Project Summary Abstract Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use causing significant personal impairment or distress and may lead to overdose and death. In 2021, there were over 2.7 million Americans living with OUD and 106,699 Americans who died from an opioid related overdose. Unfortunately, approved medications to treat OUD carry a high risk of dependence and have had a limited effect. Therefore, new strategies for treating people with OUD should be developed to address the significant unmet need. A new drug class of psychoplastogenic compounds (PC) is being explored for therapeutics promoting structural and functional neural plasticity to treat substance use disorders (SUD). Evidence of anti-addictive effects and pharmacology of PCs have recently been pioneered in the context of psychopathological disorders, including depression, anxiety, and SUD. Single doses of a potent PC, 5-MeO-DMT, have demonstrated long-lasting effects on participants, but little is known about the dosing strategy and potential efficacy of reducing rates and severity of symptoms of patients living with OUD. Inhalation is the primary route of administration of 5-MeO-DMT, but dosing remains uncertain due to means of collection, purification, and inhalation drug delivery. In this case, it seems inhalation is the most efficient systemic delivery mechanism to improve bioavailability and avoid first pass hepatic metabolism but reaching the periphery of the lung for effective systemic delivery is technically challenging. Given the strong need, we propose to create and test in-vivo a highly effective, consistent, and efficiently targeted inhalation treatment using our proprietary dry powder aerosol technology for pulmonary-to-systemic delivery of 5-MeO-DMT. A successful outcome of this project will be the creation and in-vivo efficacy testing of a new type of targeted inhalation formulation containing 5-MeO-DMT to treat OUD. Quench Medical's technology has the potential to have a ground- breaking impact on the field of SUD by delivering 5-MeO-DMT safely, consistently, and effectively to patients living with OUD.