Pilot Study of the Safety and Efficacy of Four Different Potencies of Smoked Marijuana in 76 Veterans With PTSD

Study Overview
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Brief Summary
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This pilot study gathered preliminary evidence of the safety and efficacy of four potencies of smoked cannabis to manage chronic, treatment-resistant PTSD among veterans: (1) High THC/ Low CBD (High THC), (2) Low THC/High CBD (High CBD), (3) High THC/ High CBD (THC/CBD) and (4) Low THC/Low CBD (placebo). The study will produce preliminary evidence to help elucidate the potential effects of THC, CBD, or a combination of both constituents to reduce PTSD symptoms. Smoked cannabis will be tested in two stages of three weeks each (Stage 1 and Stage 2), with a two-week cessation period after each stage, verified by blood/urine cannabinoid analysis. The primary objective was to compare three active concentrations of smoked cannabis and placebo on PTSD symptom severity measured by CAPS-5 total severity scores during Stage 1.

Detailed Description
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PTSD is a serious, worldwide public health problem resulting from traumatic experiences such as sexual assault, war, or abuse. PTSD is associated with high rates of psychiatric and medical co-morbidity, disability, suffering, and suicide. Despite available treatments for PTSD, many individuals continue to experience marked PTSD symptoms following treatment. In response to overwhelming demand for new treatments, several U.S. states have passed laws allowing the medical use of cannabis by individuals with PTSD. Emerging observational and early clinical evidence suggest that cannabis may have the potential to reduce or ameliorate a number of symptoms experienced by those with PTSD, including sleep difficulty and anxiety. Indeed, some evidence has suggested that delta-9-tetrahydrocannabinol (THC) may serve to reduce nightmares among those with PTSD, while other studies have shown anxiolytic effects of cannabidiol (CBD). However, there have been no randomized controlled trials of cannabis, in any form, for PTSD. The present triple-blind, randomized, placebo-controlled crossover trial aims to examine the safety and efficacy of four types of cannabis (i.e., high THC, low CBD; high CBD, low THC; equal ratio THC/CBD; and placebo) among 76 military veterans with chronic treatment-resistant PTSD of at least six months' duration. The study will produce preliminary evidence to help elucidate the contribution of THC, CBD, or a combination of both constituents to potential attenuation of PTSD symptoms. Smoked cannabis was tested in two stages lasting three weeks each (Stage 1 and Stage 2), with a two-week cessation after each stage, verified by blood/urine cannabinoid analysis. The primary objective was to compare three active concentrations of smoked cannabis and placebo on PTSD symptom severity measured by CAPS-5 total scores during Stage 1. Study participants received one of four different types of cannabis during Stage 1 with crossover and re-randomization, less the placebo cannabis, at Stage 2. The four potencies of cannabis were High THC/ Low CBD (High THC), Low THC/High CBD (High CBD), High THC/High CBD (THC/CBD) and Low THC/Low CBD (placebo). High is defined as marijuana containing a target of 7-15% concentration by weight of the respective cannabinoid and Low is defined as < 2% concentration by weight. Prior to each stage, participants completed two introductory sessions where they were trained on cannabis self-administration. During each stage, participants were provided 1.8 grams of cannabis daily to smoke ad libitum. Each stage was followed by a two-week cessation period. The primary objective was to compare three active concentrations of smoked cannabis and placebo on PTSD symptom severity measured by CAPS-5 total severity scores during Stage 1.

Official Title
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Placebo-Controlled, Triple-Blind, Randomized Crossover Pilot Study of the Safety and Efficacy of Four Different Potencies of Smoked Marijuana in 76 Veterans With Chronic, Treatment-Resistant Posttraumatic Stress Disorder (PTSD)

Conditions
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Posttraumatic Stress Disorder

