Skip to main content
ADxS.org

Melatonin for ADHD

Melatonin for ADHD

Melatonin is a hormone. It is produced by the pineal gland from tryptophan through several intermediate steps. The onset of darkness (the absence of light, which inhibits melatonin production) is detected by the retina and stimulates melatonin production via the suprachiasmatic nucleus in the hypothalamus. Melatonin regulates the circadian rhythm. Blind people are more likely to have sleep problems and benefit from melatonin supplementation.1 In Germany, immediate release melatonin is available over the counter in doses up to 1 mg.2 In the U.S., melatonin is available over the counter as a dietary supplement. In other countries, such as Australia and Scandinavia, melatonin is available only by prescription.

Melatonin appears to be an effective, well-tolerated, and safe treatment for comorbid sleep disorders in both adults and children with ADHD. We are not aware of any reports of inappropriate side effects.

Difficulties falling asleep and staying asleep occur in 15% to 25% of all children and adolescents and in 25% to 50% of those with ADHD. Numerous studies and reviews confirm the benefits of melatonin for sleep disorders, particularly in children and adolescents with ADHD, ASD, or other neuropsychiatric disorders, while side effects are minimal.3 There is limited data on the safety and efficacy of long-term melatonin use.45 Others report a 75% prevalence of circadian rhythm disorders among children and adults with ADHD.6
A systematic review of 62 studies involving a total of 4,462 participants with ADHD found consistent evidence that ADHD is associated with an evening/latechronotype and a phase delay in circadian phase markers, such as a weak melatonin response to twilight and delayed sleep onset. There was evidence that melatonin is an effective treatment for sleep problems associated with ADHD. A small number of genetic association studies report links between polymorphisms in circadian clock genes and ADHD symptoms. Overall, there was consistent evidence of a circadian rhythm disorder in ADHD.7
Several other meta-analyses and reviews on sleep problems in children and adults with ADHD also confirmed that melatonin can shorten the time it takes to fall asleep and improve sleep quality without significant side effects.891011

For ADHD-related difficulty falling asleep, immediate release melatonin in doses between 0.5 and 3 mg is recommended (plasma half-life approx. 20–50 minutes, duration of action 3–4 hours), and it should be taken at least about 1 hour before bedtime and not after midnight.12
For those who have trouble staying asleep (which is more common among older adults), sustained-release melatonin may be helpful.

1. Melatonin for Sleep Disorders

1.1. Melatonin for Sleep Disorders in Children and Adolescents

1.1.1. Melatonin for Sleep Disorders in Children and Adolescents with ADHD

According to various studies, melatonin is also effective in treating sleep problems in children with ADHD,1314 15 16 17 although melatonin has no direct effect on the ADHD symptoms themselves.18
In a study involving 74 children and adolescents with ADHD (mean age 11.6 years) who received MPH, 60.8% showed a large or very large improvement in sleep behavior following melatonin treatment (mean dose 1.85 mg/day).19 A small study found that melatonin improved the ability to fall asleep, reduced sleep disruptions, and increased total sleep time in a group of children with mental disorders, including ADHD. No serious side effects were reported.20

A systematic review on the treatment of sleep problems in children and adolescents with ADHD found that melatonin had a positive effect on the ability to fall asleep, sleep duration, and sleep quality. Clonidine also improved insomnia (which is why we suspect the same is true for guanfacine), whereas zolpidem and L-theanine showed barely any improvement.21

A meta-analysis on the use of melatonin to treat sleep problems in children with ADHD reports that melatonin is frequently prescribed as an adjunctive pharmacotherapy when optimizing stimulant dosing, sleep hygiene, and behavioral therapy have proven insufficient. Melatonin regulates circadian rhythm-related sleep disturbances, such as difficulty falling asleep in children with ADHD. A Swedish registry study found that 65% of boys and 49% of girls who regularly received melatonin were also regularly taking ADHD medications.(E 3)22 Four studies in children aged 6 to 14 with ADHD and insomnia showed an improvement in sleep onset and sleep latency. Adverse events were transient and mild in all studies.23 Another meta-analysis also found a significant improvement in sleep duration and sleep onset latency in children with ADHD or ASD compared to placebo, with a high response rate. Melatonin was well tolerated at doses ranging from 2 to 10 mg/day in children and adolescents in both short- and long-term trials, with few side effects.24 Additional reviews support these findings.2526
A meta-analysis found that melatonin caused a 40-minute earlier bedtime and a 24-minute reduction in the time it took to fall asleep in children and adults with difficulty falling asleep.9

A cohort study from Sweden showed that in 2017, about 2% of all children aged 0 to 17 had been prescribed melatonin at least once. Overall, melatonin prescriptions increased 15-fold among girls and 20-fold among boys between 2006 and 2017. Fifteen percent of girls and 17% of boys who were first prescribed melatonin in 2009 at ages 5 to 9 continued to receive it consistently over the following 8 years. Half of the children prescribed melatonin had at least one mental health disorder. The most common mental health disorder was ADHD, across all age groups and for both genders.27
This is consistent with another Swedish cohort study, which found that 40% of girls and 50% of boys aged 5 to 9 who were regularly given melatonin in 2010 were still receiving it regularly 3 years later. Among 15- to 19-year-olds, only about 10% were still regular users three years later. In 2013, 65% of boys and 49% of girls who took melatonin regularly were also taking ADHD medication regularly. The daily dosage of melatonin appeared to have decreased by nearly 30% between 2006 and 2012.28
Similarly, a Norwegian cohort study shows a steady increase in the use of melatonin (off-label in Norway), primarily to treat sleep problems that occurred alongside other disorders. A large number of children continued the treatment for 3 years, taking it daily. The average annual dosage in the third year was 2.95 mg (1.60 to 4.93 mg) per day for boys and 2.47 mg (1.10 to 4.44 mg) per day for girls.29
A very large cohort study involving 48,296 people with ADHD between the ages of 0 and 17 from 2008 to 2012 found that 30% of them received additional medications in addition to their ADHD medications, with melatonin being the most commonly prescribed additional medication, followed by antidepressants and antipsychotics.30

Given these factors, it is hard to imagine that melatonin would have been used without providing some benefit, or that serious side effects of melatonin would have gone unnoticed.

In a Canadian survey, melatonin was the medication most commonly prescribed by doctors (73%) for sleep disorders in children, regardless of whether the children also had ADHD.31

A Japanese survey found that just under half of the children who had trouble falling asleep were treated with melatonin (n = 220). The following study found that effective doses ranged from 0.2 to 8 mg, depending on age (n = 254).32

1.1.2. Melatonin for Sleep Disorders in Children and Adolescents with Autism

Doses of 1–4 mg taken 30–60 minutes before bedtime significantly reduced the time it took to fall asleep.3334

1.2. Melatonin for Treating Sleep Disorders in Adults with ADHD

1.2.1. Melatonin for Sleep Disorders in Adults with ADHD

In a review of 41 studies, an international group of experts concluded that sustained-release melatonin (2–10 mg, 1–2 hours before bedtime) may be helpful for adults with symptoms of insomnia or comorbid insomnia associated with mood disorders, schizophrenia, autism spectrum disorders, neurocognitive disorders, or during the withdrawal of sedative-hypnotics, whereas for adults with disorders associated with circadian sleep problems (such as ADHD), immediate release melatonin (1 mg or less) is generally more appropriate.35

A French commission of experts concluded that melatonin is a helpful medication for adults with sleep disorders and comorbid mental health disorders such as ADHD.36
A meta-analysis found that melatonin caused a 40-minute earlier bedtime and a 24-minute reduction in the time it took to fall asleep in children and adults with difficulty falling asleep. (Meta-analysis, n = 9)37

1.2.2. Melatonin for Sleep Disorders in Older Adults with Primary Insomnia

In older adults (aged 55 and older), 2 mg of sustained-release melatonin has been shown to be more effective—particularly in terms of sleep efficiency—than immediate release melatonin.38

2. Dosage and Timing of Melatonin Intake

Depending on when melatonin is taken, it has different effects.
Taking 2 to 4 mg immediately up to (ideally) 3 hours before bedtime shortens the time it takes to fall asleep and improves sleep quality without affecting the circadian rhythm.
Taking it 7 hours before bedtime (in lower doses) shifts the circadian rhythm forward, thereby improving sleep onset latency and sleep quality. Additionally, there is evidence that this may reduce existing ADHD symptoms.

