Dramatic increases in rates of opioid use disorder (OUD) and overdoses necessitate the testing and development of novel therapeutic agents to target the opioid epidemic. This application proposes phased preclinical (UG3) and clinical (UH3) assessments of the NMDA modulator NYX-783 for treatment of opioid drug-seeking and relapse to OUD. NYX-783, a novel small molecule being developed by Aptinyx, has shown evidence of safety/tolerability in Phase 1 studies and is currently in Phase 2 trials for Post-traumatic Stress Disorder. Data from animal models suggests efficacy in reducing opiate seeking behavior and the proposed UG3 experiments will evaluate this more rigorously over multiple models and dose-ranges while also testing the safety of NYX-783 in combination with oxycodone. Progress to the UH3 component (human testing) is contingent upon the successful completion of safety and efficacy milestones in the UG3 component, including either submission of a new IND and/or amendment of Aptinyx’s existing IND for UH3 testing in humans with OUD. Experiments in the UH3 component will test the safety, tolerability and pharmacokinetics (PK) of NYX-718 in morphine-maintained inpatient human subjects. This will be completed both alone and in combination with oxycodone to confirm the absence of potentially adverse drug-drug interactions. This will be followed by a combined inpatient (safety/tolerability/PK) / outpatient (preliminary efficacy) study testing NYX-783’s effects on opioid use and relapse, stress/cue reactivity, craving and quality of life in OUD subjects maintained on standard extended release naltrexone (NTX-XR, Vivitrol) over a 10-week period. Successful completion of the UG3 and UH3 aims will thus set the stage for larger scale Phase 2/3 studies of efficacy in OUD that will ultimately be required for FDA approval of NYX-783 for the treatment of drug-seeking and relapse in OUD.