There is an urgent need for mechanism-based novel pharmacological approaches to treat trauma-related disorders such as posttraumatic stress disorder (PTSD), as 40-60% of patients do not respond to current pharmacological or behavioral therapies. High heterogeneity of symptom patterns and trajectories in PTSD suggests alterations in multiple neurobiological systems. Negative valence processing and arousal in response to affective stimuli (AS) and conditioned fear stimuli (CFS) have been proposed as translational multi-level processes within the NIMH Research Domain Criteria (RDoC) that are relevant to trauma and other stress- related disorders. Reliable disruptions have been observed in the functioning of brain systems that regulate AS and CFS reactivity in individuals with PTSD. A class of medications acting on the endocannabinoid system, inhibitors of fatty acid amide hydrolase (FAAHi) are hypothesized, based on a large body of preclinical research, to modulate activity in AS and CFS regulatory systems (e.g., enhancement of fear extinction). FAAHi may therefore offer clinical benefit for patients with PTSD—and trans-diagnostically for other anxiety and stressor-related conditions—who show consistent dysfunction in those circuits. The proposed project evaluates the ability of a FAAHi developed and characterized by Janssen, JNJ-42165279, to engage systems that regulate AS (e.g., amygdala activation during emotion face processing; primary target) and CFS (e.g., fear extinction; secondary target) in the service of reducing hyperarousal (primary clinical outcome) and re- experiencing symptoms (secondary outcome). The project aims are supported by extensive preliminary data in healthy humans indicating that JNJ-42165279 dose-dependently inhibits FAAH as evidenced by dose- dependent increases in plasma anandamide; saturation of FAAH (>80%) is achieved at doses that have no clinically significant adverse effects in humans; and once steady state is achieved, AS and CFS reactivity is attenuated. Based on these observations, we propose a two-site, randomized double-blind fixed dose (25 mg BID) placebo-controlled trial of JNJ-42165279 in N=150 patients with PTSD. Aim 1 seeks to confirm target engagement through reduced amygdala activation during AS processing (primary target) as well as reduced physiological and subjective CFS reactivity during exposure to a trauma narrative and fear extinction recall (secondary targets) from baseline to steady state (5 days of treatment). Aim 2 will test the hypothesis that attenuation of amygdala reactivity from baseline to Day 5 in the JNJ-42165279 group will be associated with symptom change from baseline to week 8. We will explore links between changes in secondary measures of target engagement (trauma-specific arousal reactivity and fear extinction recall) and changes in hyperarousal and re-experiencing symptoms at 8 weeks. If these predictions are confirmed, this project will support future studies of FAAHi (and othe...