Glossary:

  • Sleep latency (SOL):
    • Time from going to bed/turning off the lights until falling asleep for the first time. Measured in minutes. A shorter time is better.
      Wake after sleep onset (WASO): The sum of all periods of wakefulness from the time of initial sleep onset until final morning awakening. Measures sleep continuity / the ability to sleep through the night. A lower value is better.
  • Sleep Efficiency (SE):
    • The percentage of time spent in bed that was actually spent sleeping. Values of ≥ 85% are conventionally considered normal. Higher is better,
      Calculation of Sleep Efficiency (SE) = Total Sleep Time (TST) / Time in Bed (TIB) × 100%
  • Total Sleep Time (TST):
    • Total sleep time in minutes. Higher is better.
  • Sleep Quality (SQ):
    • The definition varies depending on the study. Sleep quality can be a subjectively reported measure—standardized, for example, using the Pittsburgh Sleep Quality Index (PSQI), a sleep diary, or the Insomnia Severity Index (ISI)—or a measure obtained through actigraphy or PSG, which may take several parameters into account: SE, WASO, number of awakenings, sleep architecture (% N3, % REM), sleep fragmentation index, and, if applicable, SOL.

2.1. Melatonin (up to) 3 hours before bedtime: Helps you fall asleep and stay asleep

While non-retard-release melatonin taken 7 hours before or several hours after bedtime shifts the circadian melatonin rhythm forward or backward, respectively, non-retard-release or sustained-release melatonin taken immediately before sleep has little effect on the DLMO.

Melatonin achieved its maximum effectiveness in children at a dose of between 2 and 4 mg/day, taken 3 hours before bedtime. This correlated with (meta-analysis, k = 21)39

  • a reduction in the time it takes to fall asleep when taken early relative to bedtime
  • an increase in sleep efficiency and total sleep time with a longer duration of treatment

In adults, doses of 3 (up to 5) mg taken 3 hours before bedtime were optimal for reducing sleep latency and increasing sleep duration. In contrast, most studies used 2 mg of melatonin 30 minutes before bedtime. (Meta-analysis, k = 26 RCTs, n = 1,689)40 Studies in which the medication was taken more than 3.5 hours before sleep were not included in the meta-analysis. Up to a dose of 3 to 5 mg, the pooled sleep latency decreased; above that, it rose again slowly. Interestingly, a dose of 1 mg was even associated with worse outcomes. In patients with insomnia, melatonin was less effective than in healthy controls, and its effectiveness gradually increased as the time of administration was brought earlier relative to the sleep period.

