Cannabinoid Control of Fear Extinction Neural Circuits in Post-traumatic Stress Disorder

Study Overview
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Brief Summary
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The goal of this study is to look at how a type of drug called cannabinoids are related to the processing of fear signals, the experience of emotions and fear, and the pattern of activity in the brain that is involved in these processes and how this relates to the development of post-traumatic stress disorder (PTSD). PTSD is an anxiety disorder that occurs after experiencing a traumatic event(s) and is characterized by unwanted memories of the trauma(s) through flashbacks or nightmares, avoidance of situations that remind the person of the event, difficulty experiencing emotions, loss of interest in activities the person used to enjoy, and increased arousal, such as difficulty falling asleep or staying asleep, anger and hypervigilance. The information gained from this study could lead to the development of new treatments for persons who suffer from anxiety or fear-based disorders.

Detailed Description
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The total time that for each participant involved in this study is 4 visits, as outlined below: Visit 1: Questionnaires, Screening, and Orientation: During this visit the potential participant will learn about the study procedures, sign the informed consent documents, and fill out a packet of forms that ask about his or her race and ethnic background, use of drugs and alcohol and physical and mental health. Visit 2: Behavioral Tests: During this visit the participant will complete several computer tasks, and the study staff will be measuring reaction time and psychophysiological measures.The tasks that the participant will perform will show three different images and an aversive stimulus (e.g. loud burst of noise or mild wrist shock) may follow one image most of the time, while the other images may never be followed by a noise or mild wrist shock. The participant will need to try to predict whether the aversive cue will occur or not based on which image is shown and will be asked to repeatedly rate on a scale how likely it is that he or she thinks a noise/shock will occur after each image. Lastly, during the session the participant will also be asked to report his or her level of anxiety on a scale from 0 to 100. Visit 3: Behavioral Tests with Drug or Placebo and MRI scan: For safety reasons participant will not be allowed to take any drugs for at least 24 hours before this visit, and should not use marijuana for at least 2 weeks before. Participants will be required to pass a urine drug test (and pregnancy test for women) and breathalyzer test before being allowed to continue with this visit. The participant will also not be allowed to drive himself or herself home from this visit, so he or she should arrange a friend or family member to pick him or her up or a taxi can be called by our research staff. The participant will view the same images he or she did on the previous day (Visit 2), and may experience the same aversive stimulus as during Visit 2. The participant will again be asked to rate how much he or she expects to experience the aversive stimulus after each image and he or she will also be asked to report his or her level of anxiety on a scale from 0 to 100. However, about 2 hours before the task begins, the participant will be asked to swallow a capsule containing either a marijuana-like drug (Dronabinol) or a placebo (sugar pill). Dronabinol is a Food & Drug Administration (FDA) approved drug and the dose (7.5mg; one time) is unlikely to have any effects that last beyond the duration of the study visit. About every 30 minutes after taking the pill, the participant will fill out some questionnaires about mood and how he or she is feeling at the moment. Visit 4: Behavioral Tests and MRI scan: This visit will be very similar to Visit 2. Participants will participate in the same type of task inside the MRI scanner, while the study staff measures reaction time and psychophysiological responding and brain activation. Participants will view the same images he or she did previously, and may experience the same aversive stimulus as during Visit 2. Participants will again be asked to rate how much they expect to experience the aversive stimulus after each image and will also be asked to report their level of anxiety on a scale from 0 to 100.

Official Title
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Cannabinoid Control of Fear Extinction Neural Circuits in Post-traumatic Stress Disorder

Conditions
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Post-Traumatic Stress Disorder

Intervention / Treatment
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* Drug: Dronabinol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for All Participants: Able to give informed consent Physically and neurologically healthy [confirmed by a comprehensive medical history] Age between 21-45 years old Right-handed Inclusion Criteria for Participants with PTSD: Current PTSD diagnosis [related to civilian trauma] Inclusion Criteria for Trauma-Exposed Participants without PTSD: Experience with a civilian trauma without a PTSD diagnosis Free of a lifetime Axis I or Axis II diagnosis Inclusion Criteria for Non-Trauma-Exposed Healthy Participants: Free of a lifetime Axis I or Axis II diagnosis Exclusion Criteria for All Participants: Clinically significant medical or neurological condition Less than a high school education Lack of fluency in English Night shift work Currently pregnant; planning pregnancy; or lactating Unwilling/unable to sign informed consent document Inability to tolerate small, enclosed spaces without anxiety (e.g. claustrophobia) Left-handed Presence of ferrous-containing metals within the body (e.g., aneurysm clips, shrapnel/retained particles) Under 21 or over 45 years of age Anticipation of a required drug test in the 4 weeks following study participation Positive urine drug screen and/or alcohol breathalyzer Current or past allergic or adverse reaction or known sensitivity to cannabinoid-like substances [dronabinol/marijuana/cannabis/thc, cannabinoid oil, sesame oil, gelatin, glycerin, and titanium dioxide] Participation in an experiment involving white noise bursts or shocks in the last 6 months Exclusion Criteria for Participants with PTSD: Primary comorbid anxiety disorder (defined by which disorder was the more debilitating and clinically salient) Life history of bipolar disorder, schizophrenia, or presence of an organic mental syndrome, mental retardation, or pervasive developmental disorder Current or in the past 6 months alcohol/drug abuse of dependence Current or in the past 6 months major depressive disorder Current suicidal ideation Diagnosis of an Axis II personality disorder Concomitant treatments with psychotropic/psychoactive medication [including beta-adrenergic blockers, selective serotonin reuptake inhibitor (SSRI), benzodiazepines, tricyclic or monoamine oxidase inhibitor (MAOI) antidepressants, lithium, antiepileptic/anticonvulsants, neuroleptics/antipsychotics, etc.) or in the past two weeks [8 weeks for fluoxetine and 4 weeks for MAOIs) before screening (Visit 1) currently receiving exposure-based therapy for PTSD Exclusion Criteria for Trauma-Exposed Participants without PTSD and Non-Trauma Exposed Healthy Participants: Current or past Axis I psychiatric disorder [including alcohol/substance abuse of dependence disorder]

