Medicine, Faculty of
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Children 12 (5): 648 (2025)
Children's Hospital (Vancouver, B.C.). Research Institute
Paditz, Ekkehart
Renner, Bertold
Koch, Rainer
Schneider, Barbara M.
Schlarb, Angelika A.
Ipsiroglu, Osman S.
Background: To date, it remains unclear which oral doses and preparation forms of melatonin should be recommended for children and adolescents with non-organic sleep disorders and autism spectrum disorder (ASD). We reviewed the current state of knowledge on this topic based on randomised placebo-controlled trials (RCTs) and diagnosis-related blood melatonin concentrations available in this age group. Method: Two investigators independently searched PubMed, PsycINFO, MEDLINE, and Cochrane CENTRAL on 1 March 2025 for the keywords “melatonin”, “autism”, and “randomised” in titles and abstracts in all languages, including an evaluation of the references of the reviews, systematic reviews, and meta-analyses published up to that date, some of which were based on searches in numerous databases. Based on this, additional in-depth searches were carried out in PubMed for pharmacokinetic, physiological, and pathophysiological data on melatonin in children and adolescents, with a special focus on ASD. Results: To date, five RCTs on non-organic sleep disorders in children and adolescents with the sole diagnosis of ASD or with subgroup analyses in the presence of several initial diagnoses such as ADHD, epilepsy, Smith–Magenis, or Fragile X syndrome are available. In these studies, rapid-release, non-delayed preparations were administered orally. In one of these studies, the clinical efficacy of a combination preparation with a sustained-release and a non-released active substance component was tested. Pharmacokinetic data with multiple determinations of melatonin concentrations in the blood are only available for children with ASD in the form of a case series (N = 9). Discussion: RCTs comparing the efficacy of delayed melatonin preparations with non-delayed rapid-release oral preparations are not yet available. Physiological data and clinical effects documented in five RCTs indicate that non-delayed melatonin preparations with an initial rapid onset of action are effective for non-organic sleep disorders in children and adolescents with ASD. Conclusions: From a clinical, pharmacokinetic, and physiological point of view, the RCTs available to date and the data on melatonin concentrations in the blood of children with ASD, measured several times over 24 h, suggest that a low oral melatonin dose and a non-delayed preparation with rapid onset should be started in children and adolescents with non-organic sleep disorders in ASD, if sleep hygiene advice and psychotherapeutic interventions have not demonstrated sufficient effects.
Academic Editor: FrancescaSantamariaReceived: 25 March 2025Revised: 29 April 2025Accepted: 10 May 2025Published: 16 May 2025Citation: Paditz, E.; Renner, B.; Koch,R.; Schneider, B.M.; Schlarb, A.A.;Ipsiroglu, O.S. The Pharmacokinetics,Dosage, Preparation Forms, andEfficacy of Orally AdministeredMelatonin for Non-Organic SleepDisorders in Autism SpectrumDisorder During Childhood andAdolescence: A Systematic Review.Children 2025, 12, 648. https://doi.org/10.3390/children12050648Copyright: © 2025 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license(https://creativecommons.org/licenses/by/4.0/).Systematic ReviewThe Pharmacokinetics, Dosage, Preparation Forms, and Efficacyof Orally Administered Melatonin for Non-Organic SleepDisorders in Autism Spectrum Disorder During Childhood andAdolescence: A Systematic ReviewEkkehart Paditz 1,* , Bertold Renner 2 , Rainer Koch 3, Barbara M. Schneider 4, Angelika A. Schlarb 5and Osman S. Ipsiroglu 61 Centre for Applied Prevention/Zentrum für Angewandte Prävention, 01307 Dresden, Germany2 Institute of Clinical Pharmacology, Faculty of Medicine Carl Gustav Carus, Dresden University of Technology,01069 Dresden, Germany; bertold.renner@tu-dresden.de3 Formerly Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, DresdenUniversity of Technology, 01069 Dresden, Germany; rainer.koch.01@gmx.de4 Paediatric Sleep Medicine Centre in Foundation, Vancouver, BC V5Z 4H4, Canada;b.schneider@kinder-schlaf.de5 Faculty of Psychology and Sports Science, Bielefeld University, 33615 Bielefeld, Germany;angelika.schlarb@uni-bielefeld.de6 Interdisciplinary Sleep Program, Sleep/Wake-Behaviour Clinic, Departments of Pediatrics & Psychiatry,University of British Columbia, Vancouver, BC V6T 1Z4, Canada; oipsiroglu@bcchr.ca* Correspondence: praxis@paditz.euAbstract: Background: To date, it remains unclear which oral doses and preparation formsof melatonin should be recommended for children and adolescents with non-organic sleepdisorders and autism spectrum disorder (ASD). We reviewed the current state of knowledgeon this topic based on randomised placebo-controlled trials (RCTs) and diagnosis-relatedblood melatonin concentrations available in this age group. Method: Two investigatorsindependently searched PubMed, PsycINFO, MEDLINE, and Cochrane CENTRAL on1 March 2025 for the keywords “melatonin”, “autism”, and “randomised” in titles andabstracts in all languages, including an evaluation of the references of the reviews, sys-tematic reviews, and meta-analyses published up to that date, some of which were basedon searches in numerous databases. Based on this, additional in-depth searches werecarried out in PubMed for pharmacokinetic, physiological, and pathophysiological dataon melatonin in children and adolescents, with a special focus on ASD. Results: To date,five RCTs on non-organic sleep disorders in children and adolescents with the sole di-agnosis of ASD or with subgroup analyses in the presence of several initial diagnosessuch as ADHD, epilepsy, Smith–Magenis, or Fragile X syndrome are available. In thesestudies, rapid-release, non-delayed preparations were administered orally. In one of thesestudies, the clinical efficacy of a combination preparation with a sustained-release and anon-released active substance component was tested. Pharmacokinetic data with multipledeterminations of melatonin concentrations in the blood are only available for childrenwith ASD in the form of a case series (N = 9). Discussion: RCTs comparing the efficacy ofdelayed melatonin preparations with non-delayed rapid-release oral preparations are notyet available. Physiological data and clinical effects documented in five RCTs indicate thatnon-delayed melatonin preparations with an initial rapid onset of action are effective fornon-organic sleep disorders in children and adolescents with ASD. Conclusions: From aclinical, pharmacokinetic, and physiological point of view, the RCTs available to date andthe data on melatonin concentrations in the blood of children with ASD, measured severaltimes over 24 h, suggest that a low oral melatonin dose and a non-delayed preparationChildren 2025, 12, 648 https://doi.org/10.3390/children12050648Children 2025, 12, 648 2 of 25with rapid onset should be started in children and adolescents with non-organic sleepdisorders in ASD, if sleep hygiene advice and psychotherapeutic interventions have notdemonstrated sufficient effects.Keywords: melatonin in children and adolescents; autism spectrum disorder; sleep; phar-macokinetics; RCT; non-delayed preparations1. Introduction1.1. Sleep Disorders in Children and Adolescents with ASDSleep disorders in children and adolescents with autism spectrum disorder (ASD)have been detected in 19.7% (11.9 to 30.7%) of the individuals in eight population-basedstudies [1]. At 26.5% (15.4 to 41.6%), significantly higher prevalences were found in childrenthan in adolescents (6.6%; 4.5–9.5%) [1]. At the same time, children and adolescents withASD exhibit Attention Deficit Hyperactivity Disorder (ADHD) in 26.2% of cases, althoughthe mean ADHD prevalence rates for ASD do not differ significantly between childrenand adolescents (26.2 vs. 35.4%) [1]. Anxiety disorders and intellectual disabilities arefurther significant psychiatric comorbidities in ASD, with prevalences of 11.1% and 22.9%,respectively. In the case of anxiety disorders, it is striking that these are observed lessfrequently in children (7.8%) than in adolescents (21.5%) [1].Baldini et al. reported recently on the close connection between insomnia and de-pression in adolescents with psychiatric disorders (r = 0.94, p = 0.02) [2]. Both disordersare associated with an increased risk of suicide (ibid.). In children and adolescents withASD, an almost 3-fold increase in suicidal risk was observed at first presentation in pae-diatric emergency departments (12.7% vs. 4.4% compared to children and adolescentswithout ASD) [3]. These data indicate that insomnia in children and adolescents with ASDshould be diagnosed early (see comparison in [4]) and should be taken seriously. Treatmentrequires multimodal approaches with