Clinical trial NCT02759185
Conditions: Posttraumatic Stress Disorder
Keywords: PTSD marijuana cannabis sleep THC CBD
Sponsor: Multidisciplinary Association for Psychedelic Studies
Start date: 2017-01-02; Completion date: 2019-01-01
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: Provided up to 1.8 g of cannabis per day with more tetrahydrocannabinol than cannabidiol arm 2: Provided up to 1.8 g of cannabis per day of marijuana with more cannabidiol than tetrahydrocannabinol arm 3: Provided up to 1.8 g of cannabis per day with an approximately equal amount of tetrahydrocannabinol and cannabidiol arm 4: Provided 1.8 g of cannabis per day with very low levels of tetrahydrocannabinol and cannabidiol
Interventions: intervention 1: High THC cannabis intervention 2: High CBD cannabis intervention 3: THC/CBD cannabis intervention 4: Placebo cannabis
Intervention descriptions: intervention 1: Three weeks of smoking cannabis containing more THC than CBD with amount smoked limited to no more than 1.8 g per day. intervention 2: Three weeks of smoking cannabis containing more CBD than THC with amount smoked limited to no more than 1.8 g per day. intervention 3: Three weeks of smoking cannabis containing equal amounts of THC and CBD with smoking limited to no more than 1.8 g per day. intervention 4: Three weeks of smoking cannabis with low levels of THC and CBD with smoking limited to no more than 1.8 per day.

Protocol documents:
ICF_002.pdf: 


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What is the purpose of this form? 
• The purpose of this form is to help you decide if you want to be in the research 
study.  It is up to you to decide if you want to take part in this study.  You should 
take part in this study only if you want to. 
• Please read it carefully and take as much time as you need.  
• Ask your study doctor or the study team to explain any words or information in 
this informed consent that you do not understand. 
• You are being asked to join a research study. This consent form explains the 
research study and your part in the study.   
• You are a volunteer.  If you join the study, you can change your mind later. You 
can decide not to take part or you can quit at any time. There will be no penalty 
or loss of benefits if you decide to quit the study.   
• During the study, we will tell you if we learn any new information that might affect 
whether you wish to continue to be in the study. 
• If you receive routine medical treatment (including medical or laboratory tests) in 
the study, information about your research study participation will be included in 
your medical record. Other doctors may not have access to this information.  You 
can ask the research team to send this information to any of your doctors. 
• Biospecimens will be collected in this study.  Biospecimens may include blood 
and urine. Most biospecimens contain DNA, which is the genetic code for each 
person. 
• A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law.  This Web site will not include information that can 
identify you.  At most, the Web site will include a summary of the results.  You 
can search this Web site at any time. 
• During this study, you will not have access to certain medical information and test 
results collected for study purposes.  If an emergency occurs while you are in the 
study, medical information needed for your treatment can be made available to 
your study physician and other physicians who treat you.  When the study is 
completed, all the information in your medical record will be available to you. 
• After reading this form and talking with the study staff, you should know which 
parts of the study are medical care and which are experimental.  Please ask any 
questions you have. 
• You may talk with your family, friends, and your doctor to help you make your 
decision.  You can take as much time as you like to make this decision. 
• The sponsor is paying for this research study.  Your study doctor will be paid by 
the sponsor. 
 
Why is this research being done? 
This research is being done to find out if marijuana will reduce nightmares and other 
posttraumatic stress disorder (PTSD) symptoms in people with PTSD.  You are being 
asked to take part in this research study because you are a military veteran and you 
have been diagnosed with PTSD from your military service and because your 
symptoms have not gone away after psychotherapy or medicines. 
 


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The use of marijuana in this research study is investigational. The word “investigational” 
means that marijuana is not approved for marketing by the Food and Drug 
Administration (FDA).  The FDA is allowing the use of marijuana in this study. Marijuana 
is also a controlled substance, meaning that it is still illegal at the federal level to use 
outside of research. This small (“pilot”) study was created to see if one of four different 
strengths (potencies) of marijuana are safe and helpful for people with PTSD. 
 
The study is sponsored by a U.S.-based non-profit organization called the 
Multidisciplinary Association for Psychedelic Studies (MAPS, www.maps.org). This 
organization funds research that studies the possible medical uses of psychedelic 
(hallucinogenic) drugs like MDMA and marijuana.  
 
Marijuana or marijuana-based products have been and are used for state-regulated 
medical and recreational reasons in and outside of the U.S. In states that allow medical 
use of marijuana it is most often used by people suffering from insomnia, anxiety, and 
pain. People with PTSD can have trouble sleeping and relaxing and some report that 
use of marijuana helps reduce these symptoms. So far though, there have been no 
scientific studies looking at marijuana as a way of helping people with PTSD deal with 
nightmares, anxiety, and sleep difficulties. This research is being done to find out if 
marijuana will reduce nightmares and other PTSD symptoms in people with PTSD. 
 
People with PTSD from being in the military may join the study if they meet all of the 
requirements to be in the study.  Additional study requirements are that you must be 
available for study visits, you must agree to follow the rules of study participation, and 
must not be pregnant or become pregnant.  There are more criteria you must meet and 
your study doctor will talk to you about those. 
 
How many people will be in this study? 
Up to 232 people will be enrolled in the study at 
 to ensure 
76 participants complete the study through Visit 5.  
 
What are the study procedures?  
If you agree to be in this study, you will sign this form before any study procedures are 
done. 
 
If you agree to be in this study, we will ask you to do the following things: 
 
Talk with your study doctor before starting any new medicine.  This includes drugs you 
buy at the drug store and herbal or dietary supplements (vitamins). Some drugs could 
cause serious side effects if taken with the study drug. 
 
Please ask your study doctor if you have any questions about the medicine(s) you are 
taking.  He/she will tell you which medicine you cannot take during the study. 
 
 
 


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Study Overview 
You will be in the study for up to 18 weeks and then you will have a visit approximately 
15 weeks after that as a part of the long term follow up.  
 
The study has three parts: Stage 1 (where one type of marijuana is smoked for three 
weeks), Stage 2 (where a different type of marijuana is smoked for three weeks), and 
an optional Stage 3 (where you may smoke a fresh supply of marijuana in the same 
amount as your left over marijuana from Stage 1 or Stage 2 over two months or less).  
 
If you smoke, vape or use any form of marijuana now for non-medical or state-regulated 
medical reasons, you will need to stop using non-study marijuana or marijuana-based 
products for two weeks before and during the active participation part of the study. You 
may not use any other type of marijuana including THC or CBD products like, edibles, 
vape pens or topical ointments during your active participation in the study. You will also 
need to stop smoking all marijuana, including study marijuana, for two weeks after 
Stage 1 and Stage 2 (Cessation 1 and 2). 
 
During each study stage, you will meet with the study staff at least five times, for a total 
of 10 times. The study staff will also talk with you by phone daily for the first three days 
after your introductory sessions in Stage 1 and Stage 2, and weekly after that.  
 
If you choose, you may take part in the optional Stage 3 and have a fresh supply of 
marijuana in the same amount as your left over marijuana from Stage 1 or Stage 2.  In 
Stage 3 you will continue to visit the researchers weekly for up to two more months or 
until you use up the amount available based on the amount of marijuana you returned in 
Stage 1 or Stage 2.  If any marijuana remains at the end of Stage 3, it will be returned to 
the study site and destroyed as the Drug Enforcement Agency (DEA) requires. There 
will be a remote (video chat) follow-up visit that will happen 6 months after Stage 2, 
whether you choose to take part in Stage 3 or not.   
 
Screening (Evaluation and Beginning of Study) 
If you agree to be in this study, you will first sign this consent form. Before you can 
begin, the study staff must first make sure that you are eligible to be in the study and 
that you are generally physically healthy. The screening process will take about five 
hours and will involve some tests and two visits. The study staff will ask your permission 
to contact your doctor or therapist to get more information about your medical history. 
They may need to do this to know if you can be in the study. 
 
The tests during screening will include the following:  
 
• Two telemedicine (video chat) interviews one about your PTSD symptoms and 
how you deal with them in your everyday life and another to assess your 
psychiatric health.  The people asking you these questions will be different from 
the study doctor.  These interviews may be recorded for research purposes. 
• A questionnaire about your PTSD symptoms that you fill out yourself. 
• A questionnaire about feelings of anxiety and depression.  


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• A questionnaire about your sleep quality, including how well you sleep and any 
sleep problems you are having. 
• Testing of your sleep patterns using a device like a wristwatch to wear while 
sleeping or awake. You should only take this off when showering or washing 
dishes. You will need to wear this for one week before you learn if you can be in 
the study. 
• A questionnaire about daily behaviors and functioning. 
• Questions about thoughts or feelings you might have about hurting or killing 
yourself. 
• Questions about your past and any recent experience with marijuana use. 
• Questions about your medical history, therapy, and medicines you have taken.   
• Questions about the emotional and mental health history of you, your parents, 
and sisters or brothers if you have any. This may include questions about difficult 
experiences you may have had during childhood or at other times of your life.  
• A physical health examination.     
• An ECG (electrocardiogram) will also be taken, which is a recording of the 
electrical activity of your heart.   
• A sample of your blood (about 2 tablespoons) and a urine sample for routine 
laboratory testing, including tests of metabolism, thyroid, and liver function. 
Laboratory tests will also include testing for the human immunodeficiency virus 
(HIV). If tests find out that you test positive for HIV we will inform you. State law 
requires reporting this information.  If you do not want to be tested you should not 
take part in this study.  
• A simple urine drug test. If you test positive for marijuana, your blood and urine 
may be tested for marijuana using a more sensitive test. Two weeks later, the 
simple urine drug test will be repeated. If you test positive for marijuana again, 
your blood and urine may be tested for marijuana using a more sensitive test. 
Results will be kept confidential, but you may not be eligible to take part in the 
study. 
• Once you know you can be in the study, another blood sample (about 2 
tablespoons) will be needed to measure your immune function for the study. 
• A urine pregnancy test if you are able to get pregnant. You may not take part in 
the study if you are pregnant and you must agree to not become pregnant while 
you are in the study.  
• A simple urine test will be done at each face-to-face visit to assess recent alcohol 
use. 


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Table 1. Schedule of Events and Visits in Stage 1 
Visit/weeks 
Screen 
1 
Screen 2/ 
Enrollment 
2 Intro 
Visits 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
5 
 
 
 
 
 
 
 
Stop Using 
Marijuana 
Sign consent 
X 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
Blood draw 
X 
X 
 
 
 
 
 
X 
Telemedicine 
interview 
X 
X 
 
 
 
X 
 
X 
Clinic Visit 
 
X 
 
 
 
 
 
 
Questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs* 
X 
 
X 
X 
X 
X 
 
X 
Urine drug test 
X 
X 
X 
X 
X 
X 
 
X 
Urine pregnancy 
test 
X 
X 
X 
X 
X 
X 
 
X 
Urine Alcohol 
Test 
X 
X 
X 
X 
X 
X 
 
X 
Use marijuana 
 
 
X 
X 
X 
X 
 
 
Phone calls for 
3 days 
 
 
 
X 
 
 
 
 
Weekly phone 
calls 
 
 
 
 
X 
X 
X 
X 
Daily watch 
measuring sleep  
 
X 
X 
X 
X 
X 
X 
X 
Daily video 
recording 
 
 
 
X 
X 
X 
 
 
Daily Diary 
 
 
 
X 
X 
X 
 
 
Stop using 
Marijuana 
 
 
 
 
 
 
X 
X 
Receive 
marijuana 
 
 
 
X 
X 
X 
 
 
Return 
marijuana 
 
 
 
X 
X 
X 
 
 
End of Stage 1 
 
 
 
 
 
 
 
X 
 
• Vital signs = Measuring blood pressure, heart rate, oxygen in blood, and 
temperature 
 
Activities not shown on this table:  
 
These activities will be repeated in Stage 2, and some of the activities will be repeated 
in Stage 3 if you chose to participate in Stage 3. Six months after visit 12 (Week 9), you 
will complete the 6-month follow-up visit.  
 
 


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Study Marijuana 
The marijuana that will be provided to you as part of this study has been provided for 
research purposes by the National Institute on Drug Abuse (NIDA).  There are 4 different 
types of marijuana being studied.  The difference between the 4 types of marijuana has 
to do with the amount of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) 
found in each type.  At different times during the study, you will be provided with 
marijuana to smoke in the laboratory and at home.  
 
This study is triple-blind, meaning that you, the study doctors, and the researchers who 
give you your tests won’t know which type of marijuana you will get. The type of 
marijuana that you get will be decided at random, as in pulling numbers from a hat. Each 
person in Stage 1 has a 25% chance of getting one of the four strengths of marijuana. 
One of the types of marijuana used will have very low levels of both THC and CBD, and 
is considered a “placebo,” which means it looks and smells like the other types of 
marijuana but is missing some of the chemicals known to produce marijuana intoxication. 
When you start Stage 2, you will switch groups and get one of two different strengths of 
marijuana, as in flipping a coin, with a 50% chance of getting one.  The study staff will 
find out what type of marijuana you got for Stage 1 and Stage 2 once the entire study 
(not just your participation) is complete. The study staff can also let you know at that time 
if you are interested in finding out. 
 
The marijuana provided to you as part of this study is an investigational drug intended 
solely for your use as directed in the instructions outlined in this form and by the study 
staff.  You must agree not to share, give away, sell, or otherwise divert the marijuana 
given to you in any way.  You must also agree not to smoke or otherwise consume 
marijuana in public.  Failure to follow these rules will result in immediate removal from 
the study and possible prosecution by law enforcement.  
 
Stage 1 
 
Beginning of study 
Once you are in the study, you will need to tell the study staff about any changes in 
medications or therapies you are receiving during the study. You will need to give the 
study staff the name of a person to reach in case of emergency and how best to reach 
them (such as a telephone number). You will also be asked to give the name of a 
support person you know well and who you see almost every day who will be able to 
verify how you use the marijuana from the study and that you are not using non-study 
marijuana, as well as any changes in your mood or how you act. These questions mostly 
focus on your daily routine and social interactions with others. The study team will call 
this person each week.  Your emergency contact and support person can be the same 
individual if you think that is best. 
 
You will have two introductory marijuana smoking sessions that will last about four hours. 
At the beginning of the first introductory session, you will smoke at least one puff of 
marijuana through a pipe that will be given to you for use during the study (or more if you 
choose).  At the beginning of the second introductory session, you will be given a fixed 


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amount of marijuana and be allowed to select your own “dose” of marijuana to smoke 
using the same pipe.  
During introductory sessions, the study staff will:  
 
• Tell you more about marijuana, including what to expect when you smoke it. 
They will show you how to smoke marijuana using a pipe, even if you have done 
this before. This is to make sure you know how to use marijuana and so people 
in the study all smoke it the same way.  
• Watch you while you smoke marijuana, and they will watch how you feel and 
learn what you experience after using marijuana. They will also give you 
information on how to deal with any side effects such as anxiety that you may 
experience. 
• Measure your pulse and how much oxygen is in your blood using a small device 
that fits on your finger. This will be done before, right after, and every 30 minutes 
after you smoke.  
• Lend you a portable tablet computer to answer questions about how you feel 
• At the end of the second introductory session, you will be provided with a tablet 
computer and instructions on how to use it during the study.  You will use the 
video camera in the tablet to record your use of study marijuana at home.  You 
will save these recordings and when you meet with the study staff, they will copy 
and watch the recordings. You will also use the portable tablet to fill out a daily 
diary about your experience with smoking marijuana. You will also receive a one-
week supply of marijuana to take home with you.  The marijuana will be divided 
into separate containers, one for each day between that day and your next 
scheduled appointment.  The containers will be placed in a lockable storage box 
with a combination lock to keep your study marijuana safe and to prevent other 
people from accessing it. 
• You will need a ride back to your home or wherever you were staying after each 
of the introductory sessions. If you cannot find a ride, then we will help you 
arrange for a taxi service.  
 
Smoking Marijuana at Home 
After the introductory sessions, you will be provided 1.8 grams of marijuana to smoke 
each day for the rest of the week. You will return to the study clinic each week to get a 
supply for the next week for the remaining two weeks of Stage 1. Each day, it will be up 
to you if you decide if you want to smoke marijuana and how much you smoke, up to 
1.8 grams per day.  You must agree to keep the study marijuana stored in the lockable 
box provided to you. You will need to record any use of the study marijuana with the 
camera on your tablet as instructed.  You will need to return any leftover marijuana from 
the supply to the study staff at the end of the week. Study staff will weigh any unused 
marijuana, and if you want to have that amount back, the study staff will give that 
amount to you from a fresh supply after Stage 2 of the study if you choose to take part 
in Stage 3 (details below).  
 


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For the first week, the study staff will call you on the phone for 3 days to check in on 
how you are doing. These calls may take between five and fifteen minutes. After the first 
week, the study staff will call you once a week to check in on how you are doing.  
 
You will complete a daily diary entry on your tablet. You will record how much marijuana 
you used, how often you used it, and when you used it. You will record the use of any 
medications you use and how you are feeling. You will complete an electronic 
questionnaire on how smoking marijuana in this study makes you feel each time you 
use marijuana. 
 
You will return to the study site to meet with the study staff each week for all of Stage 1.  
 
During each visit for the first three weeks, you will: 
 
• Bring your tablet for the study staff to review the videos of you smoking. 
• Bring your sleep watch for the study staff to download the data, charge it, and 
return it to you. 
• Have a simple urine drug test and if you are female, a pregnancy test. 
• Have a simple urine drug test to assess your recent alcohol consumption. 
• Have your blood pressure, heart rate (pulse), and body temperature measured. 
• The study staff will ask you about your health and medications you are taking. 
• Complete questionnaires on your PTSD symptoms, feelings of depression, and 
other symptoms you might have, your experience with marijuana use, and on 
thoughts you might have of hurting or killing yourself.  
• Return any leftover marijuana from the past week in your lockable box. The study 
staff will give you another one-week supply if you have followed instructions for 
the study. 
 
At the end of three weeks of smoking marijuana, a researcher will ask you questions 
about your PTSD symptoms by video chat.  When you have finished the three weeks of 
smoking marijuana, you will go back to the study site to return any leftover marijuana. 
You will need to bring your lockable box with the marijuana in it, your tablet, and sleep 
device. You will also answer the same questionnaires on your PTSD symptoms, 
feelings of anxiety, depression, sleep quality, other symptoms you are experiencing, 
and thoughts or feelings of hurting yourself. You will give a blood sample (about 2 
tablespoons) for a blood test for immune system function. The study staff will give you a 
urine drug test and a pregnancy test (if you are female), recent alcohol consumption 
urine test and measure your blood pressure, heart rate, and body temperature.  
 
Cessation 1 (Stopping Marijuana Use)  
After using the study marijuana for three weeks, you will be asked to not use any 
marijuana for two weeks. This is called a washout period.  You will continue to get 
phone calls from the study staff once a week during these two weeks. After one week, 
you will answer questionnaires about your PTSD symptoms, feelings of depression and 
anxiety, other symptoms you might have, experiences with marijuana use, sleep quality, 
and thoughts or feelings about hurting or killing yourself.  


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At the end of the two weeks, you will return to the study site to give a blood sample (about 
4 tablespoons) for a blood test for marijuana-related chemicals and immune system 
function, a urine drug test, recent alcohol consumption urine test and the study staff will 
measure your blood pressure, heart rate, and body temperature. A researcher will ask you 
questions about your PTSD symptoms on video chat, and you will complete the 
questionnaires on your PTSD symptoms, symptoms of depression and anxiety, sleep 
quality, other symptoms you might have, and thoughts of hurting or killing yourself. You will 
continue to record medications you take and how you feel in your electronic daily diary. 
 
Stage 2 
Stage 2 of the study is almost exactly like Stage 1, except that during Stage 2 you will be 
given a different type of marijuana to smoke than what was given to you in Stage 1. You 
will have two more four-hour long introductory sessions with the study staff so you can gain 
experience with this new type of marijuana.  In the first of these sessions you will be asked 
to smoke at least one puff of marijuana from your pipe (or more if you choose) and in the 
2nd session you will be able to determine your own dose.  After smoking, we will measure 
your heart rate and blood oxygen levels and ask you questions about how you feel.  You 
will again need to arrange a ride home from the study site.  
 
After completing the 2 introductory sessions, you will be provided marijuana to take home, 
in the same way as you did in Stage 1.  As in Stage 1, the marijuana will be provided in 
containers with a supply for each day, you will need to record your use and the daily diaries 
on the tablet computer, and come in to the study site to return unused marijuana, receive a 
new supply, and to complete study tests and questionnaires once each week as you did in 
Stage 1.  
 
Cessation 2 (Stopping marijuana use) 
After using the study marijuana for three weeks in Stage 2, you will be required to not use 
any marijuana for another 2-week washout period.  You will continue to get phone calls 
from the study staff once a week during these two weeks. After one week, you will answer 
questionnaires on your PTSD symptoms, feelings of depression and anxiety, other 
symptoms you might have, experiences with marijuana use, sleep quality, and thoughts or 
feelings about hurting or killing yourself. You will continue to record medications you take 
and how you feel in your electronic daily diary. 
 
At the end of the two weeks, you will return to the study site to give a blood sample (about 
4 tablespoons) for a blood test for marijuana-related chemicals and immune system 
function, a urine drug test, recent alcohol consumption urine test and the study staff will 
measure your blood pressure, heart rate, and body temperature. A researcher will ask you 
questions about your PTSD symptoms on video chat, and you will complete the 
questionnaires on your PTSD symptoms, symptoms of depression and anxiety, sleep 
quality, other symptoms you might have, and thoughts of hurting or killing yourself. At the 
end of Cessation 2, you will give your sleep device back to study staff.  
 
At the end of Cessation 2, or after Stage 3 if you choose to participate in it, the study staff 
will give you a memory aid card. This card is to help you to remember any new medical 
problems, including mental health or changes in medication during the months between this 


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visit and the 6-month follow-up visit. You will record any new important health problems, 
changes to your mental health, hospitalizations and medications to treat these problems on 
this memory aid card.  
 
Stage 3 
Stage 3 is an optional study period that will allow you to use the amount of your 
returned marijuana from Stage 1 or Stage 2. If you choose to participate in Stage 3, you 
will continue to smoke marijuana until the amount returned from Stage 1 or Stage 2 runs 
out, you decide to stop participation, or until two months have passed. The marijuana 
dispensed in Stage 3 will be from a fresh supply in the amount of the type and weight of 
your returned marijuana from Stage 1 and Stage 2.  You still may only use up to 1.8 
grams of marijuana per day. During this time, you will still video record yourself smoking 
marijuana and continue to come to the study site for weekly visits when the study staff 
will check on your health. You will continue to record medications you take and how you 
feel in your electronic Daily Diary. 
 
Each week, you will have your urine drug tested and you will also have a pregnancy test 
weekly if you are able to become pregnant. You will have your blood pressure, heart 
rate, and body temperature measured by the study staff. The study staff will continue to 
call your support person to ask about your marijuana use and any changes in your 
mood or how you act. You will bring your handheld tablet with your video data, and any 
remaining marijuana from the last week’s supply in the lockable box. The study staff will 
weigh your left over marijuana and will give you more marijuana for the next week if you 
follow study instructions, until the amount returned in Stage 1 or Stage 2 is used.  At the 
end of Stage 3, you will need to return the handheld tablet and lockable box back to the 
study staff.  
 
6-Month Follow-Up 
Six months after your last Stage 2 visit, you will have a video meeting with the study 
staff.  
 
One week before this visit, you will receive the sleep device in the mail. You will need to 
wear the sleep device for one week like you did before, and then mail it back to the 
study staff. During the video meeting, you will be asked about your PTSD symptoms 
again and you will fill out questionnaires about your PTSD symptoms, feelings of 
anxiety, depression, other symptoms you may have, daily functioning, and sleep quality. 
You will have a urine drug test at a local drug testing facility. You will also answer 
questions about your health and any new types of treatment or medications you have 
had between the end of the marijuana smoking period and the follow-up. 
 
How long will you be in the study? 
This study lasts about eight and a half months.  There are at least 10 weeks of active 
participation (main study) with a follow-up by phone or video chat six months later. The 
study has three parts: Stage 1 (where one type of marijuana is smoked for three 
weeks), Stage 2 (where a different type of marijuana is smoked for three weeks), and 
an optional Stage 3 (where you may smoke the amount of leftover marijuana from 
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medical or state-regulated medical reasons, you will need to stop using non-study 
marijuana or marijuana-based products for two weeks before and during the active 
participation part of the study. You will also need to stop smoking all marijuana, 
including study marijuana, for two weeks after Stage 1 and Stage 2 (Cessation 1 and 2). 
 
During each study stage, you will meet with the study staff at least five times, for a total 
of 10 times. The study staff will also talk with you by phone each day for 3 days during 
the first week of Stage 1 and Stage 2, and weekly after that.  
 
If you choose, you may take part in the optional Stage 3 and use the leftover amount of 
marijuana from Stage 1 or Stage 2.  In Stage 3 you will continue to visit the researchers 
weekly for up to two more months or until you use up the amount of the returned 
marijuana from Stage 1 or Stage 2.  If any marijuana remains at the end of Stage 3, it 
will be returned to the study site and destroyed as the Drug Enforcement Agency (DEA) 
requires. There will be a remote (video chat) follow-up visit that will happen 6 months 
after Stage 2, whether you choose to take part in Stage 3 or not.   
 
You can call the study doctors at any time during study if you have questions or 
concerns. 
 
What are the risks or discomforts of the study? 
Your PTSD may not improve and could worsen if you take part in this study.   
 
Many scientists have studied marijuana in humans, and doctors in 28 states are allowed 
to recommend marijuana as a treatment for medical conditions. Eight states have made 
marijuana legal to use for non-medical reasons. There are few serious problems 
associated with marijuana use.  
 
Serious problems:  
Your ability to drive a motor vehicle and to operate heavy machinery may be harmed by 
use of marijuana. Some people have been in road accidents that might have been 
related to their regular marijuana use. In order to be in this study, you must agree not to 
drive a motor vehicle, operate heavy machinery, or otherwise engage in tasks that could 
result in harm to yourself or others for a minimum of three hours after your last time 
using marijuana and after you no longer feel intoxicated.  
 
People who use marijuana are at increased risk of developing mental health problems 
such as schizophrenia or other types of psychoses (seeing or hearing things that aren’t 
there, believing that other people are out to harm or “get” you) compared with people 
who do not use marijuana. Though marijuana is not believed to cause psychosis on its 
own, psychosis or psychotic symptoms seem to be more likely to happen in people who 
are already at risk of being psychotic.  If you have an immediate family member (parent 
or sibling) who has been diagnosed with schizophrenia or other type of psychosis, you 
should not participate in this study.  
 
 


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Common effects:  
Common effects of marijuana include anxiety, changes in time perception (time 
seeming faster or slower than usual), difficulty concentrating, difficulty remembering 
things, dry mouth, feeling “high” (aware of intoxicating drug effect), feeling hungry, 
changes in sensations or senses (as stronger or more intense sight or sound), feeling 
like your heart is beating fast, sedation, and feeling stimulated. Less often, some people 
may experience paranoia (belief or feeling that people are working against them 
personally, sense of being in danger from others), or have unusual thoughts. These 
effects usually only last for two to three hours after smoking.  
 
Potential for addiction:  
Marijuana, like many other drugs, has a risk of abuse or addiction. Studies have found 
that 1.6% of people asked about their marijuana use reported some level of problems 
related to their marijuana use. The rate that people become addicted to marijuana is 
slightly lower than the rate at which people become addicted to alcohol.  
 
Effects on the mind:  
Marijuana is a psychoactive drug, meaning it changes the way people view, think or feel 
about things, including the world around them or themselves. Marijuana can make 
people feel anxious or nervous, including feeling panicky. People may find it harder to 
concentrate, be attentive, and remember things when under the influence of marijuana. 
Marijuana may make people feel paranoid or have unusual thoughts. These effects 
should be gone around two to three hours after use. As stated in “Serious Problems,” 
some people can become psychotic after using marijuana.  Marijuana can also have a 
calming, euphoric, and pleasant effect. 
 
Effects on the body:  
Marijuana increases heart rate and elevates blood pressure when lying down. Higher 
doses can produce low blood pressure when standing up. Marijuana can increase the 
amount of blood pumped by the heart during a specific time interval and can decrease 
maximum exercise performance. Marijuana may reduce inflammation (swelling and 
irritation or tenderness) and suppress the immune system or parts of it. It is possible 
that marijuana could increase risk of certain types of infections. 
 
Effects of regular use:  
Regular or heavy use can interfere with logical thinking, short-term memory and 
decision making, perhaps because it changes attention, mood and memory, and the 
combined effects can make it harder to think, remember or make decisions. These 
problems can last for several weeks after people stop using marijuana regularly. 
Regular and heavy marijuana use can lead to increased likelihood of coughing, 
wheezing, producing spit, and having chronic bronchitis. It can reduce function in a type 
of immune cell in the lungs, and this might lead to increased chances of lung infection. 
Though studies found regular marijuana use is related to reduction in lung function, 
many of these studies also found it hard to separate out whether the reduced lung 
function is due to use of marijuana or use of tobacco or other smoked drugs reduced 
lung function.   


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In addition to the risks or discomforts listed here, there may be other risks that are 
currently not known. Also, the risks or discomforts described may occur more often or 
be more severe than has been seen before.   
 
Other Risks 
You should not drive or use heavy machinery for a minimum of three hours after 
smoking marijuana and not before you no longer feel intoxicated. This is because 
marijuana may cause drowsiness, lack of co-ordination or slower reaction time. Though 
the effects of marijuana on driving can be different from person to person, it may impair 
driving skills, such as response speed, attention used in driving cars and other vehicles. 
Some studies have found a relationship between higher levels of THC and road 
accidents.  
 
If you have a drug test for your workplace or for any other reason, you may test positive 
for marijuana during and for up to two months after the study ends. The study staff will 
give you an information card (research subject ID card) in case you have a drug screen 
or test.  If you are tested for drugs of abuse while you are in this study, you can have 
the person(s) testing you call the study staff to verify that you are in this study. This card 
may not protect you from discipline at work or loss of employment.  The study staff will 
discuss when and how to present the information card. The card will not prevent you 
from being stopped or cited if you are driving erratically or poorly.  
 
The interviews you have during the study involve no specific risks or discomforts 
beyond those of a normal visit to the doctor. You may feel upset during the review of 
your emotional experiences, or you may feel boredom or fatigue. Answering questions 
about thoughts you might have of hurting or killing yourself may be upsetting. You do 
not have to answer any question you do not want to answer. 
 
The medical evaluation, testing for blood cannabinoid levels and immune system 
function during the study involves blood tests. The risks of blood draws include 
temporary discomfort from the needle stick, bruising, and rarely, infection at the site of 
the needle stick. Fainting could also happen. 
 
If other people see or learn that you are using marijuana, they may think of you as a 
certain sort of person or treat you differently, as if you were doing something bad. The 
study doctors can talk about this if this idea bothers you, and they can help you develop 
plans for how to deal with other people’s judgments about your using marijuana for this 
study. 
 
There is a possibility that while the handheld tablet is still storing the recordings of your 
marijuana use, someone else other than the person you have selected to observe you 
may view the recordings. The study staff will talk to you about how to store the tablet 
safely and securely to make the chance of this happening very small. 
 
There may be side effects and discomforts that are not yet known.   
 


