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Ketamine with Psychotherapy for PTSD

This study is testing if combining ketamine with a week-long intensive therapy is more effective for Posttraumatic Stress Disorder (PTSD) than combining midazolam (a sedative) with the same therapy. Researchers want to see if ketamine helps the therapy work faster and better by creating a "window of opportunity" for the brain to learn and change. They will measure changes in your brain's activity and your PTSD symptoms. The study aims to help people with PTSD find significant relief in a shorter amount of time than traditional treatments.

Study design
This interventional study plans to enroll 162 participants. It compares two groups: one receiving ketamine and therapy, and another receiving midazolam and therapy.
What's involved
You would undergo a clinical interview to confirm a PTSD diagnosis. If eligible, you would participate in a 7-day rapid treatment trial, including infusions on day 2 and 4, and follow-up visits.
Compensation
Not stated in the trial record.
Follow-up
Your PTSD symptoms will be checked at 7 days, 30 days, and 90 days after treatment. Brain activity will be measured at 7 days and 30 days after treatment.

AI-generated from the public study record. Only the study team can confirm whether you're eligible — confirm details with them before making decisions.

NCT05737693

Enhancing Week-long Psychological Treatment for PTSD With Ketamine

Active, Not Recruiting
PHASE2Ages 21–70InterventionalTreatment
Yale University
~350 participants
Updated 2026-08-24 on ClinicalTrials.gov
What's tested:KetamineMidazolam

At a glance

Recruiting sites
0 of 2 listed sites are recruiting right now
RecruitingSuspended, closed, or not yet open
What they're measuring
Amygdala activation to trauma memory (Phase 1; R61)
Measured over Changes from baseline to 30-day post-treatment in amygdala activation to the trauma memory
+2 more outcomes measured

Conditions

Posttraumatic Stress Disorder

Explore related trials

Post-Traumatic Stress Disorder

Where it's being run

2 sites across 2 states
Connecticut1
Israel1

Study leadership

  • Ilan Harpaz-Rotem, PhD ABPP · PRINCIPAL_INVESTIGATOR · Yale University

Who to contact

This trial hasn't published a contact. View it on ClinicalTrials.gov

Do you actually qualify for this trial?

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Eligibility criteria

Inclusion

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

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

What this trial measures

  • Amygdala activation to trauma memory (Phase 1; R61)Changes from baseline to 30-day post-treatment in amygdala activation to the trauma memory

    Phase 1 (R61) investigators will analyze the first 60 participants (20 per arm). Using MRI scan data, the investigators will compare changes in the amygdala bold activation from baseline to 30-day post treatment in response to the trauma scripts between the the 3 study arm. Greater activation of the amygdala is an indicator of a greater distress. Investigators will also measure the effect size resulting from the mean changes in amygdala activation from pre to post treatment between each of the experimental groups and the active comparator to determine the dose that will be carried to phase 2.

  • To determine if ketamine + exposure therapy results in clinical improvement in PTSD symptoms which are significantly greater than midazolam + exposure therapy (Phase 2; combined R61/R33 data)Baseline, 7 days, 30 days and 90 days

    Change in PTSD symptoms from baseline up to 90-day post treatment. PTSD Symptoms severity will be evaluated overtime using PTSD Check List (PCL-5). Evidence for the PCL suggests that 10 points difference in the measure is a reliable indicator for a clinically meaningful change. The PCL scores ranges from 0 (no symptoms) to a maximum score of 80 (PCL Score \> 33 indicates probable PTSD diagnosis).

  • To determine if ketamine + exposure therapy results in more profound changes in task-based connectivity in region of interest than midazolam + exposure therapy (Phase 2; combined R61/R33 data)Baseline, 7 days and 30 days (no MRI scan at 90 days post-treatment)

    Using MRI brain activation data, the investigators will compare changes in the connectivity between participants' different brain regions (brain network connectivity) from baseline to end of treatment and 30-day post treatment. Investigators will examine the neural connectivity between the amygdala, hippocampus, prefrontal cortex, striatum and insula and other major brain areas associated with PTSD.