Glutamatergic Mechanisms: Aim2

Inclusion Criteria

• Age between 18-55 at screen
• Medically healthy, as assessed by study physician at screen
• Capable of understanding the study procedures and able to provide informed consent
• Eligible men and women must agree to use a reliable method of birth control (See section 5.3) during the study. Women who are post-menopausal or otherwise not of childbearing potential are also eligible.
• Willing and reliable to participate in XT or placebo phase as an outpatient and/or agreeable to participate as an inpatient.

Exclusion Criteria

• Current or past Axis I psychiatric history (including Substance Use Disorder/Alcohol Use Disorder, with the exception of nicotine use disorder) as assessed at screen
• Positive urine toxicology or alcohol at screen
• History of recreational ketamine use, recreational PCP use, or an adverse reaction to ketamine. Participants who have participated in prior research ketamine studies will be eligible. Participants can have infusions not more frequently than biweekly, and not more than 1/month on average, therefore participants entering the study will need to wait one month if they had a single infusion and 6 weeks if they have had two closely spaced infusions.
• History of first-degree relative with schizophrenia
• Pregnancy or breast-feeding. This exclusion criterion applies only to females of child-bearing potential (not surgically sterilized and between menarche and 1 year postmenopausal). Must test negative for pregnancy at the time of screening based on a serum pregnancy test.
• History of violence, including any history of using a gun, knife, or other weapon with intent to harm someone, as well as more than one physical fight without a weapon after the age of 18 years old (not including fights that happen during sports competition).
• Presence or positive history of significant medical illness at screen, including:

• Contraindications to XT (urinary retention, moderate or severe hepatic impairment, gastric retention, untreated narrow-angle glaucoma, hypernasality)
• renal problems (GFR\<60)
• high blood pressure (defined as supine systolic blood pressure (SBP) > 140 or supine diastolic blood pressure (DBP) > 90)
• low blood pressure (defined as supine SBP \< 100, DBP \< 60)
• abnormal orthostatic blood pressure (change in mean arterial pressure [1/3 systolic + 2/3 diastolic] of > 20% between supine and standing blood pressures)
• clinically significant cardiac illness, as determined by the site physician
• clinically significant abnormal screening labs, as determined by the site physician
• Participants with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the 6 months prior to screening or participants who represent a significant risk of suicide in the opinion of the investigator.
• Presence or positive history of neurological illness, including seizures, mental retardation or any other disease/procedure/accident/intervention associated with significant injury to or malfunction of the central nervous system (CNS), or history of significant head injury.
• Any material in the body that is a contraindication for MRI procedures
• Currently taking any psychotropic medication, including antidepressant medications, benzodiazepines, antipsychotic medications, mood stabilizers, anti-epileptic medications, and stimulants. We will exclude any participant who requires treatment with any psychotropic medication from one of these classes.