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What are the reproductive risks (risks related to pregnancy)? 
Regular marijuana use during pregnancy may affect a child’s birth weight and may harm 
a child’s ability to do specific tasks involving visual skills. To date there are no studies 
indicating that marijuana is associated with birth defects in humans; however, THC and 
other cannabinoids may pass into human breast milk.  For this reason, people in this 
study who are able to get pregnant need to use effective birth control and will have 
pregnancy tests during the study. You cannot be in this study if you are already 
pregnant, breast-feeding or otherwise giving a child your breast milk.  
 
Marijuana used during this research may hurt an embryo or fetus in ways we do not 
currently know.  
 
Are there benefits to being in this study? 
There is no guarantee that you will benefit from taking part in this research study; 
however, information obtained from this study may help doctors and researchers 
improve treatment for PTSD in future.  
 
It is possible that your PTSD symptoms will improve when you take part in this study.  
 
Will it cost you anything to be in the study? 
• The procedures, tests, drugs or devices that are part of this research and that will 
be paid for by the study (no cost to you).  The sponsor of this study, 
Multidisciplinary Association for Psychedelic Studies (MAPS), will cover the costs 
that are directly related to this study. This includes the costs for all the 
psychological and laboratory testing during the study, medical examinations, 
including any extra tests you might have solely to see if you can be in the study 
(if you are eligible), and for the study drug.  
• You, your private medical insurance (if any), and the public health insurance plan 
will not be charged for any procedures (examinations, tests or measures) done 
solely for the purpose of the study. You or your insurance company will remain 
responsible for on-going treatment unrelated to the study. The procedures, tests, 
drugs or devices unrelated to the study will be billed to you and/or your health 
insurer.  If you have health insurance, you will be responsible for any co-pays or 
deductibles not covered by your insurance. 
 
What are the alternatives if you do not want to be in the study? 
If you decide not to join this study, other options are available.  You do not have to join 
this study to get treatment for PTSD. One alternative to being in this study is to decide 
not to participate. You may decide to try other treatments for PTSD such as various 
forms of counseling or group therapy. The study doctor can talk to you about the 
alternatives and their possible risks and benefits with you. You do not have to join this 
study.  If you do not join, your current care will not be affected. 
 
 
 
 


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Will you be paid if you join this study? 
You will be compensated for your time and effort for completing the tasks described in 
this form. Compensation will be adjusted for visits and tasks as they are completed. If 
you complete screening visits but are not enrolled, you will receive $20.00 per screening 
visit. Table 2 describes the schedule of payments. 
 
 
Table 2. Schedule of Compensation for Time and Effort 
Study Stage 
Compensation 
Amount 
Total 
Compensation 
Stage 1 
$125.00/week 
$375.00 total 
Cessation 1 (Completion Bonus) 
$75.00/week 
$150.00 total 
Stage 2 
$125.00/week 
$375.00 total 
Cessation 2 (Completion Bonus) 
$75.00/week 
$150.00 total 
Stage 3 (optional) 
No compensation 
$0.00 total 
Long-term Follow-up (Completion Bonus) 
$50.00 
$50.00 total 
Total Possible Compensation 
--- 
$1100.00 total 
 
You may be required to provide your social security number to be paid for taking part in 
this study. Federal tax law requires that you report your research payments when you 
file your taxes. If your total payments from 
 exceed $600 
per year, the 
 will report these payments to the Internal 
Revenue Service and you will receive a 1099-MISC form from us. 
 
Can you leave the study early? 
• You can agree to be in the study now and change your mind later. 
• If you wish to stop, please tell us right away. 
• Leaving this study early will not stop you from getting regular medical care.  
 
If you leave the study early, 
 may use your health 
information that it has already collected if the information is needed for this study or any 
follow-up activities.  
 
Why might we take you out of the study early? 
You may be taken out of the study if: 
 
• Staying in the study would be harmful. 
• You need treatment not allowed in the study. 
• You fail to follow instructions. 
• You become pregnant. 
• The study is cancelled. 
• There may be other reasons to take you out of the study that we do not know at 
this time.  
 
The Sponsor, the FDA, or the IRB may decide to stop the study at any time.  
 


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How will my information be protected?  
All information that you give will be kept strictly confidential.  The information collected 
about you usually will not directly identify you (for example, by name, address, or social 
security number).  Instead, your initials and a code number will be used for your 
information.   
 
Your records may be reviewed by: 
• the study sponsor. 
• people who work with the sponsor on the study. 
• Government agencies, such as the FDA.  
• Copernicus Group Independent Review Board (IRB).  The IRB is a group of 
scientists and non-scientists who review the ethics of research. The goal of the 
IRB is to protect the rights and welfare of study subjects.  
 
These people may look at your records to make sure the study has been done the right 
way.  They also want to make sure that your health information has been collected the 
right way, or for other reasons that are allowed under the law. 
 
If information about this study is published, you will not be identified. 
 
There is a risk of loss of confidentiality in research studies. Every effort will be made to 
protect you and your health information to the extent possible.  
 
What if I am injured or get sick in the study?  What treatment costs will be paid if 
you are injured? 
Scottsdale Research Institute does not have a program to pay you if you are hurt or 
have other bad results from being in the study.  However, the study doctor can refer you 
to medical care if needed. 
 
• If you have health insurance:  The costs for any treatment or hospital care you 
receive as the direct result of a study-related injury will be billed to your health 
insurer.  If your health insurer does not pay these costs, the study sponsor, 
MAPS, has agreed to pay the usual and standard costs of this care (provided the 
costs are not the result of care required to treat your underlying disease or 
condition). Any costs that are not paid for by your health insurer or the study 
sponsor will be billed to you. 
• If you do not have health insurance:  The study sponsor, MAPS, has agreed to 
pay the usual and standard costs of treatment or hospital care you receive as a 
direct result of a study-related injury (provided the costs are not the result of care 
required to treat your underlying disease or condition). Any costs that are not 
paid for by the study sponsor will be billed to you. 
 
By signing this form, you will not give up any rights you have to seek compensation for 
injury.  
 






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SUBJECT’S STATEMENT OF CONSENT 
 
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) 
 
I consent to take part in this research study.  This study and the information in this 
consent form have been explained to me. I have read all pages of this form.  I have had 
an opportunity to ask questions and they have been answered to my satisfaction.  I 
have been told that I have not given up any legal rights.  I will receive a copy of this 
signed and dated consent form. 
 
I voluntarily agree to take part in this research study. 
 
 
__________________________________________ 
Printed Name of Subject 
 
 
__________________________________________  
_____________________ 
Signature of Subject 
 
 
 
 
 
Date 
 
The information about the study was described to the subject in language he/she 
understood. 
 
 
__________________________________________ 
Printed Name of Person Obtaining Consent  
 
 
__________________________________________  
_____________________ 
Signature of Person Obtaining Consent 
 
 
Date 


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HIPAA AUTHORIZATION 
 
We have rules to protect information about you.  Federal and state laws 
and the federal medical Privacy Rule also protect your privacy.  By signing 
this form you provide your permission, called your “authorization,” for the 
use and disclosure of information protected by the Privacy Rule. 
 
The research team working on the study will collect information about you.  
This includes things learned from the procedures described in this consent 
form.  They may also collect other information including your name, 
address, date of birth, and information from your medical records. This 
could include information about HIV and genetic testing, or treatment for 
drug or alcohol abuse or mental health problems.  All records are subject to 
subpoena by a court of law. 
 
The research team will know your identity and that you are in the research 
study. We make this information available to your doctors for your safety.   
 
We cannot do this study without your authorization to use and give out your 
information.  You do not have to give us this authorization.  If you do not, 
then you may not join this study. 
 
The study doctor and study staff will share your personal health information 
with: 
 
• the sponsor, including persons or companies working for or with the 
sponsor 
• Copernicus Group Independent Review Board  
• the U.S. Food and Drug Administration (FDA) 
• Department of Health and Human Services (DHHS) agencies 
• other regulatory agencies  
 
We will use and disclose your information only as described in this form 
and in our Notice of Privacy Practices; however, people outside Scottsdale 
Research Institute who receive your information may not be covered by this 
Authorization or by the federal Privacy Rule.  We try to make sure that 
everyone who needs to see your information keeps it confidential – but we 
cannot guarantee that your information will not be re-disclosed. 
 


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The use and disclosure of your information has no time limit. You may 
revoke (cancel) your permission to use and disclose your information at 
any time by notifying the Principal Investigator of this study by phone or in 
writing.  If you contact the Principal Investigator by phone, you must follow-
up with a written request that includes the study number and your contact 
information.  The Principal Investigator’s name, address, and phone 
information are on page one of this consent form.   
 
You have the right to check your study records and ask for changes if the 
information is not correct.  However, your access to this information may be 
delayed until the study is complete.  
 
If you do not withdraw this Authorization it will remain in effect.  If you do 
cancel your authorization to use and disclose your information, your part in 
this study will end and no further information about you will be collected. 
Your revocation (cancellation) would not affect information already 
collected in the study, or information we disclosed before you wrote to the 
Principal Investigator to cancel your authorization.  If you withdraw from the 
study but do not withdraw your Authorization, new health information may 
be collected until this study ends.   
 
Your decision to withdraw your Authorization or not to participate will not 
involve any penalty or loss of access to treatment or other benefits to which 
you are entitled.   
 
By signing this form, you allow the collection, access, use and disclosure of 
your information as described above. 
 
 
__________________________________________ 
Printed Name of Subject 
 
 
__________________________________________ 
_____________ 
Signature of Subject 
 
 
 
 
 
 
Date 
 
 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
PROTOCOL MJP-1 
 
IND #110513 
 
Original: November 5, 2010 
Amendment 1: March 9, 2011 
Amendment 2 Version 1: September 14, 2012 
Amendment 2 Version 2: October 11, 2012 
Amendment 2 Version 3: December 19, 2014 
Amendment 3 Version 1: April 7, 2015 
Amendment 3 Version 2: June 8, 2015 
Amendment 3 Version 3: August 3, 2015 
Amendment 3 Version 4: September 1, 2015 
Amendment 4 Version 1: October 13, 2015 
Amendment 5 Version 1: June 28, 2016 
 
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) 
 
SPONSOR
Multidisciplinary Association for Psychedelic 
Studies (MAPS) 
1115 Mission Street  
Santa Cruz, CA 95060 
Phone: 831-429-6362 
SPONSOR DESIGNEE
Amy Emerson 
MAPS Public Benefit Corporation (MPBC) 
Phone: 510-393-7224 
COORDINATING 
INVESTIGATOR 
Marcel O. Bonn-Miller Ph.D. 
Adjunct Assistant Professor of Psychology 
Department of Psychiatry 
University of Pennsylvania 
3440 Market Street, Suite 370  
Philadelphia, PA 19104  
Phone: 650-493-5000 ext. 27908 


 
 
 
SITE INVESTIGATORS
Site 01: Arizona 
Suzanne Sisley, M.D. 
1225 West Deer Valley Road  
Phoenix, AZ 85027  
Phone: 480-326-6023 
 
Site 02: Maryland 
Ryan Vandrey, Ph.D. 
Associate Professor 
Johns Hopkins University School of Medicine 
5510 Nathan Shock Drive 
Baltimore, MD 21224 
Phone: 414-550-4036 
 
MEDICAL MONITORS
Julie Holland 
200 East 33rd Street, Suite 16H 
New York, NY 10016 
Phone: 212-358-5808 
 
Michael C. Mithoefer, M.D. 
Assistant Clinical Professor of Psychiatry 
Medical University of South Carolina 
208 Scott Street 
Mt. Pleasant, SC 
Phone: 843-849-6899 
 
 
 


MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
Page  3 of 76 
Table of Contents 
1.0 List of Abbreviations .................................................................................................. 5 
2.0 Introduction ................................................................................................................. 7 
2.1 Protocol Purpose ....................................................................................................... 7 
2.2 Supporting Information ............................................................................................. 8 
2.2.1 Condition............................................................................................................ 8 
2.2.2 Marijuana as a Treatment for PTSD Symptoms ................................................ 9 
2.3 Rationale for Concentration Selection .................................................................... 11 
3.0 Protocol Objectives ................................................................................................... 12 
3.1 Primary Objective ................................................................................................... 12 
3.2 Secondary Objectives.............................................................................................. 12 
3.3 Safety Objectives .................................................................................................... 13 
3.4 Process Objectives .................................................................................................. 14 
4.0 Protocol Design.......................................................................................................... 14 
4.1 Planned Duration of Study ...................................................................................... 15 
4.2 Randomization and Participant Numbering ............................................................ 15 
4.3 Recruitment and Participant Population ................................................................. 16 
4.3.1 Inclusion Criteria ............................................................................................. 17 
4.3.2 Exclusion Criteria ............................................................................................ 18 
5.0 Methods ...................................................................................................................... 19 
5.1 Assessments and Measures ..................................................................................... 19 
5.1.1 Outcome Measures........................................................................................... 19 
5.1.2 Safety Measures ............................................................................................... 21 
5.1.3 Process Measures ............................................................................................. 23 
5.2 Study Procedures and Visit Descriptions ................................................................ 28 
5.2.1 Pre-screening.................................................................................................... 28 
5.2.2 Screen 1 ............................................................................................................ 28 
5.2.3 Screen 2  ........................................................................................................... 30 
5.2.4 Enrollment........................................................................................................ 30 
5.2.5 Introductory Sessions in Stage 1 and Stage 2 .................................................. 31 
5.2.6 Daily Contact after Introductory Sessions ....................................................... 32 
5.2.7 Self Administration during Stage 1 and Stage 2 .............................................. 33 
5.2.8 Weekly Evaluations during Stage 1 and Stage 2 ............................................. 33 
5.2.9 Primary and Secondary Endpoint Evaluations in Stage 1 and Stage 2  ........... 34 
5.2.10 Two Weeks of Abstinence from Marijuana Self-Administration during 
Cessation 1 and Cessation 2 ...................................................................................... 34 
5.2.11 Re-Baseline Evaluation at end of Cessation 1 and Cessation 2 ..................... 36 
5.2.12 Stage 3  ........................................................................................................... 36 
5.2.13 Long-term Follow-up ..................................................................................... 37 
5.3 Removal of Enrolled Participants from the Study .................................................. 38 
5.4 Premature Discontinuation of the Study ................................................................. 38 
6.0 Investigational Product ............................................................................................ 39 
6.1 Substance Description and Activity Related to Proposed Action ........................... 39 
6.2 Substance Concentrations, Packaging and Labeling .............................................. 40 
6.2.1 Doses ................................................................................................................ 40 
6.2.2 Packaging ......................................................................................................... 41 


MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
Page  4 of 76 
6.2.3 Labeling ........................................................................................................... 41 
6.3 Substance Accountability........................................................................................ 42 
6.4 Substance Storage and Handling ............................................................................ 42 
6.5 Substance Stability .................................................................................................. 42 
7.0 Risks of Participation ............................................................................................... 42 
7.1 Risks of Screening, Study Procedures, Assessments and Measures ....................... 42 
7.2 Risks of Self-administering Marijuana ................................................................... 43 
7.3 Risk Mitigation ....................................................................................................... 47 
7.4 Medical Emergencies .............................................................................................. 50 
8.0 Adverse Events .......................................................................................................... 51 
8.1 Spontaneously Reported Reactions......................................................................... 52 
8.2 Serious Adverse Events .......................................................................................... 53 
8.3 Adverse Event Collection ....................................................................................... 54 
8.4 Adverse Event Reporting ........................................................................................ 54 
9.0 Collection of Concomitant Medications and Therapies ........................................ 56 
10.0 Laboratory Assessments ......................................................................................... 56 
10.1 Clinical Laboratory Assessments .......................................................................... 56 
10.2 Blood Cannabinoid Analysis ................................................................................ 59 
10.3 Research Lab Biomarker Analysis ........................................................................ 59 
11.0 Study Monitoring, Auditing and Documentation ................................................ 59 
12.0 Data Analysis ........................................................................................................... 60 
12.1 Statistical Power.................................................................................................... 61 
13.0 Informed Consent ................................................................................................... 62 
13.1 Confidentiality ...................................................................................................... 62 
13.2 Costs to Participants and Compensation ............................................................... 63 
13.3 Treatment and Compensation for Study Related Injury ....................................... 64 
14.0 Record Retention .................................................................................................... 64 
15.0 Publication Policy.................................................................................................... 65 
16.0 References ................................................................................................................ 66 
 


MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  5 of 76 
1.0 List of Abbreviations 
 
ACT  
Actigraphy 
AE(s)  
Adverse Event(s) 
ALT/SGPT 
Alanine aminotransferase 
AMI   
Acute Myocardial Infarction 
AST/SGOT 
Aspartate aminotransferase 
BAI 
 
Beck Anxiety Inventory  
BDI-II  
Beck Depression Inventory II 
C 
 
Celsius 
CAP 
 
College of American Pathologists 
CAPS  
Clinician Administered PTSD Scale for DSM-5 
CBD  
Cannabidiol 
CB1 
 
Cannabinoid Receptor 1 
CB2 
 
Cannabinoid Receptor 2 
CCK  
Cholecystokinin 
CI 
 
Clinical Investigator (e.g. lead investigator, co-investigators) 
CLIA  
Clinical Laboratory Improvement Amendment 
CPT 
 
Cognitive Processing Therapy  
CRA  
Clinical Research Associate 
CRF(s) 
Case Report Form(s) 
CRP 
 
C-Reactive Protein 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CUDIT-R 
Cannabis Use Disorders Identification Test-Revised  
DBP 
 
Diastolic Blood Pressure 
DEA  
Drug Enforcement Administration 
DEQ  
Drug Experiences Questionnaire 
DMF  
Drug Master File 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – 5 
ECG/EKG 
Electrocardiogram 
EDC  
Electronic Data Capture 
EMDR  
Eye Movement Desensitization and Reprocessing  
ePRO  
Electronic Patient Reported Outcomes 
EtG 
 
Ethyl Glucuronide 
F 
 
Fahrenheit 
FDA  
Food and Drug Administration  
GABA  
Gamma-aminobutyric acid 
GCP 
 
Good Clinical Practice 
HCL  
Hydrochloric acid 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV 
 
Human Immunodeficiency Virus  
5-HT  
5-Hydroxytryptamine 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IDAS  
Inventory of Depression and Anxiety Symptoms 
IL-1β  
Interleukin-1beta  
IL-6 
 
Interleukin-6  


MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  6 of 76 
IND 
 
Investigational New Drug  
IPF 
 
Inventory of Psychosocial Functioning 
IR 
 
Independent Rater 
IRB 
 
Institutional Review Board 
IRS 
 
Internal Revenue Service 
ISF 
 
Investigator Site File 
ISI 
 
Insomnia Severity Index 
LTFU  
Long-term Follow-up 
MAOI  
Monoamine Oxidase Inhibitor 
MAPS  
Multidisciplinary Association for Psychedelic Studies  
MDMA 
3,4-methylenedioxymethamphetamine 
MI 
 
Myocardial infarction 
MWC  
Marijuana Withdrawal Checklist 
NCT  
National Clinical Trial Registry  
NIDA  
National Institute on Drug Abuse 
OEF 
 
Operation Enduring Freedom 
OIF 
 
Operation Iraqi Freedom 
PCL-5  
Posttraumatic Symptom Checklist based on DSM-5 
PE 
 
Prolonged Exposure 
PTSD  
Posttraumatic Stress Disorder 
RCT 
 
Randomized Controlled Trial 
SAE(s) 
Serious Adverse Event(s) 
SBP 
 
Systolic Blood Pressure 
SCID-RV  
Structured Clinical Interview for DSM-5 Diagnoses Research Version 
SE 
 
Sleep Efficiency 
SNRI  
Serotonin Norepinephrine Reuptake Inhibitor 
SOL 
 
Sleep Onset Latency 
SOP(s)  
Standard Operating Procedure(s) 
SSRI  
Selective Serotonin Reuptake Inhibitor  
Stage 1 
The initial, fully randomized, blinded study arm 
Stage 2 
The second, randomized, blinded study arm 
Stage 3 
The optional third study arm 
THC  
∆-9-tetrahydrocannabinol 
TLFB  
Time-Line Follow-Back 
TST 
 
Total Sleep time 
US 
 
United States of America 
VA 
 
Veterans Administration 
VAMM  
Veterans Alliance for Medical Marijuana 
WASO 
Wake After Sleep Onsent 
WBR  
Weekly Behavior Report  
WDS  
Withdrawal Discomfort Score 
 


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2.0 Introduction 
 
This study is sponsored by the Multidisciplinary Association for Psychedelic Studies 
(MAPS), a US-based, IRS-approved, 501(c)3 non-profit research and educational 
organization. MAPS sponsors clinical research evaluating the potential of psychedelics 
and marijuana to become FDA-approved generic prescription medicines. MAPS is 
currently sponsoring a series of Phase 2 pilot studies in the US and internationally for 
treatment-resistant posttraumatic stress disorder (PTSD). The ongoing Phase 2 program 
includes multiple active protocols investigating the therapeutic potential of 3,4-
methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in treating people 
with chronic, treatment-resistant PTSD. Results from two MAPS-supported studies of 
MDMA-assisted psychotherapy for PTSD have recently been published and include 
indications that the treatment can create durable improvements in PTSD symptom 
severity [1-3]. This study will continue MAPS investigation into the treatment of PTSD 
with the first randomized controlled trial (RCT) to test the therapeutic potential of 
smoked marijuana and its components as a treatment for PTSD. This study is essential for 
understanding potential risks and therapeutic benefits of marijuana for PTSD patients.  
 
MAPS is seeking to conduct the marijuana/PTSD pilot study described in this protocol in 
response to many reports of marijuana attenuating PTSD symptom expression among 
individuals with chronic, treatment-resistant PTSD, including veterans with service-
related PTSD [4]. As of December 2014, 23 states and the District of Columbia have 
medical marijuana legislation, and seven of these list PTSD as a qualifying condition for 
medical marijuana, including Arizona but not Maryland [5]. As of August 18, 2010, 633 
of a total of 2316 individuals enrolled in the New Mexico medical marijuana program 
(27%) list PTSD as the primary condition they seek to treat with medical marijuana [6], 
making it the most common reason for enrollment. Similar prevalence has been observed 
in other states and among other populations, including military veterans [7, 8]. At present, 
there are no published data from randomized, placebo-controlled studies of the risks and 
benefits of marijuana for participants with chronic PTSD from any cause.  
 
In this groundbreaking randomized, triple-blind, placebo-controlled, crossover study, 
marijuana will be tested as a pharmacological agent to manage PTSD symptoms in 76 US 
military veterans. This will be the first controlled clinical trial testing the therapeutic 
potential of marijuana for treating PTSD, and is essential for understanding potential 
risks and therapeutic benefits of marijuana for PTSD patients. Results will provide 
physicians, patients, scientists and regulators with critical knowledge regarding whether 
marijuana benefits individuals with PTSD, whether adverse consequences occur, and the 
impact of the chemical composition of marijuana, specifically ∆-9-tetrahydrocannabinol 
(THC) and cannabidiol (CBD) content, on clinical outcomes.  
 
2.1 Protocol Purpose 
 
This pilot study will gather preliminary evidence of the safety and efficacy of four 
potencies of smoked marijuana to manage chronic, treatment-resistant PTSD among 
veterans. By working with chronic treatment resistant veterans, we address a national 
emergency and limit variability at the potential expense of generalizability. Further 


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research will be needed to determine if these results will apply to other groups of PTSD 
sufferers. Smoked marijuana will be tested in two stages of three weeks each (Stage 1 and 
Stage 2), with a two-week cessation after each stage, verified by blood/urine cannabinoid 
analysis. 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.  This study is critically important for understanding the potential risks and 
benefits of marijuana as a treatment for PTSD and can inform the development of larger 
randomized controlled clinical trials. Ad-libitum self-administration of smoked marijuana 
with a range of THC and CBD ratios will be used in this study to provide a naturalistic 
comparison that is generalizable to what many veterans are currently using to manage 
PTSD symptoms in states with legalized medical marijuana. Results will provide 
information regarding marijuana dosing, composition, side effects, and specific areas of 
benefit to clinicians and legislators considering marijuana as an acceptable treatment for 
PTSD. This study will also provide information on the predictive value and/or assessment 
of the impact of marijuana on selected biomarkers of inflammation, and effects of 
marijuana concentration upon these biomarkers as a measure of PTSD treatment 
response.  
  
2.2 Supporting Information   
 
2.2.1 Condition 
 
PTSD is a serious, worldwide public health problem for which a wider array of effective 
treatments is needed. In the US, the lifetime prevalence of PTSD in the general 
population is between 6 and 10% [9, 10]. PTSD is common in other countries as well 
[11-15]. Incidence of PTSD in US Operation Iraqi Freedom (OIF) and Operation 
Enduring Freedom (OEF) veterans is as high as 18% [16], and it is estimated that the 
number of service members returning home with PTSD will be between 75,000 and 
225,000 [17]. In 2004, the US Veterans Administration (VA) spent $4.3 billion on PTSD 
disability payments to approximately 215,000 veterans, most of them from the Vietnam 
War [18].  Due to OIF/OEF, the number of veterans disabled by PTSD, and the cost of 
providing disability payments, has increased substantially since 2004.  In countries where 
there is endemic armed conflict, the incidence of PTSD in civilians is often far greater 
[19-21].  PTSD is typically a chronic illness [22, 23], associated with high rates of 
psychiatric and medical co-morbidity, disability, suffering and suicide [13, 22, 24, 25].  
An array of psychotherapeutic options exists for treating PTSD that include cognitive 
behavioral psychotherapies, such as Prolonged Exposure (PE), Cognitive Reprocessing 
Therapy (CPT), and therapies such as Eye Movement Desensitization and Reprocessing 
(EMDR) [26, 27], as well as two Selective Serotonin Reuptake Inhibitors (SSRIs; 
sertraline and paroxetine) that are approved as PTSD treatments by the FDA. However, a 
significant percentage of PTSD patients fail to respond adequately to established PTSD 
psychotherapies [28, 29], including SSRIs [30], or respond in ways that are statistically 
significant but clinically inadequate. At least one study of paroxetine indicated that men 
with PTSD did not respond to this drug [31].  These findings suggest that there is still 
substantial need for innovative treatments for PTSD.  
 


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There is limited data about whether or not patients with military service-related PTSD are 
more difficult to treat than those with PTSD from other causes.  A recent comprehensive 
review found that, most, but not all, RCTs with combat (mostly Vietnam War) veterans 
showed less treatment efficacy than RCTs with non-veterans whose PTSD was related to 
other traumatic experiences. Therefore some experts believe that combat veterans with 
PTSD are less responsive to standard or widely used treatments. More clinical trials with 
combat veterans would be important and welcome additions to this literature [26].    
 
Clinical reports suggest that patients with PTSD may have a tendency to favor 
depressants, such as alcohol, benzodiazepines, and marijuana to “self-medicate” 
symptoms of hyperarousal as opposed to stimulants (such as cocaine), which may 
exacerbate symptoms [32]. However, the extent to which illicit substances are used for 
symptom relieve in veterans with PTSD may be under-appreciated in clinical trials 
associated with the VA system [33-35]. Substance use in this group may be under-
reported due to concerns that it might jeopardize potential claims for disability 
compensation or result in arrest or prosecution. Thus there is potential benefit of 
conducting studies of PTSD and substance use outside of the VA system that include 
multimodal assessments and measures of both PTSD and substance use.   
 
2.2.2 Marijuana as a Treatment for PTSD Symptoms 
 
The principal active component in the complex mixture of cannabinoids present in the 
marijuana plant is THC, which acts primarily as an agonist at the CB1 cannabinoid 
receptor. This receptor is found at high concentrations in the brain, including the basal 
ganglia and cerebellar regions, and also in the hippocampus and hypothalamus. THC has 
been shown to inhibit the release of a wide spectrum of neurotransmitters including L-
glutamate, GABA, norepinephrine, dopamine, serotonin (5-HT), and acetylcholine [36]. 
Preliminary findings from assessing current and recalled PTSD symptoms in 80 patients 
suggests that use of medical marijuana can reduce PTSD symptoms [37], and a case 
study of a young man with PTSD assessed before and after he began using cannabis 
supports the therapeutic potential of marijuana for PTSD [38]. An open-label study in ten 
people reported that sublingual THC reduced PTSD symptoms, reduced nightmares and 
improved sleep quality [39]. Given evidence highlighting marijuana as a possible means 
of improving sleep [4], with retrospective reports of marijuana use and associated 
psychopathology indicating reductions in PTSD symptoms after use [37], it is not 
surprising that population-based studies have found PTSD to be associated with increased 
marijuana use [40]. These reports warrant further systematic investigation into marijuana 
as a potential adjunctive treatment for PTSD.  
 
The presence of CB1 receptors in the hippocampus, amygdala, prefrontal and anterior 
cingulate cortex suggests that endocannabinoids are involved in regulating anxiety, 
attention to and response to stressful situations, and may be involved in the extinction of 
conditioned fear [41-43]. This hypothesis is supported by the observation that availability 
of CB1 receptors is particularly elevated among individuals with PTSD, compared to 
trauma-exposed or healthy controls [44]. Further support of this theory came from studies 
using CB1 receptor antagonists or CB1 receptor knockout mice. Several CB1 receptor 
agonists increased time mice spent in open arms of the elevated plus maze, a sign of 


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reduced anxiety [45], while CB1 receptor antagonist SR141716 produced anxiogenic 
effects in the elevated plus-maze and the defensive withdrawal tests in adult rats [46, 47]. 
Furthermore, another selective CB1 receptor antagonist, AM251, increased anxiety-like 
behavior in wild-type mice but had no effect in the knockouts, in support of a CB1 
receptor-mediated anxiolysis.  
 
Cannabinoids also modulate GABA-ergic transmission and the release of cholecystokinin 
(CCK), a peptide that may contribute to both anxiolytic and anxiogenic effects of THC 
and endocannabinoids [48-51]. Furthermore, cannabinoids enhance the release of 
endogenous opioids, and these may be involved in the functional interplay between the 
endocannabinoid and the opioid system and the production of analgesic responses. Some 
researchers hypothesize that the relationship between these two systems plays a role in 
antidepressant-like effects and in various addiction-related processes [52-54]. Studies in 
rodents suggest that cannabinoids and their interaction with endogenous opioids might 
also modulate anxiety [53, 55, 56]. Rodent studies detected antidepressant-like responses 
to CB1 agonists, and CB1 agonists can increase the synaptic concentration of biogenic 
amines, much like antidepressants do. Thus, pharmacological modulation of the 
endocannabinoid system holds considerable promise in the treatment of both anxiety-
related and mood disorders. 
 
The results of a recent study implicated endocannabinoids and CB1 receptors in the 
extinction of aversive memories by demonstrating that CB1 knockout mice show 
impaired extinction in auditory fear-conditioning tests, and this could be mimicked in 
wild-type mice by treatment with SR141716 [57], a finding supported through use of 
receptor agonists and antagonists [58, 59]. The synthetic cannabinoid nabilone was 
effective in reducing treatment-resistant nightmares in people with PTSD [60]. These 
findings raise the possibility that pharmacological amplification of CB1 signaling, for 
example, may have therapeutic value in obsessive-compulsive disorder or PTSD. 
 
Benzodiazepines and related GABA agonists are frequently used to treat anxiety and 
sleep disruption in PTSD. Other treatments, such as the centrally acting adrenergic alpha1 
antagonist prazosin, have been investigated as a treatment for PTSD-related sleep 
disorders [61]. However, these compounds can produce physical dependence and are not 
always well tolerated. Investigating alternate avenues of treatment for PTSD symptoms 
may lead to helping a greater number of individuals control their symptoms.  
 