structured advice on sleep hygiene [5], advice onphysical activation [6], psychological–psychiatric treatment using cognitive-behaviouraltherapy [7–9], and drug treatments, with a particular interest in melatonin if organic causesof the sleep disorder have been ruled out [10–12].Sleep disorders in ASD are phenotypically characterised by difficulty falling asleep,restless sleep, nocturnal awakenings and fragmented sleep due to nocturnal arousals (53 vs.40 vs. 34 vs. 32%; information from parents via standardised questionnaires) [13]. Thesesymptoms were associated with daytime sleepiness in 15% of 60 children with ASD fromChina [14].1.2. ObjectivesThe possibility that the psychiatric comorbidities described and the different types ofsleep disorders are present simultaneously in at least some of the patient groups examinedin the studies means that subgroup analyses are necessary. This aspect is taken into accountin the present study. We were interested in the current state of knowledge on the use ofmelatonin in children and adolescents with sleep disorders in ASD.1.3. Preliminary Considerations on the Dosage, Pharmaceutical Formulation and Pharmacokineticsof Orally Administered Melatonin PreparationsSince the discovery of melatonin in 1958 by Lerner [15], and the first descriptionsof the circadian day–night rhythmicity of melatonin synthesis and secretion in humansin 1976 [16] and in almost all mammalia and vertrebralia since 1963 [17–26] and someother species studied to date [27–31], to the best of our knowledge, 36 randomised placebo-Children 2025, 12, 648 3 of 25controlled trials (RCTs) on the efficacy of melatonin in non-organic sleep disorders inchildren and adolescents have been published since 1998 [6,11,32–34], demonstratingheterogeneous quality standards with regard to the recording of parameters associatedwith sleep [35]. These data show that the diurnal rhythmicity of melatonin concentrationsrepresents evolutionary biological adaptations to the day–night and light–dark rhythmsdue to the Earth’s rotation, and that disorders of pineal melatonin synthesis and secretioncan be influenced in an age- and diagnosis-related manner. Interestingly, the ability tosynthesise and secrete melatonin rhythmically in the pineal gland in the dark of night onlydevelops in humans postnatally during the first year of life [36,37].General recommendations for the administration of melatonin for non-organic sleepdisorders in children and adolescents—which also relate to the form of preparation, thedosage, the time of evening administration, and the resulting efficacy on defined param-eters associated with restful sleep—are missing so far. In our view, diagnosis-relatedrecommendations are required [11].These questions of practical relevance are influenced in particular by age, the age-related elimination half-life, and underlying disorders, as follows:- In 13 children with Angelman syndrome aged 2–10 years, low evening oral dosesof 0.3 mg were associated with relatively high blood melatonin concentrations andimprovements in actigraphic parameters, such as total sleep time (TST) [38].- Niederhofer et al. showed in 2003 that 0.3 mg of melatonin in the non-delayed formled to an improvement in sleep parameters in adolescents aged 14 to 18 years withinsomnia and intellectual disabilities in a placebo-controlled RCT, in which bloodwas taken every 15–60 min within 24 h via a venous vascular access to determine themelatonin concentration and polysomnographic controls were carried out [34].- The first case report on the oral administration of melatonin during childhood andadolescence involved a blind child, aged 8, with non-24, for whom an initial non-delayed oral dose of 0.5 mg was effective (Figure 1) [39,40].- In 74 children with insomnia in ASD in an open-label setting, Yuge et al. found that1 mg of an orally administered rapid-release non-delayed melatonin preparationwas associated with a significant reduction in SOL (mean 37%; 95% CI 26 to 48%;p < 0.0001) [41].- Van Geijlswijk et al. studied 72 children and adolescents with delayed sleep phasedisorder (DSPD), who were treated in parallel in four groups for 1 week with 0.05, 0.1,or 0.15 mg/kg body weight (1.6 mg, 2.91 mg, or 4.39 mg, respectively) of melatonin orwith a placebo. The results showed that no dose–response correlations were observedfor these three doses, as several sleep parameters (sleep onset, SO; sleep onset latency,SOL; evening melatonin increase = dim light melatonin onset, DLMO) improvedindependently of the doses investigated (Figure 2) [42].The effect on these parameters was stronger the earlier the oral melatonin was ad-ministered; significant correlations were observed between the time of evening melatoninadministration, which took place in the evening between 5:58 p.m. and 8:17 p.m., and theshortening of sleep onset time or DLMO (p = 0.004 and 0.022, respectively) [42].The authors suggested conducting further pharmacokinetic studies with lower dosesto search for dose–response correlations.Children 2025, 12, 648 4 of 25Children 2025, 12, x FOR PEER REVIEW 4 of 26 Figure 1. Disturbed day–night rhythm (“non-24”) in an 8-year-old blind child with microphthalmia and epilepsy after congenital toxoplasmosis reported by Palm et al. in 1991 and 1997 [39,40]. This is a graphical representation of records from the sleep diary which the parents had recorded. The black bars correspond to the visually recorded total sleep time (TST). There was normalisation of the cir-cadian sleep–wake rhythm after the start of the treatment, comprising an evening oral administra-tion of 0.5 mg of a rapid-release, non-delayed melatonin preparation. This study is also remarkable from a methodological point of view, as informative results were obtained on the basis of sleep logs filled out by the parents without technical appliances, which are relatively similar to today’s stand-ard actigraphic measurements. From Palm et al., 1997 [40]. Reproduced with permission. Figure 1. Disturbed day–night rhythm (“non-24”) in an 8-year-old blind child with microphthalmiaand epilepsy after congenital toxoplasmosis reported by Palm et al. in 1991 and 1997 [39,40]. Thisis a graphical representation of records from the sleep diary which the parents had recorded. Theblack bars correspond to the visually recorded total sleep time (TST). There was normalisationof the circadian sleep–wake rhythm after the start of the treatment, comprising an evening oraladministration of 0.5 mg of a rapid-release, non-delayed melatonin preparation. This study is alsoremarkable from a methodological point of view, as informative results were obtained on the basis ofsleep logs filled out by the parents without technical appliances, which are relatively similar to today’sst n rd actigraphic measurements. Fro Palm et al., 1997 [40]. Reproduced with permission.Children 2025, 12, 648 5 of 25 Figure 2. Improvement in sleep onset latency (SOL shift) after the administration of 0.05, 0.1, or0.15 mg of melatonin per kilogram of body weight in 72 children and adolescents with delayed sleepphase disorder (DSPD) who were studied in parallel in a randomised setting compared to a placebogroup (0 mg melatonin) (Van Geijlswijk et al., 2010) [42]. In this dosage range, there was no dose–response correlation in the sense of an increase in efficacy with an increase in dose (N = 16–19 pergroup). Reproduced with permission.The authors interpreted the surprising result as either of the following options:(a) As a “lid effect” in relation to the saturation range of traditional dose–responsecurves, or (b) as an “all or nothing principle”, which was described in a comparableway [42].