PROJECT SUMMARY Opioid use disorder (OUD) is a chronic and relapsing brain disease that is characterized by loss of control over opioid use. It affects over 2 million Americans and causes one overdose death every 20-minutes. Despite effective evidence-based treatments in the form of both behavioral interventions and FDA-approved medication for addiction treatment (MAT), relapse rates are high and are associated with lack of retention in treatment and a continued cycle of illicit opioid use. Further research is urgently needed to better understand the mechanisms that contribute to ongoing illicit opioid use and poor retention in MAT and identify novel treatments. In response to RFA-HL-19-029 and its call to conduct “mechanistic studies to determine the directionality of sleep and OUD interactions in humans… and to identify new opportunities for prevention and improved therapy,” The Collaboration Linking Opioid Use Disorder and Sleep (“CLOUDS”) Study will investigate patients on MAT to elucidate potential causal mechanisms between sleep deficiency and OUD. We will conduct an observational cohort study of N= 220 patients with OUD who were recently stabilized on MAT at a large opioid treatment program in New Haven, CT. At baseline, all patients will undergo: (1) comprehensive assessments of sleep and circadian rhythmicity (i.e., polysomnography, melatonin onset/offset, wrist actigraphy, and validated sleep and circadian surveys); (2) a task-enriched functional magnetic resonance imaging (fMRI) functional connectivity protocol; (3) blood assays for measures of stress and sex hormones; (4) neuro-clinical status using validated interviews, and surveys; and (5) physical home microenvironment and psychosocial family assessments. Patients will be followed for 6 months for the primary outcome of % days of illicit opioid use. In this context, we will pursue several specific aims. Aim1: Using fMRI network analyses, test whether there are different neurocognitive connectivity patterns between patients with adequate vs. deficient sleep in brain systems involved in addiction (e.g., executive function, reward processing) and assess the extent to which these “neural fingerprints” predict ongoing opioid use. Aim 2: Evaluate the potential biologic, psychiatric, and pharmacologic mechanisms that explain the causal pathway between sleep deficiency and opioid use by analyzing the mediating effect of other selected known OUD risk factors including stress, pain, negative affect, and other substance use. Aim 3: Test the extent to which ecologic factors such as psychosocial, family, and neighborhood contextual factors associated with OUD contribute to sleep deficiency among patients in MAT. An experienced multidisciplinary team of investigators with expertise in Sleep and Circadian Medicine, Biomedical Imaging, Psychiatry, Addiction Medicine, Nursing, and Psychology will conduct this research. This proposal will fulfill a critical step towards identifying novel sleep and circadian-focused treatment approaches that may lead to improved outcomes for patients with OUD.

PROJECT NARRATIVE Opioid use disorder (OUD) is a chronic and relapsing brain disease that is characterized by loss of control over opioid use, and affects over 2 million Americans causing one overdose death every 20 minutes. Further research is urgently needed to better understand the mechanisms that contribute to ongoing illicit opioid use. The Collaboration Linking Opioid Use Disorder and Sleep (“CLOUDS”) Study examines sleep and circadian mechanisms that may contribute to OUD and proposes to fulfill a critical step towards identifying novel treatments that may lead to improved outcomes for patients with OUD.