In addition to THC, whole plant marijuana contains a number of other active constituents, 
most notably CBD. Research indicates that THC acts upon receptors in brain areas 
involved in memory and fear processing, and preclinical studies in rodents suggest 
cannabinoids reduce fear [42, 45]. Research in mice found that CBD was comparable to 
the antidepressant imipramine in tests of antidepressant-like effects [62]. Findings of 
reduced PTSD symptoms, by orally administered THC or comparable synthetic 
cannabinoids, including nightmares and sleep difficulties suggest a potential role for 
cannabinoids in the alleviation of PTSD symptoms [63, 64]. Further, CBD may oppose 
anxiogenic effects of THC in humans [65, 66], and a naturalistic study found smoking 
marijuana with higher CBD levels was associated with less memory impairment and 
lower anxiety during intoxication [67]. It appears that CBD attenuates amygdalar 


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activation in response to facial expressions of fear in healthy participants [68], a 
potentially beneficial effect for people with PTSD, who may exhibit enhanced amygdalar 
reactivity to fearful faces [69]. Anecdotal reports from Veterans Alliance for Medical 
Marijuana (VAMM) indicate that veterans prefer a balanced THC to CBD intake for 
management of PTSD symptoms. These studies suggest that it is worth investigating the 
effects of marijuana that varies in THC and CBD content on the ability to suppress 
symptoms of PTSD.  
 
Another potential mechanism by which marijuana may confer benefit in the treatment of 
PTSD relates to reductions in inflammation. A longitudinal study in US Marines reported 
an association between higher pre-deployment levels of C-reactive protein (CRP) and 
post-deployment development of PTSD [70]. In other research, reduction in PTSD 
symptoms following treatment with SSRIs was associated with a reduction in interleukin-
1Beta  (IL-1β) [71], and women whose PTSD symptoms were in remission exhibited 
lower levels of CRP and interleukin-6 (IL-6) compared with those with current PTSD 
[72]. Further, a meta-analysis supported a link between IL-1β and IL-6 and exposure to 
trauma [73], with stress-related elevation in IL-6 potentially higher among those with 
PTSD [72, 74]. Because both THC and CBD have potent anti-inflammatory and 
immunomodulatory properties [75, 76], marijuana use may have therapeutic benefit in 
PTSD treatment simply via reductions in inflammation. Biomarkers of inflammation will 
be assessed to investigate whether the anti-inflammatory properties of THC/CBD 
mediates the treatment effect of marijuana on PTSD symptom expression.  
 
2.3 Rationale for Concentration Selection 
 
Four potencies of marijuana obtained through the National Institute on Drug Abuse 
(NIDA) drug supply program that vary in THC and cannabidiol CBD content will be 
used: High THC/ Low CBD (High THC), Low THC/High CBD (High CBD), High 
THC/High CBD (THC/CBD) or Low THC/Low CBD (placebo) marijuana. “High” is 
defined as marijuana containing a target of 9-15% concentration by weight of the 
respective cannabinoid and “Low” is defined as <2% concentration by weight; actual 
cannabinoid concentrations are subject to the capabilities of the NIDA Drug Supply 
Program to produce different strains of marijuana based on these targets and are provided 
in Section 6. In the Stage 2 crossover, two of three concentrations will be compared: 
High THC, High CBD, and THC/CBD. Ad-libitum self-administration will be permitted 
up to a maximum of 1.8 grams of marijuana/day.  
 
The doses of marijuana (excluding placebo) in this study were chosen because they 
contain a range of THC and CBD ratios and potencies generalizable to what many 
veterans are currently using to manage PTSD symptoms in non-clinical settings in states 
with legalized medical marijuana.  Prior to the study start, laboratory testing of the study 
marijuana will be completed to verify the chemical composition of each concentration 
group.  
 
The active (non-placebo) doses are expected to produce commonly reported subjective 
effects of marijuana. The physiological effects are expected to be tolerable based on 
previous observational studies in the literature. The placebo is expected to produce 


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minimal side effects, without the full range of psychological and subjective effects seen 
with the active doses.  
 
Analysis of the differential efficacy of these distinct marijuana concentrations will help 
elucidate whether the ratio of THC to CBD is a significant factor in the attenuation of 
PTSD symptoms, as reported anecdotally and based on the differential pharmacology of 
THC and CBD.  Ad-libitum use will provide the most naturalistic comparison to real 
world examples of smoked marijuana.  
 
3.0 Protocol Objectives 
 
The objectives of this study are to evaluate whether i) smoking whole plant marijuana 
attenuates PTSD symptoms, ii) to compare the efficacy of varying ratios of THC and 
CBD to placebo using standard clinical measures, and to iii) collect safety data. 
 
3.1 Primary Objective 
 
To compare independent effects of three active concentrations of smoked marijuana and 
placebo on PTSD symptom severity measured by changes in CAPS-5 total scores during 
3-weeks of ad-libitum self-administration during Stage 1 of the study protocol.  
 
3.2 Secondary Objectives 
 
The following secondary objectives will be used to support the results of the primary 
objective: 
 
1. Assess independent effects of three active concentrations of marijuana and 
placebo in reducing self-reported symptoms of PTSD with the PCL-5, anxiety and 
depression with the IDAS, and improving psychosocial functioning with the IPF 
and WBR (self-report and observer) among veterans during Stage 1. 
2. Assess independent effects of three active concentrations of marijuana and 
placebo in reducing self-reported symptoms of PTSD with PCL-5, anxiety and 
depression with IDAS, and improving psychosocial functioning with the IPF and 
WBR (self-report and observer) among veterans during Stage 2.  
3. Assess comparative efficacy between placebo and each active dose of marijuana 
based on a within-subjects analysis of PTSD symptoms as measured by the 
CAPS-5 in crossover participants at Baseline, End of Stage 1, Stage 2 Baseline, 
and End of Stage 2. 
4. Assess whether Stage 2 crossover participants’ preferences for marijuana 
concentrations in Stage 1 and Stage 2 correlate with reduction in PTSD symptoms 
as measured by the CAPS-5 total score.  
5. Assess whether participants experience a clinically significant increase in PTSD 
symptoms based on CAPS-5 and PCL-5 total scores during the washout period 
between Stage 1 and Stage 2 compared with measures assessed at Baseline and 
during Stage 1.  
6. Explore correlation of treatment outcomes measured by CAPS-5 score with 
objective changes in sleep via Actigraphy throughout the study and self-reported 


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changes in sleep quality using the ISI on a weekly basis. 
7. Explore correlation of Daily Diary items related to sleep with objective changes in 
sleep via Actigraphy and self-reported changes in sleep quality using the ISI on a 
weekly basis. 
8. Explore correlation of treatment effects measured by CAPS-5 total score with 
amount of marijuana used based on Daily Diary across Stage 1 and Stage 2. 
9. Explore treatment outcomes measured by CAPS-5 total score by marijuana 
concentration, with concomitant substance and medication use as a covariate 
throughout the treatment period. 
10. Explore durability of treatment outcomes measured by CAPS-5 total score, with 
any PTSD treatments based on the LTFU questionnaire treated as a covariate, six 
months after completing Stage 2. 
 
3.3 Safety Objectives 
 
The safety of participants will be measured throughout the study by assessing 
physiological and subjective drug effects, psychological distress, adverse events (AEs), 
and suicidality, repeatedly as described in the following steps.  Summaries of safety data 
by study stage will be provided to the Medical Monitors for review during the study.   
 
1. Explore correlations of subjective effects with the DEQ and cardiovascular effects 
with heart rate of each active dose of marijuana and placebo during introductory 
sessions. 
2. Explore independent effects of each active dose of marijuana and placebo on 
blood pressure and body temperature during introductory sessions. 
3. Assess independent effects of each active dose of marijuana and placebo on 
marijuana withdrawal symptoms during screening and Cessation 1 and 2. 
4. Assess independent effects of each active dose of marijuana and placebo on 
problems associated with marijuana use during the study, including follow-up, 
with the CUDIT-R.  
5. Evaluate the subjective effects of each active dose of marijuana and placebo in 
both controlled laboratory and outpatient settings, including ratings of unpleasant 
drug effects, using the DEQ and Daily Diary entries. 
6. Assess independent effects of each active dose of marijuana and placebo on 
suicidality with the CSSRS on a weekly basis throughout the treatment period, 
and more frequently if needed. 
7. Assess independent effects of each active dose of marijuana and placebo on 
whether and for how many days participants were incarcerated throughout the 
study. 
8. Assess independent effects of each active dose of marijuana and placebo on 
whether and for how many days participants were hospitalized throughout the 
study. 
9. Assess metabolites of alcohol use through urine testing at face-to-face visits. 
10. Collect, review, and report Serious Adverse Events (SAEs) and AEs in 
accordance with FDA regulations and Section 8.0 of the protocol.  
 


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3.4 Process Objectives 
 
The following objectives will include exploratory analyses intended to inform future 
studies: 
 
1. Evaluate protocol compliance based on comparison of Daily Diary entries, 
including information on amount, time and frequency of marijuana use, and the 
weight of any unused marijuana across each study stage. 
2. Evaluate protocol compliance using quantitative blood and/or urine cannabinoid 
levels. 
3. Evaluate whether markers of inflammation CRP, IL-1β, and IL-6 levels in blood 
predict PTSD severity at baseline and treatment outcome as a function of 
marijuana concentration. 
 Assess the ability of site staff and participants to accurately guess condition 
assignment in Stage 1 and Stage 2. 
4.0 Protocol Design 
 
This Phase 2 randomized, placebo-controlled, triple-blind, crossover, multi-site study will 
assess the safety and efficacy of four types of smoked marijuana to manage chronic, 
treatment-resistant PTSD symptoms among 76 veterans in an outpatient setting.  The 
study will consist of a baseline period and three distinct study stages, which are described 
in detail below. 
 
An initial 2-week screening period will be conducted to determine study eligibility prior 
to randomization, to obtain baseline measures of PTSD and substance use, to conduct 
study training, and ensure participants are willing and able to attend scheduled 
appointments and complete the study procedures.  
 
Following randomization, participants will complete Stage 1, a three-week period of ad-
libitum marijuana self-administration followed by a two-week period of marijuana 
abstinence (Cessation 1). This will be immediately followed by Stage 2, another three-
week period of marijuana self-administration and two-week period of abstinence 
(Cessation 2).  Stage 1 and Stage 2 will consist of identical procedures and measures, but 
the marijuana available to individual participants will vary.   
 
During Stage 1, participants will be randomized to receive High THC, High CBD, 
THC/CBD, or Placebo marijuana to self-administer (up to 1.8 g/day) for the 3-week 
marijuana use period.  As described in Section 4.2, randomization will be balanced across 
drug conditions (N=19 per marijuana type; total N=76).  During Stage 2, the Placebo 
marijuana condition will be removed and all participants will be re-randomized to receive 
a different type of marijuana than they were assigned in Stage 1. Thus, Stage 2 will 
permit a within-subjects comparison of changes in CAPS-5 total score as a function of 
marijuana concentration, including differences in preferences for a specific marijuana 
concentration by self-report, and the removal of placebo as a possibility ensures that all 
study participants receive active marijuana at some point during the study.  
 


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Following completion of Stage 2, participants will be invited to participate in an optional 
Stage 3.  During Stage 3, participants can choose to receive the amount equivalent to the 
unused and returned marijuana from Stage 1 or Stage 2 from a new supply.  This design 
feature discourages diversion of unused marijuana and encourages participant use of 
marijuana in a naturalistic manner during Stages 1 and 2.  Marijuana will be dispensed 
during Stage 3 based on the average daily rate of use during Stages 1 and 2 and will not 
last more than two months.  
 
There will be a long-term follow-up assessment conducted six months after the end of 
Stage 2. Participants will complete the long-term follow-up questionnaire concerning 
their mental health, substance use, and changes in PTSD therapies and medications. A 
blinded Independent Rater (IR) will administer the CAPS-5. Participants will complete 
self-report measures and one week of Actigraphy (ACT) monitoring, followed by study 
termination. 
 
4.1 Planned Duration of Study 
 
Study duration for each participant will be eight and a half months from the time the 
participant is enrolled in the study. The study will start after marijuana is obtained from 
the NIDA Drug Supply Program, and composition may be verified by an appropriately 
qualified laboratory. Assuming that eight participants can be enrolled each month across 
sites, the study should take approximately two years to complete.  
 
4.2 Randomization and Participant Numbering 
 
To achieve sufficient statistical power and account for dropouts, about 116 participants 
will be stratified by site and randomized in a 1:1:1:1 ratio across the four treatment 
groups (High THC, High CBD, THC/CBD, or Placebo) based on a sequential order of 
enrollment into the study.  Participants will be assigned a randomization code that will 
correspond to a blinded condition assignment. Randomization and enrollment will halt 
when 76 participants complete Stage 1 (at least N=19 per group). In order to maintain the 
blind for participants, site staff, IRs, and sponsor staff, a central electronic database will 
be utilized for randomization based on validated computer-generated lists. The Stage 1 
randomization list will utilize blocks to balance treatment assignments. Stage 2 
randomization will utilize multiple validated randomization lists that re-randomize 
participants in a blinded manner to one of two new treatment assignments in a 1:1 ratio, 
excluding the previously assigned Stage 1 dose and the placebo condition as possibilities. 
 
The blind may be broken for an individual participant if there is an AE or other 
emergency requiring knowledge of the participant's marijuana condition assignment. This 
emergency unblinding would require approval from the site CI and Coordinating 
Investigator. For this purpose, the Randomization Monitor will provide dose assignment 
through the electronic randomization system. In all other cases, the blind will be 
maintained until all participants have completed the study and the database is locked.  
The Coordinating Investigator, Co-investigator, CIs, IR, and participant will be blind to 
condition assignment.  
 


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Prior to enrollment, participants at Site 01 will be tracked with a screening number 
assigned sequentially starting at "S1001," and participants at Site 02 will be tracked with 
a screening number assigned sequentially starting at "S2001." Participants who meet 
eligibility criteria will be enrolled in the study and assigned a five-digit participant 
number. The first two digits will be “01 or 02” and will identify the study site. The next 
three digits identify the participant within the site and will be assigned sequentially, with 
101 corresponding to the first participant enrolled, e.g. the first participant enrolled at site 
01 will be 01101, second 01102, and the first participant enrolled at Site 02 will be 
02101, second 02102, etc.  
 
4.3 Recruitment and Participant Population 
 
Candidates for participation will be 76 veterans over 18 years of age with chronic, 
treatment-resistant PTSD arising from their combat-related service in the US armed 
forces and with duration of PTSD lasting at least six months. A participant would not be 
excluded for having more than one traumatic event, but would be excluded if the primary 
or traumatic event related to PTSD diagnosis was not related to combat during military 
service. Participants may be men or women and of any race or ethnicity. Participants will 
be 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 website, and word of mouth.   
 
Study volunteers will be interviewed by telephone to learn if they meet initial screening 
criteria according to an IRB-approved phone script. If the prospective participant is 
eligible and interested in taking part in the study based on the telephone assessments, 
qualified site staff will continue phone prescreening and will provide them with consent 
materials for review and consideration. If, after review, an applicant remains eligible and 
interested in taking part in the study, an appointment will be made to obtain informed 
consent to participate and for a face-to-face screening assessment to further evaluate 
eligibility to participate. If the prospective participant is not eligible or interested in 
taking part in the study based on the telephone assessments and do not complete the 
consent process, documentation on eligibility information will be destroyed at the end of 
the study, apart from the summary reason for ineligibility, which will be retained on the 
Screening Log.  
 
Participants must be able to give adequate informed consent and be able to attend all 
required visits. Participants are required to pass an initial urine drug screen that is 
negative for opiates, benzodiazepines, cocaine, methamphetamines, THC, and 
amphetamines (unless prescribed), at the start of screening and agree to adhere to a 
minimum of two weeks abstinence from marijuana use prior to randomization. Cessation 
during the final two weeks of screening will be confirmed by pre and post blood/urine 
cannabinoid tests (methods described in Section 5.2.3 “Screen 2”)[77]. Participants must 
agree to use only the marijuana provided to them by the study team while they are 
participating in the study and to not use any marijuana during the screening and two 
study washout periods. Participants must meet all study eligibility criteria by the end of 
the two-week screening period in order to be eligible for enrollment.   
 


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All study participants will be asked to identify an individual with whom they interact 
with directly at least 2 times per week, and who would be willing to participate in the 
study as an independent observer of the participants behavior.  The community observer 
will provide written informed consent, provide detailed information about their 
interactions with the study participant and agree to complete weekly interviews via 
telephone directly with study staff for the duration that the study participant is actively 
enrolled. 
 
4.3.1 Participant Inclusion Criteria  
 
Eligible individuals based on initial screening criteria must: 
 
1. Meet DSM-5 criteria for chronic PTSD of at least six months duration.   
2. Have PTSD of at least moderate severity (CAPS-5 score of 25 or more) at the 
time of baseline assessment. 
3. Be a military veteran with primary index trauma of combat service-related PTSD. 
4. Have treatment-resistant PTSD, defined as meeting DSM-5 diagnostic criteria for 
PTSD after failing on, or being unable to tolerate, FDA-approved medication or 
empirically supported psychotherapy for PTSD of adequate dose and duration, as 
determined on a case-by-case basis by the site CI. 
5. Be at least 18 years old. 
6. Be willing to commit to medication dosing and delivery method, to completing 
evaluation instruments, and attending all study visits. 
7. Agree to use only marijuana provided by site staff and agree to required cessation 
periods for the duration of the study. 
8. Report no current hazardous marijuana use, as defined by a score of < 8 on the 
CUDIT-R at time of screening, and completely abstain from marijuana during the 
2-week baseline assessment period (biochemically verified via urine and/or blood 
cannabinoid concentrations).  
9. Agree to video record all marijuana administrations and provide video to the site 
staff for review during study participation.  
10. 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. 
11. Provide a qualified self-appointed community observer who they interact with an 
average of at least twice per week in the prior month and can knowledgeably 
report on at least 2 domains of the Weekly Behavior Report as judged by study 
staff. 
12. Be stable on any pre-study medications and/or psychotherapy regimen for PTSD 
prior to study entry, agree to inform physician(s)/clinician(s) providing current 
care about participation in the study, and agree to report any changes in 
medication or psychotherapy treatment regimen during the study, to study staff. 
13. 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. Adequate birth control methods 
include intrauterine device (IUD), injected or implanted hormonal methods, 
abstinence, oral hormones plus a barrier contraception or double barrier 
contraception. Two forms of contraception are required with any barrier method 


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or oral hormones (i.e. condom + diaphragm, condom or diaphragm + spermicide, 
oral hormonal contraceptives + spermicide or condom). Not of childbearing 
potential is defined as permanent sterilization or postmenopausal females. 
14. Be proficient in reading and writing in English and able to effectively 
communicate with site staff. 
15. Agree not to participate in any other interventional clinical trials during the study. 
 
4.3.2 Participant Exclusion Criteria 
 
Individuals who meet any of the following criteria will be excluded from participation: 
 
1. Are pregnant or nursing, or are women of child bearing potential who are not 
practicing an effective means of birth control. 
2. Current or past DSM-5 diagnosis of dissociative identity disorder, eating disorder 
with active purging, personality disorders, primary psychotic disorder, bipolar 
affective disorder type 1, positive family history (first degree relative) of 
psychotic disorder or bipolar affective disorder type 1. 
3. Have any allergies to marijuana or contraindication for smoking of marijuana.  
4. Would present a serious suicide risk as assessed by the investigators, or who 
investigators believe are likely to require psychiatric hospitalization during the 
course of the study. 
5. Current diagnosis or evidence of significant or uncontrolled hematological, 
endocrine, cerebrovascular, cardiovascular, coronary, pulmonary, gastrointestinal, 
or neurological disease. 
6. During the 2-week screening period, have a positive urine drug screen for opiates, 
methamphetamine, cocaine, and amphetamines (unless prescribed); meets DSM-5 
criteria for a current substance use disorder (other than marijuana, caffeine or 
nicotine). 
7. Meets criteria for current cannabis use disorder of moderate severity (4 or more of 
11 DSM-5 criteria) and continued marijuana use during two 2-week screening 
period confirmed by quantitative blood and urine testing. 
8. Are not able to give adequate informed consent. 
9. Are not able to attend face-to-face visits or those who plan to move out of the area 
within the treatment period. 
10. Meet criteria for current severe depression (BDI-II score > 30). 
11. Have any current problem, which in the opinion of the investigators or medical 
monitor, might interfere with participation in the study. 


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4.3.3 Observer Inclusion Criteria  
 
Eligible community observers must: 
 
1. Have personal interaction with the study participant at least twice weekly the 
month prior to participation with no expectation that the frequency of interaction 
will decrease below this level during the study. 
2. Be able to report on at least 2 domains of the Weekly Behavior Report based on 
direct weekly observations of the study participant.  
3. Be willing to complete weekly telephone interviews with study staff. 
 
4.3.4 Observer Exclusion Criteria  
 
Community observers who meet any of the following criteria will be excluded from 
participation: 
1. Weekly interaction does not include direct (face-to-face) observation or 
communication with the study participant. 
2. Expectation that interaction with study participant will decrease below 2 times per 
week during the course of the study.  
3. Lack of reliable method for study staff to contact observer to complete weekly 
interviews. 
4. Study staff judge individual to be unsuitable during consent and initial evaluation. 
 
 
5.0 Methods 
 
5.1 Assessments and Measures 
 
5.1.1 Outcome Measures 
 
Primary Outcome Measure:   
 
The Clinician-Administered PTSD Scale (CAPS-5) [78] is a semi-structured clinical 
interview administered by a blinded IR and is used to assess index history of DSM-5-
defined traumatic event exposure [79], including the most distressing event, time since 
exposure, and total number of exposures, as well as frequency and severity of 
posttraumatic stress symptoms, as evidenced by CAPS-5 total score. The CAPS-5 
provides diagnostic status (presence versus absence) of PTSD as well as PTSD symptom 
severity. Changes in the CAPS-5 total score will be used as the primary PTSD outcome 
measure, and will be the primary determinant of effect size for this pilot study. The IR 
will administer the CAPS at visits described in the Time and Events table either in person 
or via telemedicine. IRs will receive training on administering this measure from a 
research reliable trainer. Interviews will be recorded in as many instances as necessary to 
establish reliability of a random selection of interviews for accuracy. The CAPS-5 will be 


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administered by trained interviewers throughout the study, who will be supervised by 
qualified personnel.  
 
Secondary Outcome Measures:  
 
The PTSD Checklist (PCL-5) with LEC plus criterion A (at baseline only) [80] is a 20-item 
self-report questionnaire in which respondents indicate the presence and severity of PTSD 
symptoms, derived from the DSM-five symptoms of PTSD [79].  Participants indicate how 
much distress they have experienced due to symptoms such as “Repeated, disturbing 
memories, thoughts, or images of a stressful experience from the past,” “Trouble 
remembering important parts of a stressful experience from the past,” and “Feeling 
irritable or having angry outbursts” on a five-point Likert-type scale (1=not at all, 
5=extremely). The total PCL-5 score (a sum of all 20 items) provides an index of overall 
PTSD symptom severity. 
 
The Inventory of Depression and Anxiety (IDAS) [81] is a 64-item self-report measure of 
depression and anxiety symptoms.  Factor analytic research indicates that the IDAS has 
strong convergent and discriminate validity, as well as criterion validity [82]. 
Additionally, factor analytic research indicates that the general depression and anxiety 
subscales of the IDAS differentiate anxiety from depression [81, 82].  
 
The Insomnia Severity Index (ISI) is a brief self-report measure of insomnia. It consists 
of seven questions, with responses made on a five-point Likert scale [83, 84]. 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. The ISI exhibits adequate to 
very good validity when compared with other self-report measures of sleep quality, 
statements concerning sleep quality and polysomnography, and is sensitive to changes in 
sleep quality  [84-86].  
 
Actigraphy (ACT) with ActiSleep and Monitor Actigraph devices will be used to 
measure objective sleep at baseline and all follow-up assessments. This noninvasive 
objective assessment device provides accurate and reliable measurements of sleep and 
wake including the following: amount of sleep, number and duration of awakenings, 
sleep efficiency, amount and intensity of physical activity, energy and activity, and sleep 
position. 
 
Weekly Behavior Report for Community Observers/Participants (WBR) is a 50-item 
questionnaire developed to assess current psychosocial functioning across seven 
domains: romantic relationships, family, work, education, social, self-care and alcohol 
and drug use. The community observer and participant would each complete the WBR in 
relation to the participant. The WBR will be completed based on the last seven days and 
will be administered according to the Time and Events Table. 
 
The Inventory of Psychosocial Functioning (IPF) [87] is an 80-item measure that that was 
developed for use among individuals with PTSD. It assesses current psychosocial 


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functioning across seven domains: romantic relationships, family, work, friendships, 
parenting, education, and self-care. Summation of scores across domains yields a total 
score for psychosocial functioning. The IPF has excellent psychometric properties [87]. 
 
5.1.2 Safety Measures 
 
The Time-Line Follow-Back (TLFB) method will be used to track medical and non-
medical drug/substance use [88, 89].  A retroactive TLFB assessment will be conducted 
to record substance use during the 90-days prior to the intake assessment during 
screening.  It will then be repeated at the six-month follow-up visit to collect substance 
and medication use for each day since the last visit.   
 
The Cannabis Use Disorders Identification Test-Revised (CUDIT-R) [90] is an eight-item 
self-report questionnaire used to assess problematic marijuana use within the past six-
months. Questions assess consumption (frequency), marijuana abuse (e.g., use in 
hazardous situations, inability to fulfill obligations), marijuana dependence (e.g., not able 
to stop using, spending a lot of time obtaining, using, or recovering from use), and 
negative consequences of use (e.g., problems with memory or concentration). Responses 
are summed, thus providing a continuous score of problematic marijuana use. The 
CUDIT has demonstrated high internal consistency and acceptable test-retest reliability, 
high specificity and sensitivity, as well as satisfactory predictive power [90]. 
 
The Marijuana Withdrawal Checklist (MWC) [91, 92] will be used to assess the presence 
of marijuana withdrawal symptoms during prior periods of abstinence.  The MWC will 
be labeled the Behavior Checklist to minimize expectancy effects.  It lists 32 symptoms 
for which participants indicate severity on a four-point scale (0=not at all, 1=mild, 
2=moderate, 3=severe).  The symptom list comprises the valid items found in prior 
marijuana withdrawal studies and additional non-specific items to minimize response 
bias.  During the intake assessment, participants will be instructed to indicate whether 
and to what degree they experienced each symptom during past periods of 
marijuana abstinence lasting at least 48 hours, if they are current marijuana users. 
Instructions will be slightly different during the study than during the intake 
assessment.  Participants will be asked to rate how they have felt since last completing 
the questionnaires.  Administered in this way, the MWC has been used effectively to 
detect reliable marijuana withdrawal effects in several prior studies [91-96].  A total 
withdrawal discomfort score (WDS) will be computed from the Checklist and will be the 
outcome variable for this measure.  This summary score will include the symptoms 
reliably observed in prior marijuana withdrawal studies [97]. 
 
The Columbia Suicide Severity Rating Scale (C-SSRS) is a clinician-administered 
measure of suicidal behavior devised to detect potential suicidal thoughts or behaviors 
during a clinical trial [97]. It consists of a “Baseline” form that assesses lifetime suicidal 
ideation, intensity, and behavior, and a form for assessing current suicidal ideation and 
intensity. The C-SSRS consists of a series of questions, and can be administered via face-
to-face interview or over the telephone. The C-SSRS is a detailed interview, but the full 
interview is needed only if the initial screening questions about suicidal ideation and 
behavior are positive.  The screening questions should be completed for every participant 


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according to the Time and Events Table and as needed if the participant is showing any 
signs of being suicidal. For management of suicidal thoughts, see Section 7.3 Risk 
Mitigation.  
 
Site staff will assess general wellbeing (GWB) during each face-to-face visit and phone 
contact. Ratings on current demeanor and state of mind are collected on a scale of 1 
“Very Stable and Calm” to 6 “Very Distressed.” Ratings on likelihood of deterioration 
are collected from A “Does Not Face Risk” to C “Faces Risk.” Results of this scale are 
intended to maintain participant safety throughout the study. 
 
The subjective ratings of cannabis intoxication will be determined using the Drug Effect 
Questionnaire (DEQ). The individual items of the DEQ, 15 total, include ratings of drug 
effects (i.e. high, drug effect, good effect, bad effect), craving, and behavioral/mood 
states often associated with marijuana intoxication (i.e. relaxed, paranoid, hungry/have 
munchies, anxiety, irritability, feelings of heart racing/ pounding in chest). Participants 
will rate each item using a visual analog scale (VAS) anchored with “not at all” at one 
end and “extremely” at the other end. VAS measures have been reliably shown to be 
sensitive to detecting dose effects of a variety of drug classes including smoked 
marijuana. An analysis across studies assessing response to the DEQ found items to 
assess unique factors, with each item moderately to strongly related to others [98]. The 
DEQ has been used in studies assessing the effects of d-amphetamine [99] and MDMA 
[100]. This analysis also detected an association between “liking” and positive mood 
effects. 
 
Participant vital signs, including blood pressure (systolic/diastolic), heart rate and body 
temperature, will be assessed at baseline and during each weekly visit, as described in the 
Time and Events table. Vital signs will be measured before, during, and after self-
administration during introductory sessions. In addition, pulse oximetry will be assessed 
at baseline and before, during, and after introductory sessions. 
 
Urine dipstick testing will detect the alcohol metabolite Ethyl Glucuronide (EtG). EtG is 
detectable in human urine for up to 80 hours after alcohol consumption. This will be 
performed to monitor recent alcohol consumption in study participants and confirm 
participant self-reports at each face-to-face visit. 
 
The BDI-II is a 1996 revision of the BDI, a 21-item self-report measure [101, 102], that 
will serve as a screening measure for severe depression [103]. The BDI-II has been 
validated, has high internal consistency and good test/re-test reliability and is not overly 
sensitive to daily variations in mood. It takes five to ten minutes to complete [103]. Score 
cutoffs indicate: 0-13 minimal depression, 14-19 mild depression, 20-28 moderate 
depression, and 29-63 severe depression.  Subjects will complete the BDI-II at screening.  
 
The SCID-5-RV [104] is a structured clinical interview that assesses the dichotomous 
diagnoses (with indicators of severity) of psychological disorders, including substance 
use disorders. The SCID-5-RV has excellent psychometric properties and is a valid and 
reliable diagnostic tool [104]. The SCID for personality disorders (SCID-PD) will be 
used to assess for Axis 2 personality disorders. Staff will receive training on 


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administering these measures from a research reliable trainer. Interviews will be recorded 
in as many instances as necessary to establish reliability of a random selection of 
interviews for accuracy. These assessments will be administered at baseline by trained 
interviewers throughout the study, who will be supervised by qualified personnel.  
 
The STOP-Bang Questionnaire (Chung et al., 2013) will be used as a self-report 
screening assessment for obstructive sleep apnea.  Scores on the STOP-Bang will be 
collected to inform whether study participants are at high risk for sleep-related breathing 
disorders and will be considered as a possible covariate in analysis of sleep continuity 
outcomes (e.g. Actigraphy). 
 
AEs, including spontaneously reported reactions, will be collected as described in Section 
8.0 of the protocol. Concomitant medications and therapies will be collected as described 
in Section 9.0 of the protocol. 
 
5.1.3 Process Measures 
 
The Daily Diary is an instrument developed by the sponsor to track AEs and assess daily 
use of study marijuana as well as other substances. The Daily Diary will be an electronic 
data capture form completed on an electronic device. Information collected with this 
diary will include participants’ self reported quality and duration of sleep, the daily 
amount of marijuana used concomitant use of alcohol, medications, or other drugs, as 
well as AEs. Daily diary reports will be confirmed and verified by phone contact, 
reviewing video of participants’ self-administration of marijuana, and qualitative urine 
drug testing at the sites.  
 