- In 18 premature infants within their first week of life, the melatonin eliminationhalf-life was between 16.9 and 21.0 h after intravenous melatonin administration [43].In a further 15 premature infants, an elimination half-life of between 6.2 and 15.5 hwas measured after intragastric melatonin administration via a nasogastric tube [44].In nine children with ASD aged 3–8 years, the elimination half-life after the oraladministration of 1 mg of melatonin was 1.3 ± 0.42 h (range: 0.68–2.0 h) [45]. Nineprepubertal adolescents had a slightly shorter elimination half-life than sixteen youngadults (0.67 ± 0.12 vs. 0.79 ± 0.10 h, corresponding to a mean of 40.2 and 47.4 min, re-spectively) [46]. In young adults, the elimination half-life after the oral or intravenousadministration of melatonin was less than one hour (53.7 + 7.0 min and 39.4 + 3.6 min,respectively) [15]. Other authors measured comparable values after the oral adminis-tration of melatonin in young adults aged 21 to 32 years (47 + 3 min) [47].Children 2025, 12, 648 6 of 25- Pharmacokinetic data on melatonin sustained-release preparations have not yet beenpublished (except for the reference by Lalanne et al. in 2021 to unpublished datain an assessment report for the EMA from 2007 (https://www.ema.europa.eu/en/documents/scientific-discussion/circadin-epar-scientific-discussion_en.pdf (accessedon 9 May 2025), p. 16), which were measured by Ruth Kitzes-Cohen et al. in eighthealthy male volunteers after the administration of a 2 mg sustained-release prepara-tion for adults, and these would represent the only data to date on the pharmacokinet-ics of a melatonin sustained-release preparation with an active ingredient content of2 mg [48]).It can be concluded from these data that diagnosis- and age-related studies are requiredto clarify at which oral dose, in which formulation, and at what time melatonin can berecommended for children and adolescents with ASD and non-organic sleep disorders.2. MethodInclusion criteria: Randomised placebo-controlled trials (RCTs) in which the efficacyof treatment with melatonin in children and adolescents with ASD was tested (a) if ASDwas specified as the sole diagnosis or (b) in which a subgroup analysis was performed inthe presence of psychiatric comorbidities or other diagnoses.Exclusion criteria: All studies that either did not address the topic of melatonin inASD with non-organic sleep disorders in childhood and adolescence or that included ASDwith psychiatric or other diagnoses without subgroup analysis.Using the PubMed medical database on 1 March 2025, two authors (E.P.; A.S.), inde-pendently of each other, searched for the keyword combination “((melatonin[title/abstract])AND (autism[title/abstract])) AND (randomised[Title/Abstract])”, taking all languagesinto account. In total, 26 publications were retrieved [7,49–73] (Figure 3). In these publi-cations and in the literature references contained in these publications, we searched forRCTs on non-organic sleep disorders in children and adolescents with ASD. For studiesthat included not only ASD but also other underlying conditions such as SMS, fragileX syndrome, Rett syndrome, epilepsy, and/or ADHD, we checked whether subgroupanalyses had been conducted for these diagnoses (see Supplementary S1).PsycINFO, MEDLINE, and Cochrane CENTRAL were searched using the keywordcombination “autism, melatonin, sleep”. In these databases, 3, 25, and 42 publications, re-spectively, were found, of which the same 4 RCTs fulfilled the inclusion criteria “childhoodand adolescence” and “evidence of subgroup analyses in the presence of multiple initialdiagnoses”, as in PubMed (see Figure 3 and Supplementary S1).The searches were conducted independently by only two authors, as the number ofstudies found was limited to N = 26 (PubMed), and for each of these studies, it is declaredin Supplementary S1 why it was included or excluded. In our view, a selection bias wasthus ruled out (see Supplementary S2 and S3).Children 2025, 12, 648 7 of 25Children 2025, 12, x FOR PEER REVIEW 7 of 26 Figure 3. Flow chart showing the selection procedure applied here. For the list of excluded items, please see the Results and Supplementary S1: Protocols without own data on results [53,54] and 5 topics not related to this study [59–63]). Records screened N = 19, incl. two RCTs [7,49], two sys-tematic reviews with meta-analyses [51,52], and two systematic reviews [50,55–58], incl. one sys-tematic review of RCT [55] and six reviews [64–69], incl. one review of paediatric prolonged-release melatonin for sleep in children with ASS [67], two OL [70,71], and two RCTs without subgroup N=26 records identified from PubMed, March 01, 2025; RCTs meeting the inclusion criteria in PsycInfo N=3; MEDLINE N=25; Cochrane CENTRAL N=42. Databases (n = 3) Registers (n = 0) Records from PubMed removed before screening: duplicates removed (n=0); removed for other reasons (n=7; incl. 2 protocols without own data on results and 5 topics not related to this study). Records screened N=19, incl. two RCTs, two systematic reviews with meta-analyses and two systematic reviews, incl. one systematic review of RCT and six reviews, incl. one review of paediatric prolonged-release melatonin for sleep in children with ASS, two OL, and two RCTs without subgroup analyses) Records excluded (n = 1; Persico 2025, without melatonin) Reports assessed for eligibility (n = 18) Reports excluded (for reasons, see main text) (n = 13) RCTs included in review (n = 5) Identification of studies via databases and registers Identification Screening Included Fig re 3. Flow chart showing the selection procedure applied here. For the list of excluded items,l s s t s lts le entary S1: Protocols without own data on results [53,54] and 5 top-ics not relat d to this study [59–63]). Records screen d N = 19, incl. two RCTs [7,49], two systematicr views with meta-analyses [51,52], and two systematic rev ews [50,55–58], incl. one systematic re-view of RCT [55] and six reviews [64–69], incl. one review of paediatric prolonged-releas melatoninfor sleep in children wit ASS [67], two OL [70,71], and two RCTs without subgroup analyses [72,73]).Records excluded (without melatonin [50]). Source of the flow chart [74]. This work is licenced underCC BY 4.0.Children 2025, 12, 648 8 of 253. Results3.1. The Results of the Five RCTs Representing the Outcome of the Present Systematic ReviewAt present, five randomised placebo-controlled studies on non-organic sleep disordersin children and adolescents with autism spectrum disorder (ASD) are available (Table 1),in four of which ASD was stated as the single underlying disease [6,7,75,76], and in theother study [49] (Table 1), ASD was declared with a differentiated evaluation in the form ofsubgroup analyses, with ADHD also being present in some of the patients.In an interesting study by Tse et al. in 2024 [6], it was unfortunately not recorded(a) at what time of day and in what lighting conditions the physical training took placeand (b) whether the physical training was associated with changes in body weight ormetabolic parameters. Further assessments of the quality of these RCTs are provided inSupplementary S2.Table 1. (a) Overview of the RCTs available to date on the efficacy of melatonin in children andadolescents with non-organic sleep disorders and ASD alone or ASD in combination with otherunderlying conditions for which a subgroup analysis was presented. (b) Characteristics of theRCTs available to date on the efficacy of melatonin in children and adolescents with non-organicsleep disorders and ASD alone or ASD in combination with other underlying conditions for which asubgroup analysis was presented.Author,Country Diagnosis N, AgeMelatonin(Dose, Preparation) Result ConclusionGarstang,2006 [75]UKASS withinsomnia.N = 7,5–15years.Five-milligram oral capsules,immediate release, 4 weeks vs.placebo, crossover afterwashout for 1 week.TST ↑, SOL ↓, WASO ↓This non-delayed preparation waseffective in terms of falling asleep,sleeping through the night, and TST.Wright, 2011[76]UKASS withinsomnia.N = 17,9± 2.9(4–16) years.Two-milligram oralnon-delayed,30–40 min before the expectedsleep; increased every 3 days bytwo milligrams to max. tenmilligrams (average sevenmilligrams).SOL ↓, TST ↑, WASO ↓ Improvementin behaviour, communication, anddyssomnia.This non-delayed preparation waseffective in terms of falling asleep,sleeping through the night, TST, andimprovement in behaviour andcommunication.Cortesi, 2012[7]ItalyASS withinsomnia.Comparisonof melatoninalone and incombinationwith CBT(cognitivebehaviouraltherapy; foursessions).N = 134,6.8± 0.9years.Three milligrams of acombined preparation (onemilligrams rapid release, twomilligrams sustained release (6h)) oral administration at 9:00p.m.Four randomised groups inparallel; 3 months for each of thefollowing:•Melatonin (N = 34);•CBT (N = 33);•Melat. + CBT (N = 35);• Placebo (N = 32).SOL ↓ to 44% with melatonin alone, to23% after CBT, and to 61% withmelatonin + CBT.TST ↑, WASO ↓, sleep anxiety ↓ afterKVT to 17%, after melatonin to 14%,and after both to 34%.Thiscombined 3 mg preparation alone wasmore effective than CBT alone. Thecombination of both was more effectivethan either method alone.Hayashi,2022 [49]JapanASS withinsomnia.ADHD at55%(108/196):comparableeffectsregardingimprovementin SOL bymelatonin inboth doses.N = 196,aged11.2± 2.5(6–15) years.Three parallel randomised,double-blind groups:1 milligram or 4 milligramsnon-delayed melatonin vs.placebo for 2 weeks,administered 45 min beforebedtime.SOL ↓, SE ↑.Sleep hygiene alone in the prephasewith lower effects compared to bothmelatonin doses.The administration of this non-delayedpreparation with 4 mg 45 min beforebedtime was associated withcomparable effects to 1 mg, but morefrequent AEs.In the OL phase with up to 10 mg, afurther increase in AEs wasdocumented.Tse, 2024 [6]Hong KongASS withinsomniaN = 62,aged9.6 to 10.4yearsFour randomised arms:• Three milligrams of liquidMelatonin 30 min beforebedtime (N = 14);•Cycling in the morning only(N = 18);•Melatonin and cycling(N = 12);• Placebo alone (N = 18).SOL ↓, TST ↑, SE ↑,WASO ↑.Melatonin or cycling alone ormelatonin with cycling exerted bettereffects