Target group Dose Administration (in min/h) before bedtime Number of subjects Improvement in sleep onset latency (SOL) Improvement in total sleep time (TST) Improvement in sleep quality (SQ) / sleep efficiency (SE) Study
_________________ _________ ___________ ___________ ___________
ADHD: Children and Adolescents with Sleep Problems
Children with ADHD, ages 6–14 on stimulants (non-responders to sleep hygiene) 5 mg immediate release 20 min before bedtime n = 27 60 min faster through sleep hygiene + melatonin unknown improved, ADHD symptoms unchanged Weiss et al., 200641
Children with ADHD receiving 1 mg/kg of MPH, ages 7–12 3 or 6 mg of immediate release melatonin or placebo 30 minutes before bedtime, 8 weeks N = 50 Significantly earlier sleep onset; Reduced bedtime resistance significantly increased improved sleep quality; ADHD symptoms unchanged Mohammadi et al., 201242
Children with ADHD and MPH-induced insomnia, ages 9.5 to 14 average dose 1.85 mg immediate release (titrated in 0.5 mg increments, 1 to 2.7 mg) 60–120 min before bedtime, ≥ 4 weeks n = 74 significantly reduced unknown CGI-I mostly showed much or very much improvement Masi et al., 201943
Children with ADHD and a long SOL (mean 135 min.) unknown before bedtime n = 24 SOL shortened by more than 1 hour unknown Tjon Pian Gi et al., 200244
Children with ADHD-C on MPH, ages 7–12 3 to 6 mg of melatonin based on body weight vs. placebo N = 50, n = 26 Shorter SOL (18 min vs. 23.2 min) Sleep duration + 51 min Reduced sleep disruption Improved height and weight gain; appetite correlated with sleep duration, independent of melatonin Mostafavi et al., 201245
Delayed Sleep Phase Syndrome (DSPD)
DSPS with delayed melatonin rhythm compared to bedtime 0.5 mg immediate release 1 hour n = 116 -34 min earlier (95% CI: -60 to -8) unknown Increased sleep efficiency; PROMIS scores improved Sletten et al. 201846
Children and Adolescents with Autism
Target group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Children with ASD 1 mg Before bedtime n = 65 -22.0 min (p = 0.0001 vs. placebo -5.0 min) unknown unknown Hayashi et al. 202233
Children with ASD 4 mg Before bedtime n = 65 -28.0 min (p = 0.0001 vs. placebo -5.0 min) unknown unknown Hayashi et al. 202233
Children with ASD, ages 4–10 3 mg sustained release (1 mg immediately, 2 mg within 6 hours) 9:00 p.m. n = 32, N = 64 Actigraphy: -34.39 min; CSHQ-SOD: -0.83 unknown unknown Cortesi et al., 201247
Children and adolescents with ASD, n = 125 –25.3 min (95% CI: –44.7 to –5.9) unknown unknown Gringras et al., 2017 48
Children and adolescents with ASD, ages 3–16 2 mg to a maximum of 10 mg (immediate release), titrated until “good results” 30–40 minutes N = 17 –46.7 min +52 min No change in nighttime awakenings Wright et al., 201149
Children with ASD, mean age 5 years 5 mg immediate release 20 min, 4-week crossover n = 7 Sleep latency reduced from 2.6 hours to 1.06 hours Extended from 8.05 to 9.84 hours Nighttime awakenings reduced to 30% Garstang & Wallis 200650
Children with ASD, Fragile X syndrome, or both, ages 2–15, mean age 5.5 years 3 mg immediate release 30 min before bedtime, 2-week crossover n = 12 28 min faster, 42 min earlier 21 min longer Wirojanan et al., 200951
Children with ASD, ages 3–10 1 (n = 7), 3 (n = 14), 6 (n = 3) mg immediate release (dose titration) 30 min before bedtime, 14-week open-label study following a 2-week placebo run-in n = 24 16 min faster 15 min longer Improvement on sleep, behavior, and parental stress scales Malow et al., 201252
Children with ASD and Asperger syndrome, ages 6–17 (open-label, not an RCT) 3 mg immediate release in the evening before bedtime, 14 days n = 15 18 minutes faster unchanged behavioral measures significantly improved (effect disappeared after discontinuation) Paavonen et al., 200353
Children with neurodevelopmental disabilities, including ASD and DSPS, ages 2–18 5 mg sustained release (CR) in the evening before bedtime; 10-day crossover, followed by 3 months of open-label treatment n = 50 34 minutes shorter 30 minutes longer Improved clinical and global functioning; Family stress reduced Wasdell et al., 200854
Children with neurodevelopmental disorders (~60 of whom have ASD), ages 3–15 (MENDS study) 0.5 / 2 / 6 / 12 mg immediate release (titrated) 45 min before bedtime, 12 weeks n = 146 58.3 min shorter (actigraph) 15.7 min longer 7.3% fewer nights with unsatisfactory sleep Gringras et al., 2012 (MENDS)55
Children and Adolescents with Other Disorders
Target group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Children with Rett syndrome, n = 9 19 minutes faster (p < 0.05) TST +22 min (n.s.) Wake-up time unchanged McArthur & Budden, 1998 56
Children with Angelman syndrome and chronic insomnia, ages 2–15 2.5–5 mg immediate release 30 min before bedtime, 4-week crossover n = 8 32 min faster (p < 0.001) 56 minutes longer (p = 0.001) Significantly reduced awakenings Braam et al., 200857
Children and adolescents with chronic (idiopathic) sleep disorders
Target group Dose Time before sleep Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Children with idiopathic CSOI, ages 6–12 5 mg immediate release 7:00 p.m. (~2–3 hours before bedtime) n = 62 17 min (latency) / 57 min faster (onset) (p < 0.001) 33 min longer RAND-GHRI / FS-II health and sleep status significantly improved Smits et al., 200358
Adults 45 and older
Target group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Primary insomnia in individuals aged 45 to 60 years 3 mg immediate release 1 hour n = 51 (melatonin group), N = 97 (total) No significant improvement -30.63 min earlier wake-up time (p=0.001) PSQI unchanged Xu et al. 202059
Adults with insomnia aged 51 and older 0.1 mg 30 minutes n = 15 not significant improvement reported sleep efficiency: 84% (vs. 78% placebo) Zhdanova et al. 200160
Adults with insomnia aged 51 and older 0.3 mg 30 minutes n = 15 not significant reported improvement sleep efficiency: 88% (vs. 78% placebo, p = 0.0001) Zhdanova et al. 200160
Adults with insomnia aged 51 and older 3 mg 30 minutes n = 15 not significant reported improvement sleep efficiency: 84% (vs. 78% placebo) Zhdanova et al. 200160
n = 170 patient reports, variable +2.2 min vs. placebo improvement in sleep quality Lemoine et al., 2007 61
Adults aged 55 and older 2 mg sustained release 2 hours before bedtime, after a meal n = 40 6.9 min / 10.6 min faster vs. placebo unknown Luthringer et al., 200962
Adults aged 55 to 80 years 2 mg sustained release 2 hours before bedtime N = 354, n = 171 24.3 min (3 weeks, ages 65–80); 25.9 min faster (19 weeks, 65–80 years) unknown improvement in sleep quality Wade et al., 200763
Adults aged 55 and older (mean age 64.2 years) 0.3 mg 30 minutes n = 24 unknown Trend toward an increase (mainly during the day) Increased sleep efficiency (mainly during the biological day) Duffy et al., 202264
Adults aged 56 and older (mean age 64.2 years) 5 mg 30 minutes n = 24 unknown Significant increase (day and night) Sleep efficiency significantly increased (day and night) Duffy et al., 202264
Adults with chronic insomnia, ages 70–90 2 mg immediate release 2 hours n = 24 Significant improvement after 1 week unknown Sleep efficiency: 78.8% (vs. 77.4% placebo) Haimov et al., 1995 65
Adults with chronic insomnia, ages 70–90 2 mg sustained release 2 hours n = 24 Significant improvement after 1 week unknown Sleep efficiency: 80.4% (vs. 77.4% placebo) Haimov et al., 1995 65
Adults with chronic insomnia, ages 70–90 1 mg sustained release 2 hours n = 17 Significant improvement after 2 months unknown Sleep efficiency: 84.3% (vs. 77.4% placebo) Haimov et al., 1995 65
Adults with primary insomnia
Target Group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Healthy middle-aged subjects 0.3 mg immediate release in the evening before bedtime n = 15 (crossover) 4.1 minutes faster, 5.8 minutes earlier 8.4 minutes longer sleep efficiency tended to increase Attenburow et al., 199666
Healthy middle-aged subjects 1.0 mg immediate release in the evening before bedtime n = 15 (crossover) 3.6 minutes faster, 10.9 minutes earlier 21.6 minutes longer (significant) Sleep efficiency significantly increased Attenburow et al., 199666
Adults with primary insomnia, ages 18–80 2 mg sustained release (PRM) 2 hours before bedtime, 3 weeks + 26 weeks n = 791 19.1 minutes faster in those aged ≥ 55 years approximately 40 minutes longer PSQI and WHO-5 significantly improved Wade et al., 201067
Adults with Intellectual Disabilities
Target group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Adults and children with intellectual disabilities and chronic insomnia 5 mg immediate release 30 min before bedtime, 4 weeks n = 51 29 min shorter, 34 min earlier (p < 0.001) 48 min longer 40% fewer awakenings per night Braam et al., 200868
Adults with intellectual disability and chronic insomnia (follow-up RCT on daytime behavior) 5 mg immediate release 30 minutes before bedtime, 4 weeks N = 49, n = 27 40 minutes faster 53 minutes longer 30% fewer nighttime awakenings; significantly reduced challenging behavior during the day Braam et al., 201069
Adults and children with ID 0.5–10 mg immediate release or sustained release variable 34 min faster 50 min longer reduced nighttime awakenings Braam et al., 2009 (Meta-analysis, k = 9 RCTs, n = 183)70
Adults: Older Adults with Insomnia and Dementia
Target group Dose Administration before bedtime Number of participants Sleep latency (SOL) Sleep duration Sleep quality / sleep efficiency Study
Older patients (~76 years) with insomnia and chronic conditions 2 mg sustained release 2 hours before bedtime, 3 weeks n = 12 (crossover) SOL 24 minutes faster (not significant), WASO 49 min shorter (significant) unchanged Sleep efficiency and subjective sleep quality significantly improved Garfinkel et al., 199571
Patients with Alzheimer’s dementia and nocturnal sleep disturbances 2.5 mg sustained release or 10 mg immediate release 1 hour before bedtime, 8 weeks n = 157 (3-arm study) no change (actigraphic) no change (actigraphic) Trends, but no significant effects Singer et al., 200372
Patients with institutionalized Alzheimer’s dementia 8.5 mg immediate release + 1.5 mg sustained release 10:00 p.m., 10 days N = 41 unchanged (actigraphically) unchanged (actigraphically) unchanged (actigraphically); agitation also unchanged Gehrman et al., 200973
Patients with mild to moderate Alzheimer’s dementia, age 75 , 2 mg sustained release (add-on to standard therapy) , 1–2 hours before bedtime, 24 weeks , n = 80 , unknown , unknown , PSQI significantly improved; ADAS-Cog and IADL significantly improved in Alzheimer’s patients with insomnia Wade et al., 201474
Adults with Parkinson’s
Target Group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
XML-PH-0000@deepl.internal 3 mg immediate release 30 min before bedtime, 2 weeks n = 18 not significant (PSG) not significant subjective sleep quality (GSDS) improved; PSG parameters unchanged Medeiros et al., 2007 75
76
Parkinson’s disease with sleep disturbances 50 mg (very high dose) 30 min before bedtime, 2 weeks n = 40 unknown 5 min longer (5 mg), 8 min longer (50 mg) subjective sleep quality significantly improved Dowling et al., 200577
Adults: Shift Workers
Target group Dose Administration before sleep Number of participants Sleep latency Sleep duration Sleep quality / Sleep efficiency Study
Nurses working the night shift, ages 24–46 5 mg immediate release 30 min before daytime sleep after night shift n = 86 (crossover) subjective SOL significantly shortened vs. placebo and baseline unchanged unchanged Sadeghniiat-Haghighi et al., 200878
Shift workers with difficulty falling asleep, mean age ~ 36 years 3 mg immediate release 30 min before daytime nap n = 39 (crossover) SOL 7 min faster (actigraphy, p < 0.05), WASO not significant TST not significant Sleep efficiency significantly increased Sadeghniiat-Haghighi et al., 201679
Young adults (27 years old) in a simulated night shift (8 hours of daytime sleep) 1.8 mg sustained release 30 minutes before daytime sleep n = 21 (crossover) unknown Loss of daytime sleep time on the first day prevented; more pronounced in “poor daytime sleepers” no hangover effects; MSLT unchanged Sharkey et al., 200180
Nurses on the night shift 6 mg non-sustained-release 30 minutes before daytime napping n = 47 TST significantly increased during daytime napping TST +94 minutes on some days subjective sleep quality not significantly different Source unverifiable
Adults: Jet Lag
Target Group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Travelers on eastbound flights across 6–8 time zones 5 mg immediate-release at bedtime at the destination, for 4 days n = 234 SOL significantly shorter (p < 0.05) unknown Sleep quality significantly improved. Suhner et al., 199881
Travelers on eastbound flights across 6–8 time zones 0.5 mg immediate release at bedtime at the destination, for 4 days n = 234 tended to be shorter (less than 5 mg) unknown tended to be improved (less than 5 mg) Suhner et al., 199881
81
Travelers on eastbound flights (Cochrane meta-analysis) Jet lag symptoms significantly reduced in 9 out of 10 studies not systematically evaluated Sleep quality significantly better at 5 mg vs. 0.5 mg; higher doses were not helpful; sustained release melatonin was less effective Herxheimer & Petrie 2002 (Cochrane) 82
Insomnia with Comorbidities
Target group Dose Administration before bedtime Number of participants Sleep latency Sleep duration Sleep quality / sleep efficiency Study
Inpatients in internal medicine with difficulty falling asleep average stable dose 5.4 mg immediate release (flexible) in the evening before bedtime, 8–16 days N = 33, n = 18 Significantly faster sleep onset (p < 0.05) Significantly increased sleep duration Significantly improved sleep quality and depth; no hangover Andrade et al., 200183
Ventilated ICU patients after tracheostomy 10 mg 9:00 p.m., 4 nights n = 24 unknown 60 min longer Sleep efficiency tended to be better; lower doses (1–2 mg) might be better Bourne et al., 200884
Hemodialysis patients with insomnia 3 mg immediate release at bedtime = 10:00 p.m., 6 weeks n = 50 (crossover) SOL 21 minutes faster (actigraphy) 1 hour longer (p < 0.01) Sleep efficiency significantly increased Edalat-Nejad et al., 201385
Patients with chronic obstructive pulmonary disease (COPD) 3 mg immediate release 10:00 p.m., 3 months n = 25, n = 12 shortened (p = 0.008) prolonged (p = 0.046) PSQI total score and sleep disturbance subscale significantly improved Nunes et al., 200886
Breast cancer patients with insomnia (ages 30–75) 6 mg immediate-release 30 min before bedtime, 8 weeks n = 43 unknown 37 min longer PSQI total score and subscales (sleep disturbances, sleep quality, sleep duration) significantly improved Hansen et al., 201487

2.2. Melatonin 7 hours before bedtime: Brings sleep on earlier

Taking melatonin at the right times can shift the circadian rhythm forward or backward.88 The so-called “phase-advance zone” for melatonin—the time period during which it shifts the circadian rhythm forward—is the afternoon or early evening. This can help treat delayed sleep phases, such as the difficulty falling asleep commonly seen in ADHD (Delayed Sleep Phase Syndrome, DSPS; also known as DSWPD or ZSPS) or jet lag when traveling east.89 The phase-advance zone for melatonin ranges from CT 6 to CT 18, while the phase-delay zone ranges from CT 18 to CT 6.90
Delayed melatonin release is thought to play a key role in the pathophysiology of DSPS.