The LTFU questionnaire is a sponsor-developed self-report instrument that will gather 
information on current psychiatric health and wellbeing, including the occurrence of new 
traumatic events, and questions concerning the number and type of new treatments for 
PTSD the participant has undergone since his or her final visit during the treatment 
period. The LTFU questionnaire takes approximately five minutes to complete, and will 
be completed by the participants at the six-month follow-up.  
 
Laboratory testing of blood/urine cannabinoids will be conducted by an accredited 
laboratory with an appropriately sensitive, specific and validated assay, as specified in 
Section 10.2. Peripheral blood samples will be collected and stored for biomarker 
analysis of cannabinoids (THC, 11-OH-THC, THC-COOH), CBD metabolites and 
inflammation markers with appropriately sensitive, specific and validated assays for 
CRP, IL-1β, and IL-6. Peripheral blood will be drawn at specified times in the Time and 
Events Labs table and analyzed according to procedures described in Section 10.0. 
 
Questions regarding the belief of condition assignment and certainty of the belief will be 
asked of site staff and participants at the End of Stage 1 and End of Stage 2. These beliefs 
are collected as a part of the sponsor’s ongoing initiative to optimize the double-blind as 
a part of drug development studies.  


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Table 1: Time and Events (Administrative Procedures)   
A= Initial phone screen with coordinator, secondary phone screen to be performed by CI/Qualified designee or Clinician. B= Participants will have 3 days of phone contact after each second 
introductory session in Stage 1 and Stage 2. (more contact may occur as needed) Participants will have a mid-week phone contact during Stage 1 and Stage 2 self-administration weeks 2 and 3. C= 
Participants will be contacted one week after the beginning of Cessation. D= Participants will have a mid-week phone contact.
Stage 1
Cessation 1
Stage 2
Cessation 2
Stage 3
 
Screen 
Baseline 
Introduct
ory 
Sessions
Self-
administr
ation
Primary 
Endpoint 
Cessati
on 1 
Stage 2 
Baseline 
Introduct
ory 
Sessions
Self-
administrati
on
Secondar
y 
Endpoint
Cessati
on 2 
LTFU 
Baselin
e
Stage 3 
(optional) 
LTFU 
Visit # 
Prescreen 
& Screen 1
Screen 2 
Enrollment 
V1 & V2 
V3 & V4 
V5 
V6 
V7 
V8 & V9 
V10 & V11 
V12 
V13 
V14 
V15-V23 
(as needed)
LTFU 
Type of Visit 
Telemed 
Visit & Site 
Visit 
Telemed 
Visit & 
Site Visit  
Site Visit  
 
Site Visit  
 
Weekly 
Site Visits 
Telemed 
Visit  
Site 
Visit  
 
Telemed 
Visit & 
Site 
Visit  
Site Visit  
 
Weekly Site 
Visits 
Telemed 
Visit  
Site 
Visit  
 
Teleme
d Visit 
& Site 
Visit  
Weekly 
Site Visits  
(as needed) 
Teleme
d Visit 
and/or 
Site 
Visit
Visit Timing 
Prescreen 
calls up to 
2 months 
prior, in-
person and 
Telemed 
procedures 
at least 2 
weeks prior 
to 
Enrollment 
2 weeks 
after 
Screen 1 
2 weeks 
after Screen 
1, once 
cannabinoi
d results are 
obtained  
(Day 0 
begins at 
Enrollment) 
Occur on 
2 
consecuti
ve days 
(Week 1 
begins 
following 
Intro 
Session 2) 
Between 
start of 
Week 2 & 
start of 
Week 3 
Between 
end of 
Week 3 & 
start of 
Week 4 
 
May be 
combined 
with V6 
Within 
2 days 
of 
Primar
y 
Endpoi
nt  
Between 
end of 
Week 5 
& start 
of Week 
6 
Post 
cannabino
id results 
Occur on 
2 
consecuti
ve days 
(Week 6 
begins 
after Intro 
Session 4) 
Between 
start of Week 
7 & start of 
Week 8 
Between 
end of 
Week 8 &
start of 
Week 9 
 
May be 
combined 
with V13 
Within 
2 days 
of 
Second
ary 
Endpoi
nt 
Betwee
n end 
of 
Week 
10 & 
start of 
Week 
11 
Post 
cannabinoi
d results  
Week 11-
18  
6 
months 
after 
V12 
(may 
take 
place 
over 
more 
than 
one 
day)
Phone Screen
A
ICF
 
Brief Medical 
& Psych 
History
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed 
Physical 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
Therapy & 
Medications
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment & 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on 
Self-
Administration
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video Data 
Review
 
 
 
 
Weekly 
 
 
 
 
Weekly 
 
 
 
Weekly 
 
Dispense Drug
Post V2
Weekly
Post V9
Weekly
Weekly
Weigh Unused 
Marijuana
 
 
 
 
Weekly 
 
 
 
 
Weekly 
 
 
 
Weekly 
 
Phone Calls 
 
 
 
 
WeeklyB 
 
Weekly
C
 
 
WeeklyB 
 
Weekly
C
 
WeeklyD 
 
Collect AEs
 
 
 
 
 
 
 
 
 
 
 


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Table 2: Time and Events (Laboratory Procedures)   
 
A = Quantitative THC testing to be conducted in THC positive participants only. Blood and urine will be obtained and stored regardless of THC results. B = Completed before & immediately after self-administration and 
every 30 minutes thereafter until end of the visit. C= BP and BT will be obtained prior to self-administration, 30 minutes after starting self-administration and again at the end of each session, approximately four hours after 
starting self-administration.  
 
 
Stage 1
Cessation 1
Stage 2
Cessation 2
Stage 3
 
Screen 
Baseline 
Introductory 
Sessions
Self-
administration
Primary 
Endpoint
Cessation 1 Stage 2 
Baseline
Introductory 
Sessions
Self-
administration
Secondary 
Endpoint
Cessation 2
LTFU 
Baseline
Stage 3 
(optional)
LTFU 
Visit # 
Prescreen & 
Screen 1
Screen 2 
Enrollment 
V1 & V2 
V3 & V4 
V5 
V6 
V7 
V8 & V9 
V10 & V11 
V12 
V13 
V14 
V15-V23 
(as needed)
LTFU 
Type of Visit 
 
 
 
Telemed Visit 
& Site Visit 
Telemed 
Visit & Site 
Visit  
Site Visit  
Site Visit  
 
Weekly Site 
Visits 
Telemed 
Visit  
Site Visit  
Telemed 
Visit & 
Site Visit
Site Visit  
 
Weekly Site 
Visits 
Telemed 
Visit 
Site Visit  
 
Telemed 
Visit & 
Site Visit 
Weekly Site 
Visits  
(as needed) 
Telemed 
Visit 
and/or Site 
Visit
Visit Timing 
Prescreen calls 
up to 2 months 
prior, in-person 
and Telemed 
procedures at 
least 2 weeks 
prior to 
Enrollment 
2 weeks 
after Screen 
1 
2 weeks after 
Screen 1, 
once 
cannabinoid 
results are 
obtained  
(Day 0 
begins at 
Enrollment) 
Occur on 2 
consecutive 
days 
(Week 1 
begins 
following 
Introductory 
Session 2) 
Between start of 
Week 2 & start 
of Week 3 
Between 
end of 
Week 3 & 
start of 
Week 4 
Within 2 
days of 
Primary 
Endpoint 
Between 
end of 
Week 5 
& start of
Week 6 
Post 
cannabinoid 
results 
Occur on 2 
consecutive 
days 
(Week 6 
begins after 
Introductory 
Session 4)
Between start of 
Week 7 & start 
of Week 8 
Between 
end of 
Week 8 &
start of 
Week 9 
Within 2 
days of 
Secondary 
Endpoint 
Between 
end of 
Week 10 
& start of 
Week 11 
Post 
cannabinoid 
results  
Week 11-18 
6 months 
after V12
(may take 
place over 
more than 
one day) 
Blood 
Cannabinoid
A 
A 
 
 
 
 
A 
A 
 
 
 
A 
A 
 
 
Biomarker 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualitative 
Urinary Drug
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
Quantitative 
Urinary Drug
A 
A 
 
 
 
 
 A 
 A 
 
 
 
 A 
 A 
 
 
Urinary EtG
 
 
 
 
 
 
 
 
 
 
 
Urinary 
Pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Labs
 
ECG
 
BP & BT 
 
 
 
C 
Weekly 
 
 
 
 C 
Weekly 
 
 

Weekly 
 
Pulse Oximetry
 
B
B


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Table 3: Time and Events (Study Measures) 
 
 
Stage 1 
Cessation 1 
Stage 2 
Cessation 2 
Stage 3 
 
 
Screen 
Baseline 
Introductory 
Sessions
Self-
administration
Primary 
Endpoint
Cessation 1 Stage 2 
Baseline
Introductory 
Sessions
Self-
administration
Secondary 
Endpoint
Cessation 2
LTFU 
Baseline
Stage 3 
(optional)
LTFU 
Visit # 
Prescreen & 
Screen 1
Screen 2 
Enrollment 
V1 & V2 
V3 & V4 
V5 
V6 
V7 
V8 & V9 
V10 & V11 
V12 
V13 
V14 
V15-V23 
(as needed)
LTFU 
Type of Visit 
Telemed Visit 
& Site Visit 
Telemed 
Visit & Site 
Visit  
Site Visit  
 
Site Visit  
 
Weekly Site 
Visits 
Telemed 
Visit  
Site Visit  
 
Telemed 
Visit & 
Site Visit
Site Visit  
 
Weekly Site 
Visits 
Telemed 
Visit  
Site Visit  
 
Telemed 
Visit & 
Site Visit 
Weekly Site 
Visits  
(as needed) 
Telemed 
Visit 
and/or Site 
Visit
SCID
 
CAPS-5
 
 
F
 
 F
 
BDI-II
 
IDAS
 
 
 
 
 
 
 
 
ISI
 
 
 
 
 
 
 
 
IPFG
 
 
 
 
 
 
PCL-5E
 
 
 
 
 
 
 
 
 
ACT 
  
C  
 
 
 
  
 
 
 
 
  
 
 
  
D 
MWCH
 
 
 

 
 
 
CUDIT-R
 
 
 
DEQ
A
B
A
B
B
Daily Diary
 
 B
 B
 
 
 
 B
 B
 
 
 
 B
CSSRS & GWB
 
 
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WBR
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STOP-Bang
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Belief of 
Condition
 
 
 
 
 
 
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LTFU 
Questionnaire
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TLFB
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 A = Completed before & immediately after self-administration and every 30 minutes thereafter until end of session. B = Completed immediately after each self-administration C = Actigraphy use must begin one week prior 
to the first Introductory Session. D = Final week only. E= Will measure past week. LEC plus Criterion A to be assessed at baseline only. F= CAPS-5 assessments at these timepoints will measure the last week.G= Visit 6 will 
be based on past 3 weeks, Visit 7 will be based on the past 2 weeks, Visit 13 will be based on the past 3 weeks, Visit 14 will be based on the past 2 weeks, LTFU will be based on the last month. H= Will measure the past 2 
weeks. 
 
 
 
 
 
 
 


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Figure 1: Summary of Events 
 
 
 
 


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5.2 Study Procedures and Visit Descriptions 
 
5.2.1 Pre-screening  
 
All individuals who enter pre-screening, as defined in this section, should be assigned a 
screening number and recorded on the “Screening Log”. The candidate’s screening 
number will also be noted on the signed informed consent form (ICF). Candidates who 
do not meet all eligibility criteria will not be enrolled. An IRB-approved phone screening 
script will be used to initially screen candidates. Pre-screening information will be 
retained for candidates who provide specific permission via the ICF for utilization and 
retention of this information. If candidates do not provide this permission, only the reason 
for not enrolling will be retained in study records. A Case Report Form (CRF) will not be 
completed for candidates who are not enrolled. These candidates will be documented 
only on the screening log and source records completed during screening. The site staff 
should record either the reason why an individual was not enrolled or the enrollment date 
and assigned participant number on this log. It is the responsibility of the investigator to 
file this document in the investigator site file (ISF) to be readily available for on-site 
monitoring and/or for inspection by the relevant authorities.   
 
5.2.2 Screen 1 
 
If pre-screening information after telephone screening with site staff and the CI or 
qualified designee suggests the candidate may be suitable for the study, site staff will 
schedule the Screen 1 visit. The Screen 1 visit consists of an in-person site visit and an IR 
visit in person or by telemedicine or phone.  
 
a) Explain and obtain written informed consent from the candidate. Written 
informed consent must be obtained prior to performing any study-specific tests or 
evaluations.  
b) Ensure that the candidate has been issued a screening number. Complete the 
Screening Log for this visit.  
c) The candidate will provide a medical and psychological history including current 
and past medications and therapies. Prior to enrollment the subject should sign a 
medical release form to allow the CI to review medical records to ensure the 
participant has no underlying medical conditions and to confirm PTSD diagnosis. 
d) Review with participants of childbearing potential their ability to become 
pregnant and commitment to practice appropriate birth control as determined by 
the CI or qualified designee for the total duration of the study. 
e) The CI or qualified designee will assess prior substance use through the TLFB 
procedure for the past three months. 
f) The CI or qualified designee will assess GWB. 
g) The CI or or qualified designee will administer the C-SSRS to assess suicide risk.  
h) The candidate will complete the PCL-5, MWC, CUDIT-R, BDI-II, and STOP-
Bang.   
i) The IR will perform all relevant portions of the Structured Clinical Interview for 
DSM -5 Diagnoses – Research Version (SCID-RV) and SCID for personality 
disorders, which are module-based structured psychiatric interviews, to assess 


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study eligibility.  To establish reliability, the IR will have the option to video 
record the SCID interviews in as many instances as necessary. 
j) A physician, who may be the CI or qualified site staff, will perform a medical 
history directed physical examination. The examination will involve the following 
procedures:  
 Blood pressure 
 Pulse  
 Height/weight 
 Body temperature 
 Examination of head, eyes, ears, nose, throat, skin, heart, lungs, abdomen 
and extremities 
 Brief neurological exam (cranial nerves 2-12, sensory, motor, reflexes and 
cerebellar function) 
k) The following clinical assessments will be collected and reviewed by the CI or 
qualified site staff: 
 
Electrocardiogram (ECG), the ECG will be used to establish eligibility and 
any clinically significant findings would be captured in the Medical History. 
 
Serum electrolytes, metabolic profile, urinalysis and complete blood count. 
The clinical laboratory values will not be captured in the CRF, but will be 
used to establish eligibility and will be kept with the participant’s source 
record. Clinically significant findings would be captured in the Medical 
History. 
 
Qualitative Urine drug screening  
 
Qualitative urine-dip EtG test to assess alcohol consumption 
 
Urine-dip pregnancy test in participants with childbearing potential 
 
Blood cannabinoid analysis will be collected (will be sent for analysis only if 
quantitative urine analysis is inconclusive in determining abstinence) 
 
Quantitative Urine drug testing (will send for analysis only if pre- and post-
cessation qualitative urine drug screens are positive for THC-COOH) 
 
Pulse oximetry 
l) If, upon examination, there are questions raised about possible medical problems, 
the CIs will request a review of medical records and request additional tests or 
assessments as indicated. 
m) The site staff will discuss having participant identify a community observer who 
can be contacted to participate in the study. This is a person who the participant 
typically interacts with on at least a weekly basis (e.g. friend, family member, co-
worker, counselor/therapist) and who can comment on their health, behavior, and 
psychosocial engagement. The participant will provide the site staff with a 
telephone number in order to reach the community observer for the WBR.  
n) If the candidate meets all initial screening criteria, site staff will schedule the 
Screen 2 Visit. 
 


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5.2.3 Screen 2  
 
The Screen 2 visit should be completed approximately two weeks after Screen 1 and 
consists of an in-person site visit and an IR visit by telemedicine or phone.  
 
a) A blinded IR will administer the last month CAPS-5 in a face-to-face visit or via 
telemedicine.  
b) To establish reliability, the IR will have the option to video record the CAPS 
interview in as many instances as necessary. 
c) Peripheral blood will be collected for:  
 Blood Cannabinoid testing 
 Biomarker analyses 
d) Participants will be required to stop using non-study marijuana for a 2-week 
baseline screening period (and for the duration of the treatment period). 
Compliance will be assessed by either: 1) Qualitatively negative urine drug 
screen, or 2) Sequential quantitative urine drug screens that indicate 90% or 
greater confidence in abstinence based on the algorithm developed by Huestis and 
colleagues [77], or 3) 80% confidence in compliance based on the Huestis 
algorithm and ratios of THC to 11-OH-THC and THC-COOH in blood that 
suggest no recent use has occurred. If a participant fails the test for abstinence, 
they will be given one additional chance at the 2-week baseline abstinence period. 
e) Perform a urine-dip pregnancy test on females with childbearing potential. 
f) Perform a urine-dip EtG test on all participants to assess alcohol consumption. 
g) The participant will complete the WBR. 
h) Site staff will contact the community observer for completion of the WBR. 
i) Participants will be issued and receive orientation on use of the Actigraph. The 
Actigraph should be used for one week prior to the first Introductory Session. 
Participant will be instructed to wear the Actigraph 24 hours a day, removing only 
when there is potential for water damage (e.g. dishwashing or showering). 
 
5.2.4 Enrollment 
 
Day 0 of the study will be the day of enrollment. Enrollment will be completed after 
the two-week screening period and obtaining quantitative Cannabinoid Results from 
applicable participants. 
 
a) Inquire about any possible changes in the participant’s health to ensure they 
continue to meet eligibility criteria.  
b) After eligibility is confirmed, the candidate may be enrolled. Issue a participant 
number. 
c) The CI or site staff will schedule introductory sessions and the beginning of the 
period of active dosing.  
d) Collect information on any changes in psychotherapy or medications for the 
participant.  
e) Participants will receive a research participant identification card (“wallet card”) 
stating that they are a research participant and may test positive for drugs and 


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listing CI contact information, the telephone number for a 24-hour hotline for 
participant support, and instructions on how and when to present the card. 
f) Obtain/confirm the name and telephone number of an emergency contact from the 
participant for use throughout the study. 
g) The participant will complete the IDAS, ISI, IPF, WBR, PCL-5, MWC, and Daily 
Diary.  
h) Site staff will contact the community observer for completion of the WBR. 
i) The CI or qualified site staff will administer the CSSRS and GWB. 
j) Perform a urine-dip EtG test on all participants to assess alcohol consumption. 
k) Randomization will occur after enrollment and prior to the day of the first 
introductory session. 
l) Throughout the study, concomitant medications and therapies and AEs will be 
collected at each contact as described in Sections 8.0 and 9.0 of the protocol. 
 
5.2.5 Introductory Sessions in Stage 1 (Visit 1 and Visit 2) and Stage 2 (Visit 8 and 
Visit 9) 
 
This visit will be conducted one week after the Screen 2 visit. To standardize method of 
self-administration and to assess psychological risk, this protocol will include two four-
hour long introductory sessions, where the participants will self-administer marijuana 
under observation and receive training, on two consecutive days as an added safety 
procedure prior to the initiation of each treatment phase.  
 
a) At the first introductory session, the participant will bring their Actigraph to the 
study site. The site staff will copy all recording files, note the time and date stamp 
and save for baseline analysis. The Actigraph memory will be cleared, the device 
charged and returned to the participant to use for the self-administration period. 
b) Site staff will provide the participant with information about marijuana, including 
expected psychoactive and physical effects, and a standardized procedure for 
smoking marijuana using the pipe provided for use throughout the study. Methods 
will be discussed for documenting and managing any side effects of smoking 
marijuana. This will include information about community support, breathing 
strategies, as well as what rescue psychotherapy or medications are available for 
participants to use if needed. 
c) Participants will complete a qualitative urine drug test and a pregnancy test (if of 
childbearing potential). 
d) Perform a urine-dip EtG test on all participants to assess alcohol consumption. 
e) On the first of the two introductory sessions, participants will self-administer 5 
standardized puffs (5 second inhale, 10 second breath hold, 40 second inter-puff 
interval) of marijuana using the provided marijuana pipe.  This will provide a 
standardized level of initial exposure across participants.  On the second session, 
participants will be allowed to self-administer marijuana in an ad-libitum manner 
for up to 45 minutes from the first inhalation to simulate outpatient use. After this 
point, the measurements to be taken immediately after smoking will be obtained. 
f) In both sessions, pulse oximetry and DEQ assessments will be conducted before, 
immediately after, and then every 30 minutes for four hours post-marijuana 


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exposure. 
g) In both sessions, CSSRS and GWB will be collected before self-administration 
and four hours after self-administration. 
h) Vital signs (blood pressure/body temperature) will be obtained at the beginning of 
each introductory session prior to self-administration, 30 minutes after starting 
self-administration and again at the end of each session, approximately four hours 
after starting self-administration. 
i) Participants will be oriented on the use of a lockable storage box and a portable 
tablet device. 
j) The site staff will instruct the participants on electronic diary entry completion. 
k) Participants will either arrange a ride from the study site to their current place of 
residence or the site staff will assist them in finding a means of transport from the 
study site. 
l) Participants will not be provided marijuana to take home between introductory 
session 1 and session 2. 
m) The introductory visits will be conducted again at the beginning of Stage 2 
because the type of marijuana provided to participants will be different, and 
participants randomized to placebo in Stage 1 will be receiving active marijuana 
for the first time in Stage 2. 
n) At the end of the second introductory session in the absence of contraindications, 
site staff will provide the participant with a weekly kit containing seven packages 
of 1.8 grams of marijuana for participants to self-administer for one week of the 
three-week self-administration period. The type of marijuana provided will 
change from Stage 1 to Stage 2, but will not change within stages.  Participants 
will receive clear instructions to not use marijuana not provided to them as part of 
the study and not to share the study marijuana with any other individual. 
 
5.2.6 Daily Contact after Introductory Sessions 
 
a) Starting after the second introductory session, one of the CIs or site staff will 
contact the participant via telephone or in person on a daily basis for three days. 
Additional contact may be made as participants or clinicians feel necessary. 
b) The daily telephone contact is expected to last between 5 and 15 minutes, or as 
long as necessary to address any participant’s concerns and to assess the 
participant’s wellbeing. 
c) Collect information on any changes in psychotherapy, AEs, or medications for the 
participant. 
d) The CI or qualified designee will administer the C-SSRS. 
e) Site staff will record GWB and responses to questions on any changes in mood or 
behavior after each telephone call. If the CI or qualified designee has any 
concerns about emerging psychiatric symptoms, then he or she will refer the 
participant to the site CI for evaluation. 
f) After the first week, participants will return to the study site for another week’s 
worth of marijuana. 
 


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5.2.7 Self Administration during Stage 1 and Stage 2 
 
Participants will self-administer marijuana for three weeks during Stage 1 and Stage 2. 
They will come to the study site for weekly visits. Weekly visits may be completed 
within three days of when they are scheduled. If any visits are completed out of window, 
the CI and sponsor should assess effects on protocol compliance on a case-by-case basis. 
Week 1 starts on the day after Introductory Session 2. 
 
a) During each three week self-administration period, there will be a daily upper 
quantity limit of 1.8 grams per day, which participants may use at any time that 
day, with a day defined as a period of 24 hours in this study, from 12:00 AM 
(midnight) to 11:59 PM of that day. There will be no lower quantity limit, and 
participants do not have to use any of the daily allotment should they decide that 
symptoms do not require medication on any particular day.   
b) Participants will be required to video record each self-administration on the same 
portable tablet. The participants will be instructed on reducing risks of others 
viewing or publicly presenting their recordings on the Internet.  
c) The DEQ and Daily Diary will be completed electronically though a portable 
tablet immediately after each self-administration. 
d) Participants will be required to wear the Actigraph daily. 
e) The CI or site staff will telephone the participant midweek to assess GWB and 
any AEs. 
f) The participant will undergo weekly assessments at the study site as described 
below. 
 
5.2.8 Weekly Evaluations during Stage 1 (Visit 3 and Visit 4) and Stage 2 (Visit 10 
and Visit 11) 
 
Participants will meet with the CI or site staff at the study site once a week during the 
self-administration period. 
 
a) Inquire about any possible changes in the participant’s health to ensure they 
continue to meet eligibility criteria.  
b) Collect information on any changes in psychotherapy, AEs or medications for the 
participant. 
c) Obtain vital signs from the participant. 
d) Obtain a urine sample to test drugs of abuse.   
e) Females of childbearing potential will have a pregnancy test performed. 
f) The CI or qualified site staff will administer the C-SSRS. 
g) The participant will complete the IDAS, ISI, WBR, PCL-5 and the DEQ. 
h) The CI or site staff will telephone the community observer on a weekly basis to 
complete the WBR assessment. 
i) Participants will return any unused marijuana in the original package dated by day 
of use from the last week of self-administration. Any unused marijuana from each 
weekly allotment will be returned to the CI or designee to be weighed and 
accounted for at the end of the week prior to receiving the next weekly supply. 


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Marijuana will be labeled with the participant number and date. The remaining 
marijuana will be preserved and securely stored at the site until destruction 
following DEA regulation. 
j) The participant will bring their portable tablet to the study site. The site staff will 
review all video recording files, noting the time and date stamp. Study staff will 
verify participant identity, safety, and compliance through review of video 
recordings, as well as telephone contact reports. The portable tablet will be 
cleared of content and returned to the participant. 
k) The participant will bring their Actigraph to the study site. The site staff will copy 
all recording files, note the time and date stamp and save for analysis. The 
Actigraph memory will be cleared, the device charged and returned to the 
participant to use for the next week. Upon analysis, if any days are missing from 
recordings, participants will be re-trained the next time they are contacted by site 
staff. 
l) If video data review indicates compliance with the protocol, the site staff will 
provide the participant with a week of daily marijuana for take-home use and will 
remind the participant to complete the Daily Diary.  
m) Perform a urine-dip EtG test on all participants to assess alcohol consumption. 
n) Identical weekly evaluations like this will occur until the next cessation period.  
 
5.2.9 Primary and Secondary Endpoint Evaluations in Stage 1 (Visit 5) and Stage 2 
(Visit 12) 
 
This visit will be conducted at the end of self-administration in each stage. This meeting 
will take place in person, via telemedicine or phone. This visit may take place on the 
same day as Visit 6 or Visit 13 (Day 1 of cessation in Stage 1 or Stage 2). 
 
a) Participants will meet with the IR for a 60 to 90 minute evaluation.  
b) The IR will administer the last month CAPS-5.  
 
5.2.10 Two Weeks of Abstinence from Marijuana Self-Administration during 
Cessation 1 (Visit 6) and Cessation 2 (Visit 13) 
 
Participants will cease to self-administer marijuana for a two-week interval. After a face-
to-face visit, participants will complete a telephone contact and self-report measures one 
week after the start of cessation. The Daily Diary will continue to be completed daily. 
 
a) At the start of the Cessation period, immediately after completion of the 
primary/secondary endpoint assessment, participants will visit the study site. This 


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visit may be conducted on the same day as the endpoint assessment or within two 
days of it. 
b) The participant will complete the IDAS, ISI, IPF, WBR, PCL-5 and the MWC. 
c) Site staff will contact the community observer for completion of the WBR. 
d) The CI or qualified designee will administer the C-SSRS and GWB. 
e) The participant and a blinded site staff member will provide their belief of 
condition assignment. 
c) Inquire about any possible changes in the participant’s health to ensure they 
continue to meet eligibility criteria.  
d) Collect information on any changes in psychotherapy, health or medications for 
the participant. 
e) Obtain vital signs from the participant. 
f) Obtain a urine sample to test drugs of abuse.  Participants of childbearing 
potential will have a pregnancy test performed. 
g) Participants will return any unused marijuana in the original package dated by day 
of use from the last week of self-administration. Any unused marijuana from each 
weekly allotment will be returned to the CI or designee to be weighed and 
accounted for. Marijuana will be labeled with the participant number and date. 
The remaining marijuana will be preserved and securely stored at the site until 
destruction per DEA instruction. 
h) Peripheral blood will be collected for:  
 Blood Cannabinoid analyses 
 Biomarker analyses 
i) The participant will bring their portable tablet to the study site. The site staff will 
review all video recording files, noting the time and date. Upon receipt, site staff 
will verify participant identity, safety, and compliance through review of video 
recordings, as well as telephone contact reports. Upon review, if any days are 
missing from recordings, participants will be re-trained by site staff. The portable 
device will be cleared of content and returned to the participant.  
j) The participant will bring their Actigraph to the study site. The site staff will copy 
all recording files, note the time and date stamp and save for analysis. The 
Actigraph memory will be cleared, the device charged and returned to the 
participant to use for the next week. Upon analysis, if any days are missing from 
recordings, participants will be re-trained the next time they are contacted by site 
staff. 
k) The site staff will instruct the participant to complete the Daily Diary to assess, 
sleep patterns, continuing substance and medication use patterns and AEs during 
cessation. 
l) The site staff and participant will discuss the two-week period of cessation of 
marijuana use.  
m) One week after the beginning of cessation, participants will complete the MWC , 
IDAS, ISI, IPF, WBR, and PCL-5 electronically. Participants will be reminded to 
complete self-report measures in a timely manner. 
n) One week after the beginning of cessation the CI or site staff will telephone the 
community observer to complete the WBR assessment. 
 


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5.2.11 Re-Baseline Evaluation at end of Cessation 1 (Visit 7) and Cessation 2 (Visit 
14) 
 
At the end of the Cessation period, two weeks after completion of the primary/secondary 
endpoint assessment, participants will visit the study site.  
 
a) The participant will complete the IDAS, ISI, IPF (past 2 weeks), WBR, PCL-5 
and the MWC. 
b) The participant will complete the CUDIT-R only at Visit 14. 
c) Site staff will contact the community observer for completion of the WBR. 
d) The CI or qualified site staff will administer the C-SSRS and GWB. 
e) Participants will meet with the IR for a 60 to 90 minute evaluation, either in a 
face-to-face or telemedicine meeting to administer the last week CAPS-5. 
f) During the site visit, site staff will inquire about any possible changes in the 
participant’s health to ensure they continue to meet eligibility criteria.  
g) Collect information on any changes in psychotherapy, AEs or medications for the 
participant. 
h) Obtain vital signs from the participant. 
i) Obtain a urine sample to test drugs of abuse.  
j) Females of childbearing potential will have a pregnancy test performed. 
k) The participant will bring their Actigraph to the study site. The site staff will copy 
all recording files, note the time and date stamp and save for analysis. Participants 
will not be given the Actigraph in Stage 3. 
l) The site staff will instruct the participant to complete the Daily Diary during 
upcoming self-administration through electronic patient reported outcomes 
(ePRO). 
m) Perform a urine-dip EtG test on all participants to assess alcohol consumption. 
n) Peripheral blood will be collected for:  
 Blood Cannabinoid levels analysis  
 Biomarker analyses  
o) After this assessment, participants will either continue in the crossover arm (Stage 
2) with associated introductory sessions as described in Section 5.2.3, or they may 
continue to the optional Stage 3 as described in Section 5.2.9 if they have already 
completed Stage 2. Participants who do not continue to Stage 3 will be required to 
return the lockable storage box and portable tablet to site staff. 
 