compared to placebo.The administration of this non-delayedliquid preparation with 3 mg 30 minbefore bedtime was associated withcomparable effects to cyling. Thecombination of both methods was justas effective as each method on its own.Children 2025, 12, 648 9 of 25Table 1. Cont.Author,Country DiagnosisN, Age,Dropouts,MissingDataTarget ValuesMelatonin(Dose,Preparation)Result Conclusion Side EffectsGarstang,2006 [75]UKASS withinsomnia *.N = 7 (6♂),5–15 years. *Dropouts:36.4% (4/11).Missingdata: none.SOL; TST; WASO; waking-upactivity in the morning via asleep log written by parents.Five-milligramoral capsules,immediaterelease ** 4 weeksvs. placebo,crossover afterwashout for 1week.Instructions onsleep hygieneshowed no effectbefore the start ofthe study andwere maintainedduring the study.Signif. #TST ↑ 8.05 to 9.84h;SOL ↓ 2.60 to1.06 h;awakenings ↓from 0.35 to 0.08.Thisnon-delayedpreparation waseffective interms of fallingasleep, sleepingthrough thenight, and TST.No dataavailable.Wright, 2011[76]UKASS withinsomnia ***.N = 17 (10♂),9± 2.9(4–16) years.Dropouts:15% (3/20).Missingdata:5.9% (1/17).Previousstatisticalcase numberplanning andpoweranalysis.As above; also, fourstandardised questionnaires onsleep, behaviour, health, andcomplications ##.Two-milligramoralnon-delayed §,30–40 min beforethe expectedsleep; increasedby the parentsevery 3 days bytwo milligrams tomax. tenmilligrams(average sevenmilligrams) until“good sleep” withan “improvementof≥50%” wasachieved.Instructions onsleep hygieneshowed no effectbefore the start ofthe study andwere maintainedduring the studyafter furtherinstruction of theparents.SOL ↓ 135 to 82min (baseline vs.melatonin atbedtime), 130 vs.78 min onmelatoninapplication vs.placebo.TST ↑ 500 to 556min.Number ofawakenings ↓0.5 to 0.43/night.Improvement inbehaviour,communication,and dyssomnia.Thisnon-delayedpreparation waseffective interms of fallingasleep, sleepingthrough thenight, TST, andimprovement inbehaviour andcommunication.No statisticallysignificantdifferencesbetween verumand placebo withregard to allcharacteristicssuch as headache,vomiting,reduced appetite,and reducedattention,according toSEQ ##.Cortesi, 2012[7]ItalyASS withinsomnia +.Comparisonof melatoninalone and incombinationwith CBT(cognitivebehaviouraltherapy; foursessions).N = 134(82%♂in themelatoningroup with atotal of 34children)aged 6.8±0.9 years.Dropouts:10%(16/160).Missingdata:6.9%(10/144).SOL; TST; WASO (sleep diaryand actigraphy);two standardisedquestionnaires on sleep andbehaviour ++.Threemilligrams of acombinedpreparation (onemilligram rapidrelease, twomilligramssustained release(6 h)) §§ oraladministration at9:00 p.m.Four randomisedgroups in parallel;3 months each offollowing:•Melatonin(N = 34);•CBT (N = 33);•Melat. + CBT(N = 35);• Placebo(N = 32).SOL ↓ to 44%with melatoninalone, to 23%after CBT, and to61% withmelatonin + CBT.TST ↑. Numberof awakenings ↓.Sleep anxiety ↓after KVT to 17%,after Melat. to14%, and afterboth to 34%.Thiscombined 3 mgpreparationalone was moreeffective thanCBT alone. Thecombination ofboth was moreeffective thaneither methodalone.No side effectswere observed.Children 2025, 12, 648 10 of 25Table 1. Cont.Author,Country DiagnosisN, Age,Dropouts,MissingDataTarget ValuesMelatonin(Dose,Preparation)Result Conclusion Side EffectsHayashi,2022 [49]JapanASS withinsomnia.ADHD at55%(108/196):comparableeffectsregardingimprove-ment in SOLbymelatonin inboth doses.Nodifferencesregardingthe improve-ment in SOLafter 1 mg or4 mg ofmelatonin inchildrenwith a height<145 cm.N = 196,(62%♂)aged11.2± 2.5(6–15) years.Dropouts:14.4%(33/229).Missingdata:4.6% (9/196).Preliminarystatisticalcase numberplanning andpoweranalysis.SOL; TST; SE; WASO;sleep diary; actigraphy;standardised recording of fivecharacteristics for irregularbehaviour(ABC-J); height; weight;standardised checklist forrecording adverse events (AEs))+++.Three parallelrandomised,double-blindgroups: 1 mg or 4mg non-delayedmelatonin vs.placebo for 2weeks,administered 45min beforebedtime.Then, 42 days OLwith doseincrease ifrequired after 7days, up to max.4 mg.Then, 14-dayfollow-up toexclude reboundsand withdrawalsymptoms.Compliance withdefinedinstructions onsleep hygienebefore and duringthe study.SOL ↓ to21/20/1 minafter 1 mg mel./4mg mel./placebo,respectively(actigraphy,p < 0.0001).SE ↑/= to 2.35resp. 2.07% after4 mg resp. 1 mg(p = 0.04 resp.0.13 n.s.).TST unchanged.WASOunchanged.Sleep hygienealone in theprephase withlower effectscompared toboth MEL doses.Theadministrationof thisnon-delayedpreparation with4 mg 45 minbefore bedtimewas associatedwith comparableeffects to 1 mg,but morefrequent AEs.In the OL phasewith up to 10 mg,a furtherincrease in AEswasdocumented.Discontinuationat 4 mg duringthe RCT phase inone child due toAEs. No changein the fivecharacteristics foraberrantbehaviours in theremainingchildren duringthe RCT phaseaccording toparents andphysicians.Drug-related AEs0/5/3 = 0%/7.7%/4.5% for 1 mg/4mg/placeboduring RCT.AEs total incl. theOL phase:RCT 1 mg: 13.8%;RCT 4 mg: 29.2%;RCT Plac.: 18.2%;OL 1–10 mg:36.3%.Tse 2024 [6]Hong KongASS withinsomniaN = 62(81%♂; nineboys andfive girls inthemelatoningroup)aged 9.61 to10.36 years.Dropouts:22.5%(18/80).Missingdata: none.Preliminarystatisticalcase numberplanning andpoweranalysis.SOL; TST;SE; WASO;sleep diary; actigraphy. $Four randomisedarmsfor 2 weeks:3 mg liquidmelatonin 30 minbefore bedtime(N = 14);cycling 5× 60min/week(N = 18);melatonin andcycling (N = 12);placebo (N = 18).SOL ↓, TST ↑, SE↑, WASO ↑.Melatonin orcycling alone orMelatonin withcycling withbetter effectscompared toplacebo(Figure 4).Theadministrationof thisnon-delayedliquidpreparation with3 mg 30 minbefore bedtimewas associatedwith comparableeffects to cycling.The combinationof both methodswas just aseffective as eachmethod on itsown (Figure 4).No side effectswere observedafter theadministration ofmelatonin.*: No ADHD as concomitant disorder; initial group N = 11; evaluation of seven cases with complete data sets; inthe initial group, two had dyspraxia, one had severe learning difficulties, two had moderate and three had mildlearning difficulties. ASD was confirmed using four cumulative criteria, as follows: (a) difficulties in verbal andnon-verbal communication, (b) difficulties in social interaction, (c) perceptual disorders (“lack of imagination”), and(d) diagnosis confirmed by a paediatric and adolescent psychiatrist. Insomnia was defined using five criteria, as follows:(a) sleep latency≥ 1 h or nocturnal waking with parental stress, (b) at least 4 nights/week, (c) persistent for at least 6months, (d) with effects on the child or family members, and (e) lack of effect of behavioural management techniques.**: Company Penn Pharmaceuticals Ltd., Tridig UK. #: No indication of the statistical method; indication of mean values,95% confidence intervals, tables and graphs for all results. ***: Diagnosis of ASD according to ICD 10 criteria; if uncertain,additional standardised tests were used (ADOS and ADI-R). Insomnia is defined as “sleep disorders” including increasedsleep latency, insomnia, “excessive nocturnal waking”, or reduced TST. ##: Questionnaires: SDQ = Sleep DifficultiesQuestionnaire, DBC = Behavioural, five subscales on anxiety, disruptive behaviour, etc., GHQ = General HealthQuestionnaire, and SEQ = Side Effects Questionnaire. §: Company “DHP pharma”, UK. +: Insomnia: Within 3 monthsprior to screening for the study and during the 14-day screening phase, on at least 3 nights per week, SL > 20–30 min,and waking after falling asleep for > 30 min; ASA according to DSM IV-TR, incl. ADOS and ADI-R testing; exclusion ofbrain malformations, epilepsy, metabolic diseases, chromosomal abnormalities, and perceptual disorders by meansof MRI, EEG, evoked potentials, high-resolution karyotyping, and neurometabolic laboratory screening. Preliminaryexclusion of obesity, sleep-related breathing disorders (anamnestic), and exclusion of periodic leg movements duringsleep during the 12-week study. ++: CBCL = Child Behaviour Checklist, CSHQ = Children’s Sleep Habits Questionnairewith 33 questions. §§: Armonia Retard 3 mg, Nathura, Montecchio Emilia, Italy. +++: ASD diagnosis, according to DSMV; sleep disturbance defined via SL≥ 30 min on at least 3 days/week in the last 3 months, measured using an electronicdiary; actigraphy using an FS-760 device (only movement analyses), standardised checklist for recording NW accordingto Aman 1994 (AEs, documented in detail in the Supplementary Materials); structured, consistent instructions on sleephygiene before and during the study, no concomitant medication, exclusion of patients with indications of sleep-relatedbreathing disorders, severe intellectual impairment, liver dysfunction, bipolar disorders, and/or schizophrenia. Sponsorand provision of the MEL preparation and the placebo: Nobelpharma C., Ltd. $: Confirmation of the diagnosis of ASDChildren 2025, 12, 648 11 of 25according to DSM-5 including