Co-occurring anxiety is prevalent in more than 50% of individuals with Opioid use disorder (OUD). This is of major concern as safe and effective treatment options are lacking for this high-risk population. Anxiety in those with OUD is linked to earlier and more rapid progression of OUD, and high probability of co-use of other substances, particularly GABAA receptor positive modulators, such as benzodiazepines (BZDs). BZDs are currently the standard of care treatment for fast-acting relief for general anxiety and panic disorder. Although highly effective in the short-term, BZDs represent amajor, but often overlookedcontributorto the opioid overdose epidemic. BZDs are involved in an estimated 12,000 overdose fatalities each year in the US, largely due to the concomitant use with other CNS depressants, such as opioids. In fact, more than 90%of BZD overdose fatalities involve opioids and up to 30% opioid overdoses involve BZDs. Additionally, BZD prescription rates are directly linked to opioid overdose rates per state. With a lack of safe alternatives that can offer comparable efficacy, BZD market predictions indicate their use will remain steady or increase globally. Thus, there is an urgent need to develop safe and comparably effective alternatives to BZDs for those with OUD. We have discovered a novel series of promising synthetic GABAAR active molecules Our lead molecule, RU-EC2-118, is a partial GABAAR PAM with nanomolar potency at GABAAR subtypes and high oral bioavailability. Our in vivo studies in rodent models, strongly support the potential for the mechanismof RUEC2-118 to provide effective fast-actinganxiolytic activity and a safer profile with co-use with other CNS-depressing substances. The major technical aims of the STTR parent grant is to provide proof-of-concept data supporting the feasibility of our approach in maintaining efficacy and reducing overdoserisks. Specific aim3 is to test the desirability of our innovation through enrollment in the NIH I-Corps program. Having previously completed the NSF National ICorps program, we successfully validated the need for our innovation. During the NIH ICorps program, our main objective is to further investigate the best pathways towards funding and commercialization of our innovation .