5.2.12 Stage 3  
 
Stage 3 is an optional continuation of the study for participants who request the amount 
of returned marijuana from Stage 1 or Stage 2 to be issued from a new supply of 
marijuana. Site visits will be conducted weekly as needed to complete Stage 3, which will 
last up to two months or until remaining marijuana is consumed. 
 
a) The CI will dispense marijuana in the amount that was left over from Stage 1 or 
Stage 2 according to the participants randomization in Stage 1 and/or Stage 2 
from a new supply if the participant requests to take part in Stage 3.  Participants 


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will be able to choose to receive a weekly kit containing the same blend of 
marijuana from a new supply as their Stage 1 or Stage 2 study product supply at 
each weekly visit. 
b) Participants will retain the locked storage box and portable tablet to be used for 
Daily Diary and DEQ completion as in Stage 1 and Stage 2 if they chose to 
participate in Stage 3. 
c) Participants will be required to video record each self-administration on the same 
portable tablet.   
d) The CI or site staff will telephone the participant midweek to assess GWB and 
any AEs. 
e) The CI or site staff will telephone the community observer on a weekly basis to 
complete the WBR assessment. 
f) The participant will undergo weekly assessments at the study site as described 
below. 
 
During each weekly visit: 
 
a) Inquire about any possible changes in the participant’s health to ensure they 
continue to meet eligibility criteria.  
b) Collect information on any changes in psychotherapy, AEs or medications for the 
participant. 
c) Obtain a urine sample to test drugs of abuse.  Participants of childbearing 
potential will have a pregnancy test performed. 
d) Perform a urine-dip EtG test on all participants to assess alcohol consumption. 
e) The CI or qualified site staff will administer the CSSRS. 
f) Continued weekly visits will end when the participant has used an amount 
equivalent to the amount of returned marijuana or does not wish to continue using 
study marijuana, or two months have passed, at which point he or she must return 
all remaining marijuana to the study site. The CI or site staff will weigh any 
returned marijuana. The marijuana will be stored securely at the site for drug 
accountability. 
g) The participant will return the portable tablet and locked box to the site staff. 
 
5.2.13 Long-term Follow-up 
 
This visit will be conducted 6 months after end of Cessation 2.  Visit may take place over 
more than one day, and will be conducted via telemedicine or in person at the study site. 
 
a) One week before the visit, site staff will clear the Actigraph memory, charge the 
device and mail it to the participant to use for the week prior to the six-month 
follow-up.  
b) On the day of the visit, inquire about any changes in the participant’s health to 
obtain resolution on any outstanding AEs. 
c) Collect information on any changes in psychotherapy, healthcare utilization, and 
medications for the participant. 
d) Substance use will be ascertained using the TLFB procedure for the past six 


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months. 
e) Participants will meet with the independent rater for a 60 to 90 minute evaluation. 
either in a face-to-face or telemedicine meeting to administer the last month 
CAPS-5. 
f) The participant will complete the IDAS, ISI, IPF (last month), WBR, PCL-5, 
MWC and CUDIT-R. 
g) Site staff will contact the community observer for completion of the WBR. 
h) The CI or qualified site staff will administer the C-SSRS and GWB. 
i) The participant will mail or bring their Actigraph to the study site. The site staff 
will copy all recording files, note the time and date stamp and save for analysis. 
Participants will not be given the Actigraph after this visit. 
j) A urinary drug test will be administered to test for drugs of abuse. 
k) The participant will complete the LTFU questionnaire. 
l) Upon completion of this visit, and after site staff obtain all outstanding data, 
participants will complete the study. 
 
5.3 Removal of Enrolled Participants from the Study 
 
Participants can withdraw consent at any time without prejudice. The CI can withdraw a 
participant if, in his or her clinical judgment, it is in the best interest of the participant or 
if the participant cannot comply with the experimental procedures and related visits that 
are critical for safety, and this will be recorded in the participant’s source records and 
CRF. Participants who are not able to comply with required periods of abstinence from 
marijuana use will be withdrawn from treatment. If the CI withdraws a participant from 
treatment, the CI will explain the reason for withdrawing to the participant, and refer 
them to standard clinical care for PTSD. Participants who are withdrawn will not be 
denied care within or outside of the VA or participating institutions. Participants will be 
clinically monitored after withdrawal by the CI. Whenever possible, the tests and 
evaluations listed for the termination and outcome visits will be carried out. Efforts will 
be made to obtain information about AE resolutions, if applicable. All participants who 
sign informed consent , meet study eligibility criteria including 2 weeks abstinence 
period prior to randomization, and who receive initial dose of study medication will be 
included in intent to treat analyses (including data/outcome data for study participants 
who withdraw consent up to the time consent is withdrawn). 
 
Participants who discontinue treatment during the study will not be replaced. Recruitment 
and enrollment will continue until 76 participants have completed the Primary Endpoint.  
 
5.4 Premature Discontinuation of the Study 
 
The sponsor or the CIs (following consultation with the sponsor) have the right to 
discontinue this study at any time. If the trial is prematurely terminated, the CIs are to 
promptly inform the study participants and will arrange appropriate follow-up. If the trial 
or study is prematurely discontinued, all procedures and requirements pertaining to the 


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archiving of documents will be observed. All other study materials will be returned to the 
sponsor, and will be treated in accordance with federal and local regulations.  
 
6.0 Investigational Product 
 
6.1 Substance Description and Activity Related to Proposed Action 
 
The active material to be used in this protocol is dried plant material from the cannabis 
plant (marijuana). Cannabis refers to the genus within the cannabacae family, containing 
possibly two species c. sativa and c. indica. They are hardy annual flowering plants, and 
dioecious, meaning there are male and female plants [105]. This plant or extracts from 
this plant have been used medicinally for thousands of years, and were legal in the US 
until 1937. Marijuana was removed from the United States Pharmacopeia and National 
Formulary [106]. Currently, it is a Schedule 1 controlled substance, meaning that it is 
illegal to possess, sell or distribute marijuana outside of research studies under federal 
laws. Individual states within the US have significantly reduced penalties for possessing 
small quantities of marijuana, have legalized marijuana, or have laws or legislation 
permitting physicians to recommend medical use of marijuana. Marijuana contains 
several active compounds, with THC acting as the chief psychoactive compound. THC 
acts on cannabinoid CB1 receptors in the brain, as well as CB2 receptors in the periphery, 
particularly within the immune system. These recently discovered receptors are activated 
by at least three endocannabinoids and endogenous fatty acids related to arachidonic acid. 
CB1 receptors are found throughout the human brain. CBD may also contribute to the 
psychoactive profile of marijuana [65, 107, 108], and possess therapeutic potential [108, 
109]. The subjective and potentially therapeutic actions of marijuana may be directly or 
indirectly influenced by other compounds found in the plant [108].  
 
The marijuana to be used in this study will be provided at cost by NIDA, should the study 
receive all the required regulatory approvals. Four types of marijuana obtained through 
the NIDA Drug Supply Program that vary in ratios of THC to CBD will be used: High 
THC, High CBD, THC/CBD, or placebo. Concentrations of 7-15% will be considered 
“High” and <2% will be considered “Low,” subject to availability of marijuana grown 
and harvested by NIDA. Ad-libitum self-administration will be permitted up to a 
maximum of 1.8 grams/day.  
 
The doses of marijuana (excluding placebo) were chosen because they contain a range of 
THC and CBD ratios and potencies generalizable to what many veterans are currently 
using to manage PTSD symptoms in non-clinical settings in states with legalized medical 
marijuana. The final doses and concentration to be tested are subject to availability 
through the NIDA Drug Supply Program. Prior to the study start, laboratory testing of the 
marijuana will be completed to verify chemical composition of each concentration group. 
The active doses are expected to produce all of the commonly reported subjective effects 
of marijuana. The physiological effects are expected to be tolerable based on previous 
observational studies in the literature. The placebo is expected to produce minimal side 
effects, without the range of psychological and subjective effects seen in active doses. 
 


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6.2 Substance Concentrations, Packaging and Labeling 
 
This protocol will compare marijuana differing in THC or CBD concentrations. Any 
unused portions of the marijuana that participants did not consume during each day will 
be placed back in the daily packet and kit from which it came and collected on a weekly 
basis, with all packages labeled with day of use returned to the CI at the end of the self-
administration in Stage 1 and 2. Participants may choose to receive the amount of 
marijuana returned in Stage 1 or Stage 2 as a part of Stage 3. Any unused marijuana will 
be tracked during the study and stored for drug accountability until destruction per DEA 
recommendations. 
 
6.2.1 Doses 
 
Study participants will be assigned to receive one of four marijuana conditions based on 
cannabinoid content: ~12.40% THC/~0.03%CBD (High THC), ~0.53% THC/~13.94% 
CBD (High CBD), ~7-9% THC/~7-9% CBD (THC/CBD) or ~0% THC/~0% CBD 
(placebo). Marijuana will be self-administered by the participant through smoking the 
study material.  
 
Participants will be introduced to the marijuana concentration and the self-administration 
method to be used during introductory sessions during which they will smoke the study 
material. The CI or qualified designee, under the direction of  a Schedule 1 license 
holder, will supply participants with packages containing seven doses of 1.8 mg per day 
for self-administration daily during a three-week period. Any daily unused portions will 
be placed in the packaging for that day and labeled with the date of use, with all unused 
material returned to the CI or designee during each weekly evaluation during the period 
of self-administration, and at the conclusion of the three-week period of active dosing, for 
precise weighing.  The CI or designee will store each participant’s unused study drug in a 
DEA approved secured container until destruction.  
 
 
Table 4: Participant Distribution by Concentration and Stage 
Stage 1: N= 76 (up to 116) Participants Randomized 1:1:1:1 to the Following Four Dose Groups
Stage 1 Arms 
High THC
High CBD
THC/CBD
Placebo
 
Stage 2: Participants from Stage 1 are Re-randomized 1:1 to the Following Dose Groups
Stage 1 Arms
Stage 2 
High THC 
High CBD
THC/CBD
High CBD 
High THC
THC/CBD
THC/CBD 
High THC
High CBD
Placebo
High THC
High CBD
 
 
 


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Table 5: Marijuana Doses in Stage 1 
Dose 
Min number of Participants receiving dose 
High THC/Low CBD
19
Low THC/High CBD
19
High THC/High CBD
19
Low THC/Low CBD
19
Table 6: Marijuana Doses in Stage 2 
Dose 
Approximate number of Participants receiving dose* 
High THC/Low CBD
25
Low THC/High CBD
25
High THC/High CBD
26
* Due to enrollment and dropouts to achieve N=76 for primary endpoint, the actual number of Stage 2 participants may be higher 
or lower
 
6.2.2 Packaging 
 
Marijuana will be sent in bulk from the NIDA to Johns Hopkins University in Maryland 
and to the Scottsdale Research Institute in Arizona. The marijuana will be received and 
packaged by appropriately qualified site personnel per the Schedule 1 license. There will 
be a designated unblinded witness observing all marijuana packaging following site SOPs 
and Sponsor requirements at each site. The qualified individuals will package all 
marijuana in blinded daily packets. Daily packets for weekly self-administration will be 
placed in blinded kits. Stage 3 kits will be packaged according to study needs upon 
subject requests based on returned Stage 1 or Stage 2 marijuana.   
 
6.2.3 Labeling 
 
Each concentration of marijuana will come in large tins labeled by NIDA. Unblinded Site 
staff, under observation by a designated unblinded witness, will package 1.8 grams of 
bulk marijuana in separate packages following site SOPs. Each blinded kit label will 
include the protocol number, substance name, kit number, sponsor name, a place for 
participant number to be entered, and a statement that the material is for self-
administration limited by law to investigational use only. Additional labels may be 
required per site SOPs. Marijuana will be individually packaged for each day in the 
amount of 1.8 grams for use during each introductory session, with marijuana 
concentration matching condition assignment for each participant in each stage according 
to the Randomization List. Each blinded packet label will include the protocol number, 
substance name, kit number, packet number (1-7), sponsor name, a place for participant 
number to be entered, a place for date of use to be entered,  and a statement that the 
material is for self-administration only in clinical trials. Blinded labels will be provided 
by the sponsor and applied by qualified individuals at the site . The package labels will 
not contain any information about the concentration of the marijuana in order to assure 
blinding of participant and CIs. A record linking the kit number to the concentration of 


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the marijuana provided to that participant will be maintained as part of the randomization 
system 
 
Figure 2: Drug Package Labels 
Kit Label 
MAPS Study# MJP1 
Investigational Product: Cannabis (marijuana)  
Dose: Blinded  
Kit #: XXXX 
Participant Number _____________ 
Keep in the lock box 
Store in a cool location. Keep out of heat 
Self-Administer as per protocol 
Caution-Limited by Law to Investigational Use Only 
Daily Packet Label 
MAPS Study# MJP1 
Investigational Product: Cannabis (marijuana)  
Dose: Blinded  
Kit #: XXXX 
Packet #: X 
Participant Number _____________ 
Date of use: ___/___/____ 
Keep in the lock box 
Store in a cool location. Keep out of heat 
Self-Administer as per protocol 
Caution-Limited by Law to Investigational Use Only
 
 
6.3 Substance Accountability 
 
Forms will be provided to the site to track drug accountability and administration 
throughout the study.  Equivalent forms of the sites choosing may be used. Blinded drug 
accountability will be reviewed during routine monitoring visits. Records pertaining to 
the use of Schedule 1 compounds will be maintained in accordance with relevant Federal 
and State Regulations, and institutional policies, where applicable. Marijuana dispensed 
during the study will be tracked by individual kit number, packet number, date, and 
participant number.  
 
6.4 Substance Storage and Handling 
 
Cannabis (marijuana) is a Schedule 1 controlled substance and will be stored and handled 
in compliance with relevant institutional policies (if applicable), Federal and State 
regulations and in accordance with Drug Enforcement Administration (DEA) 
requirements.  
 
6.5 Substance Stability 
 
Information on the concentrations of THC and CBD, and stability of these compounds, 
will be provided by NIDA. The sponsor may obtain an additional analysis from an 
independent testing laboratory with required DEA Schedule 1 license registration. 
 
7.0 Risks of Participation 
 
7.1 Risks of Screening, Study Procedures, Assessments and Measures 
 
Blood draws and a full medical examination are required to establish eligibility for the 
study. Blood draws are also required to assess quantitative cannabinoid levels during 
marijuana self-administration and during cessation of use as well as biomarkers for 
effects on inflammation. Temporary discomfort, inflammation or infection could arise as 
a result of sampling blood at the punctured vein. Measures of blood pressure, body 


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temperature, and heart rate will be taken to assess drug effects and participant safety. 
Participants may experience mild discomfort from having blood pressure assessed. 
Submitting to a full medical examination may also cause discomfort or psychological 
distress. Since medical examinations and blood draws are required to establish eligibility 
for the study, they cannot be omitted from the protocol. Psychological assessments will 
be obtained through interviews.  Because these interviews require individuals to discuss 
their condition, they may prove upsetting for some. Because psychiatric interviews and 
discussion of PTSD symptoms are used during screening, they cannot be avoided. The 
CIs have experience working with people with PTSD, and they will seek to reduce 
anxiety and distress during these interviews.  
 
A screen lock and pin will always be used on the tablet and encryption will be used to 
minimize the likelihood that anyone without the computer passcode could access stored 
files on the hard drive.  Recording marijuana use with video is necessary to verify that the 
participant is using the marijuana as directed, and to assure that the participant is not 
diverting any of the marijuana.  The Sponsor will enable the ability to delete files from 
the tablet computer remotely in the case that a device is lost or stolen.  Breech of 
confidentiality may still happen even with these measures, another individual may be 
able to view recordings of participant marijuana use during self-administration should 
they obtain the participant’s portable tablet. If this happens, it is possible that such 
recordings could be uploaded to a computer or displayed on a social media website.  A 
breech may also happen through mishandling of participant records.  This risk is 
mitigated by the use of standard research procedures for the secure storage and 
management of participant PHI described in more detail in Section 7.3.  
 
As with any medical procedure, there are potential risks associated with the use of 
telemedicine. In rare cases, information transmitted may not be sufficient (e.g. poor 
resolution or choppy video connection) to allow for appropriate medical decision making 
by site staff. Delays in medical evaluation and treatment could occur due to deficiencies 
or failures of the equipment or internet service. Though the telemedicine system that will 
be used is HIPAA compliant and secure, in very rare instances, security protocols could 
fail, causing a breach of privacy of personal medical information.  
 
7.2 Risks of Self-administering Marijuana 
 
There is an extensive literature on the risks of habitual marijuana use in humans, and a 
sizeable but considerably smaller literature on the acute effects of marijuana, including 
AEs. Most risks associated with ingesting or inhaling marijuana relate to its psychoactive 
effects, though marijuana can also produce acute effects on the cardiovascular system and 
continued use can produce effects on the pulmonary system. Psychoactive and acute 
cardiovascular effects are transient and dissipate after the effects of the substance have 
waned.  
 
Marijuana can alter mood, affect, and perception, producing increases in positive and 
negative mood states (as euphoria and anxiety), and intensifying sensory experiences, 
such as music seeming more intense [110]. Marijuana can impair attention, memory, and 


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visual tracking, and slow psychomotor performance. In a review of the literature, 
subjective effects were more strongly associated with marijuana than other effects [111]. 
One study found impaired visual tracking in male occasional cannabis users 
approximately an hour after administration [112]. The combination of alcohol and 
marijuana impaired simulated driving, particularly night-time driving, with regular 
cannabis users making a greater number of errors than occasional users [113], and the 
same team of researchers reported that alcohol and marijuana affected performance on a 
field sobriety test more than either substance alone [114]. Marijuana may provoke 
psychotic symptoms or psychosis in vulnerable individuals, though marijuana use alone 
is not a "cause" of psychosis [115, 116]. The literature is inconclusive, but indicates an 
association between regular marijuana use and psychosis or exacerbated psychotic 
symptoms. 
 
Regular, heavy use of marijuana is associated with impairments in cognitive function, 
especially in the area of short-term memory and executive functioning, with impairment 
retained up to a week after abstaining from use, but no longer detectable after 28 days of 
abstinence [117-119]. Visual tracking and divided attention was impaired in heavy daily 
cannabis users compared with ecstasy-user controls [120], but tracking and attention 
improved with three weeks of abstinence from marijuana. Since marijuana interferes with 
attention, alters mood and may generate shifts in sensory attention and perception, it is 
not surprising that regular use may be taxing on cognitive task performance. The degree 
of potential impairment experienced after a month of daily use cannot be estimated from 
these findings. It is likely that if impaired cognitive function is present, it will not remain 
after prolonged abstinence [121].   
 
Marijuana use may be associated with increased occurrence of panic attacks.  A 
prospective (longitudinal) study in adolescents reported that marijuana use or dependence 
was associated with a greater likelihood of experiencing panic attacks[122], and people 
with marijuana dependence were more likely to report experiencing panic attacks [123]. 
 
Van Ours and colleagues (2013) examined the predictive value of marijuana use onset 
and monthly use upon self-reported suicidal ideation through examining data from a 
longitudinal study of a cohort born in 1972, concluding that onset of marijuana use 
preceded likelihood of reporting suicidal ideation in males, but not females [124]. The 
authors did not find that suicidal ideation preceded marijuana use, though it is notable 
that questions concerning suicidal ideation were not posed until respondents were 15 
years old. Previous research has addressed suicidal ideation in marijuana users, largely in 
samples of adolescents.  
 
Though a review of studies found that marijuana impairs most skills used in driving 
motor vehicles, driving and simulation studies fail to find strong effects of marijuana 
upon driving [125]. Researchers conducting controlled studies of people driving under 
the influence of marijuana reported that effects, while present, were relatively small and 
comparable to other medicines or alcohol [126]. This may be the result of people under 
the influence of marijuana overestimating their level of impairment, and thus driving 
more conservatively [125, 127]. Nonetheless, epidemiological studies of road accidents 


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have found a relation between use of marijuana, including blood THC levels, and road 
accidents [128-131], with higher levels of THC associated with greater impairment in 
driving. Elvik (2012) carried out a meta-analysis of illicit psychoactive drug use and the 
likelihood of a road traffic accident [129], reporting that cannabis was associated with 
minor, but not significantly, increased odds of traffic accidents -  lower than the rate 
associated with benzodiazepines.  Sewell and colleagues concluded that a review of the 
literature suggests a degree of inter-individual variability in degree of impairment 
experienced by drivers after marijuana, including less impairment in experienced users 
[125].  They recommend that people not drive or use heavy machinery for up to three 
hours after marijuana use, and that people using marijuana seek a designated driver. 
Other recent analyses support Sewell and colleagues’ recommendation that people restrict 
driving for three hours after marijuana use [132, 133].  
 
Like many substances that produce increased positive mood and relaxation, marijuana 
can lead to abuse or dependence in some people, with approximately 1.6% of the general 
population  experiencing dependence upon marijuana [134]. The rate at which people 
who try marijuana become dependent is estimated as either slightly lower than or similar 
to that for alcohol, and higher than rates of dependence for hallucinogenic (psychedelic) 
compounds [135].  
 
Acutely, marijuana increases heart rate, increases supine blood pressure, and, after higher 
doses, produces orthostatic hypotension; it increases cardiac output, decreases peripheral 
vascular resistance, and dose-dependently decreases maximum exercise performance. 
Changes in cardiovascular function may occur with prolonged use. These include: 
hypotension when lying down, an increase in blood volume, slowed heart rate and 
diminished circulatory response to exercise [136]. These findings are in line with findings 
in animals of enhanced parasympathetic activity. After reviewing the literature, Jones 
(2002) concluded that the cardiovascular effects of marijuana posed little risk to young, 
healthy adults, while increased cardiac work, increased hypotension, and increased 
catecholamines might pose greater risk for older adults [136].  
 
A case report detailed an instance of a type of heart attack [ST-segment elevation 
myocardial infarction (MI)] in a 37-year old man who reported smoking marijuana prior 
to arrival at the emergency department [137], possibly as  a result of having an 
inadequate myocardial oxygen supply from smoking marijuana. Cardiac events 
associated with marijuana have been reported since 1979 [138], and a previous ST-
segment elevation MI was reported in 2010 [139]. Researchers presented a case series 
addressing marijuana use and stroke [140]. The existence and nature of the relationship 
between marijuana use and stroke remains controversial [141]. 
 
Regular and heavy marijuana use is associated with increased symptoms of chronic 
bronchitis, coughing, production of sputum, and wheezing [142, 143]. Regular marijuana 
use may impair function of alveolar macrophages, a type of immune cell found in the 
lung [143, 144]. Reduced alveolar macrophages could place individuals at increased risk 
of lung infection. One of three studies of lung function in people reporting regular, and 
often heavy, use of smoked marijuana failed to find a reduction in lung function, and 


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another found reduced lung function but concluded that this was related to confounding 
factors [142, 145, 146]. A review of literature addressing marijuana use and lung injury 
concluded that findings were often inconsistent [147]. Marijuana use does not appear to 
be associated with lung cancer [147-149]. Rather, the positive association between 
extended periods of marijuana use and lung cancer may be related to other confounding 
factors, such as co-occurring tobacco use. Duration of use in the studies reviewed by 
Hashibe and colleagues is considerably longer than the three-week periods occurring in 
this study [149].  
 
There are several reports of cannabis-associated hyperemesis syndrome in regular 
marijuana users, marked by excessive, cyclical vomiting and abdominal pain that is 
relieved by taking a hot bath or shower [150-152]. 
 
The immunological effects of marijuana and cannabinoids are complex and largely 
appear to arise from effects on CB2 receptors rather than central CB1 receptors. Some of 
the benefits of marijuana, such as for multiple sclerosis, may relate in part to anti-
inflammatory and immunosuppressive effects [153, 154]. However, marijuana and 
cannabinoids failed to affect immune function in HIV-positive individuals [155, 156]. 
Regular marijuana users have greater numbers of a cannabinoid receptor implicated in 
regulating immune function, the CB2 receptor, which is generally considered to have 
immunosuppressive and anti-inflammatory effects [157], and in vitro studies suggest that 
THC and marijuana may reduce immunosupportive Th1 cytokines and increase 
immunosuppressive Th2 cytokines [153, 158]. It is possible that marijuana may increase 
the risk of opportunistic infections. However, in studies of HIV-positive individuals using 
either marijuana or oral THC (as dronabinol) at similar use levels to this study failed to 
find any changes in T-cell (CD4 or CD8) profiles, findings that do not support this form 
of immunosuppression [155, 159].   
 
Participants who receive the placebo marijuana are exposed to combustion products 
without receiving either THC or CBD. They will also be less likely to experience the 
adverse effects associated with marijuana and THC described above, such as anxiety or 
impaired performance on tests of cognitive function. Participants will be permitted to 
remain on medications and therapies to allow for continued symptom management 
throughout the study. 
 
Published reports of events associated with cannabis use include seizures upon cessation 
of use, pancreatitis, and gingival (gum) enlargement. In a report discussing the potentially 
anti-convulsant properties of cannabis, Hegde and colleagues (2012) discuss two cases 
where seizures increased in two patients after cessation of cannabis use and upon entry 
into an epilepsy unit [160]. Two case reports describe acute pancreatitis in marijuana 
users, with one report acknowledging the difficulty of linking the previous cannabis use 
with subsequent pancreatitis [161, 162]. According to Howaizi and colleagues (2012), 
only six cases of pancreatitis associated with marijuana have been reported in the 
literature [162]. A recent case report describes gingival enlargement in two extensive 
marijuana users [163]. 
 


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Beyond these risks, there are only a few reports of adverse effects occurring outside the 
organs and systems listed above. There are no known effects on the liver (and only a few 
case reports of effects on the kidneys [110]).  
 
Regular use of marijuana throughout pregnancy may have effects on birth weight, as well 
as specific tasks involving visual analysis or processing. However, to date, there are no 
reports of teratological effects from marijuana use [110, 164-167]. THC can pass into 
breast milk [167]. Women of childbearing potential enrolled in this study will be required 
to use an effective method of birth control, and the study will exclude participants who 
are pregnant or lactating. 
 
Using the study drug poses a social risk of actual or perceived stigmatization. Marijuana 
use is a socially stigmatized activity [168, 169]. Participants may be ostracized or 
experience social stigma from relatives, friends or community members who view or hear 
about their smoking marijuana, or they may be aware of and internalize these prejudices 
relating to marijuana use.  
 
Participants may test positive after urinary assay for drugs of abuse, as those used for 
workplace drug testing, or as a result of police response to a traffic violation. Even 
participants who are not using their marijuana on a daily basis may test positive for 
marijuana for up to three weeks after study participation. Testing positive for marijuana 
could pose risk of arrest or job termination. 
 
For further information, please view Information for Health Care Professionals [170] 
that has been submitted along with the protocol. 
 
7.3 Risk Mitigation 
 
Marijuana is associated with acute risks as well as risks of continued daily use. Chief 
amongst these are unwanted psychological effects, including anxiety or paranoia, 
cardiovascular and pulmonary effects, impaired driving, and abuse liability. 
 
The CIs will minimize risks by carefully screening participants for the presence of any 
contraindicating factors and by carefully preparing participants for the expected effects of 
marijuana. Contraindicating factors include presence or history of psychotic disorder, a 
positive family history in first-degree relative (parent or sibling) of psychotic disorder or 
bipolar affective disorder Type 1, cerebrovascular, cardiovascular or coronary conditions, 
and past or current substance abuse. Prior to receiving supplies of marijuana, study 
participants will be prepared for the effects of the substance during two extensive 
supervised introductory sessions described in Section 5.2.5. They will be informed of 
what to expect and they will have an opportunity to smoke the marijuana that they have 
been randomly assigned to receive in a standardized manner and in the presence of the C 
CIs. Participants will be telephoned on a daily basis for the first three days following the 
second introductory session of Stage 1 and Stage 2, and telephone contact will be made 
once, midweek, during the next three weeks to assess participant GWB and to detect any 
new psychiatric symptoms distinct from PTSD.  


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The CI or qualified designee will administer the CSSRS according to the Time and 
Events table and as needed depending on clinical presentation of the participant to 
monitor for development and severity of suicidal ideation or behavior.  The clinician will 
follow the Standard Operating Procedure for management of suicidal participants to 
assess elevated or imminent risk using best clinical judgment.  
 
If the Since Last Visit CSSRS reveals current serious Suicidal Ideation (Scores of 4 or 
greater), indicating low risk, at the time of the assessment or positive Suicidal Behaviour 
(Scores of 1 or greater) then the participant will be referred appropriately for further 
management as described below.  
 
1. If the participant has current suicidal ideation, but has no specific plan to 
commit suicide (Suicidal Ideation Score = 4), the clinician administering the 
CSSRS will:  
a. Recommend the participant call the National Suicide Prevention 
Lifeline at 1-800-273-8255 before leaving the laboratory.   
b. Participants would be required to speak with a study clinician for 
evaluation and appropriate course of action, and encouraged to contact 
their personal therapist, if they have one. 
c. Participants would be provided with a list of mental health resources.  
d. If revealed prior to enrollment, these participants may not be enrolled 
according to the Exclusion criteria based on the clinical judgment of 
the CI. 
e. If this finding is treatment-emergent, the participant may be removed 
from participation in the study based on clinical judgement of the CI or 
qualified designee. If these events emerge after enrollment and are 
clinically significant, they will be collected on the Adverse Events 
page.  The participant's continuing eligibility will be assessed by the 
CI and the Medical Monitor. 
f. Unless the steps above result in the participant leaving for psychiatric 
care right away or the clinician advises otherwise, the visit would be 
continued.  
g. If it is determined that the participant is at imminent risk of suicide, the 
CI or CI-designated staff member will do one of the following: 1) 
Escort the participant to the Emergency Department; 2) Escort the 
participant to an appropriate mental health services facility (e.g. 
hospital psychiatric unit); or 3) call 911 and ensure that the participant 
is transferred to the responding medical personnel.   
2. If the subject has suicidal ideation, and a plan to commit suicide (Suicidal 
Ideation Score = 5), the clinician administering the CSSRS will assess 
whether the risk is imminent. A score of 5 does not necessarily indicate an 
immediate risk if the thoughts are fleeting, fairly easily controlled, and 
deterrents are strong. If there is no imminent risk, the clinician will follow the 
procedure described in number 1. If there is imminent risk of suicidal 
behavior, the CI will: 


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a. Call the National Suicide Prevention Lifeline at 1-800-273-8255 
immediately. 
b. Participants would be required to speak with a study clinician for 
evaluation and appropriate course of action, and encouraged to contact 
their personal therapist, if they have one, prior to leaving the 
laboratory. 
c. If it is determined that the participant is at imminent risk of suicide, the 
CI or CI-designated staff member will do one of the following: 1) 
Escort the participant to the Emergency Department; 2) Escort the 
participant to an appropriate mental health services facility (e.g. 
hospital psychiatric unit); or 3) call 911 and ensure that the participant 
is transferred to the responding medical personnel.   
d. If the participant will not comply and wishes to leave without 
consultation, call 911. Explain that the participant is in immediate 
danger of committing suicide. Provide a complete description of the 
participant and give any other needed details to ensure the subject’s 
safety.  
e. Provide the subject with a list of mental health resources. 
f. Notify the study team as soon as possible.  This includes all site staff 
and all study team members representing the Sponsor.  
g. If revealed during screening, these participants would not be enrolled 
according to the Exclusion criteria. 
h. If this finding is treatment-emergent, the participant may be removed 
from participation in the study based on clinical judgment of the CI or 
qualified designee. If these events emerge after enrollment and are 
clinically significant, they will be collected on the Adverse Events 
page.  The participant's continuing eligibility will be assessed by the 
CI and the Medical Monitor.  
 
The CIs will address a number of risks by enrolling participants without contraindicating 
conditions, including psychotic disorders and major medical conditions affecting the 
heart or lungs. Participants who pose a major suicide risk will not be enrolled in the 
study. Risks posed by cessation of marijuana use will be reduced by requiring a period of 
abstinence from marijuana upon the start of screening. Participants using marijuana 
before entering the study are required to abstain from use for two weeks before receiving 
study marijuana. Any participant that the CI or Medical Monitor believes has 
contraindicating history of, or current, moderate to severe substance use disorder will not 
be enrolled.  
 