Delayed Sleep Phase Syndrome (DSPS) should be diagnosed,

  • if
    • Difficulty falling asleep at the desired bedtime after 11:30 p.m. and/or
    • Sleep latency of more than 30 minutes
  • lead to daytime impairments in social and/or occupational functioning, and
  • Symptoms
    • have existed for at least 6 months
    • cannot be explained by other factors

2.2. Melatonin According to DLMO: Delays the Onset of Sleep

Taking melatonin in the middle of the night or immediately after waking up can shift the circadian melatonin rhythm later.

3. Other Information About Melatonin

The daily doses of melatonin as a medication range from 0.5 milligrams to 8 milligrams.

Melatonin sustained release should only be used in cases of complete failure of melatonin production.91

3.1. Synthesis of Melatonin

Melatonin is synthesized in the pinealocytes of the pineal gland from L-tryptophan via the intermediate steps of 5-hydroxytryptophan and serotonin. The last two steps (N-acetylation by AANAT and methylation by ASMT/HIOMT) are regulated in a night-specific manner.
L-tryptophan → 5-HTP (via tryptophan hydroxylase) → serotonin (via AADC) → N-acetylserotonin (via AANAT) → melatonin (via HIOMT/ASMT).

Light is detected by melanopsin-containing retinal ganglion cells, which, through the suprachiasmatic nucleus (SCN), suppress melatonin synthesis in the pineal gland.
In the dark, this inhibition is lifted. The SCN then activates noradrenergic fibers to the pineal gland via the paraventricular nucleus, the spinal intermediolateral column, and the superior cervical ganglion, which induces AANAT and increases melatonin release.

3.2. What Is Affected by Melatonin

Melatonin stabilizes and strengthens the synchronization of circadian rhythms, particularly core body temperature and the sleep-wake cycle.
Melatonin also appears to influence the circadian regulation of numerous other physiological functions, such as92

  • antioxidant defense
  • Hemostasis
  • Glucose regulation
  • Immune system
    • Pro-inflammatory cytokines (especially IL-6) peak at night when cortisol levels are low (which is influenced by melatonin)
      • Example: morning joint stiffness in rheumatoid arthritis 93
    • The immune system is regulated by the circadian rhythm94
  • Dexamethasone induces circadian gene expression in cultured fibroblasts and transiently shifts the phase in the liver, kidneys, and heart, but not in the SCN95
  • Core body temperature
    • Under normal conditions, the melatonin peak occurs approximately 1.8 ± 0.2 hours before the temperature minimum96
    • The melatonin rhythm is less easily influenced by environmental factors (other than light) than body temperature. Melatonin is therefore a more reliable marker of the circadian phase than core body temperature.9798
    • The temporal course of the decline in core body temperature is closely linked to nocturnal melatonin secretion (r = 0.97). Melatonin is believed to be causally responsible for at least 40% of the amplitude of the temperature rhythm.
      Inhibition of melatonin secretion with the β-blocker atenolol attenuated the nighttime drop in body temperature. Administration of melatonin lowered body temperature during the day.99
    • The DLMO occurs approximately 7 hours before the core body temperature reaches its lowest point and 1.25 hours before melatonin synthesis ceases.100101

3.3. Breakdown of Melatonin

Because melatonin is metabolized by CYP1A2 and (to a lesser extent) CYP2C19, caution should be exercised when combining it with medications that are also metabolized by these enzymes.
This mechanism also explains the sedative effect of imipramine/desipramine; when this effect is pronounced, it means that imipramine should be taken in the evening.

A decrease in melatonin’s effectiveness could be due to CYP1A2 underactivity. In this case, a reduction in dosage is recommended.102

3.4. Measurement of Melatonin

Melatonin is released as it gets dark; the release begins slowly and typically accelerates between 10:00 p.m. and 11:00 p.m. (acrophase). The high level of melatonin begins to decline again around 2:00 a.m. to 4:00 a.m.91

A test can be performed using serum, the first morning urine sample, or saliva.
A measurement based on serum or the first morning urine sample is not suitable for determining the daily profile.

3.5. Risks and Side Effects of Melatonin

Melatonin appears to be a safe treatment for improving sleep problems in children and adults with ADHD. Its widespread use, the long duration of use among people with ADHD, and the rising number of users all point to evidence of its successful use. The fact that there are only a few large clinical studies on the use of melatonin for sleep problems associated with ADHD is likely due, in part, to the fact that off-patent active ingredients (such as melatonin) are understandably of no economic interest to pharmaceutical companies. It is not the responsibility of pharmaceutical companies to investigate the efficacy or safety of patent-free active ingredients. On the contrary, from an economic perspective, there would be a greater incentive to identify negative aspects of melatonin in order to avoid competition from melatonin as a generic active ingredient. Yet even such reports are lacking.

We were unable to find any studies documenting the occurrence of significant side effects associated with melatonin. Given the large number of users and its long history of use in treating sleep problems, including in children and adults with ADHD, we consider the absence of reports of side effects to be an indication of good tolerability.
Nevertheless, there are reports of side effects associated with long-term melatonin use. In such cases, intermittent use is recommended, including a 1- to 2-day break from taking the supplement every 1 to 2 weeks.

A review states that there are no known relevant side effects of melatonin.102

Adults produce approximately 20 to 60 micrograms of melatonin daily. Melatonin is rapidly absorbed and metabolized during its first pass through the liver, with a half-life of 30 to 40 minutes (in children aged 3 to 8 years as well as in adults, while newborns showed a half-life of up to 20 hours) and a bioavailability of 1 to 37%. In the liver, it is metabolized by CYP1A220 to 6-hydroxymelatonin and then sulfated to 6-sulfatoxymelatonin or conjugated to glucuronide and excreted.103

Excessively high melatonin levels can cause depression (seasonal affective disorder).
Possible side effects may include:

  • Night sweats104
  • Nighttime hot flashes104
  • Mood swings104
    • Restlessness
    • Nervousness
    • Anxiety
    • Lethargy
  • Nightmares
    • Occasional (in 1 out of every 100–1,000 patients treated) to rare (in 1 out of every 1,000–10,000 patients treated)105
  • very vivid dreams
    • occasionally to rarely105
  • Stomach cramps
    • occasionally to rarely105
  • Dizziness
    • occasionally to rarely105
  • Headaches
    • occasionally to rarely105
  • Irritability
    • occasionally to rarely105
  • decreased sexual desire
    • occasionally to rarely105

3.6. Interactions with Melatonin

Interactions with antithrombotic agents and antiepileptic drugs are possible.

