Lemoine P, Bablon J-C, Da Silva C. A combination of melatonin, vitamin B6 and medicinal plants in the treatment of mild-to-moderate insomnia: a prospective pilot study. Complement Ther Med. 2019 Aug;45:104-8. https://doi.org/10.1016/j.ctim.2019.05.024
https://doi.org/10.1016/j.ctim.2019.05.0...
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Prospective Study |
40 participants between 20 and 75 years old. |
To investigate the effect of a combination of melatonin, vitamin B6 and medicinal plants in patients with mild to moderate sleep disorders. |
1 mg of melatonin; 0.42mg of vitamin B6; 8.4 mg of California Poppy; 150 mg of passion fruit extract; 240 mg of lemon balm for 14 days. |
Total sleep duration, sleep onset latency, number of nightmares per night and number of daytime naps and their duration, daytime fatigue was also subjectively assessed by participants in their sleep diary. |
There was an improvement in sleep quality, latency of sleep onset, total sleep duration and daytime parameters related to sleep. No serious adverse events have been reported. |
Seiden & Shah4141. Seiden DJ, Shah SM. A randomized, crossover, pharmacokinetics evaluation of a novel continuous release and absorption melatonin formulation. Prim Care Companion CNS Disord. 2019 Aug 1;21(4):19m02450. https://doi.org/10.4088/PCC.19m02450
https://doi.org/10.4088/PCC.19m02450...
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Randomized clinical trial |
10 patients, 4 men, 6 women aged between 18 and 40 years old. |
To evaluate the pharmacokinetic and safety profile of a new melatonin of continuous release and absorption (CRA-melatonin) in comparison with the melatonin of immediate release (IR-melatonin). |
5 mg. The subjects were confined to the clinic, included daytime dosing, blood collection and exposure to standard ambient light, to prevent significant endogenous production of melatonin. |
For each individual, the melatonin plasma concentration time data was used to calculate the following pharmacokinetic parameters: maximum concentration, maximum time and threshold (time above the target threshold concentration). |
The formulation demonstrated rapid release and then continuous release and absorption of melatonin for up to 7 hours, making it a significant advance in the pharmacokinetic release profile of exogenous melatonin delivery and therefore an important potential consideration as a therapy for sleeping disorder. Improves the quality of sleep of secondary sleep disorders. |
Li et al.1313. Li T, Jiang S, Han M, Yang Z, Lv J, Deng C, et al. Exogenous melatonin as a treatment for secondary sleep disorders: a systematic review and meta-analysis. Front Neuroendocrinol. 2019 Jan;52:22-8. https://doi.org/10.1016/j.yfrne.2018.06.004
https://doi.org/10.1016/j.yfrne.2018.06....
|
Systematic review and meta-analysis. |
205 patients between 29 and 41 years old. |
To determine the effectiveness of melatonin versus placebo in the treatment of sleep disorders. |
3 - 6 mg for 3 to 9 days. |
Sleep onset latency, total sleep time and sleep efficiency. |
Improves the quality of sleep of secondary sleep disorders. |
Malow et al.4242. Malow BA, Findling RL, Schroder CM, Maras A, Breddy J, Nir T, et al. Sleep, growth, and puberty after 2 years of prolonged-release melatonin in children with Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2021 Feb;60(2):252-61. https://doi.org/10.1016/j.jaac.2019.12.007
https://doi.org/10.1016/j.jaac.2019.12.0...
|
Double-blind placebo-controlled clinical trial. |
80 children and adolescents aged between 2 - 17.5 years old. |
To report the long-term effects of prolonged-release melatonin treatment appropriate for children on sleep, growth, body mass index and pubertal development. |
2, 5, 10 mg daily intake for up to 104 weeks, followed by a 2-week placebo period to assess withdrawal effects. |
Infant sleep was assessed at each visit during the one-year study period using the Compound Sleep Disorders Index, which scores the frequency and duration of the participant's sleep habits in the previous month (six habits: sitting at bedtime, sleep induction, waking up at night, resettlement, time of wake up, and early sleep. |
It is safe and effective for long-term treatment in children and adolescents with autism spectrum disorder and insomnia. There were no detrimental effects on children's pubertal growth and development and no abstinence or safety problems related to the use or discontinuation of the medication. |
Low, Choo & Tan4343. Low TL, Choo FN, Tan SM. The efficacy of melatonin and melatonin agonists in insomnia - an umbrella review. J Psychiatr Res. 2020 Feb;121:10-23. https://doi.org/10.1016/j.jpsychires.2019.10.022
https://doi.org/10.1016/j.jpsychires.201...
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Systematic review |
Patients aged 18 - 65 years old. |
To summarize all available systematic reviews and meta-analyzes that investigate the effectiveness of melatonin and melatonin agonists in primary insomnia disorders. |
0.3 - 75 mg, 3 days to 6 months |
Actigraphy, waking time during sleep, awakenings, day to night sleep ratio. |
There was a statistically significant improvement in latency and total sleep time, with a lack of consensus on whether these are clinically significant. |
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