PROJECT SUMMARY/ABSTRACT Obsessive-compulsive disorder (OCD) is a disabling illness affecting about 4.2 million Americans,4 and current treatments including serotonin reuptake inhibitors and cognitive behavioral therapy with exposure and response prevention (EX/RP) will help fewer than 50% of patients achieve remission. This goal of this K23 Award is to promote Dr. Kayser’s development into an independent physician-investigator who applies an experimental medicine approach to develop new treatments for severe mental illnesses like OCD. The activities proposed herein focus on the endocannabinoid system (ECS) as a potential new area for developing OCD treatments and a model system from which to gain experience in experimental medicine research. Preclinical data implicate the ECS in OCD-relevant neurocognitive processes (i.e., threat response,5,6 fear extinction learning,7,8,17–21,9–16 and the balance between goal-directed and habitual behavior22,23), which could be modulated by cannabinoids to therapeutic benefit. As a T32 fellow, Dr. Kayser began to explore this premise in preliminary studies, showing that a) smoked cannabis alone did not affect OCD symptoms and b) nabilone, an FDA-approved synthetic analogue of ∆-9-tetrahydrocannabinol (THC, the primary psychoactive component of cannabis), had no effect as monotherapy but enhanced the effectiveness of EX/RP when both treatments were combined.3 This leads to the hypothesis that nabilone may have facilitated fear extinction, which is thought to occur during EX/RP, since imaging studies of healthy adults show that THC enhances extinction learning by modulating activity in parts of the brain’s fear network.16,17,21,24 Dr. Kayser’s K23 research project will test this hypothesis using an experimental medicine design to evaluate how a single dose of nabilone vs. placebo affects OCD-relevant targets at the neural (e.g. fMRI), physiological (e.g. skin conductance response, electromyography), and psychological (e.g. behavioral response) level in 60 unmedicated adults with OCD. His K23 training plan will capitalize on an outstanding research environment and multidisciplinary mentorship team and enable him to develop skills in (a) clinical trial design, (b) experimental medicine methods, c) translational neuroscience techniques, d) advanced biostatistical analyses, and e) grantwriting, research presentation, and manuscript preparation. Hands-on experience from designing and conducting the study will support the above training goals and provide preliminary data to support a future R61/R33 application. In addition to expanding current knowledge of the ECS’ role in OCD, study results could provide a mechanistic explanation for nabilone’s effects in OCD and identify biomarkers to index the effects of nabilone and other cannabinoids in future trials. This research direction may ultimately yield new treatments for OCD. Moreover, the experiences this K23 supports will foster Dr. Kayser’s transition to an independen...