3.6.1. Reducing the Effects of Melatonin

  • Some psychiatric medications91
  • Alpha blockers91
  • Beta-blockers91
  • Alcohol
    • Even moderate amounts of alcohol, consumed one hour before bedtime, caused a significant decrease in melatonin levels in young adults.106

3.6.2. Increasing the Effects of Melatonin

Due to the metabolism mechanism, inhibitors of CYP1A2 and CYP2C19 increase the plasma levels and bioavailability of melatonin:

  • Fluvoxamine107108
    • inhibits the breakdown of melatonin in the liver; enhances the duration and potency of melatonin91
  • Desipramine107
    • consequently, imipramine as well, since it is converted to desipramine
  • Caffeine109
  • Theophylline103
  • Citalopram / Escitalopram as a CYP2C19 inhibitor110
  • Ciprofloxacin
    • inhibits the breakdown of melatonin in the liver; enhances the duration and potency of melatonin91

3.6.3. Melatonin’s Effect on the Efficacy of Other Medications

Melatonin enhances the sedative effects of, among other things:91

  • Benzodiazepines
  • Zaleplon
  • Zopiclone
  • Zolpidem
  • Imipramine
  • Thioridazine

  1. Skene, Lockley, Arendt (1999): Melatonin in circadian sleep disorders in the blind. Biol Signals Recept. 1999 Jan-Apr;8(1-2):90-5. doi: 10.1159/000014575. PMID: 10085469. ↥

  2. https://www.apotheke-adhoc.de/nachrichten/detail/apothekenpraxis/melatonin-rechtslage-ungewiss-arzneimittel-oder-lebensmittel/ ↥

  3. Rolling J, Rabot J, Schroder CM (2022): Melatonin Treatment for Pediatric Patients with Insomnia: Is There a Place for It? Nat Sci Sleep. 2022 Oct 27;14:1927-1944. doi: 10.2147/NSS.S340944. PMID: 36325278; PMCID: PMC9621019. REVIEW ↥

  4. Cummings (2012): Canadian Paediatric Society, Community Paediatrics Committee. Melatonin for the management of sleep disorders in children and adolescents. Paediatr Child Health. 2012 Jun;17(6):331-6. PMID: 23730172; PMCID: PMC3380753. ↥

  5. Holvoet, Gabriëls (2013): Verstoorde slaap bij kinderen met ADHD: heeft melatonine een plaats in de behandeling? [Disturbed sleep in children with ADHD: is there a place for melatonin as a treatment option?]. Tijdschr Psychiatr. 2013;55(5):349-57. Dutch. PMID: 23696337. ↥

  6. Bijlenga, Vollebregt, Kooij, Arns (2019): The role of the circadian system in the etiology and pathophysiology of ADHD: time to redefine ADHD? Atten Defic Hyperact Disord. 2019 Mar;11(1):5-19. doi: 10.1007/s12402-018-0271-z. ↥

  7. Coogan, McGowan (2017): A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder. Atten Defic Hyperact Disord. 2017 Sep;9(3):129-147. doi: 10.1007/s12402-016-0214-5. PMID: 28064405. n = 62 Studien, n = 4.462, REVIEW ↥

  8. Cortese, Brown, Corkum, Gruber, O’Brien, Stein, Weiss, Owens (2013): Assessment and management of sleep problems in youths with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2013 Aug;52(8):784-96. doi: 10.1016/j.jaac.2013.06.001. PMID: 23880489. ↥

  9. van Geijlswijk, Korzilius, Smits (2010):. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010 Dec;33(12):1605-14. doi: 10.1093/sleep/33.12.1605. PMID: 21120122; PMCID: PMC2982730. n = 9 Studien ↥ ↥

  10. Stein, Zulauf-McCurdy, DelRosso (2022): Attention Deficit Hyperactivity Disorder Medications and Sleep. Child Adolesc Psychiatr Clin N Am. 2022 Jul;31(3):499-514. doi: 10.1016/j.chc.2022.03.006. PMID: 35697398. REVIEW ↥

  11. Salanitro M, Wrigley T, Ghabra H, de Haan E, Hill CM, Solmi M, Cortese S. (2022): Efficacy on sleep parameters and tolerability of melatonin in individuals with sleep or mental disorders: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2022 Jun 9:104723. doi: 10.1016/j.neubiorev.2022.104723. PMID: 35691474. ↥

  12. Kooij (2019): ADHD and Sleep Webinar ↥

  13. Moon E, Kim K, Partonen T, Linnaranta O (2022): Role of Melatonin in the Management of Sleep and Circadian Disorders in the Context of Psychiatric Illness. Curr Psychiatry Rep. 2022 Nov;24(11):623-634. doi: 10.1007/s11920-022-01369-6. PMID: 36227449; PMCID: PMC9633504. REVIEW ↥

  14. Krause, Krause (2014): ADHS im Erwachsenenalter: Symptome – Differenzialdiagnose – Therapie ↥

  15. Herman (2015): Attention Deficit/Hyperactivity Disorder and Sleep in Children. Sleep Med Clin. 2015 Jun;10(2):143-9. doi: 10.1016/j.jsmc.2015.02.003. PMID: 26055862. REVIEW ↥

  16. Larsson I, Aili K, Lönn M, Svedberg P, Nygren JM, Ivarsson A, Johansson P (2022): Sleep interventions for children with attention deficit hyperactivity disorder (ADHD): A systematic literature review. Sleep Med. 2022 Dec 26;102:64-75. doi: 10.1016/j.sleep.2022.12.021. PMID: 36603513. REVIEW ↥

  17. Checa-Ros A, Muñoz-Hoyos A, Molina-Carballo A, Viejo-Boyano I, Chacín M, Bermúdez V, D’Marco L (2023): Low Doses of Melatonin to Improve Sleep in Children with ADHD: An Open-Label Trial. Children (Basel). 2023 Jun 28;10(7):1121. doi: 10.3390/children10071121. PMID: 37508618; PMCID: PMC10378280. ↥

  18. Bloch, Mulqueen (2014): Nutritional supplements for the treatment of ADHD. Child Adolesc Psychiatr Clin N Am. 2014 Oct;23(4):883-97. doi: 10.1016/j.chc.2014.05.002.PMID: 25220092; PMCID: PMC4170184. REVIEW ↥

  19. Masi, Fantozzi, Villafranca, Tacchi, Ricci, Ruglioni, Inguaggiato, Pfanner, Cortese (2019): Effects of melatonin in children with attention-deficit/hyperactivity disorder with sleep disorders after methylphenidate treatment; Neuropsychiatr Dis Treat. 2019; 15: 663–667. doi: 10.2147/NDT.S193891, PMCID: PMC6410756, PMID: 30880992 ↥

  20. Ayyash, Preece, Morton, Cortese (2015): Melatonin for sleep disturbance in children with neurodevelopmental disorders: prospective observational naturalistic study. Expert Rev Neurother. 2015 Jun;15(6):711-7. doi: 10.1586/14737175.2015.1041511. PMID: 25938708. n = 38 ↥

  21. Barrett, Tracy, Giaroli (2013): To sleep or not to sleep: a systematic review of the literature of pharmacological treatments of insomnia in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2013 Dec;23(10):640-7. doi: 10.1089/cap.2013.0059. PMID: 24261659; PMCID: PMC3870602. REVIEW ↥

  22. Furster, Hallerbäc (2015): The use of melatonin in Swedish children and adolescents–a register-based study according to age, gender, and medication of ADHD. Eur J Clin Pharmacol. 2015 Jul;71(7):877-81. doi: 10.1007/s00228-015-1866-3. PMID: 25995170. n = 7.389 ↥

  23. Bendz, Scates (2009): Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder. Ann Pharmacother. 2010 Jan;44(1):185-91. doi: 10.1345/aph.1M365. PMID: 20028959. METASTUDY ↥

  24. Parvataneni, Srinivas, Shah, Patel (2020): Perspective on Melatonin Use for Sleep Problems in Autism and Attention-Deficit Hyperactivity Disorder: A Systematic Review of Randomized Clinical Trials. Cureus. 2020 May 28;12(5):e8335. doi: 10.7759/cureus.8335. PMID: 32617211; PMCID: PMC7325410. METASTUDIE ↥

  25. Rzepka-Migut, Paprocka (2020): Efficacy and Safety of Melatonin Treatment in Children with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder-A Review of the Literature. Brain Sci. 2020 Apr 7;10(4):219. doi: 10.3390/brainsci10040219. PMID: 32272607; PMCID: PMC7226342. REVIEW ↥

  26. Um, Hong, Jeong (2017): Sleep Problems as Predictors in Attention-Deficit Hyperactivity Disorder: Causal Mechanisms, Consequences and Treatment. Clin Psychopharmacol Neurosci. 2017 Feb 28;15(1):9-18. doi: 10.9758/cpn.2017.15.1.9. PMID: 28138105; PMCID: PMC5290714. REVIEW ↥

  27. Kimland, Bardage, Collin, Järleborg, Ljung, Iliadou (2020): Pediatric use of prescribed melatonin in Sweden 2006-2017: a register based study. Eur Child Adolesc Psychiatry. 2020 Jul 22. doi: 10.1007/s00787-020-01598-1. PMID: 32699990. KOHORTENSTUDIE ↥

  28. Furster, Hallerbäck (2015): The use of melatonin in Swedish children and adolescents–a register-based study according to age, gender, and medication of ADHD. Eur J Clin Pharmacol. 2015 Jul;71(7):877-81. doi: 10.1007/s00228-015-1866-3. PMID: 25995170. n = 7.389, KOHORTENSTUDIE ↥

  29. Hartz, Handal, Tverdal, Skurtveit (2015): Paediatric Off-Label Use of Melatonin–A Register Linkage Study between the Norwegian Prescription Database and Patient Register. Basic Clin Pharmacol Toxicol. 2015 Oct;117(4):267-73. doi: 10.1111/bcpt.12411. PMID: 25892306. KOHORTENSTUDIE ↥

