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

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)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02759185

Enrollment

Registered

2016-05-03

Start date

2017-01-02

Completion date

2019-01-31

Last updated

2023-07-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Posttraumatic Stress Disorder

Keywords

PTSD, marijuana, cannabis, sleep, THC, CBD

Brief summary

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

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.

Interventions

DRUGHigh THC cannabis

Three weeks of smoking cannabis containing more THC than CBD with amount smoked limited to no more than 1.8 g per day.

DRUGHigh CBD cannabis

Three weeks of smoking cannabis containing more CBD than THC with amount smoked limited to no more than 1.8 g per day.

DRUGTHC/CBD cannabis

Three weeks of smoking cannabis containing equal amounts of THC and CBD with smoking limited to no more than 1.8 g per day.

DRUGPlacebo cannabis

Three weeks of smoking cannabis with low levels of THC and CBD with smoking limited to no more than 1.8 per day.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Change in CAPS-5 Total Severity Scores From Baseline to Stage 1 Primary Endpoint (Visit 5)	Baseline (3 weeks after randomization) to Primary Endpoint (Visit 5, between end of week 3 and start of week 4)	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 CAPS-5 Total Severity Score	Baseline (3 weeks after randomization)	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.
Stage 1 Primary Endpoint CAPS-5 Total Severity Scores (Visit 5)	Visit 5 (between end of week 3 and start of week 4) of Stage 1	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.

Secondary

Measure	Time frame	Description
Change in Inventory of Psychosocial Functioning (IPF) From Baseline to Stage 1 Primary Endpoint	Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation)	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.
Change in Insomnia Severity Index (ISI) Scores From Baseline to Stage 1 Primary Endpoint	Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation)	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.
Change in Inventory of Depression and Anxiety (IDAS) General Depression Total Scores From Baseline to Stage 1 Primary Endpoint	Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation)	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.
Change in PTSD Checklist (PCL-5) From Baseline to Stage 1 Primary Endpoint	Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation)	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.
Change in Inventory of Depression and Anxiety (IDAS) Social Anxiety Total Scores From Baseline to Stage 1 Primary Endpoint	Baseline (3 weeks after randomization) to Stage 1 Primary Endpoint (Visit 6, 3 weeks post self-administration and prior to cessation)	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.

Other

Measure	Time frame	Description
Actigraph Change in Sleep Efficiency	Change in sleep efficiency from baseline to end of 4-week treatment period (visit 6)	Daily sleep measures were collected using the Actigraph Watch at baseline and throughout the study period. Data were processed using the Actigraph Software according to the User Manual to measure sleep efficiency, which is defined as the proportion of the estimated sleep periods spent asleep. Change in sleep efficiency was calculated and compared across the four treatment groups to assess whether there was any improvement or worsening in sleep efficiency before and after the 4-week treatment period. Other measures included number of days data were collected and average duration in minutes of time that were excluded and not recorded. Daily data were aggregated to analyze participants' average weekly sleep patterns.

Countries

United States

Participant flow

Recruitment details

Participants were recruited via letters of referral sent to psychiatrists and psychotherapists, contact with veterans' organizations, advertisements or announcements placed in appropriate locations or on appropriate internet sites and the sponsor site, and word of mouth.

Pre-assignment details

For Stage 2, participants were re-randomized into one of three treatment groups which excluded placebo and their Stage 1 treatment assignment.

Participants by arm

Arm	Count
High THC Cannabis Provided up to 1.8 g of cannabis per day with more tetrahydrocannabinol than cannabidiol High THC cannabis: Three weeks of smoking cannabis containing more THC than CBD, with amount smoked limited to no more than 1.8 g per day.	20
High CBD Cannabis Provided up to 1.8 g of cannabis per day of marijuana with more cannabidiol than tetrahydrocannabinol High CBD cannabis: Three weeks of smoking cannabis containing more CBD than THC, with amount smoked limited to no more than 1.8 g per day.	20
High THC/ High CBD Cannabis Provided up to 1.8 g of cannabis per day with an approximately equal amount of tetrahydrocannabinol and cannabidiol High THC/high CBD cannabis: Three weeks of smoking cannabis containing equal amounts of THC and CBD, with smoking limited to no more than 1.8 g per day.	20
Placebo Cannabis Provided 1.8 g of cannabis per day a with very low levels of tetrahydrocannabinol and cannabidiol Placebo cannabis: Three weeks of smoking cannabis with low levels of THC and CBD, with smoking limited to no more than 1.8 per day.	20
Total	80

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG004	FG005	FG006
Stage 1	Adverse Event	0	1	3	0	0	0
Stage 1	Withdrawal by Subject	1	0	0	0	0	0
Stage 2	Adverse Event	0	0	0	1	2	0
Stage 2	Withdrawal by Subject	0	0	0	1	1	1