Autism Diagnostic Interview-Revised (ADI-R) in prepubertal children and adolescents(Tanner stage I), SOL≥ 30 min according to parents >3×/week, non-verbal IQ≥ 50 (WISC, Chinese revised), SocialResponse T-Score≥ 75, ability to ride a two-wheel bicycle, no drug treatment in the last 4 weeks before study start andno previous treatment with melatonin; exclusion of psychiatric comorbidities, physical limitations and neurologicaldiseases such as epilepsy, fragile X syndrome and tuberous sclerosis as well as exclusion of previous training effects,e.g., in the form of 60 min of physical training per day. Actigraphy and sleep diary to record the above-mentionedparameters. Melatonin liquid, Natrol® Chatsworth, CA, USA.Children 2025, 12, x FOR PEER REVIEW 12 of 26 concomitant medication, exclusion of patients with indications of sleep-related breathing disorders, severe intellectual impairment, liver dysfunction, bipolar disorders, and/or schizophrenia. Sponsor and provision of the MEL preparation and the placebo: Nobelpharma C., Ltd. $: Confirmation of the diagnosis of ASD according to DSM-5 including Autism Diagnostic Interview-Revised (ADI-R) in prepubertal children and adolescents (Tanner stage I), SOL ≥ 30 min according to parents >3×/week, non-verbal IQ ≥ 50 (WISC, Chinese revised), Social Response T-Score ≥ 75, ability to ride a two-wheel bicycle, no drug treatment in the last 4 weeks before study start and no previous treatment with melatonin; exclusion of psychiatric comorbidities, physical limitations and neurological diseases uch as epilepsy, fragile X syndrome and tuberous clerosis as ell l sion of previous trai ing effects, e.g., in the form of 60 min of physical training per day. Actigraphy and sleep diary to record the above-mentioned parameters. Melatonin liquid, Natrol® Chatsworth, CA, USA. Figure 4. Change in sleep efficiency (SE %) and sleep duration (TST, min) within 2 weeks after ad-ministration of placebo, 3 mg of melatonin liquid in the evening, cycling 5 × 60 min/week or mela-tonin + cycling. Derived from the mean values of the actigraphic data from Tse et al. 2024 [6]. The duration of nocturnal awakening (WASO, min) increased by 21.5% after two weeks of placebo ad-ministration, while the duration of nocturnal awakening decreased by 26.90%, 18.61% and 26.30% after the administration of melatonin, cycling, and the combined intervention of melatonin + cycling, respectively. 3.2. Critical Comparison with the Results of Reviews by Other Authors In the reviews by Zisapel (2022) [65] and Schröder et al. (2021), cited in Zisapel (2022) [77] as well as Cortese et al. (2020) [66], Parker et al. (2019) [51] and Rossignol and Frye (2011) [52], no further RCTs are specified that fulfil this requirement. In the study by Schröder et al. (2021), children with ASD and Smith–Magenis syndrome were treated with a prolonged-release preparation; no subgroup analysis was performed [67]. In another Figure 4. Change in sleep efficiency (SE %) and sleep duration (TST, min) within 2 weeks afteradministration of placebo, 3 mg of melatonin liquid in the evening, cycling 5 × 60 min/week ormelatonin + cycling. Derived from the mean values of the actigraphic data from Tse et al. 2024 [6].The duration of nocturnal awakening (WASO, min) increased by 21.5% after two weeks of placeboadministration, while the duration of nocturnal awakening decreased by 26.90%, 18.61% and 26.30%after the administration of melatonin, cycling, and the combined intervention of melatonin + cycling,respectively.3.2. Critical Comparison it t e es lts of Reviews by Other AuthorsIn the revie s by Zisapel (2022) [65] and Schröder et al. (2021), cited in Zisapel(2022) [77] as well as Cortese et al. (2020) [66], Parker et al. (2019) [51] and Rossignoland Frye (2011) [52], no further RCTs are specified that fulfil this requirement. In thestudy by Schröder et al. (2021), children with ASD and Smith–Magenis syndrome weretreated with a prolonged-release preparation; no subgroup analysis was performed [67]. Inanother systematic review of pharmacological treatments for sleep disorders in children,McDonagh et al. (2019) found 19 RCTs on melatonin [56], including 4 RCTs on ASD, whichare included in Table 1 [75,76] or in the discussion of this systematic review [72,73]. Maraset al. (2018) [70] investigated a delayed melatonin preparation in children with ASD usingthe OL method, but not in a randomised setting.In the detailed review by Tordjman et al., 2013, with 161 references, seven RCTs onmelatonin in ASD are listed, which are also considered in the current systematic review [69].Children 2025, 12, 648 12 of 25In addition, Tordjman et al. listed three case reports, three retrospective studies, and six OLstudies on melatonin in ASD, as well as seven studies in which melatonin concentrationsin blood or urine were analysed in ASD patients in their table. These included only onestudy on serum melatonin concentrations in fourteen children with ASD, four of whichshowed an inverted day–night profile, as in SMS (Kuhlman et al., 2000) [78].3.3. Missing Subgroup Analyses in RCTs on Patients with Multiple DiagnosesFurther studies also investigated melatonin in ASD; however, no conclusions specificto the diagnosis of ASD can be drawn from these studies, as no subgroup analyses werecarried out, although one or more additional diagnoses were stated at the same time, asfollows:- Gringras et al. reported on 121 children and adolescents with ASD and 4 children andadolescents with Smith–Magenis syndrome without differentiating the subgroups, inwhich 28.8% of the patients participating in the randomisation had ADHD and 12.8%had epilepsy [72]. Only 46.8% (125/267) of the originally recruited patients wereincluded in the randomisation. With dropout rates of 15% (9/60) and 32.3% (21/65)in the placebo group, data from 51 verum and 44 placebo “cases” were finally analysed.This study of the sustained-release formulation was financed by the manufacturer andstatistically analysed under its responsibility.- Schröder et al. published an analysis of some of the above data in 2019 [67]. Malowet al. analysed the data of the same(?) 51 verum vs. 44 placebo “cases” again in 2021,again without differentiating between the above-mentioned subgroups [79]. In 2012,Malow et al. had previously reported on different doses of melatonin in 24 childrenand adolescents with difficulty falling asleep and ASD, but without a randomisedsetting [71].3.4. Differences in Circadian Rhythmicity in Patients with ASD or Smith–Magenis SyndromeASD and Smith–Magenis syndrome (SMS) are fundamentally different clinicalpictures in terms of their circadian melatonin rhythms and cannot be compared witheach other, as discussed below:• In patients with SMS, no or very low melatonin concentrations are spontaneouslydetectable in the saliva between 23:00 and 07:00 without prior melatonin input, while,during the day, the paradoxical melatonin releases typical of SMS are detectable [80].• ASD, on the other hand, is associated with endogenous melatonin release at nightbetween 22:00 and 04:00 [45].• The joint biostatistical evaluation of the circadian rhythm of peripheral melatonin con-centrations in the blood, saliva, or urine of patients with ASD and SMS can thereforelead to the assumption of a nocturnal melatonin deficiency in ASD which, however,would only have to be analysed for this subgroup alone in order to obtain comprehen-sible conclusions.• The genetic background for chronodisruption with a reversal of the day–night phasein patients with SMS is, in most cases, a 17q.11.2 microdeletion, which is associatedwith a functional disorder of the retinoid acid-induced 1 gene (RAI1) [81,82].• There was a reciprocal difference between patients with ASD and SMS in terms of thefrequency of disorders of social communication behaviour (4:1 vs. 1:3) [83].- Wirojanan et al. also reported on a small group of patients in which no subgroupanalyses were performed (five patients with ASD alone, three patients with ASD withfragile X syndrome, and four patients with fragile X syndrome) [73].