Wayne State Warriors Marijuana Clinical Research Program: Cannabinoid Adjunct to Prolonged Exposure & Recovery

The total time commitment estimated per participant is 20 study visits. This is approximated below:

Visit 1: Screening Consent and Screening Assessments: During this visit the potential participant will learn about the study procedures and sign the screening informed consent documents, then complete screening measures which will include a clinical interview (i.e., assessments of PTSD and other psychiatric diagnoses, suicidality, medical history, etc.), a physical examination, and various questionnaires. At this time, they will collect blood, urine, breathalyzer and saliva samples.

Visit 2: Study consent and Baseline Assessments: During this visit the participant will be asked to read the study informed consent form and will have an opportunity to have any questions answered before agreeing to participate in the study. Particular attention will be given to reviewing required procedures and possible side effects of the drugs (THC and CBD) with participants.

Visit 3: Pre-Treatment Behavioral Tests and Magnetic Resonance (MR) Scan: 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. which will be a mild electric shock to the ankle paired with a snake hissing sound of an animated snake) may follow one image most of the time, while the other images may never be followed by the aversive cue. 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 an aversive cue 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 4: Pre-Treatment Behavioral Tests with MR Scan: This visit will be very similar to Visit 4. Participants will participate in the same type of task inside the MR 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 3. 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.

Visit 5\&6: Prolonged Exposure (PE) Sessions 1 \& 2: These sessions will consist of psychoeducation that includes discussion or reactions to trauma, treatment rationale, breathing retraining, and review of the Subjective Units of Distress Scale (SUDS) to assess level of distress from 0 to 100 (100=extreme anxiety/distress) when facing fears. One session occurs weekly across 2 weeks.

Visit 7-10: Prolonged Exposure (PE) Sessions 3-6: These sessions will consist of repeated exposures to trauma memories (imaginal exposure) and avoided situations (in vivo exposure). As is standard, patients will also practice exposures (e.g., listen to tapes of imaginal exposure, carry out in vivo exposure) outside of PE sessions as "homework". At exposure-focused sessions either cannabis or placebo (PBO) will be administered just before the session. One session occurs weekly across 8 weeks.

Visit 11: Prolonged Exposure (PE) Session 7: This visit is similar to the ones above, but it will include a mid-treatment assessment and there won't be any cannabis or placebo administration.

Visit 12-14: Prolonged Exposure (PE) Sessions 8-10: These sessions will consist of repeated exposures to trauma memories (imaginal exposure) and avoided situations (in vivo exposure). As is standard, patients will also practice exposures (e.g., listen to tapes of imaginal exposure, carry out in vivo exposure) outside of PE sessions as "homework". One session occurs weekly across 8 weeks.

Visit 15: Post-Treatment Assessments: This visit will include a review of therapeutic gains, relapse prevention, and assessments.

Visit 16: Post-Treatment Behavioral Tests and MR Scan: This visit will be very similar to Visit 3. Participants will participate in the same type of task inside the MR 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 3. 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.

Visit 17: Post- Treatment Behavioral Tests and MR Scan: This visit will be very similar to Visit 4. Participants will participate in the same type of task inside the MR 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 5. 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.

Visit 18: 3-Month Follow-Up Treatment Assessment: This session is similar to Visit 15 and will include review of therapeutic gains, relapse prevention, and assessments.

Visit 19: 6-Month Follow-Up Treatment Assessment: This session is similar to Visit 18 and will include review of therapeutic gains, relapse prevention, and assessments.

Visit 20: 9-Month Follow-Up Treatment Assessment: This session is similar to Visit 19 and will include review of therapeutic gains, relapse prevention, and assessments.

• Cannabidiol (CBD) only (Drug), also known as Cannabis: Plant cannabis that will be smoked.
• Placebo only (Drug): Plant that will be smoked.
• Delta-9-tetrahydrocannabinol (THC) only (Drug), also known as Cannabis: Plant cannabis that will be smoked.
• THC:CBD 1:1 (Drug), also known as Cannabis: Plant cannabis that will be smoked.

