Study of Four Different Potencies of Smoked Marijuana in 76 Veterans With PTSD

Posttraumatic Stress Disorder (PTSD), characterized by an inability to recover from a stress
reaction to a traumatic event, is a widely prevalent disorder within the U.S. and across the
world. Currently, several psychotherapies are empirically-supported for the treatment of
PTSD. However, because of treatment refusal due to treatment type, non-response, and dropout,
many individuals continue to experience severe symptoms and meet criteria for PTSD following
treatment.

Emerging observational and early clinical evidence suggest that cannabis (marijuana) 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 PTSD of at least six
months' duration. Participants will be recruited from one study site, the Scottsdale Research
Institute (Phoenix, AZ).

After giving written informed consent, participants will undergo screening for initial
eligibility. Potential participants will be required to stop using non-study medical cannabis
for two weeks during screening, and for the duration of the study if enrolled. After the
two-week washout, a blinded independent rater will administer the Clinician-Administered PTSD
Scale (CAPS-5) to assess presence and severity of PTSD symptoms. Self-report measures will
also be completed. Eligible participants will then be enrolled and randomized. In the active
portion of the study, participants will receive two of four different types of cannabis
during two stages (Stage 1 and Stage 2), each lasting three weeks, with crossover and
re-randomization at Stage 2. Prior to each stage, participants will complete two introductory
sessions where they will be trained on cannabis self-administration. During each stage,
participants will be provided 1.8 grams of cannabis daily to smoke ad libitum. Each stage
will be followed by a two-week cessation. To reduce the risk of diversion, after the second
cessation period, participants will have the option to complete a third stage of the study
where they can request the remaining unused cannabis from either Stage 1 or 2.

Study outcomes will be assessed objectively, behaviorally, via self-report, and by a
third-party rater. Specifically, blood and urine will be collected to confirm cannabis use
status throughout the study, participants will be required to video record
self-administration of cannabis, and any unused cannabis from each weekly allotment will be
returned to the investigator or designee to be weighed and accounted for prior to dispensing
of the next weekly supply. Sleep will be measured via self-report and tracked with
actigraphy, clinical interviews will be conducted by blinded independent raters will provide
an independent rating of participant behavior.

Participant suicidal ideation will be assessed weekly with the C-SSRS, and daily if results
indicate development of suicidal ideation. Weekly evaluations will include measures of
symptoms of PTSD, depression, anxiety, sleep quality, general functioning, and responses to
cannabis. During each evaluation, actigraph data will also be downloaded and a urine-dip EtG
test will be performed. Analysis of blood/urine cannabinoids will be conducted after
cessation periods, in addition to weekly urine drug screening for substances other than
cannabis. At Baseline and end of Stage 1, Cessation 1 and end of Stage 2, additional blood
samples will be collected for analysis of inflammation markers. At the end of Stage 1 and 2,
endpoint measures will be administered; an independent rater will evaluate symptoms of PTSD
on the CAPS-5 via telemedicine, and self-reported symptoms of anxiety, depression,
withdrawal, sleep quality, and psychosocial functioning will be assessed.

Inclusion Criteria:

- Have 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 marijuana provided by site staff and agree to required cessation
periods for the duration of the study.

- Report no current hazardous marijuana use and completely abstain from marijuana during
the 2-week baseline assessment period (verified via urine and/or blood cannabinoid
concentrations).

- Agree to video record all marijuana administrations and provide video to the site
staff for review during study participation.

- Agree to keep all marijuana provided by site staff securely stored in the provided
lock box and not to share/distribute marijuana 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 marijuana or contraindication for smoking of marijuana.

- 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;