- Wasdell et al. analysed the data of 16 patients with ASD without subgroup analysis, aspart of an unspecified group of 47 patients with neurodevelopmental disorders [84].Children 2025, 12, 648 13 of 253.5. Pharmacokinetics of Melatonin in Children and Adolescents with ASDTo our knowledge, dose–response correlations between melatonin and sleep in chil-dren and adolescents with ASD, with the documentation of melatonin concentrations inthe blood, have only been investigated by Goldman et al., in their observational studyinvolving nine children [45]. After the oral administration of a rapid-release, non-delayedmelatonin preparation, significantly different melatonin concentrations in the blood werefound (Figure 5) [45]. In all nine children, sleep onset latency was associated with a rapidinitial increase in plasma melatonin concentration (Figure 5). The mean sleep durationafter the administration of 1 mg of melatonin tended to be higher (480 min) than after theadministration of 3 mg of melatonin (380 min); this difference was not significant in viewof the small sample size (see Figure 5 for further details).Children 2025, 12, x FOR PEER REVIEW 14 of 26  There was a reciprocal difference between patients with ASD and SMS in terms of the frequency of disorders of social communication behaviour (4:1 vs. 1:3) [83]. ­ Wirojanan et al. also reported on a small group of patients in which no subgroup analyses were performed (five patients with ASD alone, three patients with ASD with fragile X syndrome, and four patients with fragile X syndrome) [73]. ­ Wasdell et al. analysed the data of 16 patients with ASD without subgroup analysis, as part of an unspecified group of 47 patients with neurodevelopmental disorders [84]. 3.5. Pharmacokinetics of Melatonin in Children and Adolescents with ASD To our knowledge, dose–response correlations between melatoni and sle p in chil-dren and adolescents with ASD, with the document tion of melatonin concentrations in the blood, have only been investigated by Goldman et al., in their observatio al study involvi g nine children [45]. After the oral administratio of a rapid-release, non-delayed melatonin preparation, significantly different melatonin concentrations in the blood were found (Figure 5) [45]. In all nine children, sleep onset latency was associated with a rapid initial increase in plasma melatonin concentration (Figure 5). The mean sleep duration after the administration of 1 mg of melatonin tended to be higher (480 min) than after the administration of 3 mg of melatonin (380 min); this difference was not significant in view of the small sample size (see Figure 5 for further details). Figure 5. Plasma melatonin concentrations in 9 children with autism spectrum disorder, aged 3–8 years, in relation to sleep onset latency (SOL; blue columns; Goldman et al. 2014) [45]. The blue columns show when each child was placed in bed and how long it takes for the child to fall asleep Figure 5. Plasma melatonin concentrations in 9 children with autism spectrum disorder, aged3–8 years, in relation to sleep onset latency (SOL; blue columns; Goldman et al. 2014) [45]. The bluecolumns show when each child was placed in bed and how long it takes for the child to fall asleep(= SOL). This time point and the associated duration were plotted in 9 children with autism spectrumdisorder in relation to the course of the melatonin concentrations in the serum. In all 9 children, fallingasleep was associated with a rapid initial increase in melatonin concentration in the evening. Thepolysomnographically determined sleep duration (TST, total sleep time) did not improve significantlyafter the evening administration of 1 mg or 3 mg of melatonin (p = 0.35); a longer mean sleep durationof 468 min was more likely to be observed with the lower dose of 1 mg than after the administrationof 3 mg of melatonin (initial value: 476 + 72.2 min; after the administration of 1 mg of melatonin:468 + 153.8 min; after 3 mg: 380.4 + 187.8 min; [45]). Reproduced with permission.Children 2025, 12, 648 14 of 25In their systematic review [85], Carmassi et al., 2019, referred to two further studies inwhich melatonin concentrations in the blood were measured, which investigated 10 adultswith ASD (Nir et al., 1995) [86] and 14 prepubertal children with ASD aged 5–10 years(median 7 years) (Kulman et al., 2000) [78]. Unfortunately, no individual measurementswere given in the Kulman study, so no pharmacokinetic parameters can be derived fromthese data. In addition, higher melatonin concentrations during the day than at night weremeasured in four of the ten children; therefore, from our point of view, it cannot be ruledout that these four patients were children with SMS and ASD. The reported mean values ofthe serum concentrations of this study, therefore, cannot be analysed pharmacokinetically.Tordjman et al. showed that, in 50 children with ASD with a mean age of11.5 + 4.5 years, compared to 88 healthy controls, the nocturnal excretion of the mela-tonin metabolite 6-sulfatoxymelatonin was only reduced prepubertally, while, pubertallyand postpubertally, there were no differences [87]. However, this study did not takeinto account that the concentration of 6-sulfatoxymelatonin in urine is influenced by theurine flow rate, so the measured concentrations in urine are related to the creatinine con-centration [88]. Using this procedure, no significant correlations between the corrected6-sulphatoxymelatonin concentrations in urine and sleep parameters (measured with thestandardised CSHQ Sleep score) were detectable in 56 children and adolescents with ASDaged 5.3 + 2.4 years (range: 2.8–13.3 years) [89].4. Discussion4.1. Importance of Diagnosis-Related RCTs with Subgroup AnalysesTo date, five randomised placebo-controlled trials (RCTs) have been conducted inwhich the efficacy of orally administered melatonin on non-organic sleep disorders inchildren and adolescents, either with the sole underlying diagnosis of autism spectrumdisorder (ASD) or with additional diagnoses, for whom subgroup analyses were conducted,was tested (Table 1). In these studies, non-delayed preparations that release the activesubstance rapidly were used (Garstang 2006, Wright 2011, Cortesi 2012, Hayashi 2022,Tse 2024) [6,7,49,75,76]; in one of these studies, a mixed preparation with a non-delayedpreparation of 1 mg and a delayed portion of 2 mg was applied (Cortesi 2012) [7].To our knowledge, dose–response correlations of melatonin and sleep in children andadolescents with ASD have only been investigated by Goldman et al. in an observationalstudy involving nine children [45]. After the oral administration of a rapid-release, non-delayed melatonin preparation of 1 mg or 3 mg, there were no dose–response correlationsand significantly different melatonin concentrations in the blood; without exception, thesleep onset latency was associated with a rapid initial increase in melatonin concentrationsin the evening [45].Similarly, van Geijlswijk et al. also found no dose–response correlations after theadministration of a non-delayed melatonin preparation in paediatric and adolescent pa-tients with delayed sleep onset (DSPD) at doses of 0.5, 1.0, or 1.5 mg of melatonin/kgbody weight [42]. To date, no studies have been published on the efficacy and pharma-cokinetics of delayed melatonin preparations in paediatric, adolescent, and adult patientswith a single initial diagnosis of ASD or with ASD in combination with several underlyingdiagnoses such as ADHD, epilepsy, Smith–Magenis syndrome, and/or fragile X syndromeand corresponding subgroup analysis. In an EMA assessment report from 2007, only briefsummary data were given with regard to pharmacokinetic data following the administra-tion of a 2 mg delayed preparation to eight adults aged 55 years and older without anyindication of ASD (see p. 16 in the following document: https://www.ema.europa.eu/en/documents/scientific-discussion/circadin-epar-scientific-discussion_en.pdf (accessed on17 March 2025)).Children 2025, 12, 648 15 of 25De Souza et al. showed that children and adolescents with ADHD have reduced pinealmelatonin synthesis and secretion at night [90]. This observation supports the need forthe effects of melatonin to be considered in relation to the initial diagnosis (the underlyingdisease), on the basis of which a non-organic sleep disorder can be observed and treatedwith melatonin.4.2. Quality Heterogeneity of Existing RCTs with Regard to the Use of Adequate Parameters andMethods for the Assessment of Sleep and the Different Types of Sleep DisordersThe quality of the RCTs available to date on the effectiveness of melatonin in non-organic sleep disorders associated with neurogenetic diseases including ASD is hetero-geneous; in particular, there is a lack of standardised and easily comparable parametersthat investigate sleep and sleep quality and their effects on well-being and performanceduring the day [35]. Within the five RCTs listed in Table 1, we can see that the qualityand differentiation of the studies have improved over time. Cortesi et al. showed thatcognitive behavioural therapy can also be effective in children and adolescents with ASD,with melatonin having more pronounced effects [7]. However, the combined use of CBTand melatonin showed the highest efficacy. Hayashi et al. showed that subgroup analysescan increase the value of an RCT [49].4.3. Physiological and Pathophysiological BasicsTo understand the use of melatonin in children and adolescents with ASD, somerecent data on the pathophysiology of the pineal gland and the specificities of the effects ofmelatonin in ASD are recalled, as follows:(a) The pineal gland appears to be involved in the pathogenesis of autism spectrumdisorder (ASD) in the following two ways:- Based on the retrospective comparison of numerous data from children with ASDcompared to control groups, Miike et al. (2020) assumed that the development ofchronobiological rhythms in children with ASD can be disturbed by the followingfactors: maternal bed rest only after midnight, prematurity, irritability, and atendency towards disturbed sleep in early infancy [91].