Cannabidiol-enhanced cognitive behavioral therapy for generalized anxiety disorder - The long-term objective of this R61/R33 is to evaluate cannabidiol as a “cognitive enhancer” to increase efficacy of cognitive behavioral therapy (CBT) for generalized anxiety disorder (GAD). Emotion regulation difficulties, particularly a diminished ability to manage negative emotions, are central to the development of GAD and other anxiety disorders, which are often linked to irregularities in prefrontal brain regions. However, despite the general effectiveness of CBT, nearly half of all patients do not show significant improvement. Successful response to CBT is evidenced by improved emotion regulation and enhanced activity of the dorsomedial prefrontal cortex (dmPFC) during cognitive reappraisal, which is a proxy of the interventions practiced in CBT (e.g., cognitive restructuring). Our prior work suggests that administration of an exogenous cannabinoid facilitates emotion regulation and enhances dmPFC activation in posttraumatic stress disorder— an anxiety-related condition sharing similarities in prefrontal engagement during emotion regulation. Further, cannabidiol, a well-tolerated non-intoxicating component of cannabis, has been linked to significant reductions in anxiety. Acute cannabidiol administration also modulates dmPFC activity during emotion processing. Therefore, both cannabidiol and CBT have converging effects on dmPFC activity, indicating that a combined therapy may have synergistic benefits. The objective of this project is to test the novel hypothesis that the combination of CBD+cannabidiol will result in greater reductions in GAD symptom severity compared to CBT alone, and this effect will be associated with increased dmPFC activation during an emotion regulation task. In the R61 phase, individuals with GAD will be randomly assigned to one of three arms to identify potential dose- dependent effects of cannabidiol (FDA-approved EPIDIOLEX®)-assisted CBT: (1) 5-week Brief CBT plus moderate-dose cannabidiol (5 mg/kg BID); (2) Brief CBT plus low-dose cannabidiol (2.5 mg/kg BID); or (3) Brief CBT plus placebo. The “go” criterion for progression from R61 to R33 is target engagement, defined as a large effect size (d≥0.8) in within-subject change in dmPFC response during the emotion regulation task from pre- to post-CBT following CBT+cannabidiol. In the R33 phase, we will combine the minimum effective dose from the R61 phase with a standard 8-week Brief CBT protocol to (1) replicate target engagement and (2) test whether cannabidiol augments the reduction in symptom severity and the maintenance of treatment gains between once-weekly sessions and post-CBT. Individuals with GAD will be randomized to either a (1) CBT+cannabidiol or (2) CBT+placebo arm. Like the R61 phase, participants will complete the emotion regulation fMRI task pre- and post-CBT to determine whether CBT+cannabidiol leads to greater increases in dmPFC activation vs. CBT+placebo. We will also assess treatment response (reduced GAD symptom severity) at each CBT session and at 3 months post-treatment to explore long-term effects. Together the R61 and R33 phases will provide the most directly translational and critical test of cannabidiol-assisted CBT for GAD.