Untoward psychological reactions to marijuana will be dealt with by preparing 
participants for the subjective effects of the substance, and through first smoking 
marijuana in the presence of site staff during two introductory sessions. During this time, 
site staff will be able to help address any anxiety or paranoid feelings that may arise.  
 
Participants will be informed of the effects that marijuana might have on driving and they 
will be advised to avoid driving immediately after use by seeking a designated driver and 


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by waiting a minimum of three hours after use prior to driving a motor vehicle. 
Participants will arrange rides home after each introductory session, and if they are 
unable to do so, the CIs will assist them in locating a ride from the study site. 
 
Potential reproductive risks will be mitigated by restricting enrollment to women who are 
not pregnant or lactating, and by requiring that women of childbearing potential use an 
effective form of birth control and weekly pregnancy testing.  
 
All study participants will be issued a study participant identification card (e.g. “wallet 
card”) stating that they may test positive for drugs of abuse as a result of being a research 
participant, listing the number of a 24-hour hotline, and containing contact information 
for the CI, identifying the sponsor and the relevant IRB, and the study National Clinical 
Trial Registry (NCT) number. The CIs will remind participants that they may still be 
cited or face penalties for erratic driving and the card will not mitigate this.  
 
The CIs will address risks to confidentiality arising from the existence of digital video 
recordings of participant marijuana use by instructing participants to store their cameras 
securely in the lockbox provided to them as part of the study and informing them of the 
risks of exposing their personal video data to the internet.  If a study computer tablet is 
lost or stolen, the study team will remotely delete files from the device, notify local 
police in the case of theft, and make every attempt to recover the unit.  All tablets will be 
password protected and encrypted to minimize the likelihood that misplaced units will 
result in breech of confidentiality.  Given the safeguards in place, breech of 
confidentiality from the tablet computer is unlikely as long as participants follow 
instructions for use and storage.  All participant PHI will be stored in locked files or on 
secure computer servers, and managed in accordance with patient confidentiality 
procedures pertaining to electronic systems. 
 
The CIs will discuss with participants the perceived stigma they ascribe to marijuana use 
and to consider the degree to which friends, family or other people within the community 
might respond if they observe or learn about the participant’s marijuana use.  
 
This study involves take-home doses of study marijuana. To discourage the risk of 
diversion of unused marijuana during Stages 1 and 2, participants can choose to receive 
the amount of unused marijuana returned during Stage 1 or  Stage 2 in Stage 3. 
 
7.4 Medical Emergencies 
 
If a participant experiences a medical emergency during the introductory sessions, the CI 
will be on call to determine course of action. If a participant experiences a medical 
emergency during the self-administration period at a location other than the study site, he 
or she will be directed to call 911 and inform the CI upon stabilization.  
 
In the event of a psychological crisis arising during the study, participants and their 
community observers will be instructed to call the Participant Hotline as soon as possible. 
This call will be routed to the CI if it is confirmed that there is indeed a crisis. The CI, or 


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qualified designee if the CI is unavailable, will be on call at all times to receive 
information from the Participant Hotline.  
 
Upon learning about the psychological crisis, the CI will assess the AE by:  
 
 Obtaining a detailed history of the event over the phone 
 Collecting information on any concomitant medications 
 Verifying the above with the community observer if necessary 
 Assessing expectedness, seriousness, severity, and relation to study drug 
 All AEs will be assessed regardless of whether they occurred prior to or after self-
administration.  
 If the participant requires immediate care, they will be referred to the Emergency 
Department of the closest hospital. 
 
The Mobile Crisis Response Team (if applicable), Emergency Department, Hospital, or 
Primary Care Provider, or the CI may prescribe medications or take steps to stabilize the 
participant experiencing an AE.  
 
While participants are participating in Stage 1 of the study, which includes a placebo 
group, results of the THC drug test could break the study blind for a participant.  During 
any discussion with a provider about how to treat a medical event, the CIs or site staff 
may need to inform the provider of the participant's medical history and course of 
treatment in the study. The CIs or site staff should inform the provider of the likelihood 
that the participant will test positive for marijuana, and determine with the provider if the 
study blind must be broken in order to effectively treat the participant. The CIs should 
discuss delaying routine drug screens administered during treatment unless it is medically 
necessary.  
 
Regardless of condition assignment, all necessary steps will be taken to ensure 
participants receive whatever medical care is necessary for an AE.  If an outside 
treatment provider informs the participant of the results of a drug test for marijuana 
during Stage 1 of a participant's study visits, the participant must be withdrawn from the 
study in order to protect the study blind.  
 
8.0 Adverse Events 
 
An AE is defined as any untoward or unfavorable medical occurrence in a clinical 
research study participant, including any abnormal sign (e.g. abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the participants' 
involvement in the research, whether or not considered related to participation in the 
research. This definition includes concurrent illnesses or injuries and exacerbation of pre-
existing conditions.  
 
An unexpected AE is one that is not listed in the current Investigator’s Brochure or an 
event that is by nature more specific or more severe than a listed event. 


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All AEs will be monitored by the CI or site staff until resolution or, if the AE becomes 
chronic, a cause identified.  If an AE is unresolved at the conclusion of the protocol, a 
clinical assessment will be made by the CI and/or Medical Monitor as to whether 
continued follow-up of the AE is warranted. 
 
The severity of events reported on the AE CRF will be determined by the CI as: 
 
 Mild: no limitation in normal daily activity 
 Moderate: some limitation in normal daily activity 
 Severe: unable to perform normal daily activity 
 
The relationship of the study treatment to an AE will be determined by the CI, 
based on the following definitions: 
 
1. Not Related 
 
The AE is not related if exposure to the investigational product has not occurred, or the 
occurrence of the AE is not reasonably related in time, or the AE is considered unlikely 
to be related to use of the investigational product, i.e. there are no facts (evidence) or 
arguments to suggest a causal relationship, or the AE is more likely related to the 
participant’s pre-existing condition. 
 
2. Possibly Related 
 
The administration of the investigational product and the AE are considered reasonably  
related in time and the AE could be explained by causes other than exposure to the  
investigational product. 
 
3. Probably Related 
 
Exposure to the investigational product and AE are reasonably related in time and the  
investigational product is more likely than other causes to be responsible for the AE, or is 
the most likely cause of the AE. 
 
The relationship of the study treatment to an AE will be determined by the CI based on 
the assessment of the participants’ report of symptoms. 
 
8.1 Spontaneously Reported Reactions  
 
Common expected AEs, that have been compiled from the literature on smoked 
marijuana reported in studies of human volunteers, are referred to as  “spontaneously 
reported reactions” are: altered time perception, anxiety, difficulty concentrating, 
difficulty remembering things, dry mouth, feeling intoxicated (as drug effect, feeling 
high), feeling of heart racing/ or pounding in chest, feeling hungry, perceptual alteration 
(as enhanced sensation), sedation and feeling stimulated [107, 171]. Some participants 
may report feelings of paranoia or unusual thoughts [65].  AEs that are included in the 


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spontaneously reported reactions list will be separated in data analysis for review of 
expected vs. unexpected AEs.  
 
8.2 Serious Adverse Events 
 
The Site CI or qualified designee is responsible for determining if an AE is serious or 
non-serious. An SAE is defined as any untoward medical occurrence that at any dose: 
 
•  Results in death 
• 
Is life-threatening (i.e., the participant was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred); it does not refer to an event 
which hypothetically might have caused death if it were more severe 
• 
Requires or prolongs inpatient hospitalization 
• 
Results in persistent or significant disability/incapacity (i.e., the event causes a 
substantial disruption of a person’s ability to conduct normal life functions) 
• 
Results in a congenital anomaly/birth defect 
• 
Requires intervention to prevent permanent impairment or damage  
• 
Is an important and significant medical event that may not be immediately life- 
threatening or resulting in death or hospitalization, but based upon appropriate 
medical judgment, may jeopardize the patient/participant or may require 
intervention to prevent one of the other outcomes listed above 
 
AEs which do not fall into these categories are defined as non-serious.  It should be noted 
that a severe AE need not be serious in nature and that a SAE need not, by definition, be 
severe. 
 
In addition, a pre-existing event or condition that results in hospitalization should be 
recorded in the medical history. The hospitalization would not result in the event or 
condition being reported as a study-related SAE unless, in the view of the investigator, 
hospitalization was prolonged as a result of participation in the clinical trial or was 
necessary due to a worsening of the pre-existing condition.  This is because the onset of 
the event (the reason for the procedure) occurred before the participant was entered into 
the trial.  Hospitalization for cosmetic procedures, non-emergency prophylaxis, or 
abortion does not result in an SAE report unless, in the view of the investigator, 
hospitalization for these procedures was prolonged as a result of participation in the 
clinical trial. 
 


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8.3 Adverse Event Collection 
 
AEs that will be collected during the protocol: 
 
 SAEs will be collected through termination.  
 All AEs will be collected from enrollment until end of the active study period 
(e.g. end of Cessation 2 or Stage 3, as applicable) 
 Events requiring medical attention will be collected during the follow-up period 
through the participant’s last six-month follow-up. 
 Events related to planned treatments or physician visits for baseline conditions 
collected in the Medical History will not be collected unless there is an 
exacerbation of the condition. 
 Any AE leading to withdrawal from the protocol will be collected throughout the 
study. 
 All AEs related to changes in psychiatric status will be collected throughout the 
study. 
 
AEs will be collected during introductory sessions and throughout Stage 1, Stage 2, and 
Stage 3, as well as associated cessation periods, on the Daily Diary. Information needed 
to determine severity and relatedness will be collected and confirmed by telephone 
contact conducted according to the Time & Events table. Each reported AE will be 
actively followed during follow-up phone calls or weekly visits until resolution. AEs will 
be recorded in the respective AE log eCRF based on onset date, e.g. an AE reported 
during Introductory Session 1 or the Stage 1 self-administration period would be recorded 
on the Stage 1 AE log eCRF. CIs or qualified site staff are responsible for review of 
safety data.  
 
A Memory Aid Card will be provided to the subject on the last visit prior to the six-
month follow-up to record information on medications taken to treat SAEs, AEs leading 
to withdrawal and psychiatric AEs during the follow-up period between the end of self-
administration and the six-month follow-up evaluation. The Memory Aid Card will not 
be collected, but information from the card will be used to aid the participants in 
providing information to site staff. This information may be collected by phone. 
 
8.4 Adverse Event Reporting 
 
All SAEs which occur during the course of the trial, whether considered to be associated 
with the study drug or not, must be reported to the sponsor within 24 hours, or at the 


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latest on the following working day, of the site CI learning that an event occurred, 
irrespective of causality: 
 
 Contact information for the MAPS Medical Monitors and Study monitor are 
provided in a separate document. 
 All SAEs are to be assessed regardless of whether they occurred after drug 
administration, comparator product, placebo, or no treatment.  
 SAEs will be assessed by the site CI and Sponsor Medical Monitor(s) for 
relatedness, seriousness, and unexpectedness and reported regulatory agencies, 
IRBs and CIs according to applicable regulations and policies.  
 CIs should notify their respective IRBs according to IRB-specific timelines 
promptly after assessment and communication with the sponsor.   
 SAE reporting to competent authorities is done by an authorized delegate of 
MAPS. 
 
The Medical Monitor(s) will provide the required medical expertise in conjunction with 
site medical personnel to address trial-related medical questions or problems. In this 
capacity, the Medical Monitor(s) are responsible for the overall safety of the participants, 
the ongoing safety evaluation of the investigational product and the notification of all 
concerned investigators/institutions of findings that could adversely affect the safety of 
participants. 
 
The site CIs will communicate as needed with the Medical Monitors and study monitor to 
determine if the SAE is subject to expedited reporting and what follow-up information is 
needed for evaluation. If no consensus can be reached, the different assessments and the 
reasons for this must be summarized in writing. In any case the most conservative 
assessment drives the reporting procedure. The time frames for reporting SAEs to 
regulatory authorities begins when the sponsor has “initial information” of the event 
regardless of the form that initial notification takes. Expedited timelines will be followed 
according to regulatory, institutional, and IRB requirements. 
 
The blind may be broken for an individual participant if there is an AE or other 
emergency requiring knowledge of the participant's condition assignment. This 
emergency unblinding would require approval from the site CI and Coordinating 
Investigator. For this purpose, the Randomization Monitor will provide dose assignment 
through the electronic randomization system.  
 
The Sponsor will collaborate with investigators to ensure that all reports are submitted to 
the appropriate agency and IRB/EC within the required time frame and that they contain 
accurate and current information. The sponsor is responsible for ongoing safety 
evaluation of the investigational product and for the prompt notification of investigators 
conducting a MAPS-sponsored study and regulatory authorities of findings that could 
adversely affect the safety of participants, impact the conduct of the trial, or alter the 
IRB’s approval/favorable opinion to continue the trial.  
 


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Such information may be distributed to investigators by means of periodically revised 
investigator brochures, reprints or published studies, reports or letters to clinical 
investigators, or other appropriate means.  Any employee, contractor, or contract 
organization working on behalf of MAPS who discovers a serious adverse experience in 
the context of a clinical trial is responsible for alerting clinical trial staff. MAPS is 
responsible for collecting serious adverse experience information, submitting safety 
reports to regulatory agencies, and notifying investigators of safety issues.  
 
9.0 Collection of Concomitant Medications and Therapies 
 
Information about all concomitant prescription medications, and only over the counter 
(OTC) medications associated with an AE, will be collected from screening up to the day 
of the final study visit in Cessation 2 or Stage 3, as applicable, including reasons for use, 
date started, date ended and dose information if available. During the follow-up period 
after this visit and before the six-month follow-up, information on new psychiatric 
medications will be gathered on the day of the six-month follow up study visit. During 
the follow-up period, healthcare utilization associated with AEs requiring medical 
attention and psychiatric AEs will be collected. Medications recorded per protocol, 
including medications taken to treat AEs, will be recorded on a concomitant medications 
form eCRF. Information on participation in evidence-based psychotherapy for PTSD will 
be collected throughout the study. Therapies and healthcare utilization recorded per 
protocol will be recorded on a concomitant therapies form eCRF. 
 
10.0 Laboratory Assessments 
 
10.1 Clinical Laboratory Assessments 
 
The CI or qualified study personnel at each site will examine laboratory assessments 
gathered at screening, for assessing participant eligibility. The CIs will use a list of 
normal ranges to conclude whether participants are eligible for the protocol, and will 
indicate justification for admitting participants with abnormal values.  
 
The following laboratory assessments will be performed as specified in the Time and 
Events table.  
 


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Serum electrolytes and the metabolic profile, which includes: 
 
 ALT/SGPT 
 Albumin:globulin (A:G) ratio 
 Albumin, serum  
 Alkaline phosphatase, serum 
 AST/SGOT  
 Bilirubin, total 
 BUN 
 BUN:creatinine ratio 
 Calcium, serum 
 Carbon dioxide 
 Chloride, serum 
 Creatinine, serum 
 Globulin, total 
 Glucose, serum 
 Potassium, serum 
 Protein, total, serum 
 Sodium, serum 
 
CBC, which includes:  
 
 Hematocrit 
 Hemoglobin 
 MCV 
 MCH 
 MCHC 
 RDW 
 Percentage and absolute differential counts 
 RBC 
 WBC 
 


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Urinalysis, which includes:  
 
 Color 
 Appearance 
 Specific gravity 
 pH 
 Protein 
 Glucose 
 Ketones 
 Occult blood 
 Leukocyte esterase 
 Nitrite 
 Bilirubin 
 Urobilinogen 
 
 
Participants who test positive on the qualitative urine drug test at both pre and post 
cessation timepoints will have a Quantitative Urine THC-COOH Drug Test to determine 
likelihood of compliance with abstinence requirements.  Quantitative testing will be 
conducted by Dominion Diagnostics using GC/MS testing methods.  An algorithm 
developed by Huestis and colleagues will then be used to determine the confidence that a 
participant completely abstained from cannabis during each 2-week cessation period.  
Participants for which samples indicate 90% or greater confidence will be considered 
compliant.  Participants who provide samples that indicate 80-90% confidence will have 
blood samples tested for additional information in order to determine compliance.  
Samples with < 80% confidence will be considered non-compliant.  Non-compliance will 
be evaluated and handled by study investigators on a case-by-case basis with regards to 
study continuation and utilization of data. 
 
Thyroid function, which includes:  
 
 TSH high sensitivity 
 
A urine-dip pregnancy test for participants of childbearing potential will be performed as 
specified in the Time & Events table.  
 
A qualitative urine drug screen will be administered at Screen 1 and 2.  A qualitative 
urine drug screen will be administered throughout the study at the study sites according to 
the Time & Events table. 
 
An 80-hour ETG urine dip test to test for recent alcohol consumption will be performed 
at the study sites according to the Time & Events table. 
 
Clinical laboratory assessments will be drawn at the site or closest available LabCorp 
facility. These samples will be processed at LabCorp. 
 


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For the Arizona site: 
 
9465 E Ironwood Square Dr. 103 
Scottsdale, AZ 85258 
 
For the Maryland site: 
 
3449 Wilkens Ave #202 
Baltimore, MD 21229 
 
 
 
10.2 Blood Cannabinoid Analysis 
 
For participants who test positive for THC-COOH (50ng/mL cut-off) on the qualitative 
urine drug tests during screening and who also show inconclusive cessation results from 
quantitative urine analysis, an accredited and certified laboratory will conduct testing of 
blood cannabinoids (THC, 11-OH-THC, and THC-COOH) using high performance 
liquid chromatography-tandem mass spectrometry (LC-MS/MS).  
 
10.3 Research Lab Biomarker Analysis 
 
Biomarker laboratory analyses will be performed using plasma for CRP, IL-1β, and IL-6 
levels collected from all participants according to the Time and Events Table. For blood 
samples, a butterfly needle will be used to draw 30mL of blood into chilled EDTA 
vacutainer tubes. Samples will be immediately placed on wet ice. Plasma will be 
extracted by centrifugation in a refrigerated (4 °C) centrifuge at 1,300g for 10 minutes, 
aliquotted into individual tubes, and stored at -80 °C prior to shipment to the 
collaborating site at University of Colorado Boulder. Biomarker analyses will be 
performed by David Smith in Dr. Lowry’s laboratory at the University of Colorado 
Boulder in Boulder, Colorado (collaborating site). Concentrations of CRP, IL-1β, and IL-
6 will be quantified using commercially available enzyme immunoassay kits (R&D 
Systems, Minneapolis, MN, USA). These kits are highly specific and exclusively 
recognize CRP, IL-1β, and IL-6 respectively, and not related peptides. Plasma samples 
are assayed in duplicate and measured using a microplate reader for 96-well format 
according to manufacturer’s instructions. 
 
11.0 Study Monitoring, Auditing and Documentation 
 
Clinical Investigators and/or their site staff will be trained prior to the start of the protocol 
by the sponsor’s clinical research staff.  The clinical study site will be monitored by site 
visits and remote communication to the CI by representatives of the sponsor.  The site 
will be monitored as appropriate for the rate of enrollment.  During each monitoring visit, 
source data verification will be performed by a Clinical Research Associate (CRA) to 
ensure compliance, including accurate and complete recording of data on CRFs, source 
documents, and drug accountability records. CRFs supplied by the sponsor will be 
completed for each participant enrolled. Monitoring and auditing procedures of the 


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sponsor will be followed, in order to comply with Good Clinical Practice (GCP) 
guidelines and to ensure validity of the study data. 
 
The sponsor will review the study documentation used for planning, conducting and  
monitoring of the study in order to ensure compliance with GCP and local regulations. 
This documentation includes, at minimum: the Investigator’s Brochure, the Study  
Protocol, the CRFs and the ICF. 
 
During or after the clinical protocol, the regulatory authorities, the IRB, and/or 
representatives of the sponsor may request access to all source documents, CRFs and 
other protocol documentation for on-site audit or inspection. 
 
12.0 Data Analysis 
 
Key Personnel, MAPS, and the biostatistician will agree on a detailed Statistical Analysis 
Plan prior to the beginning of recruitment. The biostatistician will perform an “intent to 
treat” (ITT) analysis using repeated measures analysis of covariance (ANCOVA) to 
compare demographics. Distribution of treatment dropouts will be examined by condition 
and if found to be unequal, the sponsor will control for group assignment in the ITT 
analysis.  
 
Primary analysis of observer-blind CAPS-5 data collected at Baseline and end of Stage 1 
will be conducted using ANCOVA with marijuana concentration as a between-subject 
factor and time of assessment as a within-group factor. If effects of marijuana 
concentration are detected at Stage 1, a similar secondary analysis will also be performed 
with Stage 2 data using Stage 1 data as a covariate for each outcome measure. Effect size 
will be estimated based on all outcome measures using Cohen’s techniques. The 
biostatistician will conduct secondary exploratory analyses of weekly assessments of 
PCL-5, ISI, IDAS, IPF, WBR, CSSRS, MWC, CUDIT-R, DEQ and ACT scores using 
repeated measures ANCOVA or generalized linear mixed modeling, as described in the 
Statistical Analysis Plan. Statistical significance (p < .05) will be determined for all tests. 
All available data from repeated outcome assessments of all participants who are 
randomized, even if they withdraw from the allocated treatment prior to the primary 
endpoints, will be included in ITT analysis. 
 
A repeated measures ANCOVA comparison of ratings on the DEQ and pulse will be 
conducted, with marijuana condition as the main factor in the analysis.  If a main effect of 
marijuana concentration is observed then pairwise comparisons will be conducted to 
detect differences between each marijuana concentration. 
 
Secondary exploratory analyses will be conducted examining weekly assessments of self-
reported (via the ISI) and objective (via Actigraphy) measures of sleep. Independent 
repeated measures ANCOVAs will be conducted. In terms of self-reported sleep, weekly 
total scores from the ISI will be entered as the repeated measure with group entered as the 
IV. In terms of objective sleep (via Actigraphy) repeated measures ANCOVAs will be 
conducted with weekly total sleep time (TST), wake after sleep onset (WASO), sleep 


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onset latency (SOL), and sleep efficiency (SE) entered as the repeated measure in 
independent analyses and group entered as the IV. An ITT approach will be used. 
Statistical significance will be set at p = .05 for all analyses.  
 
Quantitative levels of THC, CBD and their metabolites will be assessed in order to 
ascertain whether participants comply with only using the marijuana assigned to them 
during the study. If there is sufficient data, correlational analyses may also be conducted 
between biological cannabinoid levels and clinical outcomes to determine whether there 
is a dose-response effect between cannabinoid exposure and clinical response.   
 
Prognostic value of CRP, IL-1β and Il-6 will be examined using two regression analyses, 
one between biomarker values gathered at Baseline and at the primary endpoint CAPS-5 
global severity score, and another between biomarker values collected after two weeks of 
cessation and the CAPS-5 global severity score at the end of Stage 1. 
 
Qualitative safety analyses will examine Daily Diaries with summary tables listing 
maximum severity and duration, concomitant medications/therapies, and AEs with 
frequencies and percentages tabulated overall and by concentration group. Spontaneously 
reported reactions will be separated from unexpected AEs during analysis and presented 
separately in summary tables. Statistical analyses will be conducted to evaluate safety 
and AEs by marijuana treatment condition and individual demographic characteristics 
(e.g. gender, history of cannabis use, concomitant medication/drug use, baseline CAPS-5 
score). 
 
12.1 Statistical Power 
 
The proposed study is a pilot investigation intended to gather preliminary data on the 
safety and efficacy of marijuana in people with chronic, treatment-resistant PTSD. 
Because of their exploratory nature, pilot studies are often not powered for detecting the 
desired effect. Because it is a pilot study in a small sample, results will used to assess 
variability of the outcome measures as inputs for calculation of sample sizes for 
adequately powered subsequent studies. This study will be the first to examine the effects 
of marijuana on PTSD.   
 
This pilot RCT is the first study of its kind intended to gather estimates of effect size of 
marijuana for PTSD. In the absence of published effect sizes of marijuana for PTSD, 
possible effect sizes are estimated to be 0.4 (small to medium effect) for a between-
subject comparison to ensure an adequately powered study size, based on a recent meta-
analysis conducted with the National Center for PTSD [172]. Thus in the proposed study, 
N=76 with 19 participants randomized to each group will have 82% power to detect these 
or greater differences between groups on the same primary outcome measure (change in 
CAPS-5 total score) used to obtain FDA approval for PTSD medications. Similar 
calculations would apply for secondary analyses.  
 


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13.0 Informed Consent 
 
The CI or co-investigators are responsible for obtaining informed consent in adherence to 
GCP and according to applicable regulations prior to entering the participant into the 
trial. Information about events during the course of the study must be given both orally 
and written, in an understandable form.  In addition to the explanation of evaluation, 
introductory sessions, periods of marijuana self-administration, and periods of abstinence 
from marijuana, the information should include that access to original medical records 
and processing of coded personal information must be authorized.  The informed consent 
discussion must be conducted by a person who is qualified, according to applicable local 
regulations and GCP. The participant should have the opportunity to inquire about details 
of the study and to consider whether or not to participate. 
 
The ICF must be signed and dated by the participant and must be countersigned by the 
site staff administering the consent process.  
 
Site staff will provide a copy of the signed ICF to the participant, and will maintain the 
original in the investigator’s study file. During the study, participants will be reminded of 
upcoming study procedures at each visit to assure continued comprehension of the ICF. 
 
The written ICF and any other written information to be provided to participants should 
be revised whenever important new information becomes available that may be relevant 
to the participant's consent.  Any revised written informed consent form, and written 
information, should receive approval from an IRB before use. Written consent to take 
part in the study session includes giving the CI permission to view the participant's recent 
medical records to assess study eligibility, if needed.  Information necessary for study 
participation includes past medical history, psychiatric interview, physical examination, 
and clinical laboratory tests. 
 
The participant should be informed in a timely manner if new information becomes 
available that may affect the decision to take part in the study.  The communication of 
this information should be documented.  
 
Participants can withdraw consent for participation in the protocol at any time without 
prejudice.  If a participant withdraws consent but does not revoke the Health Insurance 
Portability and Accountability Act (HIPAA) authorization or equivalent form, MAPS 
will have full access to the participant’s medical records, including termination visit 
information.  If a participant revokes only the HIPAA authorization, MAPS will have full 
access to all of the participant’s medical records prior to the date and time of revocation. 
 
13.1 Confidentiality 
 
Every effort will be made to strictly safeguard the confidentiality of participants in their 
role as research participants. Participant Contact Information logs will be kept on paper at 
the clinical trial sites in locked secure files. Removing identifying information from data 
and restricting access to researchers directly involved in assessing the participants should 


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prevent the dissemination of confidential data, with or without identifying information.  
Despite this, privacy cannot be guaranteed.  Except for the screening log, the ICF, and a 
participant contact information sheet, all data will be identified only by the participant's 
initials on the source document and five-digit participant number numeric code.  If past 
medical records are needed, participants will sign forms for the release of information 
upon consent to permit screening for protocol enrollment. All assessment records will be 
kept in a locked file drawer or cabinet, and access to measures will be limited to 
regulatory agencies, researchers, and individuals analyzing data.  Researchers, other than 
the CIs directly involved in the protocol, with access to data will not be provided with 
any information that would identify participants by name or by other means, such as 
social security number. Staff viewing participant video recordings of marijuana use will 
sign a confidentiality form. Files will be uploaded on a secure computer in a locked 
office, and only the date of the recording and participant number will be retained in these 
files.  
 
Maintaining data in a secure environment will prevent the accidental or deliberate 
examination or removal of data. The sponsor will utilize confidentiality 
procedures to assure participant privacy. Data to be transferred to remote servers 
will be encrypted during transfer using a Virtual Private Network. Clinical trial 
data other than video data will be hosted on Medrio, an Electronic Data Capture 
(EDC) system that is FDA-compliant.  All data entered into this system will be 
de-identified. Participants will only be referred to by numbers and a secondary 
identifier code. Source Records and identifying information will be retained at 
clinical sites per GCP. The sponsor will train the study staff on EDC procedures. 
Each study staff member with access to the data will be given an individual 
password.  
 
The sponsor has developed a feature that will allow participants to create a password and 
enter their self-report questionnaire data directly into Medrio using the ePRO feature. 
Participants will be reminded by email to enter the data. Participant emails will be treated 
as Protected Health Information (PHI) in the database. Participants will receive a 
welcome email and reminder emails to ensure that they provide all necessary data.  
 
Subjects will be showed how to securely use their tablet computers.  This will include 
instruction on password protection, ePRO and video uploads to ensure security. After the 
upload is confirmed as complete at the site, the original video on the handheld device will 
be deleted by site staff. All identifying information and study related information will be 
stored in locked files, encrypted drives, or secure servers.  If a tablet is lost or stolen, 
local police will be notified and every effort made to recover the device.  Participants will 
be instructed to store their tablet computers in their study supplied lock box.   
 
13.2 Costs to Participants and Compensation 
 
The Sponsor of this study will cover the costs that are directly related to this study. This 
includes the costs for introductory sessions, for the psychological and laboratory testing, 
for medical examinations, the portable tablet with video and lockable storage box, and 


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the study drug. Neither the participant nor their medical insurance (if any) will be 
charged for any procedures done solely for the purpose of the study. The subject will not 
be charged for lost or damaged tablet computers. 
 
Charges for treatment of the participant’s condition that are unrelated to the research 
study, or any of its procedures, will continue to be billed to the health insurance provider 
of the participant or to the participant him or herself.  It is anticipated that there will not 
be any charges for treatment that is unrelated to the study. 
 
Participants will be compensated for their time and effort, up to $400 for completion of 
Stage 1 and Stage 2 and $50 for completion of the long-term follow-up visit. 
Compensation will be pro-rated for visits and tasks as they are completed. Compensation 
of this magnitude is appropriate given the length and nature of this study. 
 
Table 7: Compensation by Study Stage 
Study Stage 
Compensation Amount
Total Compensation 
Screeen Failure
$20/week
$40 total
Stage 1
$100/week
$300 total
Cessation 1 (Completion Bonus)
$50/week
$100 total
Stage 2
$100/week
$300 total
Cessation 2 (Completion Bonus)
$50/week
$100 total
Stage 3 (optional)  
No compensation
$0 total 
Long-term Follow-up (Completion Bonus)
$50
$50 total
Total Possible Compensation
---
$850 total
 
Community observers will be compensated $20 at the end of the study for participation if 
at least 75% of their scheduled assesments are completed. 
 
13.3 Treatment and Compensation for Study Related Injury 
 
Treatment of a study-related emergency would first be billed to a participant’s health 
insurance provider.  The sponsor will cover any direct costs relating to the treatment of a 
study-related emergency that are not covered by a participant’s health insurance. The 
study involves self-administration of a study drug. Participants will be directed to go to 
the nearest emergency department if they experience a medical emergency, and the 
sponsor will provide compensation for study-related medical treatment costs. 
 
14.0 Record Retention 
 
CIs must retain all study records required by MAPS and by the applicable regulations in a 
secure and safe facility. The CI must consult a MAPS representative before disposal of 
any study records.  “Essential documents” are defined as documents that individually and 
collectively permit evaluation of the conduct of a trial and the quality of the data 
produced.  It is the responsibility of the sponsor to inform the CI/institution as to when 
these documents no longer need to be retained. CIs must retain all study records required 


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by MAPS and by the applicable regulations in a secure and safe facility. The CI must 
consult a MAPS representative before disposal of any study records.   
 
