Examining Mu Opioid Mechanisms of Ketamine's Rapid Effects in OCD (MKET2)

The proposed mechanistic trial would be the first to probe the role of ketamine's opioid properties in modulating fronto-striatal circuitry and bringing about reduction of OCD symptoms.

• Ketamine (Drug), also known as Ketamine Hydrochloride, Ketalar: Ketamine is an FDA-approved dissociative anesthetic.
• Naltrexone Pill (Drug), also known as Naltrexone: Naltrexone is an oral opioid antagonist approved by the Food and Drug Administration (FDA) to treat both alcohol use disorder (AUD) and opioid use disorder (OUD)
• Placebo pill (Other): An oral inactive placebo pill will be administered to preserve the blinded nature of the study.

Primary outcomes

• Change in the severity of OCD symptoms as measured by the Yale-Brown Obsessive Compulsive Scale (YBOCS) [Baseline (Visit 2) to Post Infusion fMRI scan (Visit 4; Day 1), up to 1 week]: Change in OCD severity is measured by the YBOCS (Yale Brown Obsessive-Compulsive Scale), a gold standard measure of obsessions and compulsions. For the YBOCS the minimum units are 0 and Maximum units on the total scale are 40. The higher the number on the YBOCS, the more severe the symptoms. Response is defined as at least a 35% reduction on the YBOCS.

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

Eligibility Criteria for Participants with OCD:

Inclusion Criteria:

* Ages 18-65
* Meet the criteria for OCD diagnosis
* Failed at least 1 prior trial of standard first-line OCD treatment
* Agree to the following lifestyle modifications: comply with requirements for fasting prior to the Experimental Session, not enroll in any other interventional clinical trials during the duration of the study, and commit to medication study procedures.
* Able to provide informed consent

Exclusion Criteria:

* prior naltrexone or ketamine use/exposure
* Any current or past medical/psychiatric condition that makes participation unsafe in the opinion of the investigator or study physician
* Pregnant or nursing, or able to become pregnant and are not practicing an effective means of birth control
* the presence of metal in the body that is contraindicated for MRI scans

Eligibility Criteria for Healthy Volunteers:

Inclusion Criteria:

* Ages 18-65
* Able to provide informed consent

Exclusion Criteria:

* current or past use of psychotropic medication
* pregnant or nursing females
* the presence of metal in the body that is contraindicated for MRI scans

NIH grants: R01MH133553