PROJECT SUMMARY/ABSTRACT Social anxiety disorder (SAD) SAD is a common, early onset disorder that untreated, results in high chronicity, comorbidity, health care utilization, and functional and quality of life impairment. Novel treatments for SAD are needed, as many patients do not access, tolerate or respond to available treatments. Cannabidiol (CBD) is a natural compound from the cannabis plant that lacks the mind-altering effects of THC. With a recent surge in use of unregulated forms of CBD sold online or over the counter, patients are attempting to self-medicate without regulated formulations or evidenced based dose guidelines of CBD for anxiety disorders including SAD, creating an urgent need for rigorous biologically informed study. Together there exist strong preclinical and well-replicated human laboratory evidence for CBD’s acute anxiolytic effects, making it one of the most promising novel drug candidates for the treatment of anxiety, and social anxiety in particular. This proposal aims to build on promising preliminary scientific support for potential engagement with SAD-relevant neural and behavioral targets and clinical effects of CBD to help fill this gap. The goal of these studies is to establish a biological signature of CBD’s putative therapeutic effects in SAD and its link to core SAD symptoms, and to provide clinical effect sizes, safety, and feasibility data to guide a future definitive RCT of CBD for SAD. Our overarching hypothesis is that CBD will improve well-established abnormalities present in fear neurocircuitry and performance stress responding in adults with SAD, and that this SAD target engagement will be associated with symptom improvement. First in the R61, we will study two dose levels of a Phase 3 trial suitable hemp-derived (legal) oral CBD formulation with enhanced bioavailability versus placebo (PBO) in a 3 week double-blind RCT. Participants will undergo a modified Trier Social Stress Test (TSST) at week 2, and a standardized 2-day fear learning and extinction protocol at week 3, with fMRI brain activation accompanying fear extinction recall and fearful faces tasks on the second day. These methods will enable measurement of CBD vs PBO target engagement with three evidence- based targets: 1) Ventromedial prefrontal cortex (vmPFC) activation during fear extinction recall, 2) Amygdala activation in response to fearful faces, and 3) Visual analogue mood scale (VAMS) anxiety rating in response to the TSST speech. The GO criterion for progression from R61 to R33 will be met if target engagement is observed for at least one target, ordered as above, for at least one of the two CBD doses in the absence of clinically significant adverse effects. Next, the R33 will replicate CBD vs PBO R61 target(s) engagement using identical methods and timing of assessment, except with one (optimal) CBD dose vs. PBO continued over 8 weeks to enable association of target engagement with SAD symptom change. A pharmacokinetic study of p...