  30. Furu, Karlstad, Zoega, Martikainen, Bahmanyar, Kieler, Pottegård (2017): Utilization of Stimulants and Atomoxetine for Attention-Deficit/Hyperactivity Disorder among 5.4 Million Children Using Population-Based Longitudinal Data. Basic Clin Pharmacol Toxicol. 2017 Apr;120(4):373-379. doi: 10.1111/bcpt.12724. Epub 2017 Jan 30. PMID: 27911044. n = 48.296, KOHORTENSTUDIE ↥

  31. Bock, Roach-Fox, Seabrook, Rieder, Matsui (2015): Sleep-promoting medications in children: physician prescribing habits in Southwestern Ontario, Canada. Sleep Med. 2016 Jan;17:52-6. doi: 10.1016/j.sleep.2015.10.003. PMID: 26847974. ↥

  32. Fukumizu, Hayashi, Miyajima, Ishizaki, Tanaka, Kohyama (2015): [A nationwide survey on the uses of melatonin and ramelteon in Japanese children]. No To Hattatsu. 2015 Jan;47(1):23-7. Japanese. PMID: 25803907. ↥

  33. Hayashi M, Mishima K, Fukumizu M, Takahashi H, Ishikawa Y, Hamada I, Sugioka H, Yotsuya O, Yamashita Y (2022): Melatonin Treatment and Adequate Sleep Hygiene Interventions in Children with Autism Spectrum Disorder: A Randomized Controlled Trial. J Autism Dev Disord. 2022 Jun;52(6):2784-2793. doi: 10.1007/s10803-021-05139-w. PMID: 34181143. ↥ ↥ ↥

  34. Williams Buckley A, Hirtz D, Oskoui M, Armstrong MJ, Batra A, Bridgemohan C, Coury D, Dawson G, Donley D, Findling RL, Gaughan T, Gloss D, Gronseth G, Kessler R, Merillat S, Michelson D, Owens J, Pringsheim T, Sikich L, Stahmer A, Thurm A, Tuchman R, Warren Z, Wetherby A, Wiznitzer M, Ashwal S (2020): Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2020 Mar 3;94(9):392-404. doi: 10.1212/WNL.0000000000009033. PMID: 32051244; PMCID: PMC7238942. ↥

  35. Palagini, Manni, Aguglia, Amore, Brugnoli, Bioulac, Bourgin, Micoulaud Franchi, Girardi, Grassi, Lopez, Mencacci, Plazzi, Maruani, Minervino, Philip, Royant Parola, Poirot, Nobili, Biggio, Schroder, Geoffroy (2021): International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders. Front Psychiatry. 2021 Jun 10;12:688890. doi: 10.3389/fpsyt.2021.688890. PMID: 34177671; PMCID: PMC8222620. REVIEW ↥

  36. Geoffroy, Micoulaud Franchi, Lopez, Schroder (2019): membres du consensus Mélatonine SFRMS. The use of melatonin in adult psychiatric disorders: Expert recommendations by the French institute of medical research on sleep (SFRMS). Encephale. 2019 Nov;45(5):413-423. doi: 10.1016/j.encep.2019.04.068. PMID: 31248601. ↥

  37. van Geijlswijk, Korzilius, Smits (2010):. The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis. Sleep. 2010 Dec;33(12):1605-14. doi: 10.1093/sleep/33.12.1605. PMID: 21120122; PMCID: PMC2982730. METASTUDY ↥

  38. Maruani J, Reynaud E, Chambe J, Palagini L, Bourgin P, Geoffroy PA (2023): Efficacy of melatonin and ramelteon for the acute and long-term management of insomnia disorder in adults: A systematic review and meta-analysis. J Sleep Res. 2023 Dec;32(6):e13939. doi: 10.1111/jsr.13939. PMID: 37434463. METASTUDY ↥

  39. Bruno S, Cenerini G, Lo Giudice L, Cruz-Sanabria F, Benedetti D, Crippa A, Fiori S, Ferri R, Masi G, Faraguna U (2025): Optimizing timing and dose of exogenous melatonin administration in neuropsychiatric pediatric populations: a meta-analysis on sleep outcomes. Sleep Med Rev. 2025 Dec;84:102158. doi: 10.1016/j.smrv.2025.102158. PMID: 40914024. METASTUDY ↥

  40. Cruz-Sanabria F, Bruno S, Crippa A, Frumento P, Scarselli M, Skene DJ, Faraguna U (2024): Optimizing the Time and Dose of Melatonin as a Sleep-Promoting Drug: A Systematic Review of Randomized Controlled Trials and Dose-Response Meta-Analysis. J Pineal Res. 2024 Aug;76(5):e12985. doi: 10.1111/jpi.12985. PMID: 38888087. METASTUDY ↥

  41. Weiss MD, Wasdell MB, Bomben MM, Rea KJ, Freeman RD (2006): Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry. 2006 May;45(5):512-519. PMID: 16670647. ↥

  42. Mohammadi MR, Mostafavi SA, Keshavarz SA, Eshraghian MR, Hosseinzadeh P, Hosseinzadeh-Attar MJ, Kooshesh SM, Chamari M, Akhondzadeh S (2012): Melatonin effects in methylphenidate treated children with attention deficit hyperactivity disorder: a randomized double blind clinical trial. Iran J Psychiatry. 2012 Spring;7(2):87-92. PMID: 22952551; PMCID: PMC3428643. ↥

  43. Masi, Fantozzi, Villafranca, Tacchi, Ricci, Ruglioni, Inguaggiato, Pfanner, Cortese (2019): Effects of melatonin in children with attention-deficit/hyperactivity disorder with sleep disorders after methylphenidate treatment. Neuropsychiatr Dis Treat. 2019 Mar 7;15:663-667. doi: 10.2147/NDT.S193891. PMID: 30880992; PMCID: PMC6410756. n = 74 ↥

  44. Tjon Pian Gi CV, Broeren JPA, Starreveld JS, A Versteegh FG (2003): Melatonin for treatment of sleeping disorders in children with attention deficit/hyperactivity disorder: a preliminary open label study. Eur J Pediatr. 2003 Jul;162(7-8):554-555. doi: 10.1007/s00431-003-1207-x. PMID: 12783318. n = 24 ↥

  45. Mostafavi, Mohammadi, Hosseinzadeh, Eshraghian, Akhondzadeh, Hosseinzadeh-Attar, Ranjbar, Kooshesh, Keshavarz (2012): Dietary intake, growth and development of children with ADHD in a randomized clinical trial of Ritalin and Melatonin co-administration: Through circadian cycle modification or appetite enhancement? Iran J Psychiatry. 2012 Summer;7(3):114-9. PMID: 23139692; PMCID: PMC3488866. n = 50 ↥

  46. Sletten TL, Magee M, Murray JM, Gordon CJ, Lovato N, Kennaway DJ, Gwini SM, Bartlett DJ, Lockley SW, Lack LC, Grunstein RR, Rajaratnam SMW; Delayed Sleep on Melatonin (DelSoM) Study Group (2018): 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. doi: 10.1371/journal.pmed.1002587. PMID: 29912983; PMCID: PMC6005466. ↥

  47. Cortesi F, Giannotti F, Sebastiani T, Panunzi S, Valente D (2012): Controlled-release melatonin, singly and combined with cognitive behavioural therapy, for persistent insomnia in children with autism spectrum disorders: a randomized placebo-controlled trial. J Sleep Res. 2012 Dec;21(6):700-9. doi: 10.1111/j.1365-2869.2012.01021.x. PMID: 22616853. ↥

  48. Gringras P, Nir T, Breddy J, Frydman-Marom A, Findling RL (2017): Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957.e4. doi: 10.1016/j.jaac.2017.09.414. PMID: 29096777. ↥

  49. Wright B, Sims D, Smart S, Alwazeer A, Alderson-Day B, Allgar V, Whitton C, Tomlinson H, Bennett S, Jardine J, McCaffrey N, Leyland C, Jakeman C, Miles J (2011): Melatonin versus placebo in children with autism spectrum conditions and severe sleep problems not amenable to behaviour management strategies: a randomised controlled crossover trial. J Autism Dev Disord. 2011 Feb;41(2):175-84. doi: 10.1007/s10803-010-1036-5. PMID: 20535539. ↥

  50. Garstang J, Wallis M (2006): Randomized controlled trial of melatonin for children with autistic spectrum disorders and sleep problems. Child Care Health Dev. 2006 Sep;32(5):585-9. doi: 10.1111/j.1365-2214.2006.00616.x. PMID: 16919138. ↥

