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.