- Shomrat and Nesher (2019) summarised the results of numerous studies on de-tailed questions of ASD pathogenesis [92]. As endogenous N,N-dimethyltryptamine(DMT) is formed and secreted in the pineal gland, in addition to the pulsatilecircadian nocturnal synthesis and secretion of melatonin, synaptogenesis andneuroplasticity could be disturbed via altered DMT activity and the reduced mela-tonin concentrations in ASD, thereby resulting in the development of ASD [92].DMT is also formed from tryptophan and classified as a neurotransmitter [93].(b) Hayashi et al. (2022) identified seven further pathogenetic factors in relation to mela-tonin in ASD, as follows: abnormalities in synthesis, concentration, secretion patterns,metabolism (such as polymorphisms of genes involved in the formation of pinealenzymes for the synthesis of melatonin = polymorphisms of the AOMT gene = theacetylserotonin-O-methyltransferase gene); impaired signalling to melatonin 1A re-ceptors; the dysregulation of immunological signalling; and the inflammation of thecentral and peripheral immune system (Hayashi 2022) [49]. These factors have alsobeen considered in several whole-genome association studies and comparable studiesin which associations with such pathways have been demonstrated [94–98].(c) The “disruption of nocturnal melatonin synthesis and secretion” observed in childrenwith autism is associated with measurable interleukin-6 and tumour necrosis factoractivations during sleep, which are detectable in ASD but not in healthy controls(Figure 6); for a recent review of these neuroimmunological features in ASD, seeChildren 2025, 12, 648 16 of 25Hughes et al. (2023) [99]. To our knowledge, clinical studies have not yet investigatedwhether the anti-inflammatory and immunomodulatory effect of melatonin [100–102]is of clinical significance in children and adolescents with ASD.(d) Goldman et al. (2014) showed that, in pharmacokinetic studies on endogenousmelatonin concentrations in the blood of children with ASD, in therapeutic terms, it isnot a question of replacing reduced melatonin concentrations, as there are no simpledose–response relationships. After the oral administration of 1 mg of melatonin,the measured melatonin concentrations were significantly higher than endogenousmelatonin concentrations: “suggest[ing] that supplemental melatonin is not replacinga deficiency state but has other mechanisms of action” (Figure 4; Goldman et al. 2014,p. 9) [45].Similarly, Claustrat (2015) pointed out that, with regard to melatonin, it is the doseand not the duration of the hormonal signal that is decisive [103].Children 2025, 12, x FOR PEER REVIEW 17 of 26 acetylserotonin-O-methyltransferase gene); impaired signalling to melatonin 1A re-ceptors; the dysregulation of immunological signalling; and the inflammation of the central and peripheral immune system (Hayashi 2022) [49]. These factors have also been considered in several whole-genome association studies and comparable stud-ies in which associations with such pathways have been demonstrated [94–98]. (c) The “disruption of nocturnal melatonin synthesis and secretion” observed in chil-dren with autism is associated with measurable interleukin-6 and tumour necrosis factor activations during sleep, which are detectable in ASD but not in healthy con-trols (Figure 6); for a recent review of thes neuroimmunological features in ASD, ee Hughes et al. (2023) [99]. To ou knowledge, clinical studies have n t yet investigated whether the anti-infl mmatory and immunomodulatory effect of melatonin [100–102] is of clinic l significance in children and adolescents with ASD. (d) Goldman et al. (2014) showed that, in pharmacokinetic studies on endogenous mel-atonin concentrations in the blood of children with ASD, in therapeutic terms, it is not a question of replacing reduced melatonin concentrations, as there are no simple dose–response relationships. After the oral administration of 1 mg of melatonin, the measured melatonin concentrations were significantly higher than endogenous mel-atonin concentrations: “suggest[ing] that supplemental melatonin is not replacing a deficiency state but has other mechanisms of action” (Figure 4; Goldman et al. 2014, p. 9) [45]. Similarly, Claustrat (2015) pointed out that, with regard to melatonin, it is the dose and not the duration of the hormonal signal that is decisive [103]. Figure 6. (A) TNF and (C) Interleukin-6 concentration in saliva of 20 children with autism and sleep disorders vs. 20 healthy controls aged 4–18 years during the day and at night; (D) and (B) Day/Night Figure 6. (A) TNF and (C) Interleukin-6 concentration in saliva of 20 children with autism and sleepdisorders vs. 20 healthy controls aged 4–18 years during the day and at night; (D) and (B) Day/Nightfold-change of the same parameters; data are from Sanseray da Silveira Cruz-Machado et al., 2021:Disrupted nocturnal melatonin in autism: Association with tumour necrosis factor and Interleukin-6with sleep disturbances [104]; a review by this group of authors on this topic can be found in Pinatoet al. 2019 [105]. Reproduced with permission.Martinez-Cayuelas E. et al. (2023) reported on the effect of melatonin on sleep inchildren with ASD as a result of the first published actigraphic temperature, light, andmovement analyses in 26 children with ASD aged 6–18 years. The administration of anon-delayed immediate-release melatonin preparation (2 mg, orally, 30 min before bedtime)led to an immediate and sustained increase in peripheral temperature as a marker forlowering core temperature for several hours. This temperature effect is mediated viaChildren 2025, 12, 648 17 of 25melatonin receptors type 2 [106] and was demonstrable in this prospective study, as wasthe improvement in sleep latency and sleep efficiency within the observation period of 2months (Figure 7) [106].Children 2025, 12, x FOR PEER REVIEW 18 of 26 fold-change of the same parameters; data are from Sanseray da Silveira Cruz-Machado et al., 2021: Disrupted nocturnal melatonin in autism: Association with tumour necrosis factor and Interleu-kin-6 with sleep disturbances [104]; a review by this group of authors on this topic can be found in Pinato et al. 2019 [105]. Reproduced with permission. Martinez-Cayuelas E. et al. (2023) reported on the effect of melatonin on sleep in chil-dren with ASD as a result of the first published actigraphic temperature, light, and move-ment analyses in 26 children with ASD aged 6–18 years. The administration of a non-de-layed immediate-release melatonin preparation (2 mg, orally, 30 min before bedtime) led to an immediate and sustained increase in peripheral temperature as a marker for lower-ing core temperature for several hours. This temperature effect is mediated via melatonin receptors type 2 [106] and was demonstrable in this prospective study, as was the im-provement in sleep latency and sleep effici ncy within the observati n p riod f 2 months (Figure 7) [106]. Figure 7. Increase in actigraphically measured peripheral temperature as a marker for reduction in core body temperature due to 2 mg of immediate-release melatonin administered orally 30 min be-fore bedtime, effective prospectively over an observation period of 2 months; N = 26 children with autism spectrum disorder aged 6–18 years. This is parallel to a decrease in sleep latency from 22.6 (14.5–43.0) minutes to 9.5 (5.8–28.6) minutes (p < 0.01) and increase in sleep efficiency from 86.5 to 89.4% (p < 0.05). From Martinez-Cayuelas E et al. 2023 [106]. Reproduced with permission. 