15.0 Publication Policy 
 
The sponsor recognizes the importance of communicating medical study data and 
therefore encourages publications in reputable scientific journals and presentations at 
seminars or conferences.  It is understood by the investigators that the information 
generated in this study will be used by the sponsor in connection with the development of 
the product and therefore may be disclosed to government agencies in various 
countries.  To allow for the use of information derived from the study, it is understood 
that the CIs are obliged to provide the sponsor with complete test results, all study data, 
and access to all study records. 
 
Any results of medical investigations with the sponsor products and/or 
publication/lecture/manuscripts based thereon, shall be exchanged and discussed by the 
investigators and the sponsor clinical research representative(s) prior to submission for 
publication or presentation.  Due regard shall be given to the sponsor's legitimate 
interests, e.g. manuscript authorship, obtaining optimal patient protection, coordinating 
and maintaining submissions to health authorities, and coordinating with other ongoing 
studies in the same field. 
 
The full details of the processes of producing and reviewing reports, manuscripts, and 
presentations based on the data from this trial will be described in the Clinical Trial 
Agreement. 
 
 


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Kouri, E., et al., Attributes of heavy vs. occasional marijuana smokers in a college 
population. Biol Psychiatry, 1995. 38(7): p. 475-81. 
118. 
Pope, H.G., Jr. and D. Yurgelun-Todd, The residual cognitive effects of heavy 
marijuana use in college students. Jama, 1996. 275(7): p. 521-7. 
119. 
Solowij, N., et al., Biopsychosocial changes associated with cessation of cannabis 
use: a single case study of acute and chronic cognitive effects, withdrawal and 
treatment. Life Sci, 1995. 56(23-24): p. 2127-34. 
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Bosker, W.M., et al., Psychomotor function in chronic daily Cannabis smokers 
during sustained abstinence. PLoS One, 2013. 8(1): p. e53127. 
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Pope, H.G., Jr., et al., Cognitive measures in long-term cannabis users. J Clin 
Pharmacol, 2002. 42(11 Suppl): p. 41S-47S. 
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Zvolensky, M.J., et al., Prospective associations between cannabis use, abuse, 
and dependence and panic attacks and disorder. J Psychiatr Res, 2008. 42(12): p. 
1017-23. 
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Zvolensky, M.J., et al., Marijuana use and panic psychopathology among a 
representative sample of adults. Exp Clin Psychopharmacol, 2010. 18(2): p. 129-
34. 
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van Ours, J.C., et al., Cannabis use and suicidal ideation. J Health Econ, 2013. 
32(3): p. 524-37. 
125. 
Sewell, R.A., J. Poling, and M. Sofuoglu, The effect of cannabis compared with 
alcohol on driving. Am J Addict, 2009. 18(3): p. 185-93. 
126. 
Robbe, H.W.J. and O.H. J.F., Marijuana and Actual Driving Performance. 
National Highway Traffic Safety Administration 1993, U. S. Department of 
Transportation, DOT HS 808 078 November, 1993. 
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MacDonald, S., et al., Driving behavior under the influence of cannabis or 
cocaine. Traffic Inj Prev, 2008. 9(3): p. 190-4. 
128. 
Asbridge, M., J.A. Hayden, and J.L. Cartwright, Acute cannabis consumption and 
motor vehicle collision risk: systematic review of observational studies and meta-
analysis. BMJ, 2012. 344: p. e536. 
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Elvik, R., Risk of road accident associated with the use of drugs: A systematic 
review and meta-analysis of evidence from epidemiological studies. Accid Anal 
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Simpson, H.M., Epidemiology of road accidents involving marijuana. . Alcohol 
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Simpson, H.M., D.R. Mayhew, and R.A. Warren, Epidemiology of road accidents 
involving young adults: alcohol, drugs and other factors. Drug Alcohol Depend, 
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Grotenhermen, F., et al., Developing limits for driving under cannabis. Addiction, 
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Fischer, B., et al., Lower Risk Cannabis use Guidelines for Canada (LRCUG): a 
narrative review of evidence and recommendations. Can J Public Health, 2011. 
102(5): p. 324-7. 
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Substance Abuse and Mental Health Services Administration, Results from the 
2013 National Survey on Drug Use and Health: Summary of National Findings , 


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NSDUH Series H-48. 2014, Substance Abuse and Mental Health Services 
Administration,: Rockville, MD. 
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Anthony, J.C., L.A. Warner, and R.C. Kessler, . Comparative epidemiology of 
dependence on tobacco, alcohol, controlled substances, and inhalents: basic 
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Jones, R.T., Cardiovascular system effects of marijuana. J Clin Pharmacol, 2002. 
42(11 Suppl): p. 58S-63S. 
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Arora, S., et al., ST-segment elevation myocardial infarction in a 37-year-old man 
with normal coronaries--it is not always cocaine! Am J Emerg Med, 2012. 30(9): 
p. 2091 e3-5. 
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Charles, R., S. Holt, and N. Kirkham, Myocardial infarction and marijuana. Clin 
Toxicol, 1979. 14(4): p. 433-8. 
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Karabulut, A. and M. Cakmak, ST segment elevation myocardial infarction due to 
slow coronary flow occurring after cannabis consumption. Kardiol Pol, 2010. 
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Singh, N.N., et al., Cannabis-related stroke: case series and review of literature. J 
Stroke Cerebrovasc Dis, 2012. 21(7): p. 555-60. 
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Wolff, V., et al., Cannabis-related stroke: myth or reality? Stroke, 2013. 44(2): p. 
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Res Ed), 1987. 295(6612): p. 1516-8. 
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Tashkin, D.P., et al., Effects of habitual use of marijuana and/or cocaine on the 
lung. NIDA Res Monogr, 1990. 99: p. 63-87. 
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Baldwin, G.C., et al., Marijuana and cocaine impair alveolar macrophage 
function and cytokine production. Am J Respir Crit Care Med, 1997. 156(5): p. 
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Tashkin, D.P., et al., Heavy habitual marijuana smoking does not cause an 
accelerated decline in FEV1 with age. Am J Respir Crit Care Med, 1997. 155(1): 
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exposure on lung function in young adults. Addiction, 2002. 97(8): p. 1055-61. 
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Tashkin, D.P., Smoked marijuana as a cause of lung injury. Monaldi Arch Chest 
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cancer. J Clin Pharmacol, 2002. 42(11 Suppl): p. 103S-107S. 
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Allen, J.H., et al., Cannabinoid hyperemesis: cyclical hyperemesis in association 
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Gessford, A.K., et al., Marijuana induced hyperemesis: a case report. W V Med 
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Klein, T.W. and C.A. Newton, Therapeutic potential of cannabinoid-based drugs. 
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medicine. Br J Anaesth, 2008. 101(1): p. 59-68. 
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Yuan, M., et al., Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine 
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Hegde, M., et al., Seizure exacerbation in two patients with focal epilepsy 
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Howaizi, M., et al., Cannabis-induced recurrent acute pancreatitis. Acta 
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Rawal, S.Y., D.N. Tatakis, and D.A. Tipton, Periodontal and oral manifestations 
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SAP_001.pdf: 
MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
 
Statistical Analysis Plan 
 
 
 
 
 
 
 
 
 
Study Title: 
Placebo-Controlled, Triple-Blind, Randomized 
Crossover Multi-Site 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) 
 
Study Number: 
MJP-1 
 
Protocol Version and  
Date: 
 
Amendment 5 Version 1, June 28, 2016 
 
 
Phase of Development: 
 
 
 
Phase 2 
Sponsor: 
Multidisciplinary Association for Psychedelic Studies 
(MAPS) 
 
Investigators: 
Suzanne Sisley M.D., Ryan Vandrey Ph.D. 
Coordinating Investigator: 
 
Marcel Bonn-Miller Ph.D. 
 
Medical Monitors: 
Julie Holland M.D.; Michael Mithoefer M.D. 
 
Statistician: 
Scott Hamilton,  Ph.D. 
 
Plan Prepared by: 
Berra Yazar-Klosinski, Ph.D. 
 
Version and Date: 
 
Version 1, August 31, 2016 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
 
 
Table of Contents 
1.0 
List of Abbreviations and Definitions of Terms ............................................................. 3 
2.0 
Introduction ....................................................................................................................... 6 
3.0 
Study Objectives................................................................................................................ 7 
3.1 
Primary Objective ........................................................................................................... 7 
3.2 
Secondary Objectives....................................................................................................... 7 
3.3 
Safety Objectives ............................................................................................................. 8 
3.4 
Process Objectives ........................................................................................................... 9 
4.0 
Study Design ...................................................................................................................... 9 
4.1 
Time and Events Table .................................................................................................. 10 
Table 4.1-1: Time and Events (Administrative Procedures) ....................................................... 11 
5.0 
Randomization and Blinding ......................................................................................... 15 
6.0 
Sample Size and Power Considerations ........................................................................ 15 
7.0 
Measures .......................................................................................................................... 16 
7.1 
Screening Measures ....................................................................................................... 16 
7.2 
Outcome Measures ........................................................................................................ 16 
7.3 
Safety Measures ............................................................................................................. 17 
7.4 
Process Measures ........................................................................................................... 18 
8.0 
Analyses............................................................................................................................ 19 
8.1 
Study Population ........................................................................................................... 19 
8.2 
Handling of Dropouts, Missing Data .............................................................................. 19 
8.3 
Protocol Deviations ........................................................................................................ 20 
8.4 
Participant Demographics and Background .................................................................. 21 
8.5 
Subject Disposition and Dosing Summary ..................................................................... 22 
8.6 
Prior and Concomitant Medications .............................................................................. 22 
8.7 
Efficacy Analyses ........................................................................................................... 22 
8.7.1 
Primary Efficacy Analyses for Stage 1 .......................................................................... 22 
8.7.2 
Secondary Efficacy Analyses ....................................................................................... 23 
8.7.3 
Additional Analyses..................................................................................................... 24 
8.8 
Safety Analysis............................................................................................................... 24 
9.0 
Interim Analyses ............................................................................................................. 26 
10.0 
Timing of Analyses.......................................................................................................... 26 
11.0 
Statistical Software ......................................................................................................... 26 
12.0 
References ........................................................................................................................ 26 
 
 
 
 


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Statistical Analysis Plan 
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     Version 1 August 31, 2016 
 
 
Statistical Analysis Plan for MJP-1 
 
1.0   List of Abbreviations and Definitions of Terms 
 
Definitions of Terms 
 
Categorical data: refers to discrete (indivisible) variables, such as gender or ethnicity; data will 
be presented as total numbers of each category as needed to describe the sample 
Crossover set: all participants who completed Stage 2 in addition to completing Stage 1 
 
Descriptive data: includes mean, median, standard deviation, minimum and maximum of 
numerical data used as needed to describe the sample 
Difference scores: consist of scores computed by subtracting one value from another, as 
subtracting baseline from End of Stage 1 score, used to test for differences between and within 
groups to determine change as a function of experimental treatment over time 
Efficacy: type of analysis used to assess therapeutic effects or benefits 
Exploratory analyses: inferential or descriptive analysis of the data to determine trends that 
might lead to hypotheses for further study 
Extension set: all participants who completed Stage 3 in addition to completing Stage 2 
 
Frequency listing: tabular listing of numbers and/or percentages of events used as needed to 
describe the sample or data characteristics 
Modified Intent-to-treat (mITT): sample including all participants who signed informed consent, 
were eligible for enrollment, and who were randomized and received study drug during 
introductory session 1 or afterwards 
 
Outcome measures: primary and secondary study measures that are used to test the study 
hypotheses 
Per protocol set (PP): all completer participants who finished Stage 1, with valid CAPS-5 scores 
at the primary endpoint assessment and did not experience major protocol deviations. 
 
Process measures: study measures or qualitative observations collected during the study that 
may increase depth of understanding and that are not necessarily related to safety or efficacy 
Protocol deviation: event that represents significant divergence from the intended study design 
as described in the protocol 
Safety set: all participants who receive any study treatment. 
 
 
Safety measures: study measures that assess safety, such as pulse monitoring, risks, adverse 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
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     Version 1 August 31, 2016 
 
events, and reactions that are used to assess safety of the study drug 
Spontaneously reported reactions, reactions: specific expected reactions gathered from the 
literature on marijuana 
Study design: all elements of a research project that define the study question, experimental 
methods, study procedures including blinding and randomization, measurement techniques, flow 
sheet of data, and statistical analysis 
Tabular listing: list of each variable or item for each individual subject either in total or by 
concentration in a table format 
List of Abbreviations 
ACT = Actigraphy  
AE = Adverse Event 
ANOVA = Analysis of Variance 
ANCOVA = Analysis of covariance 
BT = body temperature 
CAPS-5 = Clinician Administered PTSD Scale 
CBD = cannabidiol 
CRP= C-Reactive Protein 
C-SSRS = Columbia Suicide Severity Rating Scale  
CUDIT-R = Cannabis Use Disorders Identification Test-Revised  
DEQ = Drug Effect Questionnaire  
DBP = diastolic blood pressure 
ES = Effect size 
FDA= Food and Drug Administration 
GLMM = Generalized Linear Mixed Model 
GWB = General Well-being  
HR = Heart Rate 
IDAS = Inventory of Depression and Anxiety 
IL-6 = Interleukin-6  
IL-1β = Interleukin-1beta 
IPF = Inventory of Psychosocial Functioning 
IR = Independent Rater 
ISI= Insomnia Severity Index  
LTFU= Long Term Follow Up  
MAPS = Multidisciplinary Association for Psychedelic Studies 
mITT= Modified Intent to Treat 
MWC = Marijuana Withdrawal Checklist 
PCL-5 = PTSD Checklist 
PP = Per Protocol 
PTSD = Posttraumatic Stress Disorder 
RCT = randomized controlled trial 
SAE= Serious Adverse Event 
SBP = systolic blood pressure 
SE = sleep efficiency 
SOL = sleep onset latency 
SpO = blood oxygen levels 
TEAE  = Treatment Emergent Adverse Events 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
THC = 9-tetrahydrocannabinol 
TLFB = Time-line Follow-back 
TST = total sleep time 
WASO = wake after sleep onset 
 WBR= Weekly Behavior Report 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
  
2.0   Introduction 
 
This document contains a Statistical Analysis Plan for the study, “Placebo-Controlled, Triple-
Blind, Randomized Crossover Multi-Site 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).” 
 
The Multidisciplinary Association for Psychedelic Studies (MAPS), a 501(c)3 non-profit, is 
collaborating with the University of Colorado, University of Pennsylvania, Johns Hopkins 
University, and Dr. Sisley on a pilot Phase 2 outpatient randomized, placebo- controlled, triple-
blind, crossover, multi-site study that will gather preliminary evidence of the safety and efficacy 
of four concentrations of smoked marijuana to manage chronic, treatment- resistant PTSD 
symptoms among 76 US veterans. This study is the first randomized controlled trial (RCT) to 
test the therapeutic potential of smoked marijuana as a treatment for PTSD. This study is 
essential for understanding potential risks and therapeutic benefits of marijuana for PTSD 
patients. Results will provide physicians, patients, scientists and regulators with critical 
knowledge regarding whether marijuana benefits individuals with PTSD, whether adverse 
consequences occur, and the impact of marijuana type on outcomes. 
 
After initial screening, including two weeks of biochemically verified abstinence, smoked 
marijuana containing different ratios of 9-tetrahydrocannabinol (THC) and cannabidiol (CBD) 
will be tested. In Stage 1, participants will be randomized to one of four marijuana 
concentrations differing by cannabinoid concentrations. Stage 1 will last for three weeks, during 
which time participants will self-administer up to 1.8 g of marijuana daily. Following a 2-week 
washout period during screening, participants will be randomized to one of the two remaining 
“active” marijuana concentrations for Stage 2, depending on Stage 1 concentration assignment. 
Stage 2 will last for three weeks, during which time participants will self-administer up to 1.8 g 
of marijuana daily. Drug assignment options for Stage 2 will be different than Stage 1 
concentration assignment and will also exclude placebo. Stage 2 will permit a within-subjects 
comparison of symptom change as a function of marijuana concentration, including differences 
in personal marijuana type preference. To discourage diversion of unused marijuana and 
encourage participant use in a naturalistic ad- libitum fashion, the amount of unused marijuana 
from Stage 1 or Stage 2 will be offered from a fresh supply to participants in an optional Stage 3 
extension that may last up to two months. Study duration for each participant will be eight and a 
half months, inclusive of the 6-month follow-up period. Marijuana will be obtained from the 
NIDA drug supply program and will be stored in compliance with DEA regulations. 
 
Clinical and statistical significance will be determined by prospective analysis of study data, 
comparing independent effects of three active concentrations of smoked marijuana and placebo 
on PTSD symptom severity, measured by changes in objective observer-blind Clinician 
Administered PTSD Scale (CAPS-5) total score after 3-weeks of ad-libitum self-administration 
from Baseline to end of Stage 1 (Primary Aim). With 19 participants randomized to each group 
(N=76) who complete the specified treatment period, the study will have 82% power to detect an 
effect size of 0.4 on the primary outcome measure (change in CAPS-5 total score) in the Per 
Protocol sample. Adverse effects will be ascertained at least weekly throughout the active 
treatment and cessation phases of the study based on clinician assessment and participant self-
reports. Biomarkers of inflammation in blood will be measured for potential predictive power 
and/or correlation with treatment outcomes, and quantitative blood/urine cannabinoid analysis 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
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     Version 1 August 31, 2016 
 
will be used to confirm qualitative urine drug tests positive for THC during required periods of 
abstinence from marijuana. Study results will provide novel and heretofore-unknown 
information regarding the safety and effect size of various marijuana concentrations compared to 
placebo among veterans suffering from chronic, treatment-resistant PTSD. 
3.0   Study Objectives 
The objectives of this study are to evaluate whether i) smoking whole plant marijuana attenuates 
PTSD symptoms, ii) to compare the efficacy of varying ratios of THC and CBD to placebo using 
standard clinical measures, and to iii) collect safety data.  
3.1   Primary Objective  
 
1. To compare independent effects of three active concentrations of smoked marijuana and 
placebo on PTSD symptom severity measured by changes in CAPS-5 total scores during 
3-weeks of ad-libitum self-administration during Stage 1 of the study protocol. 
3.2   Secondary Objectives 
 
The following exploratory secondary objectives will be used to support the results of the primary 
objective: 
 
1. Assess independent effects of three active concentrations of marijuana and placebo on 
self-reported symptoms of PTSD with the PCL-5, anxiety and depression with the IDAS, 
and psychosocial functioning with the IPF and WBR (self-report and observer) among 
veterans during Stage 1.   
2. Assess independent effects of three active concentrations of marijuana and placebo on 
self-reported symptoms of PTSD with PCL-5, anxiety and depression with IDAS, and 
psychosocial functioning with the IPF and WBR (self-report and observer) among 
veterans during Stage 2.   
3. Assess comparative efficacy between placebo and each active dose of marijuana based on 
a within-subjects analysis of PTSD symptoms as measured by the CAPS-5 in crossover 
participants at Baseline, End of Stage 1, Stage 2 Baseline, and End of Stage 2.  
4. Assess whether Stage 2 crossover participants’ preferences for marijuana concentrations 
in Stage 1 and Stage 2 correlate with changes in PTSD symptoms as measured by the 
CAPS-5 total score.   
5. Assess whether participants experience clinically significant changes in PTSD symptoms 
based on CAPS-5 and PCL-5 total scores during the washout period between Stage 1 and 
Stage 2 compared with measures assessed at Baseline and during Stage 1. 
6. Explore correlation of treatment outcomes measured by CAPS-5 score with objective 
changes in sleep via Actigraphy throughout the study and self-reported changes in sleep 
quality using the ISI on a weekly basis.  
7. Explore correlation of Daily Diary items related to sleep with objective changes in sleep 
via Actigraphy and self-reported changes in sleep quality using the ISI on a weekly 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
basis.  
8. Explore correlation of treatment effects measured by CAPS-5 total score with amount of 
marijuana used based on Daily Diary across Stage 1 and Stage 2.  
9. Explore treatment outcomes measured by CAPS-5 total score by marijuana 
concentration, with concomitant substance and medication use as a covariate throughout 
the treatment period.  
10. Explore durability of treatment outcomes measured by CAPS-5 total score, with any 
PTSD treatments based on the LTFU questionnaire treated as a covariate, six months 
after completing Stage 2.  
11. Evaluate whether markers of inflammation CRP, IL-1β, and IL-6 levels in blood predict 
PTSD severity at baseline and treatment outcome as a function of marijuana 
concentration.   
3.3   Safety Objectives 
The safety of participants will be measured throughout the study by assessing physiological and 
subjective drug effects, psychological distress, adverse events (AEs), and suicidality, repeatedly 
as described in the following steps. Summaries of safety data by study stage will be provided to 
the Medical Monitors for review during the study.  
1. Explore correlations of subjective effects with the DEQ and cardiovascular effects with 
heart rate of each active dose of marijuana and placebo during introductory sessions.   
2. Explore independent effects of each active dose of marijuana and placebo on blood 
pressure and body temperature during introductory sessions.   
3. Assess independent effects of each active dose of marijuana and placebo on marijuana 
withdrawal symptoms during screening and Cessation 1 and 2.   
4. Assess independent effects of each active dose of marijuana and placebo on problems 
associated with marijuana use during the study, including follow-up, with the CUDIT-R.  
5. Evaluate the subjective effects of each active dose of marijuana and placebo in both 
controlled laboratory and outpatient settings, including ratings of unpleasant drug effects, 
using the DEQ and Daily Diary entries.   
6. Assess independent effects of each active dose of marijuana and placebo on suicidality 
with the CSSRS on a weekly basis throughout the treatment period, and more frequently 
if needed.   
7. Assess independent effects of each active dose of marijuana and placebo on whether and 
for how many days participants were incarcerated throughout the study.   
8. Assess independent effects of each active dose of marijuana and placebo on whether and 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
for how many days participants were hospitalized throughout the study.   
9. Assess metabolites of alcohol use through urine testing at face-to-face visits.   
10. Collect, review, and report Serious Adverse Events (SAEs) and AEs in accordance with 
FDA regulations and Section 8.0 of the protocol.   
3.4    Process Objectives 
 
The following objectives will include exploratory analyses intended to inform future studies:  
1. Evaluate protocol compliance based on comparison of Daily Diary entries, including 
information on amount, time and frequency of marijuana use, and the weight of any 
unused marijuana across each study stage.   
2. Evaluate protocol compliance using quantitative blood and/or urine cannabinoid levels. 
 Assess the ability of site staff and participants to accurately guess concentration 
assignment in Stage 1 and Stage 2.  
4.0   Study Design 
 
This Phase 2 randomized, placebo-controlled, triple-blind, crossover, multi-site study will assess 
the efficacy and safety of four types of smoked marijuana to manage chronic, treatment-resistant 
PTSD symptoms among 76 veterans in an outpatient setting. The study will consist of a baseline 
period and three distinct study stages, which are described in detail below. 
 
After completion of informed consent procedures, an initial 2-week screening period will be 
conducted to determine study eligibility based on a two-week screening period of verified 
marijuana abstinence prior to randomization, to obtain baseline measures of PTSD and substance 
use, to conduct study training, and ensure participants are willing and able to attend scheduled 
appointments and complete the study procedures. 
 
Following randomization, participants will complete Stage 1, a three-week period of ad- libitum 
marijuana self-administration followed by a two-week period of marijuana abstinence (Cessation 
1). This will be immediately followed by Stage 2, another three-week period of marijuana self-
administration and two-week period of abstinence (Cessation 2). Stage 1 and Stage 2 will consist 
of identical procedures and measures, but the marijuana available to individual participants will 
vary. 
 


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     Version 1 August 31, 2016 
 
During Stage 1, participants will be randomized to receive High THC, High CBD, THC/CBD, or 
Placebo marijuana to self-administer (up to 1.8 g/day) for the 3-week marijuana use period. As 
described in Section 4.2 of the protocol, randomization will be balanced across drug 
concentrations (N=19 per marijuana type; total N=76). During Stage 2, the Placebo marijuana 
concentration will be removed and all participants will be re-randomized to receive a different 
type of marijuana than they were assigned in Stage 1. Thus, Stage 2 will permit a within-subjects 
comparison of changes in CAPS-5 total score as a function of marijuana concentration, including 
differences in preferences for a specific marijuana concentration by self-report, and the removal 
of placebo as a possibility ensures that all study participants receive active marijuana at some 
point during the study. 
 
Following completion of Stage 2, participants will be invited to participate in an optional Stage 
3. During Stage 3, participants can choose to receive the amount equivalent to the unused and 
returned marijuana from Stage 1 or Stage 2 from a new supply. This design feature discourages 
diversion of unused marijuana and encourages participant use of marijuana in a naturalistic 
manner during Stages 1 and 2. Marijuana will be dispensed during Stage 3 based on the average 
daily rate of use during Stages 1 and 2 and will not last more than two months.   
 
There will be a long-term follow-up assessment conducted six months after the end of Stage 2. 
Participants will complete the long-term follow-up questionnaire concerning their mental health, 
substance use, and changes in PTSD therapies and medications. A blinded Independent Rater 
(IR) will administer the CAPS-5. Participants will complete self-report measures and one week 
of Actigraphy (ACT) monitoring, followed by study termination. 
 
Table 4.0-1: Overall Study Design 
Treatment 
Concentration 
Min. Participants 
Baseline (N) 
Min. Participants 
End of Stage 1 (N) 
Min. Participants 
End of Stage 2 (N) 
High THC 
19 
19 
25 
High CBD 
19 
19 
25 
THC/CBD 
19 
19 
26 
Placebo 
19 
19 
 
For further details please refer to the protocol Section 6.2.1 Doses. 
4.1   Time and Events Table


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
Table 4.1-1: Time and Events (Administrative Procedures)   
 
 
 
 
 
Stage 1 
Cessation 1 
Stage 2 
Cessation 2 
Stage 3 
 
 
Screen 
Baseline 
Introduct
ory 
Sessions 
Self-
administr
ation 
Primary 
Endpoint 
Cessatio
n 1 
Stage 2 
Baseli
ne 
Introduct
ory 
Sessions 
Self-
administrati
on 
Seconda
ry 
Endpoin
t 
Cessatio
n 2 
LTFU 
Baselin
e 
Stage 3 
(optional) 
LTFU 
Visit # 
Prescreen 
& Screen 1 
Screen 2 
Enrollment 
V1 & V2 
V3 & V4 
V5 
V6 
V7 
V8 & V9 
V10 & V11 
V12 
V13 
V14 
V15-V23 
(as needed) 
LTFU 
Type of Visit 
Telemed 
Visit & Site 
Visit 
Telemed 
Visit & 
Site Visit  
Site Visit  
 
Site Visit  
 
Weekly 
Site Visits 
Telemed 
Visit  
Site Visit  
 
Teleme
d Visit 
& Site 
Visit  
Site Visit  
 
Weekly Site 
Visits 
Telemed 
Visit  
Site 
Visit  
 
Teleme
d Visit 
& Site 
Visit  
Weekly 
Site Visits  
(as needed) 
Teleme
d Visit 
and/or 
Site 
Visit 
Visit Timing 
Prescreen 
calls up to 
2 months 
prior, in-
person and 
Telemed 
procedures 
at least 2 
weeks prior 
to 
Enrollment 
2 weeks 
after 
Screen 1 
2 weeks 
after Screen 
1, once 
cannabinoi
d results are 
obtained  
(Day 0 
begins at 
Enrollment) 
Occur on 
2 
consecuti
ve days 
(Week 1 
begins 
following 
Introducto
ry Session 
2) 
Between 
start of 
Week 2 & 
start of 
Week 3 
Between 
end of 
Week 3 & 
start of 
Week 4 
Within 2 
days of 
Primary 
Endpoint  
Betwee
n end 
of 
Week 5 
& start 
of 
Week 6 
Post 
cannabino
id results 
Occur on 
consecuti
ve days 
(Week 6 
begins 
after 
Introducto
rySession
4) 
Between 
start of Week 
7 & start of 
Week 8 
Between 
end of 
Week 8 
& 
start of 
Week 9 
Within 2 
days of 
Seconda
ry 
Endpoint 
Betwee
n end 
of 
Week 
10 & 
start of 
Week 
11 
Post 
cannabinoi
d results  
Week 11-
18  
6 
months 
after 
V12 
(may 
take 
place 
over 
more 
than 
one 
day) 
Phone Screen 
✓A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Medical 
& Psych 
History 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Directed 
Physical 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect 
Therapy & 
Medications 
✓ 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Enrollment & 
Randomization 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
Training on 
Self-
Administration 
 
 
 
✓ 
 
 
 
 
✓ 
 
 
 
 
 
 
Video Data 
Review 
 
 
 
 
Weekly 
 
 
 
 
Weekly 
 
 
 
Weekly 
 
Dispense Drug 
 
 
 
Post V2 
Weekly 
 
 
 
Post V9 
Weekly 
 
 
 
Weekly 
 
Weigh Unused 
Marijuana 
 
 
 
 
Weekly 
 
✓ 
 
 
Weekly 
 
✓ 
 
Weekly 
 
Phone Calls 
 
 
 
 
WeeklyB 
 
WeeklyC 
 
 
WeeklyB 
 
WeeklyC 
 
WeeklyD 
 
Collect AEs 
 
 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
A= Initial phone screen with coordinator, secondary phone screen to be performed by CI/Qualified designee or Clinician. B= Participants will have 3 days of phone contact after each second introductory session in Stage 1 
and Stage 2. (more contact may occur as needed) Participants will have a mid-week phone contact during Stage 1 and Stage 2 self-administration weeks 2 and 3. C= Participants will be contacted one week after the 
beginning of Cessation. D= Participants will have a mid-week phone contact. 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
Table 4.1-2: Time and Events (Laboratory Procedures)   
A = Quantitative THC testing to be conducted in THC positive participants only. Blood and urine will be obtained and stored regardless of THC results. B = Completed before & immediately after self-administration and 
every 30 minutes thereafter until end of the visit. C= BP and BT will be obtained prior to self-administration, 30 minutes after starting self-administration and again at the end of each session, approximately four hours after 
starting self-administration.  
 
