The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin’s effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Sleep disorders are among the most common comorbidities in children with Autism Spectrum Disorder (ASD), and subjectively defined sleep disturbances have been related to ASD symptom severity. However, no study has investigated the differential impact of objectively measured sleep and circadian rhythm disturbances on behavioral difficulties in this population. Fifty-two children with ASD aged 3–10 years underwent assessments of sleep and circadian rest–activity rhythms objectively with actigraphy and subjectively with the Children’s Sleep Habits Questionnaire. Behavioral difficulties were assessed using the ABC-C. Group comparison analyses were used to compare sleep and circadian rhythm parameters of children with higher and lower behavioral difficulties and dominance analysis to rank predictors and address multicollinearity. Children with high irritability had a shorter continuous sleep period compared to those with lower irritability (−60 min, p = 0.04), as well as those with high stereotypic behaviors compared to children with less stereotypies (−75 min, p = 0.006). Objective circadian and sleep disturbances accounted together for, respectively, 17%, 18% and 36% of the variance in social withdrawal, irritability and stereotypic behaviors. The identification of both sleep and circadian rhythm disturbances as explanatory factors for behavioral difficulties warrants their inclusion in the existing behavioral management strategies for children with ASD.