Primary outcomes

• Treatment Response [Through study completion, an average of 12 months]: Clinician Administered PTSD Scale for DSM-5 (CAPS-5 Score), anxiety, mood, suicidality, disability. The CAPS-5 is a clinician interview that determines the presence and severity of PTSD consistent with the Diagnostic \& Statistical Manual 5 (DSM-5) and allows for assessing changes in symptom severity over time. PTSD diagnosis is based on meeting the DSM-5 symptom cluster criteria (minimum threshold of symptoms with a score ≥ 2) with a qualifying criterion A index trauma. The CAPS-5 Total Severity Score is calculated by summing the total score for each of the four symptom categories to assess past-month PTSD symptoms on a specific traumatic event: intrusion (Category B), Avoidance (Category C), Mood and Cognition (Category D), and Hyperarousal (Category E). CAPS-5 Total Severity scores range from 0-80, where higher scores indicate worse PTSD severity.

Secondary outcomes

• Brain measures [Pre and post treatment-Through study completion, an average of 12 months]: Functional magnetic resonance imaging (fMRI) will be used to measure blood oxygen level dependent (BOLD) changes in regions of interest (amygdala, ventromedial prefrontal cortex, hippocampus) during tasks.
• Skin conductance response [through study completion, an average of 12 months]: Skin conductance is a measure of physiological arousal, it can be used to measure periods of heightened emotional responses to stimuli, here it is used to confirm fear conditioning.
• Drug Effects Questionnaire (DEQ) [through study completion, an average of 12 months]: Subjective ratings of drug effects on from 1-5 on the following scale: "feel", "high", and "like"
• Visual Analogue Scale of Mood (VAS) [through study completion, an average of 12 months]: Subjective ratings of mood and drug effects on a 0-100 scale. Higher numbers on the scale reflect stronger experiences of different mood and drug effects. Each item is scored individually. There is no overall score.
• Quality of Life Inventory (QOLI) [through study completion, an average of 12 months]: assessment of well-being and satisfaction of life. The questionnaire is a 32-item scale ranging from -6 (extreme dissatisfaction) to +6 (extreme satisfaction). Scores range from 1-77 with higher scores indicating higher life satisfaction.
• Pittsburgh Sleep Quality Index (PSQI) [through study completion, an average of 12 months]: Used to evaluate overall sleep quality. Participants rate sleep quality on a 4 point scale from 0 - "not during the last month" to 3 - "three or more times per week" relating to various sleep concerns. Scores range from 1-21 with higher scores indicating worse sleep quality.
• Epworth Sleepiness Scale (ESS) [through study completion, an average of 12 months]: assessment of daytime sleepiness in adults. Participants rate feeling sleepy during various activities on a 4 point scale from 0 - "no chance of dozing" to 3 - "high chance of dozing". Scores range from 0-24 and are characterised as follows: 0-7:It is unlikely that you are abnormally sleepy. 8-9:You have an average amount of daytime sleepiness. 10-15:You may be excessively sleepy depending on the situation. You may want to consider seeking medical attention. 16-24:You are excessively sleepy and should consider seeking medical attention.
• Brief Pain Inventory (BPI) [through study completion, an average of 12 months]: assessment of the severity of pain and its impact on functioning. The scale consists of nine questions with a mixture of visual analogue scales and written answers. Questions 3-6 measure current pain levels on a scale from 1 - "no pain" to 10 "pain as bad as you can imagine" with higher ratings suggesting greater levels of pain (range 0-40). Question 9 has 7 nested questions (rated from 0 - 'Does not interfere" to 10 - "Completely interferes") relating to how much pain is interfering with mood, everyday tasks and sociability (range 0-70), a higher rating indicates greater issues arising from pain.
• Short form 36 [through study completion, an average of 12 months]: assessment of general health questions. Each question is scored on a range from 0-100 with higher scores indicating a more favourable health state.
• fMRI [through study completion, an average of 12 months]: using fMRI we can look at the differences between individuals during fear processing responses.
• Psychophysiology [through study completion, an average of 12 months]: Skin conductance response (SCR): change in SCR \[peak amplitude from 0.5-4.5 sec following stimulus presentation minus average 2 second baseline prior to stimulus presentation\].
• DNA analysis [through study completion, an average of 12 months]: Plasma samples collected are analyzed for genetic and epigenetic markers of endocannabinoid system functioning.
• Cannabinoid concentration - Blood [through study completion, an average of 12 months]: As well as measuring drug levels during treatment, blood samples allow us to track the activity of the endocannabinoid system throughout the treatment. A novel approach to determine whether Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) function differently in the endocannabinoid system.
• Urine Drug Toxicology tests [through study completion, an average of 12 months]: Urine samples are also provided on regular visits for drug testing.
• Cannabinoid concentration - Saliva [through study completion, an average of 12 months]: As well as measuring drug levels during treatment, these samples allow us to track the activity of the endocannabinoid system throughout the treatment. A novel approach to determine whether Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) function differently in the endocannabinoid system.
• TLFB [Administered at every study visit, besides fMRI scanning visits.]: The Timeline Follow-Back (TLFB) will be used to record the time of cannabis use and route of administration as well as any alcohol and other drug use.
• Blood pressure [through study completion, an average of 12 months]: Both systolic and diastolic pressure will be assessed
• Heart rate [Throughout the 12-month study]: Heart rate (bpm) will be assessed
• Skin temperature [Throughout the 12-month study]: Skin temperature (in degrees Fahrenheit) will be assessed
• Oxygen saturation [Throughout the 12-month study]: Oxygen saturation (percent oxygen in the blood) will be assessed with pulse oximeter

