The purpose of this study is to test if the combination of ketamine, vs midazolam, with an intensive trauma-focused psychotherapy will be more effective in relieving post-traumatic stress disorder (PTSD). This week-long treatment has the potential to produce a significant therapeutic effect that otherwise would take months to occur. The study will also focus on learning about the neurophysiological changes produced by the proposed clinical trial.

Based on the current research findings on the therapeutic effectiveness of trauma focus psychotherapy and of ketamine combining the two treatments may yield a promising new rapid week-long treatment for PTSD. As PTSD symptoms' structure is comprised of several unique clusters which include re-experiencing, avoidance, depression and hypervigilance the investigators hypothesize that by combining Ketamine with trauma-focused psychotherapy the proposed intervention can address these PTSD symptoms clusters more effectively than existing treatments. This proposed clinical trial has the potential to produce a significant therapeutic effect that otherwise would take months to occur by tapping on the enhanced neuroplasticity and the antidepressant effect of ketamine (which lasts between 24hrs to 7 days), to promote rapid changes in learning and memory when applying psychotherapy within a unique "window of opportunity" of neurophysiological changes produced by the investigative drug.

During the first visit participants will undergo a clinical interview to establish a PTSD diagnosis and other eligibility criteria. If found eligible participants will be invited to take part in this 7-day rapid treatment trial for PTSD.

On the first therapy visits, participants will be educated about the psychological treatment that will be provided and the potential benefit of ketamine or midazolam that may enhance the psychotherapy outcomes.

On the second day of the study, participants will receive an infusion of ketamine or midazolam and will undergo a magnetic resonance imaging (MRI) to assess their brain reactivity to PTSD before the treatment.

On days 3-6 participants will attend a 60-90 minutes psychotherapy session to address their PTSD symptoms.

A second ketamine or midazolam infusion will take place on day 4 of the study to enhance the drug therapeutic effect for the study duration.

Day 7 will include another MRI scan to assess treatment effect on PTSD.

Participants will need to attend one follow up MRI scan and clinical evaluation at 30 days and then a clinical evaluation at 90 days post-treatment to assess the long-term effectiveness of the intervention.

Inclusion Criteria:

• Male or female between the ages of 21-70 years. This age range was chosen to fit with prior samples in which no adverse effects of ketamine have been observed. Adults in the 18-20 ranges have been eliminated because previous experience indicates that they often lack the maturity to participate effectively in similar protocols. Females will be included if they are not pregnant and agreed to utilize a medically accepted birth control method (to include oral, injectable, or implant birth control, condom, diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.
• Must not have a medical/neurological problem or use medication that would render ketamine unsafe by history or medical evaluation.
• Diagnosis of chronic PTSD with a score of 25 or higher (i.e. severe PTSD) on the Clinician-Administered PTSD Scale (CAPS-5) at screening. PTSD symptoms must have persisted for >1 year post-trauma exposure to meet the DSM-5 definition of chronic.
• Subjects on FDA-approved antidepressant, trazodone, atypical neuroleptic, prazosin, or clonidine may enter the study if they have been on a stable treatment, as determined by the study clinician, for at least 4 weeks prior to randomization. Following randomization, small changes to doses may be allowable at the PI's discretion.
• Able to provide written informed consent.
• Able to read and write English.

Exclusion Criteria:

• Patients with a diagnostic history of borderline personality disorder, obsessive compulsive disorder, schizophrenia or schizoaffective disorder or currently exhibiting psychotic features as determined by the Structured Clinical Interview for DSM (SCID); dementia or suspicion thereof, are excluded. Patients with history of bipolar disorder will be included only if they have not experienced a manic or hypomanic episode in the 30 days prior to enrollment. Other DSM Axis I disorders are permitted as long as they are not considered primary disorders.
• Patients with a history of antidepressant-induced hypomania or mania as determined by open-ended psychiatric interview.
• Current, ongoing serious suicidal risk as assessed by evaluating investigator based on the Columbia-Suicide Severity Rating Scale (C-SSRS).
• Moderate severity or greater Substance Use Disorder (excepting Alcohol and Marijuana Use Disorder) during the 3 months prior to randomization, as determined by the SCID.Alcohol or Marijuana Use Disorder may be allowed based on the judgment of study physician/APRN/clinician that patients can remain sober for all study visits.
• Subjects on a prohibited medication (see Table 1). Patients will not be taken off medication for the purpose of this study.
• History of traumatic brain injury (TBI) with loss of consciousness for more than 24 hours or posttraumatic amnesia for more than 7 days may be considered if the trauma occurred more than 1 year ago, and no more than minimal symptoms have persisted over the past year.
• Positive pregnancy test at screening or prior to any study drug infusion.
• Breathalyzer showing an alcohol level > 0% at screening, or at the discretion of the investigator, prior to any study drug infusion.
• Resting blood pressure lower than 90/60 or higher than 150/90, or resting heart rate lower than 45/min or higher than 100/min.
• Any significant history of serious medical or neurological illness.
• Any signs of major medical or neurological illness on examination or as a result of ECG screening or laboratory studies.
• Abnormality on physical examination. A subject with a clinical abnormality may be included only if the study physician considers the abnormality will not introduce additional risk factors and will not interfere with the study procedure.
• A positive pre-study (screening) urine drug screen or, at the study physician's discretion on any drug screens given before the scans.
• Pregnant or lactating women or a positive urine pregnancy test for women of child-bearing potential at screening or prior to any imaging day.
• Any history indicating learning disability or mental retardation.
• Known sensitivity to ketamine.
• Body circumference of 52 inches or greater.
• Body weight of 350 pounds or greater.
• History of claustrophobia.
• Presence of cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a standard pre-MRI screening questionnaire.
• Donation of blood in excess of 500 mL within 56 days prior to dosing.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.
• Active engagement in trauma-focused CBT (TF cognitive-behavioral therapy) or any evidence-based PTSD psychotherapy (CPT, PE, EMDR) initiated within the past 3 months (continuation of established maintenance supportive therapy will be permitted
• Enrollment in another research study testing an experimental/clinical/behavioral intervention intended to affect symptoms initiated within the last 2 months, or intended enrollment within the next 3 months

Table 1. Concomitant Treatments that are prohibited

MAOIs: 4-weeks off medication prior to randomization is required.

Memantine: 4-weeks of medication prior to randomization is required.

Long Acting Benzodiazepines -Chlordiazepoxide, Diazepam, Flurazepam: 2-weeks off medication prior to randomization is required.

Notes: As above, individuals who have used any of the prohibited medications within the "weeks off" time period will not be eligible for the study. Use of sedatives, hypnotics, benzodiazepines, sedating antihistamines or other psychotropic medications are not permitted within 8 hours of treatment sessions; except - at the discretion of the investigator - for medications that will result in discontinuation/withdrawal symptoms or that may alter the risk benefit ratio.