This study proposes to examine the safety, tolerability, and pharmacokinetics (PK) of NYX-783 50 mg and 150 mg versus Placebo (PBO) in combination with acute Oxycodone 15 mg and 30 mg in an inpatient randomized, cross-over study in non-treatment seeking non-dependent, opioid experienced individuals with current recreational use.

Outcomes will be cardiovascular (ECG monitoring, heart rate, blood pressure), respiratory, Clinical Opioid Withdrawal Scale (COWS), treatment emergent adverse events (TEAEs), and PK of NYX-783 levels in combination with Oxycodone. Secondary outcomes will be drug effects, subjective opiate withdrawal scale (SOWS), Drug Effects Questionnaire (DEQ), pupillary diameter, the Opioid Symptom Checklist (OSC), craving, stress and pain, and study drug levels during NYX-783 and Oxycodone combination challenge sessions.

Inclusion Criteria:

• Voluntary, written, informed consent.
• full scale and verbal IQs > 80 (Shipley Institute of Living IQ Screening Test).
• Non-treatment seeking, non-dependent, opioid-experienced participants with low, opioid use via smoking or oral pills routes and with no need for medical detoxification from opiates and without past 12-month history of overdoses or medical detoxification for opioid withdrawal.
• Participants must agree to use dual contraceptive methods during the study and refrain from donating sperm or ova during study or for 28 days after final dose of drug for ova and for 90 days after final dose of drug for sperm. Dual contraceptive methods include the use of a barrier contraceptive (i.e., condoms) in addition to another effective method that can prevent pregnancy (i.e., oral or parenteral contraceptives, intrauterine devices, spermicide, etc.).
• Ability to understand and comply with study requirements and restrictions and provide a secondary contact if they cannot be reached.

Exclusion Criteria:

• Meet current DSM-5 criteria of moderate to severe Substance Use Disorder (SUD) on either sedative, hypnotics, cocaine, methamphetamine, opiates or alcohol.

• Daily heroin, fentanyl use requiring opiate detoxification and treatment.

• Regular daily prescribed use of anticonvulsants, sedatives/hypnotics, other antihypertensives, anti-arrhythmics, antiretroviral medications, naltrexone, antabuse, grapefruit juice and St. John's wort products, glucocorticoids, stimulants (amphetamine like compounds), CNS active medications (other than stabilized use of antidepressants and anti-anxiety medications), metformin, or other medications such as benzodiazepines and sedating antidepressants that in the opinion of the investigators interfere with the study.

• Women who are pregnant or nursing (as assessed by pregnancy tests during initial intake and upon CNRU admissions).

• HIV seropositivity, hepatitis or other acute ongoing infectious disease considered clinically significant by the investigator.

• Traumatic brain injury with loss of consciousness.

• Individuals with current or past history of seizure disorders.

• Current or recent diagnosis within past 6-months of Major Depressive Disorder (MDD), bipolar disorder, schizophrenia, and schizoaffective disorder.

• History of a neurodegenerative or neuro-inflammatory disorder including Huntington's, Parkinson's, Alzheimer's disease, or multiple sclerosis.

• Known familial history or known presence of long QT syndrome, or a known history of past or current clinically significant arrhythmias or ischemic heart disease.

• History of gastrointestinal disease or surgery (except simply appendectomy or hernia repair), leading to impaired drug absorption.

• Uncorrected hypothyroidism or hyperthyroidism. Participants with compensated hypothyroidism with normal thyroid-stimulating hormone levels may be enrolled.

• Sensitivity, allergy, or intolerance to N-methyl-D-aspartate receptor (NMDAR) ligands including ketamine, dextromethorphan, memantine, methadone, dextropropoxyphene, or ketobemidone and magnesium. Use of NMDAR-binding drugs within 60 days prior to dosing or during the study.

• Received an investigational product or device within 30 days of dosing (or 5 half-lives whichever is longer).

• Previously received NYX-783.

• Screening QT interval corrected for heart rate (HR) by Fridericia's formula (QTcF) > 450 (males) or 470 (females) milliseconds (msec) or an ECG that is not suitable for QT measurements (e.g., poorly defined termination of T-wave in the investigator's opinion.

• Heart rate ≤45 or >90 bpm at screening

• Creatinine clearance <60ml/min at screening or history of renal disease as assessed by Investigator.

• Uncontrolled Type I or Type II diabetes or uncontrolled hypertension characterized by fasting blood glucose > 126 mg/dl or postprandial blood glucose > 200 mg/dl, resting systolic blood pressure >160 mm Hg or resting diastolic >100 mm Hg, or clinically significant hypotension in the judgement of the Investigator as characterized by resting systolic blood pressure <90 mm Hg or resting diastolic blood pressure <60 mm Hg.

• Impaired hepatic function characterized by a previous known diagnosis of chronic liver disease and/or the presence of:

  1. direct bilirubin > 1.5x the upper limit of normal at screening
  2. alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, or gamma-glutamyl transferase (GGT) > 2x the upper limit of normal at screening.

• History of severe COVID-19 infection requiring hospitalization, treatment with oxygen or mechanical ventilation, that may interfere with study participation as assessment by the Investigator.

• Any participant with a medical history of Covid-19 infection (positive test) within the last 2 months, or current symptoms consistent with Covid-19 infection, as assessed by the Investigator.

• Donated blood during the past 8 weeks.

• Participants who do not report an increase in subjective opioid effect, as measured by the Drug Effects Questionnaire (DEQ, see below) by minimum of 10% or more to initial challenge with oxycodone in Session 1 will be excluded from the DDI phase sessions 2-7.

Double blind, placebo controlled.