Mood and Decision-making in Methamphetamine Use Disorder

The growing epidemic of methamphetamine use disorder (MUD) is a significant burden on public health with surging overdose deaths, high likelihood of relapse, and current lack of approved medication to treat the disorder. When it comes to decision-making, individuals with MUD often prioritize drug over non-drug rewards despite negative life consequences; in addition, they may not sufficiently "explore" all available choices to "exploit" the best one (in other words, make the optimal choice leading to positive consequences). Therefore, the "explore-exploit" trade-off is often dysfunctional in MUD. Decision-making imbalances in the explore-exploit trade-off may extend well into abstinence, a period marked by a negative affective state (low mood, high depression and anxiety, withdrawal), which in turn triggers heightened craving and subsequent drug use urges. The insula, anterior cingulate cortex and striatum are crucial brain regions involved in explore-exploit behaviors and affective state signaling that have also been linked to drug reward processing in MUD. We propose that reducing negative affective state (improving mood) could help normalize explore-exploit behaviors and the response of these brain areas in individuals currently abstinent from methamphetamine and other drugs. This project will use a non-drug-related autobiographical memory recall to improve the mood of individuals with MUD and measure whether it normalizes non-drug decision-making, using a functional magnetic resonance imaging-based 3-arm bandit task and a behavioral contextual reinforcement learning task. A mixed experimental design in n=80 (72 completers, assuming 10% attrition) allows the identification of a between-subjects effect of positive (n=40, 36 completers) vs. neutral (n=40, 36 completers) mood modulation and assess the within-subject impact on explore-exploit behaviors pre- versus post-mood modulation. Mood groups will be compared on positive and negative affect, and behavioral/brain responses to reward valuation, outcomes and learning rates.

The overarching goal is to establish that improving mood in individuals with MUD can reduce their negative affective state, normalize outcome sensitivity in key brain regions and associated learning, and reduce the influence of drug rewards on the valuation of non-drug rewards. This approach of this proposal embodies the goals of the NIH RDoC Initiative and the NeuroMAP Center by identifying an actionable disease-modifying target (mood) and studying its effect on the cognitive and neural dysfunction underlying a specific cognitive process (explore-exploit behaviors) relevant to MUD, and possibly other related neuropsychiatric disorders. By targeting the intertwined mechanisms between negative affect and explore-exploit biases, innovative, effective intervention strategies for MUD may be unveiled, addressing a critical public health challenge.

Inclusion criteria

• Adults 18-65 years old
• English proficiency as evaluated by language ability during screening
• Past-year diagnosis of DSM-5 methamphetamine use disorder (MUD) confirmed by the MINI
• Actively enrolled in treatment for substance use disorder.

Exclusion criteria

• Severe traumatic brain injury (as indicated by a score ≥3 on the Tulsa Head Injury Screen
• Any medical condition interfering with the participation in the study as determined by medical screening
• DSM-5 diagnosis of psychotic disorders, bipolar I disorder, or major depressive disorder with psychosis
• fMRI contraindications as listed on the MR environment screening form
• Positive breathalyzer for alcohol
• Positive urine drug screening, except for cannabis or prescribed benzodiazepines, as indicated in the medical screening
• Evidence of inability to comply with study procedures based on judgement of the experimenter.