  51. Wirojanan J, Jacquemont S, Diaz R, Bacalman S, Anders TF, Hagerman RJ, Goodlin-Jones BL (2009): The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome. J Clin Sleep Med. 2009 Apr 15;5(2):145-50. Erratum in: J Clin Sleep Med. 2010 Aug 15;6(4):preceding 311. PMID: 19968048; PMCID: PMC2670334. ↥

  52. Malow B, Adkins KW, McGrew SG, Wang L, Goldman SE, Fawkes D, Burnette C (2012): Melatonin for sleep in children with autism: a controlled trial examining dose, tolerability, and outcomes. J Autism Dev Disord. 2012 Aug;42(8):1729-37; author reply 1738. doi: 10.1007/s10803-011-1418-3. PMID: 22160300; PMCID: PMC3368078. ↥

  53. Paavonen EJ, Nieminen-von Wendt T, Vanhala R, Aronen ET, von Wendt L (2003): Effectiveness of melatonin in the treatment of sleep disturbances in children with Asperger disorder. J Child Adolesc Psychopharmacol. 2003 Spring;13(1):83-95. doi: 10.1089/104454603321666225. PMID: 12804129. ↥

  54. Wasdell MB, Jan JE, Bomben MM, Freeman RD, Rietveld WJ, Tai J, Hamilton D, Weiss MD (2008): A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res. 2008 Jan;44(1):57-64. doi: 10.1111/j.1600-079X.2007.00528.x. PMID: 18078449. ↥

  55. Gringras P, Gamble C, Jones AP, Wiggs L, Williamson PR, Sutcliffe A, Montgomery P, Whitehouse WP, Choonara I, Allport T, Edmond A, Appleton R; MENDS Study Group (2012): Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial. BMJ. 2012 Nov 5;345:e6664. doi: 10.1136/bmj.e6664. PMID: 23129488; PMCID: PMC3489506. ↥

  56. McArthur AJ, Budden SS (1998): Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol. 1998 Mar;40(3):186-92. doi: 10.1111/j.1469-8749.1998.tb15445.x. PMID: 9566656. ↥

  57. Braam W, Didden R, Smits MG, Curfs LM (2008): Melatonin for chronic insomnia in Angelman syndrome: a randomized placebo-controlled trial. J Child Neurol. 2008 Jun;23(6):649-54. doi: 10.1177/0883073808314153. PMID: 18539989. ↥

  58. Smits MG, van Stel HF, van der Heijden K, Meijer AM, Coenen AM, Kerkhof GA (2003): Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2003 Nov;42(11):1286-93. doi: 10.1097/01.chi.0000085756.71002.86. PMID: 14566165. ↥

  59. Xu H, Zhang C, Qian Y, Zou J, Li X, Liu Y, Zhu H, Meng L, Liu S, Zhang W, Yi H, Guan J, Chen Z, Yin S (2020): Efficacy of melatonin for sleep disturbance in middle-aged primary insomnia: a double-blind, randomised clinical trial. Sleep Med. 2020 Dec;76:113-119. doi: 10.1016/j.sleep.2020.10.018. PMID: 33157425. ↥

  60. Zhdanova IV, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU (2001): Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab. 2001 Oct;86(10):4727-30. doi: 10.1210/jcem.86.10.7901. PMID: 11600532. ↥ ↥ ↥

  61. Lemoine P, Nir T, Laudon M, Zisapel N (2007): Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res. 2007 Dec;16(4):372-80. doi: 10.1111/j.1365-2869.2007.00613.x. PMID: 18036082. ↥

  62. Luthringer, Muzet, Zisapel, Staner (2009): Int Clin Psychopharmacol. 2009 Sep;24(5):239-49. doi: 10.1097/YIC.0b013e32832e9b08. The effect of prolonged-release melatonin on sleep measures and psychomotor performance in elderly patients with insomnia. n = 40 ↥

  63. Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, Zisapel N (2007): Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin. 2007 Oct;23(10):2597-605. doi: 10.1185/030079907X233098. PMID: 17875243. N = 354 ↥

  64. Duffy JF, Wang W, Ronda JM, Czeisler CA (2022): High dose melatonin increases sleep duration during nighttime and daytime sleep episodes in older adults. J Pineal Res. 2022 Aug;73(1):e12801. doi: 10.1111/jpi.12801. PMID: 35436355; PMCID: PMC9288519. n = 24 ↥ ↥

  65. Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N (1995): Melatonin replacement therapy of elderly insomniacs. Sleep. 1995 Sep;18(7):598-603. doi: 10.1093/sleep/18.7.598. PMID: 8552931. n = 24 ↥ ↥ ↥

  66. Attenburrow ME, Cowen PJ, Sharpley AL (1996): Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacology (Berl). 1996 Jul;126(2):179-81. doi: 10.1007/BF02246354. PMID: 8856838. ↥ ↥

  67. Wade AG, Ford I, Crawford G, McConnachie A, Nir T, Laudon M, Zisapel N (2010): Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med. 2010 Aug 16;8:51. doi: 10.1186/1741-7015-8-51. PMID: 20712869; PMCID: PMC2933606. ↥

  68. Braam W, Didden R, Smits M, Curfs L (2008): Melatonin treatment in individuals with intellectual disability and chronic insomnia: a randomized placebo-controlled study. J Intellect Disabil Res. 2008 Mar;52(Pt 3):256-64. doi: 10.1111/j.1365-2788.2007.01016.x. PMID: 18261024. ↥

  69. Braam W, Didden R, Maas AP, Korzilius H, Smits MG, Curfs LM (2010): Melatonin decreases daytime challenging behaviour in persons with intellectual disability and chronic insomnia. J Intellect Disabil Res. 2010 Jan 1;54(1):52-9. doi: 10.1111/j.1365-2788.2009.01223.x. PMID: 19888921. ↥

  70. Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM (2009): Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis. Dev Med Child Neurol. 2009 May;51(5):340-9. doi: 10.1111/j.1469-8749.2008.03244.x. PMID: 19379289. METASTUDY ↥

  71. Garfinkel D, Laudon M, Nof D, Zisapel N (1995): Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995 Aug 26;346(8974):541-4. doi: 10.1016/s0140-6736(95)91382-3. PMID: 7658780. ↥

  72. Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, Thomas R, Thal LJ; Alzheimer’s Disease Cooperative Study (2003): A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep. 2003 Nov 1;26(7):893-901. doi: 10.1093/sleep/26.7.893. PMID: 14655926; PMCID: PMC4418658. ↥

  73. Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S (2009): Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry. 2009 Feb;17(2):166-9. doi: 10.1097/JGP.0b013e318187de18. PMID: 19155748; PMCID: PMC2630117. ↥

  74. Wade AG, Farmer M, Harari G, Fund N, Laudon M, Nir T, Frydman-Marom A, Zisapel N (2014): Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer’s disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 2014 Jun 18;9:947-61. doi: 10.2147/CIA.S65625. PMID: 24971004; PMCID: PMC4069047. ↥

  75. Medeiros CA, Carvalhedo de Bruin PF, Lopes LA, Magalhães MC, de Lourdes Seabra M, de Bruin VM (2007): Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. A randomized, double blind, placebo-controlled study. J Neurol. 2007 Apr;254(4):459-64. doi: 10.1007/s00415-006-0390-x. PMID: 17404779. ↥

  76. Gilat M, Coeytaux Jackson A, Marshall NS, Hammond D, Mullins AE, Hall JM, Fang BAM, Yee BJ, Wong KKH, Grunstein RR, Lewis SJG (2020): Melatonin for rapid eye movement sleep behavior disorder in Parkinson’s disease: A randomised controlled trial. Mov Disord. 2020 Feb;35(2):344-349. doi: 10.1002/mds.27886. PMID: 31674060; PMCID: PMC7027846. ↥

  77. Dowling GA, Mastick J, Colling E, Carter JH, Singer CM, Aminoff MJ (2005): Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med. 2005 Sep;6(5):459-66. doi: 10.1016/j.sleep.2005.04.004. PMID: 16084125. ↥

  78. Sadeghniiat-Haghighi K, Aminian O, Pouryaghoub G, Yazdi Z (2008): Efficacy and hypnotic effects of melatonin in shift-work nurses: double-blind, placebo-controlled crossover trial. J Circadian Rhythms. 2008 Oct 29;6:10. doi: 10.1186/1740-3391-6-10. PMID: 18957133; PMCID: PMC2584099. ↥

  79. Sadeghniiat-Haghighi K, Bahrami H, Aminian O, Meysami A, Khajeh-Mehrizi A (2016): Melatonin therapy in shift workers with difficulty falling asleep: A randomized, double-blind, placebo-controlled crossover field study. Work. 2016 Sep 27;55(1):225-230. doi: 10.3233/WOR-162376. PMID: 27612057. ↥

