Understanding the Mechanistic Interrelationship between Sleep, Co-Occurring Cannabis and Alcohol Use Disorder, and Neurocircuit Dysfunction during Early Abstinence - ABSTRACT Background: Sleep may play a key role in withdrawal. Individuals withdrawing from either cannabis or alcohol have significant reductions in slow-wave sleep, among other objective sleep disturbances. Independent from substance use, objective sleep disturbances, including impairments in slow-wave sleep duration, slow-wave activity, and homeostatic sleep drive, have been associated with aberrant fronto-limbic negative affect neurocircuitry as well as negative affect symptoms. Critically, these same fronto-limbic circuits are also impaired in cannabis use disorder (CUD) and alcohol use disorder (AUD). Thus, sleep disturbance may be a mechanistic contributor to withdrawal symptoms, with fronto-limbic dysfunction mediating this relationship. Objective: This proposal aims to characterize the temporal trajectory of these objective sleep changes in individuals with co-occurring CUD+AUD during early abstinence and establish how these changes interrelate with both fronto-limbic dysfunction and withdrawal symptoms. Methods/Design: In the R61 phase we aim to examine 40 eligible adults with co-occurring cannabis use disorder in a longitudinal observational study to record objective measures of sleep, fronto-limbic function, and negative affect withdrawal symptoms at multiple timepoints across a 28-day withdrawal period. Primary sleep measures include slow-wave sleep duration (minutes in stage N3), slow-wave activity (relative spectral power between 0.5 and 4.0 Hz during NREM), and homeostatic sleep drive (the declination of slow-wave EEG power in subsequent NREM cycles). Fronto-limbic function will be assessed using an fMRI task of negative affect reactivity. Negative affect withdrawal symptoms will focus on anxiety and depression. If the R61 milestone criteria are met, in the R33 phase we will enroll an additional 80 adults into a 2-arm randomized controlled mechanistic trial to address whether intervening in the sleep trajectory will induce downstream changes in neurocircuit targets as well as how these trajectories relate to withdrawal symptoms. Specific Aims: In the R61 phase we aim to establish the extent of objective sleep disturbance across CUD+AUD withdrawal and its associations with fronto-limbic function and symptoms according to pre-specified milestone criteria. In the R33 we aim to 1. Examine the modifiability of objective sleep disturbance during CUD+AUD withdrawal using a well-validated sleep manipulation. 2. Assess the relationships between the change in objective sleep disturbance with both fronto-limbic dysfunction and withdrawal symptoms. 3. Determine sleep and neurocircuit moderators of treatment outcome. Impact: Our neurobiological results will inform novel sleep and brain treatment targets and establish their modifiability in those who have CUD + AUD in early abstinence. These studies are needed to understand the contribution of objective sleep disturbance to withdrawal-related neurocircuit dysfunction and symptoms, and therefore will inform whether a targeted sleep intervention in early abstinence would be warranted in polysubstance use.