Baseline characteristics

Characteristic	Total	Placebo Cannabis	High THC/ High CBD Cannabis	High THC Cannabis	High CBD Cannabis
Age, Continuous	44.9 years STANDARD_DEVIATION 13.4	43.7 years STANDARD_DEVIATION 12.5	50.6 years STANDARD_DEVIATION 13.3	45.0 years STANDARD_DEVIATION 16.6	40.4 years STANDARD_DEVIATION 11.2
Body mass index (BMI)	31.9 kg/m^2 STANDARD_DEVIATION 7.4	33.1 kg/m^2 STANDARD_DEVIATION 7	31.4 kg/m^2 STANDARD_DEVIATION 7.4	32.0 kg/m^2 STANDARD_DEVIATION 8.9	31.3 kg/m^2 STANDARD_DEVIATION 6.6
Cannabis Use Disorders Identification Test-Revised (CUDIT-R)	2.6 score on a scale STANDARD_DEVIATION 2.8	1.7 score on a scale STANDARD_DEVIATION 2.6	2.4 score on a scale STANDARD_DEVIATION 2.8	3.9 score on a scale STANDARD_DEVIATION 3	2.5 score on a scale STANDARD_DEVIATION 2.8
Combat-related trauma (yes)	54 Participants	13 Participants	15 Participants	13 Participants	13 Participants
Education College Graduate	32 Participants	7 Participants	11 Participants	7 Participants	7 Participants
Education High School Graduate	6 Participants	2 Participants	1 Participants	0 Participants	3 Participants
Education Some College/Associate's Degree	42 Participants	11 Participants	8 Participants	13 Participants	10 Participants
Race/Ethnicity, Customized Race/Ethnicity Non-Hispanic White	53 Participants	14 Participants	14 Participants	11 Participants	14 Participants
Race/Ethnicity, Customized Race/Ethnicity Other	27 Participants	6 Participants	6 Participants	9 Participants	6 Participants
Sex: Female, Male Female	8 Participants	2 Participants	3 Participants	1 Participants	2 Participants
Sex: Female, Male Male	72 Participants	18 Participants	17 Participants	19 Participants	18 Participants
Sleep Apnea (STOP-bang) High risk = 3	46 Participants	11 Participants	13 Participants	11 Participants	11 Participants
Sleep Apnea (STOP-bang) Intermediate risk = 2	12 Participants	3 Participants	3 Participants	3 Participants	3 Participants
Sleep Apnea (STOP-bang) Low risk = 1	22 Participants	6 Participants	4 Participants	6 Participants	6 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk
deaths Total, all-cause mortality	0 / 20	0 / 20	0 / 20	0 / 20	0 / 29	0 / 27	0 / 18
other Total, other adverse events	17 / 20	19 / 20	19 / 20	18 / 20	22 / 29	22 / 27	13 / 18
serious Total, serious adverse events	0 / 20	0 / 20	3 / 20	0 / 20	1 / 29	1 / 27	0 / 18

Outcome results

Primary

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.

Time frame: Baseline (3 weeks after randomization)

Population: Intent-to-treat (ITT) set

Arm	Measure	Value (MEAN)	Dispersion
High THC Cannabis	Baseline CAPS-5 Total Severity Score	36.6 score on a scale	Standard Deviation 7.2
High CBD Cannabis	Baseline CAPS-5 Total Severity Score	36.8 score on a scale	Standard Deviation 8.23
THC/CBD Cannabis	Baseline CAPS-5 Total Severity Score	38.0 score on a scale	Standard Deviation 7.8
Placebo Cannabis	Baseline CAPS-5 Total Severity Score	37.3 score on a scale	Standard Deviation 6.38

Primary

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.

Time frame: Baseline (3 weeks after randomization) to Primary Endpoint (Visit 5, between end of week 3 and start of week 4)

Population: Intent-to-treat (ITT) set

Arm	Measure	Value (MEAN)	Dispersion
High THC Cannabis	Change in CAPS-5 Total Severity Scores From Baseline to Stage 1 Primary Endpoint (Visit 5)	-15.2 score on a scale	Standard Deviation 11.03
High CBD Cannabis	Change in CAPS-5 Total Severity Scores From Baseline to Stage 1 Primary Endpoint (Visit 5)	-8.4 score on a scale	Standard Deviation 10.09
THC/CBD Cannabis	Change in CAPS-5 Total Severity Scores From Baseline to Stage 1 Primary Endpoint (Visit 5)	-8.5 score on a scale	Standard Deviation 9.88
Placebo Cannabis	Change in CAPS-5 Total Severity Scores From Baseline to Stage 1 Primary Endpoint (Visit 5)	-13.1 score on a scale	Standard Deviation 12.1

Primary

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.

Time frame: Visit 5 (between end of week 3 and start of week 4) of Stage 1

Population: Intent-to-treat (ITT) set

Arm	Measure	Value (MEAN)	Dispersion
High THC Cannabis	Stage 1 Primary Endpoint CAPS-5 Total Severity Scores (Visit 5)	20.5 score on a scale	Standard Deviation 8.97
High CBD Cannabis	Stage 1 Primary Endpoint CAPS-5 Total Severity Scores (Visit 5)	28.1 score on a scale	Standard Deviation 13.26
THC/CBD Cannabis	Stage 1 Primary Endpoint CAPS-5 Total Severity Scores (Visit 5)	29.6 score on a scale	Standard Deviation 12.17
Placebo Cannabis	Stage 1 Primary Endpoint CAPS-5 Total Severity Scores (Visit 5)	24.2 score on a scale	Standard Deviation 12.79

Secondary

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.