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>In a randomized, double-blind, placebo-controlled, between-subjects design, we will administer a one-time oral dose of dronabinol (7.5mg) or placebo (PBO) approximately two hours prior to fMRI scanning and task performance in 40 patients with PTSD, 40 trauma-exposed controls without PTSD (TEC), and 40 non-exposed healthy controls (HC). Within each of the three groups half of the participants will receive dronabinol and the other half will received placebo to create the following 6 groups: PTSD-dronabinol (20) PTSD-placebo (20) TEC-dronabinol (20) TEC-placebo (20) HC-dronabinol (20) HC-placebo (20) | Drug: Placebo<br>* Placebo is administered only once (approximately 120 min prior to fMRI scanning in Visit 3) by the oral route and contains only dextrose in opaque capsules. Half of the participants in each diagnostic group [HC = 20; PTSD = 20; TEC = 20] will receive placebo.<br>* Other names: sugar pill;|
| Active Comparator: Dronabinol<br>In a randomized, double-blind, placebo-controlled, between-subjects design, we will administer a one-time oral dose of dronabinol (7.5mg) or placebo (PBO) approximately two hours prior to fMRI scanning and task performance in 40 patients with PTSD, 40 trauma-exposed controls without PTSD (TEC), and 40 non-exposed healthy controls (HC). Within each of the three groups half of the participants will receive dronabinol and the other half will received placebo to create the following 6 groups: PTSD-dronabinol (20) PTSD-placebo (20) TEC-dronabinol (20) TEC-placebo (20) HC-dronabinol (20) HC-placebo (20) | Drug: Dronabinol<br>* Dronabinol (7.5mg) is administered only once (approximately 120 min prior to fMRI scanning in Visit 3) by the oral route and is placed in opaque capsules with dextrose filler. Half of the participants in each diagnostic group [HC = 20; PTSD = 20; TEC = 20] will receive dronabinol.<br>* Other names: Marinol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Measures | Mean functional magnetic resonance imaging (fMRI) BOLD activation extracted from each region of interests [amygdala; ventromedial prefrontal cortex; hippocampus] for each stimulus type (CS+E, CS+U, CS-). The units of BOLD values are expressed as arbitrary units. | Brain measures are collected on Visit 3, 14 days from baseline (Visit 1) and Visit 4, 15 days from baseline (Visit 1), for approximately 1.5 hours each day | 
| Expectancy Ratings | To assess the expected likelihood that an aversive cue (e.g. noise burst) will occur or not based on the CS shown on the screen. Participants rate their expectancy of the aversive cue using a button box on a scale from 1 to 3 [1 = certain that the aversive cue will be presented (Yes); 2 = certain that the aversive cue will not be presented (No); 3 = uncertain whether the aversive cue will be presented (I don't know)]. Counts of yes, no, and I don't know are collected on the first (early) trial of the CS and the last (late) trial of the CS. | Collected on Visit 2, 13 days from baseline (Visit 1), Visit 3, 14 days from baseline (Visit 1), and Visit 4, 15 days from baseline, during the task. Each day the task lasted approximately 20 minutes. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjective Units of Distress (SUDS) | Subjective Units of Distress (SUDS): used to measure fear ratings/subjective anxiety on a scale from 0-10; taken at three time points throughout the tasks: before the task begins, in the middle of the task, and at the end of the task. A rating of 0 means no anxiety and a ratings of 10 means worst anxiety ever experienced. | SUDS ratings are collected at Visit 3, 14 days from baseline (Visit 1), and Visit 4, 15 days from baseline (Visit 1), at 3 timepoints within each visit: before the task begins (Pre), in the middle of the task (Mid), and at the end of the task (Post). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-Traumatic Stress Disorders, Dronabinol, Extinction, fMRI