4.4. Strengths and Limitations of the Present Systematic Review In our view, this systematic review has the following strengths and limitations: Strengths: We included the expertise of paediatricians (E.P., B.S., O.I.) and a psy-chologist (A.S.) who have been clinically and scientifically involved with sleep disorders in childhood and adolescence for several years; in addition, the expertise of a clinically Figure 7. Increase i hically measured peripheral temperature as a marke for reductionin core body temperature due to 2 mg of immediate-release melatonin administered orally 30 minbe ti e, effective prospectively over an observation period of 2 months; N = 26 children withautism spectrum disorder age s. This is parallel to a decrease in sleep latency from 22.6(14.5–43.0) minutes to 9.5 (5.8–2 . ) i t s (p < 0.01) and increase in sleep efficiency from 86.5 to89.4% (p < 0.05). From arti ez- ay elas et al. 2023 [106]. Reproduced with permission.4.4. Strengths and Limitations of the Present Systematic ReviewIn our view, this systematic review has the following strengths and limitations:Strengths: We included the expertise of paediatricians (E.P., B.S., O.I.) and a psychol-ogist (A.S.) who have been clinically and scientifically involved with sleep isor ers inchildhood an adolescen for several years; in addition, the expertise of a clinically andscientifically experienced pharmacologist (B.R.) and biostatistician (R.K.) was included.The searches were carried out in the four databases PubMed, MEDLINE, PsycInfo andCochrane CENTRAL. All languages were taken into account. The inclusion and exclusioncriteria were rigorously and objectively defined and transparently described (see Supple-mentary S1).With the RCTs by Cortesi et al. 2012 [7] and Tse et al. 2024 [6], two studies areavailable in which the effect of two interventions on the sleep of children and adolescentswith insomnia in ASD was tested in a randomised setting (melatonin alone vs. placeboor melatonin AND cognitive behavioural therapy or exercise). In both studies, it wasensured that there was no concomitant medication and that there was no comorbidity suchas ADHD, SMS or tuberous sclerosis. Subgroup analyses were, therefore, not necessary.Children 2025, 12, 648 18 of 25Almirall et al. published interesting biostatistical information on how similar RCTs can alsobe organised for sequential interventions [107].Limitations: The database searches presented here were conducted by only twoauthors (E.P., A.S.). In our view, selection bias was largely ruled out, as the number ofstudies found in four databases was limited and as the reasons for inclusion or exclusionbased on the pre-declared inclusion and exclusion criteria were explained transparentlyfor each study in Supplementary S1. A meta-analysis of the five included RCTs was notconducted, as the number of available RCTs appeared to be too small. As the RCTs listed inTable 1 only examined rapid-release oral preparations of melatonin, no statement can bemade about the efficacy of oral prolonged-release preparations. In addition, to the best ofour knowledge, there are no RCTs with subgroup analyses to date in which the efficacyof sustained-release and non-released melatonin preparations is available. The number ofstudies on the pharmacokinetics of melatonin in childhood and adolescence is insufficient,meaning that there is only a limited database on changes from infancy to adolescence.In our view, the understanding of the pharmacokinetics of melatonin in childhood andadolescence could be significantly improved if ethically acceptable ways were sought to in-vestigate the relationships between melatonin in CSF and blood in children and adolescentswith ASD, ADHD and Smith–Magenis syndrome. This could be considered in individualcases (a) if a CSF drainage is already in place, e.g., in the case of hydrocephalus, (b) if a neu-rosurgical operation or lumbar puncture is required anyway, during which a small amountof CSF could be taken for analysis, or (c) if an autopsy is required. Such investigations havebeen presented in a comparable manner in patients with hydrocephalus [108,109]—also inchildren with hydrocephalus [108]—or in animal experiments [25,26,110–116]; see also thereviews in [117–119]. These data indicate that the pineal gland as a circumventricular organsecretes the circadian melatonin produced in the pinealocytes during external darknesswith a rapid and high increase in concentration into the ventricular cerebrospinal fluid. Inthe peripheral blood circulation, pineal melatonin appears delayed with a considerablylower concentration than in the cerebrospinal fluid. The melatonin concentration in theblood, therefore, has only limited diagnostic value. Debus et al. showed in a child withhydrocephalus that after oral administration of 5 mg of melatonin, a rapid increase in themelatonin concentration in the cerebrospinal fluid occurred within 10 min; the child fellasleep 40 min after melatonin administration. Within the following 7 h, the melatonin con-centration decreased exponentially [108]. These data support the assumption that fallingasleep in the dark is physiologically associated with a rapid increase in the melatoninconcentration in the cerebrospinal fluid, an argument in favour of the oral administrationof rapid-release, non-delayed melatonin preparations.5. ConclusionsTo our knowledge, there are no RCTs to date in which the efficacy of sustained-releasemelatonin preparations has been tested in children and adolescents with ASD and non-organic sleep disorders.To our knowledge, five RCTs on ASD have been conducted to date in which non-delayed rapid-release preparations were tested and showed efficacy in relation to sleepparameters (Table 1). In one of these studies, a combination preparation with rapid-releasemelatonin and a sustained-release component was tested; in this study, it was shown inone study arm that using cognitive behavioural therapy in conjunction with this melatoninpreparation was more effective than either therapy alone. This result is remarkable, asit demonstrates that cognitive behavioural therapy can also be effective in children andadolescents with ASD and non-organic sleep disorders.Children 2025, 12, 648 19 of 25No subgroup analyses were carried out in other RCTs on the efficacy of melatoninin ASD, so no conclusions can be drawn from these studies on the diagnoses of thesesubgroups, which were only analysed in a mix, such as ASD, Smith–Magenis syndrome,epilepsy, and so on, that would allow conclusions to be drawn about the efficacy of delayedmelatonin preparations in ASD.To date, there have been no RCTs carried out in which the efficacy of rapid-releasemelatonin preparations has been investigated in comparison to sustained-release melatoninpreparations in children and adolescents with non-organic sleep disorders. Physiologicaland pharmacokinetic data available to date indicate that there are no classic dose–responserelationships and that rapid-onset (i.e., rapid-release) preparations are effective even at lowdoses (1 mg in the evening in adults [120]; 0.25 to 0.5 mg in children and adolescents [11,120]). It should be taken into account that the elimination half-life of melatonin in infancyis much longer than in young adulthood; therefore, a longer elimination half-life can alsobe assumed in childhood and adolescence.The studies cited in Table 1 and the physiological and pathophysiological principlesmentioned in the discussion indicate that, in addition to psychosocial factors, the evo-lutionary biological relationships between melatonin, sleep, circadian chronobiologicalrhythms, immunology, genetics, epigenetics, motor skills and physical activity, temperatureregulation and behaviour should also be taken into account in children and adolescentswith ASD.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/children12050648/s1.Author Contributions: Idea, conception, research, text development, and corrections: E.P., B.M.S.,A.A.S. and O.S.I.; corrections and pharmacological advice: B.R.; biostatistical advice: R.K. All authorshave read and agreed to the published version of the manuscript.Funding: This research received no external funding.Acknowledgments: We would like to thank Cathleen Muche-Borowski, MPA, from the Centre forPsychosocial Medicine at the Institute and Polyclinic of General Medicine at the University MedicalCenter Hamburg-Eppendorf, who is also a freelancer for the Association of the Scientific MedicalSocieties in Germany (AWMF), for her advice in the preparation of this article. We would like tothank Oleksandr Shevchenko from Altötting (Germany) and Kanchan Upreti from New Delhi (India)for reviewing the manuscript and for their valuable comments.Conflicts of Interest: The authors declare that there are no conflicts of interest.AbbreviationsAE Adverse eventAOMT Acetylserotonin-O-methyltransferaseASD Autism spectrum disorderCBT Cognitive behavioural therapyCSF Cerebrospinal FluidDLMO Dim light melatonin onsetDMT N,N-dimethyltryptamineDSPD Delayed sleep phase disorderEMA European Medicines AgencyG-BA Joint Federal Committee (Gemeinsamer Bundesausschuss)Non24 Non-24 syndrome; deviation from 24 h circadian rhythmicityOL Off-labelRCT Randomised controlled trialChildren 2025, 12, 648 20 of 25SE Sleep efficiencySMS Smith–Magenis syndromeSO Sleep onsetSOL Sleep onset latencyTST Total sleep timeWASO Wake after sleep onset = awakenings; number and durationReferences1. Mutluer, T.; Aslan Genç, H.; Özcan Morey, A.; Yapici Eser, H.; Ertinmaz, B.; Can, M.; Munir, K. 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melatonin in children and adolescents
autism spectrum disorder
sleep
pharmacokinetics
RCT
non-delayed preparations
The Pharmacokinetics, Dosage, Preparation Forms, and Efficacy of Orally Administered Melatonin for Non-Organic Sleep Disorders in Autism Spectrum Disorder During Childhood and Adolescence : A Systematic Review
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