  80. Sharkey KM, Fogg LF, Eastman CI (2001): Effects of melatonin administration on daytime sleep after simulated night shift work. J Sleep Res. 2001 Sep;10(3):181-92. doi: 10.1046/j.1365-2869.2001.00256.x. PMID: 11696071; PMCID: PMC3679650. ↥

  81. Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R (1998): Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiol Int. 1998 Nov;15(6):655-66. doi: 10.3109/07420529808993201. PMID: 9844753. ↥ ↥ ↥

  82. Herxheimer A, Petrie KJ (2002): Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520. doi: 10.1002/14651858.CD001520. PMID: 12076414. ↥

  83. Andrade C, Srihari BS, Reddy KP, Chandramma L (2001): Melatonin in medically ill patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry. 2001 Jan;62(1):41-5. doi: 10.4088/jcp.v62n0109. PMID: 11235927. ↥

  84. Bourne RS, Mills GH, Minelli C (2008): Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care. 2008;12(2):R52. doi: 10.1186/cc6871. PMID: 18423009; PMCID: PMC2447606. ↥

  85. Edalat-Nejad M, Haqhverdi F, Hossein-Tabar T, Ahmadian M (2013): Melatonin improves sleep quality in hemodialysis patients. Indian J Nephrol. 2013 Jul;23(4):264-9. doi: 10.4103/0971-4065.114488. PMID: 23960341; PMCID: PMC3741969. ↥

  86. Nunes DM, Mota RM, Machado MO, Pereira ED, Bruin VM, Bruin PF (2008): Effect of melatonin administration on subjective sleep quality in chronic obstructive pulmonary disease. Braz J Med Biol Res. 2008 Oct;41(10):926-31. doi: 10.1590/s0100-879x2008001000016. PMID: 19030713. ↥

  87. Hansen MV, Madsen MT, Andersen LT, Hageman I, Rasmussen LS, Bokmand S, Rosenberg J, Gögenur I (2014): Effect of Melatonin on Cognitive Function and Sleep in relation to Breast Cancer Surgery: A Randomized, Double-Blind, Placebo-Controlled Trial. Int J Breast Cancer. 2014;2014:416531. doi: 10.1155/2014/416531. PMID: 25328711; PMCID: PMC4160608. ↥

  88. Keijzer H, Smits MG, Duffy JF, Curfs LM (2014): Why the dim light melatonin onset (DLMO) should be measured before treatment of patients with circadian rhythm sleep disorders. Sleep Med Rev. 2014 Aug;18(4):333-9. doi: 10.1016/j.smrv.2013.12.001. PMID: 24388969. REVIEW ↥

  89. Pandi-Perumal SR, Smits M, Spence W, Srinivasan V, Cardinali DP, Lowe AD, Kayumov L (2007): Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jan 30;31(1):1-11. doi: 10.1016/j.pnpbp.2006.06.020. PMID: 16884842. REVIEW ↥

  90. Lewy AJ, Ahmed S, Jackson JM, Sack RL (1992): Melatonin shifts human circadian rhythms according to a phase-response curve. Chronobiol Int. 1992 Oct;9(5):380-92. doi: 10.3109/07420529209064550. PMID: 1394610. ↥

  91. Wolf, Calabrese (2020): Stressmedizin & Stresspsychologie; Seite 206 ↥ ↥ ↥ ↥ ↥ ↥ ↥ ↥

  92. Claustrat B, Brun J, Chazot G (2005): The basic physiology and pathophysiology of melatonin. Sleep Med Rev. 2005 Feb;9(1):11-24. doi: 10.1016/j.smrv.2004.08.001. PMID: 15649735. ↥

  93. Cutolo M, Masi AT (2005): Circadian rhythms and arthritis. Rheum Dis Clin North Am. 2005 Feb;31(1):115-29, ix-x. doi: 10.1016/j.rdc.2004.09.005. PMID: 15639059. REVIEW ↥

  94. Scheiermann C, Kunisaki Y, Frenette PS (2013): Circadian control of the immune system. Nat Rev Immunol. 2013 Mar;13(3):190-8. doi: 10.1038/nri3386. PMID: 23391992; PMCID: PMC4090048. REVIEW ↥

  95. Balsalobre, Brown, Marcacci, Tronche, Kellendonk, Reichardt, Schütz, Schibler (2000): Resetting of circadian time in peripheral tissues by glucocorticoid signaling. Science. 2000 Sep 29;289(5488):2344-7. doi: 10.1126/science.289.5488.2344. PMID: 11009419. ↥

  96. Shanahan TL, Czeisler CA (1991): Light exposure induces equivalent phase shifts of the endogenous circadian rhythms of circulating plasma melatonin and core body temperature in men. J Clin Endocrinol Metab. 1991 Aug;73(2):227-35. doi: 10.1210/jcem-73-2-227. PMID: 1856258. n = 8 ↥

  97. Molina TA, Burgess HJ (2011): Calculating the dim light melatonin onset: the impact of threshold and sampling rate. Chronobiol Int. 2011 Oct;28(8):714-8. doi: 10.3109/07420528.2011.597531. PMID: 21823817; PMCID: PMC3248814. ↥

  98. Benloucif S, Guico MJ, Reid KJ, Wolfe LF, L’hermite-Balériaux M, Zee PC (2005): Stability of melatonin and temperature as circadian phase markers and their relation to sleep times in humans. J Biol Rhythms. 2005 Apr;20(2):178-88. doi: 10.1177/0748730404273983. PMID: 15834114. ↥

  99. Cagnacci A, Elliott JA, Yen SS (1992): Melatonin: a major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab. 1992 Aug;75(2):447-52. doi: 10.1210/jcem.75.2.1639946. PMID: 1639946. ↥

  100. Brown EN, Choe Y, Shanahan TL, Czeisler CA; New Collective Author (1997): A mathematical model of diurnal variations in human plasma melatonin levels. Am J Physiol. 1997 Mar;272(3 Pt 1):E506-16. doi: 10.1152/ajpendo.1997.272.3.E506. PMID: 9124558. ↥

  101. Burgess HJ, Eastman CI (2005): The dim light melatonin onset following fixed and free sleep schedules. J Sleep Res. 2005 Sep;14(3):229-37. doi: 10.1111/j.1365-2869.2005.00470.x. PMID: 16120097; PMCID: PMC3841975. ↥

  102. Bruni, Alonso-Alconada, Besag, Biran, Braam, Cortese, Moavero, Parisi, Smits, Van der Heijden, Curatolo (2015): Current role of melatonin in pediatric neurology: clinical recommendations. Eur J Paediatr Neurol. 2015 Mar;19(2):122-33. doi: 10.1016/j.ejpn.2014.12.007. PMID: 25553845. REVIEW ↥ ↥

  103. Kennaway (2015): Potential safety issues in the use of the hormone melatonin in paediatrics. J Paediatr Child Health. 2015 Jun;51(6):584-9. doi: 10.1111/jpc.12840. PMID: 25643981. REVIEW ↥ ↥

  104. Wolf, Calabrese (2020): Stressmedizin & Stresspsychologie; Seite 207 ↥ ↥ ↥

  105. Netdoktor.de: Melatonin ↥ ↥ ↥ ↥ ↥ ↥ ↥

  106. Rupp, Acebo, Carskadon (2007): Evening alcohol suppresses salivary melatonin in young adults. Chronobiol Int. 2007;24(3):463-70. doi: 10.1080/07420520701420675. PMID: 17612945. n = 29 ↥

  107. Skene, Bojkowski, Arendt (1994): Comparison of the effects of acute fluvoxamine and desipramine administration on melatonin and cortisol production in humans. Br J Clin Pharmacol. 1994 Feb;37(2):181-6. doi: 10.1111/j.1365-2125.1994.tb04258.x. PMID: 8186063; PMCID: PMC1364595. ↥ ↥

  108. Härtter, Grözinger, Weigmann, Röschke, Hiemke (2000): Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clin Pharmacol Ther. 2000 Jan;67(1):1-6. doi: 10.1067/mcp.2000.104071. PMID: 10668847. ↥

  109. Härtter, Nordmark, Rose, Bertilsson, Tybring, Laine (2003): Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. Br J Clin Pharmacol. 2003 Dec;56(6):679-82. doi: 10.1046/j.1365-2125.2003.01933.x. PMID: 14616429; PMCID: PMC1884289. ↥

  110. Huuhka, Riutta, Haataja, Ylitalo, Leinonen (2006): The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: A randomized, double-blind, placebo-controlled study. Methods Find Exp Clin Pharmacol. 2006 Sep;28(7):447-50. doi: 10.1358/mf.2006.28.7.1003545. PMID: 17003850. ↥