Summary/Abstract People with opioid use disorder (OUD) experience aversive opioid withdrawal symptoms (OWS) including nausea, diarrhea, vomiting, and anxiety, which emerge when blood opioid levels wane. These symptoms perpetuate unprescribed opioid use and accompanying morbidity and mortality, costing society nearly $80 billion per year. Withdrawal symptoms also emerge upon initiation of OUD pharmacotherapy with µ opioid receptor antagonists (buprenorphine: partial; naltrexone: full), complicating, and sometimes resulting in patient refusal of, treatment initiation or continuation. Better management of OWS is considered a “gateway to opioid dependence treatment”. The a2-adrenergic receptor agonists clonidine and lofexidine attenuate opioid withdrawal symptoms by inhibiting noradrenergic signaling. However, these agents have shortcomings: they don’t fully suppress withdrawal symptoms or subjective discomfort, they induce problematic side effects (hypotension, sedation, discontinuation syndrome), their dosing must be adjusted for renal or hepatic impairment patients, and, as oral medications, they are slow acting. Thus, there is an urgent unmet need for better and faster-acting treatments. One strategy to reduce OWS severity is to lower opioid-induced inflammation and oxidative stress, which upregulate noradrenergic tone, sympathetic nervous system (SNS) activity, and OWS severity. Inhaled xenon (Xe) gas inhibits inflammation and SNS activity and is hypothesized to attenuate OWS severity. Xe is used at low concentration (28%) as an imaging agent and rarely induces hypotension or dizziness, even in critical care populations. Xe rapidly (within minutes) equilibrates in brain and other tissues and inhibits SNS activity, suggesting that it may be superior to a2-adrenergic agonists for attenuating OWS. Moreover, Xe has no demonstrable abuse liability, making it superior to opioid agonist substitution treatment for relieving OWS. In this Phase I STTR program, we propose to conduct preclinical proof of concept studies in morphine-dependent mice to determine whether 30% Xe, which is non-sedating when given by inhalation, rapidly reduces OWS severity. If Xe is effective, we will file an IND for a human STTR Phase II study to evaluate whether Xe decreases OWS during medically-managed opioid tapering required before buprenorphine initiation. Nobilis Therapeutics developed a proprietary portable hand-held Xe inhalation device and the drug/device combination has been cleared by the US Food and Drug Administration for testing in humans with Posttraumatic-Stress Disorder. This device also could be used in OUD studies, supporting capital efficiency with exit potential. Nobilis holds a patent covering Xe’s anti-inflammatory effects and licenses a patent from McLean Hospital covering Xe’s antianxiety effects. Accordingly, elements are in place to develop and market Xe therapy, if effective, to several potential clients including care providers and companies that sel...