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* Willing and able to consent to the study
* Agree to comply with requirements and procedures
* Veteran who has served in a branch of the US armed forces
* Between ages 18-60
* Report using cannabis within the past three years but not more than twice in the past month
* Exposure to Criterion A stressor defined by CAPS-5 and identified by Life Events Checklist-5 (LEC-5); trauma does not have to be related to combat or military service
* Significant PTSD severity as indicated by CAPS-5 diagnosis and/or score >= 25 of at least one month prior to study entry, PTSD is patient's primary concern
* not currently receiving any psychotherapy for PTSD

Exclusion Criteria:

* Pregnant, lactating or are a heterosexually active, pre-menopausal woman who is NOT using medically approved birth control (e.g., oral or depot contraception, contraceptive implant, IUD, condom/foam, sterilization, tubal ligation)
* Current or past diagnosis of any bipolar or related disorder or schizophrenia spectrum and other psychotic disorder as determined by the SCID-5 or previous diagnosis by a licensed psychologist or psychiatrist
* Determined to be at high risk for suicide requiring immediate intervention based on the C-SSRS and/or clinician judgment
* Meet criteria for substance use disorder other than Cannabis Use Disorder or Alcohol (Mild or Moderate) or Nicotine Use Disorder, determined by the SCID-5
* Presence of contraindications, current or past allergic or adverse reaction, or known sensitivity to smoking cannabis
* Concomitant treatment with medication taken daily that has level 1 evidence indicating severe drug-drug interactions with cannabis
* Currently receiving psychotherapy for PTSD or previously received exposure-based PTSD treatment
* Current diagnosis or evidence of significant or uncontrolled hematological, endocrine, cerebrovascular, cardiovascular, systemic, pulmonary, pulmonary fibrosis, or other forms of restrictive lung disease, immunocompromising, or neurological disease
* Current diagnosis of a mood, anxiety, or other disorder that is more clinically salient than PTSD
* Cognitive exhibit impairment
* Lack of fluency in English
* Insufficient memory of the index traumatic event
* Pervasive development disorder history
* Seeking or currently undergoing treatment for Cannabis Use Disorder.
* Traumatic brain injury (TBI) with current cognitive impairment related to TBI
* Exclusively left-handed (score of -100 on Handedness Questionnaire)
* claustrophobic
* MRI contraindications (e.g., ferrous metal in head/body)