This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT We propose to examine whether sleep problems in children with autism spectrum disorder (ASD) are related to alterations in the secretion of melatonin (MT), a hormone that plays an important role in regulating the circadian cycle and sleep. Furthermore, we will examine the efficacy of MT for improving sleep in children with ASD. Children with ASD experience high rates of sleep disturbances that potentially contribute to the severity of their cognitive and behavioral dysfunction and to poor quality of life for themselves and their families. It is unclear if irregularities in MT rhythm underlie sleep problems in children with ASD. Their sleep problems are characterized by sleep-wake rhythm abnormalities and symptoms of insomnia including difficulty initiating and maintaining sleep. MT is frequently used to treat these sleep problems;however, its effectiveness as a hypnotic to treat insomnia in children with ASD has not been clearly established. All subjects will be recruited from the Autism Treatment Network after completing rigorous diagnostic testing. Exclusionary criteria include exposure to melatonin in the month prior to the study, current psychoactive medications or medications known to suppress MT secretion, other sleep disorders, such as sleep apnea, and medical disorders that may affect sleep, such as gastroesophageal reflux disease (GERD). Participants parents will complete a validated sleep questionnaire, which will define the presence or absence of sleep problems. MT onset will be determined by measuring salivary MT levels before and after usual bedtime in ASD children with sleep problems and in a matched group of children with ASD and no sleep problems. Total 24 hour MT production will be determined from urine samples in these same two groups. A double-blind, randomized trial of three oral doses of MT (3, 6, 9 mg) and placebo in children (ages 4-9 years) with ASD and sleep problems will follow a baseline sleep and behavior evaluation. The primary outcome measure will be change in sleep latency as determined by actigraphy at baseline and at the end of the fifth week of each of the treatment trials. Another primary outcome measure will be change in validated behavioral questions given at baseline and during the fifth week of each of the treatment trials. Results from this study will provide a rationale for the development of future trials of circadian rhythm interventions and clinical parameters for the use of MT to manage sleep problems in ASD.