Intervention / Treatment
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* Drug: High THC cannabis
* Drug: High CBD cannabis
* Drug: THC/CBD cannabis
* Drug: Placebo cannabis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have chronic treatment-resistant PTSD of at least six months duration. Have PTSD of at least moderate severity at the time of baseline assessment. Be a military veteran with PTSD. Be at least 18 years old. Be willing to commit to medication dosing and delivery method, to completing evaluation instruments, and attending all study visits. Agree to use only cannabis provided by site staff and agree to required cessation periods for the duration of the study. Report no current hazardous cannabis use and completely abstain from cannabis during the 2-week baseline assessment period (verified via urine and/or blood cannabinoid concentrations). Agree to video record all cannabis administrations and provide video to the site staff for review during study participation. Agree to keep all cannabis provided by site staff securely stored in the provided lock box and not to share/distribute cannabis to any other individual. Be stable on any pre-study medications and/or psychotherapy regimen for PTSD prior to study entry, agree to notify their physician/clinician about participation in the study, and agree to report any changes in medication or psychotherapy treatment regimen during the study, to site staff. If female and of childbearing potential, agree to use an effective form of birth control during study participation and may only be allowed to enroll and continue in the study based on a negative pregnancy test. Be proficient in reading and writing in English and able to effectively communicate with site staff. Agree not to participate in any other interventional clinical trials during the study Exclusion Criteria: Upon review of medical or psychiatric history must not have any current or past diagnosis that would be considered a risk to participation in the study. Have any allergies to cannabis or contraindication for smoking of cannabis Are abusing illegal drugs. Are not able to give adequate informed consent. Are not able to attend face-to-face visits or those who plan to move out of the area within the treatment period. Are pregnant or nursing, or if a woman who can have children, those who are not practicing an effective means of birth control.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High THC cannabis<br>Provided up to 1.8 g of cannabis per day with more tetrahydrocannabinol than cannabidiol | Drug: High THC cannabis<br>* Three weeks of smoking cannabis containing more THC than CBD with amount smoked limited to no more than 1.8 g per day.<br>* Other names: Tetrahydrocannabinol;|
| Experimental: High CBD cannabis<br>Provided up to 1.8 g of cannabis per day of marijuana with more cannabidiol than tetrahydrocannabinol | Drug: High CBD cannabis<br>* Three weeks of smoking cannabis containing more CBD than THC with amount smoked limited to no more than 1.8 g per day.<br>* Other names: Cannabidiol;|
| Experimental: THC/CBD cannabis<br>Provided up to 1.8 g of cannabis per day with an approximately equal amount of tetrahydrocannabinol and cannabidiol | Drug: THC/CBD cannabis<br>* Three weeks of smoking cannabis containing equal amounts of THC and CBD with smoking limited to no more than 1.8 g per day.<br>* Other names: Cannabidiol;|
| Placebo Comparator: Placebo cannabis<br>Provided 1.8 g of cannabis per day with very low levels of tetrahydrocannabinol and cannabidiol | Drug: Placebo cannabis<br>* Three weeks of smoking cannabis with low levels of THC and CBD with smoking limited to no more than 1.8 per day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline CAPS-5 Total Severity Score | The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-5. It contains symptom subscales, a CAPS-5 total severity score, and a diagnostic score. The total severity score is a sum of symptom frequency and intensity scores for the subscales B (re-experiencing), C (avoidance), and D (hypervigilance), and ranges from 0 to 136, with higher scores indicating greater severity of PTSD symptoms. | Baseline (3 weeks after randomization) | 
| Stage 1 Primary Endpoint CAPS-5 Total Severity Scores (Visit 5) | The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-5. It contains symptom subscales, a CAPS-5 total severity score, and a diagnostic score. The total severity score is a sum of symptom frequency and intensity scores for the subscales B (re-experiencing), C (avoidance), and D (hypervigilance); and ranges from 0 to 136, with higher scores indicating greater severity of PTSD symptoms. | Visit 5 (between end of week 3 and start of week 4) of Stage 1 | 
| Change in CAPS-5 Total Severity Scores From Baseline to Stage 1 Primary Endpoint (Visit 5) | The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) is a clinician administered and scored assessment of PTSD symptoms via structured interview based upon PTSD diagnosis in DSM-5. It contains symptom subscales, a CAPS-5 total severity score, and a diagnostic score. The total severity score is a sum of symptom frequency and intensity scores for the subscales B (re-experiencing), C (avoidance), and D (hypervigilance); and ranges from 0 to 136, with higher scores indicating greater severity of PTSD symptoms. | Baseline (3 weeks after randomization) to Primary Endpoint (Visit 5, between end of week 3 and start of week 4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PTSD Checklist (PCL-5) From Baseline to Stage 1 Primary Endpoint | The PTSD Checklist (PCL-5) is a 20-item self-report questionnaire in which respondents indicate the presence and severity of PTSD symptoms. Participants indicate how much distress they have experienced due to various PTSD symptoms on a five-point Likert-type scale (0=not at all, 4=extremely). The total PCL-5 score (a sum of all 20 items) ranges from 0 to 80, with higher scores indicating greater symptom severity. | Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation) | 
| Change in Inventory of Depression and Anxiety (IDAS) Social Anxiety Total Scores From Baseline to Stage 1 Primary Endpoint | The Inventory of Depression and Anxiety (IDAS) is a 64-item self-report measure of non-overlapping scales that assess specific depression and anxiety symptoms. Respondents indicate on a scale of 1 (not at all) to 5 (extremely) how much they have felt or experienced several symptoms in the past two weeks. The IDAS consists of 10 symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. Items that assess social anxiety are summed and range from 5 to 25 with higher scores indicating greater anxiety symptoms. | Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation) | 
| Change in Inventory of Psychosocial Functioning (IPF) From Baseline to Stage 1 Primary Endpoint | The Inventory of Psychosocial Functioning (IPF) is an 80-item measure that was developed for use among individuals with PTSD. It assesses current psychosocial functioning across seven domains: romantic relationships, family, work, friendships, parenting, education, and self-care. Items are scored on a 0 (never) to 6 (always) scale. Summation of scores across domains yields a total score for psychosocial functioning, with higher scores indicating greater functional impairment. | Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation) | 
| Change in Inventory of Depression and Anxiety (IDAS) General Depression Total Scores From Baseline to Stage 1 Primary Endpoint | The Inventory of Depression and Anxiety (IDAS) is a 64-item self-report measure of non-overlapping scales that assess specific depression and anxiety symptoms. Respondents indicate on a scale of 1 (not at all) to 5 (extremely) how much they have felt or experienced several symptoms in the past two weeks. The IDAS consists of 10 symptom scales: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. Items that assess general depression are summed and range from 20 to 100 with higher scores indicating greater depressive symptoms. | Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation) | 
| Change in Insomnia Severity Index (ISI) Scores From Baseline to Stage 1 Primary Endpoint | The Insomnia Severity Index (ISI) is a brief self-reported measure of insomnia. It consists of seven questions, with responses made on a five-point Likert scale. Three items address difficulty at sleep onset, maintaining sleep, and early waking, and four questions address perceived quality of sleep and effects of sleep difficulties on daily function. Questions are summed into a total score that ranges from 0 to 28 and can be interpreted as ranging from no signs of insomnia to severe insomnia. Higher scores indicate more severe insomnia. | Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTSD, marijuana, cannabis, sleep, THC, CBD