The goal of this clinical trial is to learn if ketamine works to reduce craving for opioids in adults entering methadone treatment for opioid use disorder. The main questions it aims to answer are:

• Does ketamine reduce craving for opioids in patients with opioid use disorder?
• Does ketamine reduce symptoms of opioid withdrawal such as depression, pain, and poor sleep quality?
• Do patients who take the low dose ketamine stay in methadone treatment longer, and/or have better treatment outcomes than those given the very low dose?

Researchers will compare two low doses of ketamine to see if ketamine works to reduce craving for opioids in adults entering methadone treatment for opioid use disorder.

Participants will:

• Be given a low dose or a very low dose of ketamine 4 times over a period of 2 weeks
• Visit the clinic weekly and monthly for checkups and tests for 90 days post-intake

Inclusion Criteria:

1. Age 18 to 65 years old
2. Recent history (most recent 2 weeks prior to clinic intake) of routine use of illicit opioids, 5+ times/week
3. Fulfillment of DSM-5/ICD-10 criteria for moderate-to-severe opioid use disorder
4. Acceptance into methadone treatment for opioid use disorder within the past 21 days at the time of screening
5. Adherence to lifestyle requirements for participation

Exclusion Criteria:

1. Routine use of prescribed medications for OUD (5+ days/week) for longer than the 14 days leading up to clinic intake

2. Pregnant and/or breastfeeding

3. **Stage 2 Hypertension, defined by a systolic blood pressure (SBP) > 140mmHg or a diastolic blood pressure (DBP) > 90 mmHg

4. Abnormal oxygen saturation or abnormal heart rate (i.e. O2 saturation <95%, or HR <60 or >100bpm)

5. Clinically significant abnormal findings for which study participation is deemed unsafe

6. Severe mental illness or psychiatric disorder for which study participation is deemed unsafe (except for depression, PTSD, and substance use disorder)

7. **ALT/AST > 3 x Upper Limit of Normal (ULN), ALP 2 x ULN, or total bilirubin > 1.5 x ULN. Source: Labs

8. History of hypersensitivity to ketamine

9. Suicidal ideation with a plan or intent or suicidal behaviors as reflected in Columbia-Suicide Severity Rating Scale (C-SSRS)

10. Recent homicidal ideation or violent behaviors

11. Concomitant daily use of medications with significant CYP2B6 and CYP3A4 inhibition or induction effects that can interfere with metabolism of ketamine

12. Advanced cardiopulmonary disorders, including stroke, cardiac arrest, and myocardial infarction in the past year

13. History of aneurysmal vascular disease or dissection (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels) or arteriovenous malformation

14. **Clinically significant EKG abnormalities.

15. Current significant use (>3 days/week) of barbiturates, sedative hypnotics, benzodiazepines, ketamine, or PCP (prescribed or illicit)

    • NOTE: Due to time constraints in the study design, these exclusion criteria do not need to be met before the initial consent to participate. This criterion only needs to be established prior to the first ketamine session. Individuals that are initially enrolled and subsequently do not qualify due to severe hepatic impairment will be considered screen failures and withdrawn from the protocol.