 
 
 
 
 
Stage 1 
Cessation 1 
Stage 2 
Cessation 2 
Stage 3 
 
 
 
Screen 
Baseline 
Introductory 
Sessions 
Self-
administration
Primary 
Endpoint 
Cessation 1 Stage 2 
Baseline 
Introductory 
Sessions 
Self-
administration 
Secondary 
Endpoint 
Cessation 2 LTFU 
Baseline 
Stage 3 
(optional) 
LTFU 
Visit # 
Prescreen & 
Screen 1 
Screen 2 
Enrollment 
V1 & V2 
V3 & V4 
V5 
V6 
V7 
V8 & V9 
V10 & V11 
V12 
V13 
V14 
V15-V23 
(as needed) 
LTFU 
Type of Visit 
 
Telemed Visit 
& Site Visit 
Telemed 
Visit & Site 
Visit  
Site Visit  
Site Visit  
Weekly Site 
Visits 
Telemed 
Visit  
Site Visit  Telemed 
Visit & 
Site Visit 
Site Visit  
Weekly Site 
Visits 
Telemed 
Visit 
Site Visit  Telemed 
Visit & 
Site Visit  
Weekly Site 
Visits  
(as needed) 
Telemed 
Visit 
and/or Site 
Visit 
Visit Timing 
Prescreen calls 
up to 2 months 
prior, in-person 
and Telemed 
procedures at 
least 2 weeks 
prior to 
Enrollment 
2 weeks 
after Screen 
1 
2 weeks after 
Screen 1, 
once 
cannabinoid 
results are 
obtained  
(Day 0 
begins at 
Enrollment) 
Occur on 2 
consecutive 
days 
(Week 1 
begins 
following 
Introductory 
Session 2) 
Between start of 
Week 2 & start 
of Week 3 
Between 
end of 
Week 3 & 
start of 
Week 4 
Within 2 
days of 
Primary 
Endpoint 
Between 
end of 
Week 5 
& start of 
Week 6 
Post 
cannabinoid 
results 
Occur on 2 
consecutive 
days 
(Week 6 
begins after 
Introductory 
Session 4) 
Between start of 
Week 7 & start 
of Week 8 
Between 
end of 
Week 8 & 
start of 
Week 9 
Within 2 
days of 
Secondary 
Endpoint 
Between 
end of 
Week 10 
& start of 
Week 11 
Post 
cannabinoid 
results  
Week 11-18 
6 months 
after V12 
(may take 
place over 
more than 
one day) 
Blood 
Cannabinoid 
✓A 
✓A 
 
 
 
✓A 
✓A 
 
 
✓A 
✓A 
Biomarker 
 
✓ 
 
 
 
 
  
✓ 
✓ 
 
 
 
 
✓ 
✓ 
 
 
Qualitative 
Urinary Drug 
✓ 
 
✓ 
  
 
✓ 
  
✓ 
 
 
 
✓ 
✓ 
 
✓ 
 
✓ 
 
 
  
✓ 
✓ 
  
✓ 
  
✓ 
 
Quantitative 
Urinary Drug 
✓A 
✓A 
 
 
 
 
✓A 
✓A 
 
 
 
✓A 
✓A 
 
 
Urinary EtG 
✓ 
✓ 
✓ 
✓ 
✓ 
 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
✓ 
 
Urinary 
Pregnancy 
✓ 
✓ 
 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
 
Clinical Labs 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP & BT 
✓ 
 
 
✓C 
Weekly 
 
✓ 
 
✓C 
Weekly 
 
✓ 
✓ 
Weekly 
 
Pulse Oximetry 
✓ 
 
 
✓B 
 
 
 
 
✓B 
 
 
 
 
 
 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
Table 4.1-3: Time and Events (Study Measures) 
 
 
Stage 1 
Cessation 1 
Stage 2 
Cessation 2 
Stage 3 
 
 
Screen 
Baseline 
Introductory 
Sessions 
Self-
administration
Primary 
Endpoint 
Cessation 1 Stage 2 
Baseline 
Introductory 
Sessions 
Self-
administration 
Secondary 
Endpoint 
Cessation 2 LTFU 
Baseline 
Stage 3 
(optional) 
LTFU 
Visit # 
Prescreen & 
Screen 1 
Screen 2 
Enrollment 
V1 & V2 
V3 & V4 
V5 
V6 
V7 
V8 & V9 
V10 & V11 
V12 
V13 
V14 
V15-V23 
(as needed) 
LTFU 
Type of Visit 
Telemed Visit 
& Site Visit 
Telemed 
Visit & Site 
Visit  
Site Visit  
Site Visit  
Weekly Site 
Visits 
Telemed 
Visit  
Site Visit  Telemed 
Visit & 
Site Visit
Site Visit  
Weekly Site 
Visits 
Telemed 
Visit  
Site Visit  Telemed 
Visit & 
Site Visit  
Weekly Site 
Visits  
(as needed) 
Telemed 
Visit 
and/or Site 
Visit 
SCID 
✓ 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
CAPS-5 
  
✓ 
  
  
  
✓ 
  
✓F 
  
  
✓ 
  
✓ F 
  
✓ 
BDI-II 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IDAS 
  
  
✓ 
  
✓ 
  
✓ 
✓ 
  
✓ 
  
✓ 
✓ 
  
✓ 
ISI 
  
  
✓ 
  
✓ 
  
✓ 
✓ 
  
✓ 
  
✓ 
✓ 
  
✓ 
IPFG 
  
  
✓ 
  
 
  
✓ 
✓ 
  
 
  
✓ 
✓ 
 
✓ 
PCL-5E 
✓ 
  
✓ 
  
✓ 
  
✓ 
✓ 
  
✓ 
  
✓ 
✓ 
  
✓ 
ACT 
  
✓C  
 
✓ 
✓ 
  
✓ 
✓ 
✓ 
✓ 
  
✓ 
✓ 
  
✓D 
MWCH 
✓ 
  
✓ 
  
  
  
✓ 
 ✓ 
  
  
  
✓ 
✓ 
  
✓ 
CUDIT-R 
✓ 
  
 
 
 
  
 
 
 
 
  
 
✓ 
 
✓ 
DEQ 
 
 
 
✓A 
✓B 
 
 
 
✓A 
✓B 
 
 
 
✓B 
 
Daily Diary 
  
  
✓ 
✓ B 
✓ B 
✓ 
✓ 
✓ 
✓ B 
✓ B 
✓ 
✓ 
✓ 
✓ B 
 
CSSRS & GWB  
✓ 
  
✓ 
✓ 
✓ 
  
✓ 
✓ 
✓ 
✓ 
 
✓ 
✓ 
✓ 
✓ 
WBR 
 
✓ 
 
 
✓ 
 
✓ 
✓ 
 
✓ 
 
✓ 
✓ 
✓ 
✓ 
STOP-Bang 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Belief of 
Condition 
 
 
 
 
 
 
✓ 
 
 
 
 
✓ 
 
 
 
LTFU 
Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
TLFB 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
✓ 
 A = Completed before & immediately after self-administration and every 30 minutes thereafter until end of session. B = Completed immediately after each self-administration C = Actigraphy use must begin one week prior 
to the first Introductory Session. D = Final week only. E= Will measure past week. LEC plus Criterion A to be assessed at baseline only. F= CAPS-5 assessments at these timepoints will measure the last week.G= Visit 6 will 
be based on past 3 weeks, Visit 7 will be based on the past 2 weeks, Visit 13 will be based on the past 3 weeks, Visit 14 will be based on the past 2 weeks, LTFU will be based on the last month. H= Will measure the past 2 
weeks. 
 
 
 
 
 
 


MAPS Public Benefit Corporation 
 
Statistical Analysis Plan 
 
MJP-1 US 
 
     Version 1 August 31, 2016 
 
Figure 4.1-1: Summary of Events 
 


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Statistical Analysis Plan  
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Version 1 August 31, 2016 
 
 
                                                                                                               Page 15 of 27 
 
5.0   Randomization and Blinding 
 
To achieve sufficient statistical power and account for dropouts, about 116 participants 
will be stratified by site and randomized in a 1:1:1:1 ratio across the four treatment 
groups (High THC, High CBD, THC/CBD, or Placebo) based on a sequential order of 
enrollment into the study. Participants will be assigned a randomization code that will 
correspond to a blinded concentration assignment. Randomization and enrollment will 
halt when 76 participants complete Stage 1 (at least N=19 per group). In order to 
maintain the blind for participants, site staff, IRs, and sponsor staff, a central electronic 
database will be utilized for randomization based on validated computer-generated lists. 
The Stage 1 randomization list will utilize blocks to balance treatment assignments. Stage 
2 randomization will utilize multiple validated randomization lists that re-randomize 
participants in a blinded manner to one of two new treatment assignments in a 1:1 ratio, 
excluding the previously assigned Stage 1 dose and the placebo concentration as 
possibilities. Participants who received placebo in Stage 1 will only be permitted two 
options for Stage 2 randomization, as described in the protocol Section 6.2.1. 
The blind may be broken for an individual participant if there is an AE or other 
emergency requiring knowledge of the participant's marijuana concentration assignment. 
This emergency unblinding would be evaluated on a case by case basis and require 
approval from the site CI and Coordinating Investigator. For this purpose, the 
Randomization Monitor will provide dose assignment through the electronic 
randomization system. In all other cases, the blind will be maintained until all 
participants have completed the study and the database is locked. The Coordinating 
Investigator, Co-investigators, Sub-Investigators, Independent Raters, and participants 
will be blind to concentration assignment.  
 
For further details, refer to Section 6.0 Investigational Product of the protocol.  
6.0   Sample Size and Power Considerations 
The proposed study is a pilot investigation intended to gather preliminary data on the 
effect size and safety of marijuana in people with chronic, treatment-resistant PTSD. 
Because of their exploratory nature, pilot studies are often not powered for detecting the 
desired effect. This study will be the first to examine the effects of marijuana on PTSD.  
This pilot RCT is the first study of its kind intended to gather estimates of effect size of 
marijuana for PTSD. In this study, the marijuana concentration effect of interest is among 
subjects who comply with the treatment.  Thus in the proposed study, with 19 participants 
randomized to each group (N=76) who complete the specified treatment period, the study 
will have 82% power to detect an effect size of 0.4 on the primary outcome measure 
(change in CAPS-5 total score) in the Per Protocol sample. A meta-analysis of 
pharmacotherapies for combat-related PTSD in veterans found that the effect size of 
selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) was 
equivalent to an F-test effect size of 0.3 [1]. Additional enrollment beyond N=76 to 
compensate for anticipated dropouts may increase the statistical power in the primary 
mITT analysis.  However, the effect size may reduce among non-completers and when 
they are included in the mITT analysis the overall effect size may be reduced. The table 


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Statistical Analysis Plan  
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Version 1 August 31, 2016 
 
 
                                                                                                               Page 16 of 27 
below provides power estimates for possible effect sizes in the Per Protocol Population 
and the mITT population(s), depending upon how many subjects are required to obtain 19 
completers in each concentration group. Based on a meta-analysis of PTSD studies which 
found an average of 18% of participants dropped out without completing the 
investigational treatment, the expected dropout rate is 24% to 34% [2]. 
Table 6.0: Power Estimates for a One-Way ANOVA design, Overall mITT Test 
F-Test Effect 
Size 
N=76 
Per Protocol/ 
Completers 
Est. N=100 
mITT 
Dropouts: 24% 
Est. N=116 
mITT 
Dropouts: 34% 
0.3 
55% 
70% 
77% 
0.4 
82% 
92% 
96% 
0.5 
96% 
99% 
99% 
 
7.0   Measures 
 
7.1   
Screening Measures 
 
Screening measures will not be formally analyzed as outcomes and will only be used to 
establish eligibility for the study at Baseline 
 
Beck Depression Inventory –II (BDI-II): total score 
 
STOP-Bang: total score 
 
 
Structured Clinical Interview for DSM-5 Research Version (SCID-5-RV) 
 
SCID for Personality Disorders (SCID-PD) 
  
7.2   
Outcome Measures 
 
Primary Outcome Measure:  
 
Clinician-Administered PTSD Scale (CAPS-5): Total Severity Score, Criterion A 
Traumatic Event, Criterion E Duration of PTSD, Dissociative Subtype, Diagnostic 
criteria Met  
 
Secondary Outcome Measures: 
 
PCL-5: Total score 
 
Insomnia Severity Index (ISI): Total score 
 


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Statistical Analysis Plan  
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Version 1 August 31, 2016 
 
 
                                                                                                               Page 17 of 27 
Inventory of Depression and Anxiety (IDAS): General depression, dysphoria, lassitude, 
insomnia, suicidality, appetite loss, appetite gain, ill temper, well-being, social anxiety, 
panic, traumatic intrusions 
 
Inventory of Psychosocial Functioning (IPF): Total score 
 
Weekly Behavior Report (WBR) for Community Observer: Item-level data on 
relationship with partner or spouse, family, work, education, social, self-care, non-
medical substance use, general mood and functioning 
 
WBR for Participant: Item-level data on relationship with partner or spouse, family, 
work, education, social, self-care, non-medical substance use 
 
Actigraphy (ACT): Weekly total sleep time (TST), wake after sleep onset (WASO), sleep 
onset latency (SOL), sleep efficiency (SE)  
 
Plasma analysis of inflammation markers (CRP, IL-1β, and IL-6) 
 
7.3   Safety Measures 
 
Time-line Follow-back (TLFB):  
a. Nicotine (cigarettes): Use present, Total Cigarettes, # of Days Using Cigarettes in 
Assessment Period, % of Days Using Cigarettes, Average Cigarettes Per 
Substance Use Day, Average Cigarettes Per Day, # of Abstinent ("0") days, 
Estimated Cigarettes Per Year, Greatest # of Cigarettes in 1 Day, Cigarettes Per 
Week 
b. Marijuana (smoked cannabis flower): Use present, Total amount in weight, # of 
Days Using Marijuana in Assessment Period, % of Days Using Marijuana, 
Average amount in weight Per Substance Use Day, Average amount in weight Per 
Day, # of Abstinent ("0") days, Estimated Marijuana Use Per Year, Greatest 
Amount of Marijuana Use in Weight in 1 Day, Marijuana use in amount in weight 
Per Week 
 
c. Drinking: Use present, Total Drinks, # of Days Drinking (Out of Assessment 
Period), % of Days Drinking, Average Drinks Per Drinking Day, Average Drinks 
Per Day, # of Abstinent ("0") days, Heavy Drinking Days (Heavy Drinking is 
defined as 5 or more drinks per day for a man and 4 or more drinks per day for a 
woman.), # of Drinks in 30 Days, Greatest # of Drinks in 1 Day, Drinks Per Week 
 
d. Other drugs (specify): Use present, # of Days Using in Assessment Period, % of 
Days Using, # of Abstinent ("0") days, Percentage of Abstinent Days, Estimated 
Use Days Per Year, Average Use Days Per Week 
  
Cannabis Use Disorders Identification Test-Revised (CUDIT-R): Total score 
 
Marijuana Withdrawal Checklist (MWC): Total score 
 
STOP-Bang: Total score 


MAPS Public Benefit Corporation                                                  
Statistical Analysis Plan  
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Version 1 August 31, 2016 
 
 
                                                                                                               Page 18 of 27 
 
Columbia Suicide Severity Rating Scale (CSSR-S): Suicidal ideation, intensity of 
ideation, and suicidal behavior scores 
 
General Well-being (GWB): Not formally analyzed 
 
Drug Effect Questionnaire (DEQ): Drug effect, unpleasant drug effect, pleasant drug 
effect, sick, heart racing, anxious or nervous, relaxed, paranoid, sleepy or tired, alert, 
irritable, vigorous or motivated, restless, hungry or munchies, mouth dry, eyes dry, 
trouble with memory, throat irritated, difficulty performing routine tasks  
 
Vital signs: Systolic blood pressure (SBP), diastolic blood pressure (DBP), body 
temperature (BT)   
 
Pulse Oximetry: Pulse (HR) and blood oxygen levels (SpO) 
 
Adverse events, including spontaneously reported reactions 
 
Concomitant Medications and Therapies 
 
7.4   
Process Measures 
 
Daily Diary: Daily use of study marijuana, daily use of other substances and medications, 
amount of study marijuana used, amount of other substance used, times of day study 
marijuana is used, times of day other substance is used, frequency of use of study 
marijuana per day, reason for self-administration of marijuana per self-administration, 
daily self-reported sleep data collection (time to sleep, time to wake, time out of bed, 
sleep onset latency, wake after sleep onset, sleep quality) will be summarized by 
descriptive statistics for analysis of continuous variables, e.g. weekly N, min, max, mean, 
SD, and for analysis of dichotomous variables by weekly frequency and percentages 
 
Belief of Condition Assignment: Stage 1 concentration guess, Stage 2 concentration 
guess, participant and blinded site staff 
 
Long-term Follow-up questionnaire: Item-level data 
 
Quantitative blood and/or urine analysis of cannabinoids (THC, CBD) 


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Statistical Analysis Plan  
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Version 1 August 31, 2016 
 
 
                                                                                                               Page 19 of 27 
8.0   Analyses 
 
In general, nominal variables will be described in terms of frequencies and percentages 
and analyzed using chi square analysis. Ordinal and non-normal continuous data will be 
described using sample median and range, and analyzed by non-parametric statistical 
tests. Data that approximates a Gaussian distribution will be described using sample 
mean and standard deviations and analyzed by parametric statistical tests. Appropriate 
tests for comparative group homogeneity would be conducted and any significant lack of 
homogeneity will be appropriately addressed.  No Type 1 error adjustments will be made 
for multiplicity.  
 
8.1   
Study Population 
 
See protocol section 4.3 Recruitment and Participant Population. All participants must 
have a diagnosis of PTSD arising from their combat-related service in the U.S. military 
lasting at least six months, meet DSM-5 criteria for PTSD, have CAPS-5 Total Severity 
scores of 25 or greater upon enrollment, have undergone psychotherapy or 
pharmacotherapy of adequate dose and duration for PTSD (est. 12 weeks, as evaluated by 
the Investigator), and report no current hazardous marijuana use.  
 
8.2   
Handling of Dropouts, Missing Data 
 
Participants who discontinue treatment prior to the End of Stage 1 or End of Stage 2 
outcome assessment will be asked to complete an outcome assessment whenever possible 
prior to continuing to the long-term follow-up. Data from dropouts and at least one-
follow-up assessment will be retrieved with last observation carried forward (LOCF).  
For measures analyzed with linear modeling, data points that are missing due to subject 
attrition will be handled assuming that data are missing at random (MAR) conditional on 
observed information, which is less restrictive than missing completely at random 
assumed in fixed effects analyses such as ANCOVA. In this procedure, all available 
cases including the ones with missing information will be included in the analyses which 
increases power. 
Early termination visit data for mITT and Safety analyses will be analyzed at the closest 
scheduled outcome visit after self-administration. If the closest visit has valid data, the 
early termination data will be assigned to the next available visit. If a participant 
discontinues and does not participate in an early termination visit, data from the last 
available visit will be used to replace the missing early termination visit data.  


MAPS Public Benefit Corporation                                                  
Statistical Analysis Plan  
MJP-1 US 
 
Version 1 August 31, 2016 
 
 
                                                                                                               Page 20 of 27 
Partial or Missing Dates:  
The following conventions will be used to impute missing portions of dates for adverse 
events and concomitant medications. Note that the imputed values outlined here may not 
always provide the most conservative date. In those circumstances, the imputed value 
may be replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will be 
assigned a missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute the month and 
day of the first dose date. 
ii) Otherwise, assign ‘January.’  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month and year, then 
impute the day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
B. 
Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and will be 
assigned a missing value. 
2) 
If the month is unknown, then assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 
8.3   
Protocol Deviations 
 
All protocol deviations will be included as a categorized listing.  Participants with minor 
deviations will be included in all analyses. Analyses will be performed with and without 
deviations to examine the effects of including them in an analysis, via the mITT and PP 
populations. Participants with major deviations will be excluded from the PP analysis and 
included in the mITT analysis. Safety analyses will include all enrolled participants who 
took study drug with all available data, regardless of any deviations. The number of 
participants in each protocol deviation category listed below will be summarized by 
treatment group, and individual participants will be listed in the appendix.  
 


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Statistical Analysis Plan  
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Version 1 August 31, 2016 
 
 
                                                                                                               Page 21 of 27 
Possible protocol deviations include the following five categories: 
• Subject randomized in study did not meet entry criteria  
• Subject developed withdrawal criteria during the study but were not withdrawn  
• Subject received wrong treatment or incorrect dose  
• Subject took excluded concomitant treatment  
• Study procedures missed or performed out of window 
8.4   
Participant Demographics and Background 
 
Population: mITT, PP, crossover, extension  
 
Categorical data includes: gender (demographics), ethnicity/race (demographics), trauma 
etiology (CAPS-5), medical history (Medical History eCRF), presence of pre-study 
marijuana use (TLFB), presence of pre-study alcohol use (TLFB), presence of pre-study 
other drug use (TLFB), presence of pre-study cigarette use (TLFB), presence of pre-study 
prescribed opiate medications (Concomitant medications eCRF), presence of secondary 
traumatic events (demographics). 
 
Descriptive data includes: age (demographics), number of years with PTSD (CAPS-5), 
number and duration of past therapy for PTSD (Healthcare utilization eCRF), number 
and duration of past medications for PTSD (Concomitant medications eCRF), number 
and duration of past medications for pain if present (Concomitant medications eCRF), 
amount of pre-study marijuana use (TLFB), amount of pre-study alcohol use (TLFB), 
amount of pre-study other drug use (TLFB), amount of pre-study cigarette use (TLFB), 
amount of baseline alcohol if present (Daily Diary), amount of baseline caffeine if 
present (Daily Diary), amount of baseline amphetamines if present (Daily Diary), amount 
of baseline benzodiazepines if present (Daily Diary), amount of baseline cocaine if 
present (Daily Diary), amount of baseline heroin if present (Daily Diary), amount of 
baseline non-medical opioids if present (Daily Diary), amount of baseline MDMA if 
present (Daily Diary), dose of pre-study prescribed opiate medications (Concomitant 
medications eCRF), 
 
Format of presentation: summary tables including frequency listings in total and by 
concentration for categorical data, or mean, standard deviations, median, and range for 
descriptive data 
 
Treatment group differences in baseline characteristics and PTSD severity, as measured 
by CAPS-5 total score, will be evaluated by ANOVA. 


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8.5   
Subject Disposition and Dosing Summary 
 
All participants enrolled in the study (i.e. who sign informed consent and meet 
inclusion/exclusion criteria) will be included in the summary of subject disposition and 
accountability. No inferential statistical tests will be performed. The tabulation of number 
of participants in each treatment group and overall will be displayed for all participants in 
the Safety Population, mITT Population, Crossover Population, Extension Population, 
and PP Population. The number and percent of participants who completed or 
discontinued the study will be displayed for each treatment group and overall together 
with reasons for early termination, where the percent is with respect to the total number 
of randomized participants in that treatment group.  
8.6   Prior and Concomitant Medications and Therapies  
The number and percent of subjects who took medications or received therapy prior to 
and after signing informed consent will be summarized descriptively for each treatment 
group. The tabulation of number of participants in each treatment group and overall will 
be displayed for all participants in the Safety Population, mITT Population, Crossover 
Population, Extension Population, and PP Population. Concomitant medications and 
therapies will be summarized similarly. Prior and concomitant medications and therapies 
will be summarized for the Safety Population. Psychiatric medications will be coded to 
common drug classes and terms. 
8.7   
Efficacy Analyses 
Efficacy analyses intended to examine differences between groups in order to estimate 
effect size will be executed on the mITT population, the PP population, and the 
Crossover population, when appropriate. For all primary, secondary and exploratory 
endpoints descriptive statistics (N, mean, standard deviation, median, range, effect size 
(for measures of interest), or counts and percentages where appropriate will be provided 
by treatment group.   All statistical tests will be executed at a type I error rate of 5%.  No 
adjustments for multiplicity will be made.  Effect size will be estimated based on all 
outcome measures using Cohen’s techniques. 
8.7.1   Primary Efficacy Analyses for Stage 1 
 
The primary Stage 1 efficacy evaluation is an mITT LOCF analysis of the change from 
baseline to the primary outcome timepoint (visit 5) in the CAPS-5 Total Severity score of 
PTSD (difference score).  The primary efficacy comparison will be made with ANOVA 
at an alpha level of 0.05 [3].  If the primary null hypothesis is rejected, pairwise 
comparisons among the treatment groups will be made with Student’s t-tests.   Previous 
studies have shown that the CAPS-4 difference scores followed a Gaussian distribution, 
and it is expected to be the same for the CAPS-5 scores.  However, prior to hypothesis 
testing of the primary endpoint, the distributional properties of the CAPS-5 difference 
scores for the entire sample will be examined.  If departure from a Gaussian distribution 
is detected, appropriate nonparametric methods will be used to test the primary null 
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8.7.2   Secondary Efficacy Analyses  
 
Objective #1, 2, 3: PCL-5, ISI, ACT, IPF, and IDAS scores during Stage 1 and Stage 2 
will be analyzed with Generalized Linear Mixed Effect Modelling (GLMM) with 
participant as a random effect, visit and concentration as fixed effects to fully utilize 
repeatedly measured outcome data. Maximum likelihood estimation will be implemented. 
Overall differences in treatment concentrations will be compared with a linear contrast. 
Concentration differences will be examined with pairwise contrasts. Data points that are 
missing due to subject attrition will be handled assuming that data are MAR. In GLMM, 
the change in the outcomes (PCL-5, ISI, ACT, IDAS) will be modeled as the Dependent 
Variable predicted by treatment group. The results of these longitudinal analyses can be 
easily converted to examine the treatment effect at each assessment point and within each 
group. Baseline characteristics, such as age, ethnicity/race, trauma etiology, medical 
history, psychiatric history, etc., will be explored as potential predictors/confounders. 
 
Objective #4: Self-reported preference for marijuana assignment in Stage 1 or Stage 2 
will be examined as an independent predictor for changes in PTSD symptom severity of 
PTSD measured with CAPS-5 during Stage 2 analyzed with ANCOVA.  
 
Objective #5: Washout effects will be examined from the GLMM analysis of CAPS-5 
total score and PCL-5 total score. To assess clinically significant washout effects, defined 
as an 8-point increase in the CAPS-5 total score from end of self-administration in Stage 
1 or Stage 2, will be summarized by descriptive statistics.  
 
Objective #6: GLMM will be conducted examining weekly assessments of self-reported 
(via the ISI) and objective (via Actigraphy) measures of sleep. For objective sleep (via 
Actigraphy) repeated measures of weekly TST, WASO, SOL, and SE will be analyzed 
longitudinally. Measures throughout Stage 1 and Stage 2 will be used.  If the linear 
contrast of the effect of marijuana concentration is observed, then pairwise contrasts will 
be conducted to detect differences between each marijuana concentration. Missing data 
will be handled as described above for GLMM analyses. 
 
Objective #7: Spearman’s correlation will be used to assess the relationship between 
Daily Diary items related to sleep with objective changes in sleep via Actigraphy and 
self-reported changes in insomnia symptoms using the ISI.  STOP-Bang scores will be 
used as a covariate in a regression analysis to determine if participants at high risk of 
breathing disorders is a predictor of sleep continuity outcomes. 
 
Objective #8: Amount of marijuana used by each participant during Stage 1 and Stage 2 
based on Daily Diary will be summed and used as a predictor in the GLMM analysis with 
CAPS-5 as the outcome variable.   
 
Objective #9: The effects of marijuana concentration as measured by CAPS-5 in Stage 1 
and Stage 2 will be analyzed in a GLMM analysis with concomitant medications 
evaluated in the model as potential predictors or confounders of the treatment effect.   
Objective #10: The LTFU Questionnaire nominal variables will be described in terms of 
frequencies and percentages, while ordinal and non-normal continuous variables will be 


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described using sample mean, standard deviations, and range. Changes in CAPS-5 total 
score from end of treatment at either the end of Stage 1 (V5) or end of Stage 2 (V12) to 
the LTFU visit in participants who receive at least one type of active marijuana will be 
explored with ANCOVA. In the Extension set, the amount of Stage 3 marijuana and 
duration of Stage 3 will be collected and entered as covariates in analysis of long-term 
follow-up CAPS-5 total score. 
 
8.7.3   Additional Exploratory Analyses 
 
Additional exploratory analyses will be executed on the mITT population, the PP 
population, the Crossover population, and Extension population, when appropriate. 
 
Process Objective #2: In order to compare the blinded site staff and participant’s belief of 
condition assignment to actual marijuana concentration received, the number and 
frequency of correct guesses will be calculated and depicted by dose group and study role 
(subject and site staff). 
 
Objective #11: Independent prognostic value of CRP, IL-1β and Il-6 will be examined 
using GLMM, with biomarker values gathered at Baseline, primary endpoint CAPS-5 
total score, and biomarker values collected after two weeks of Cessation and the End of 
Stage 2. Baseline characteristics, such as age, ethnicity/race, trauma etiology, medical 
history, psychiatric history, etc., will be explored as potential predictors/confounders. 
 
Process Objective #1: Quantitative levels of THC, CBD and their metabolites will be 
assessed in order to ascertain whether participants comply with only using the marijuana 
assigned to them during the study. If there is sufficient data, correlational analyses may 
also be conducted between quantitative THC and CDB levels in urine and blood and 
clinical outcomes as measured by CAPS-5 Total Severity score to determine whether 
there is a dose-response effect between THC and CBD exposure and clinical response. 
 
Daily Diary, WBR for Participant and Observer data will be used to support protocol 
compliance with take-home dosing. Item-level data will be summarized for analysis of 
dichotomous variables by weekly frequency and percentages, while ordinal and non-
normal continuous variables will be described using sample mean, standard deviations, 
and range. 
 
8.8   
Safety Analysis 
 


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Safety analyses will be executed on the mITT population, the PP population, the 
Crossover population, and Extension population, when appropriate.  
 
Objective #10: The primary measure of safety will be the reporting of adverse events. 
The adverse events (AEs) considered are Treatment Emergent Adverse Events (TEAE) 
defined as those AE’s that occurred after dosing and existing medical history diagnoses 
that worsened during the study. Verbatim terms on case report forms will be mapped to 
preferred terms and system organ classes using the MedDRA dictionary. For incidence 
reporting if a subject has more than one AE mapped to the same preferred term, that AE 
will be reported only once using the highest severity and closest relationship to study 
drug.  Subject incidence of AEs will be displayed by concentration, by stage, and by 
system organ class. AEs will also be summarized by severity and relationship to study 
drug. Subject incidence of SAEs by concentration and by stage will also be displayed. In 
addition to the listing of all AEs, a listing of SAEs and a listing of AEs leading to 
discontinuation will be included.  
 
Objective #1, 2, 5: GLMM will be used to examine DEQ, pulse, blood pressure, and body 
temperature during introductory sessions, with participant as a random effect, visit and 
concentration as fixed effects to fully utilize repeatedly measured safety data. Maximum 
likelihood estimation will be implemented. Overall differences in treatment 
concentrations will be compared with a linear contrast. Concentration differences will be 
examined with pairwise contrasts. Missing data will be handled as described above for 
secondary efficacy analyses. 
 
Objective #3: Symptoms of marijuana withdrawal will be displayed by incidence, 
percentages and by concentration and crossover group for screening, Cessation 1 and 
Cessation 2. The MWC total score will be analyzed by GLMM to assess differences by 
concentration and crossover group.  If a main effect of marijuana concentration or 
crossover group is observed, then pairwise contrasts will be used to detect differences 
between each marijuana concentration. 
 
Objective #4: The CUDIT-R total score will be analyzed by GLMM to assess differences 
by concentration and crossover group.  If a main effect of marijuana concentration or 
crossover group is observed, then pairwise contrasts will be used to detect differences 
between each marijuana concentration. 
 
Objective #6: Suicidal ideation and behavior will be summarized according to 
suggestions made in the Columbia-Suicide Severity Rating Scale Scoring and Data 
Analysis Guide [4]. A positive response for suicidal ideation is counted when a subject 
answers “yes” to any one of the five suicidal ideation questions (Categories 1-5) on the 
C-SSRS, i.e. a score > 0 for suicidal ideation score. Serious suicidal ideation is a suicidal 
ideation score of 4 or 5. A positive response for suicidal behavior occurs when a subject 
answers “yes” to any one of the five suicidal behavior questions (Categories 6-10) on the 
C-SSRS, i.e. a score > 0 for suicidal behavior score. The number and percent of positive 
responses of Positive Ideation, Serious Ideation, and Positive Behavior will be tabulated 
by Stage I concentration and crossover group. Analyses will compare lifetime serious 
suicidal ideation and positive behavior frequencies to cumulative frequencies anytime 
during the study until end of the last stage of self-administration completed. 


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Objective #7, 8: Incidence and percentages of hospitalizations and incarcerations will be 
displayed by stage and by concentration. 
8.8.1   Additional Safety Analysis 
 
Timeline follow-back (TLFB) will be used to support severity assessment of substance 
use disorder diagnoses made during screening via SCID-5-RV. Exploratory comparisons 
of substance use descriptives pre and post-treatment will be made with ANOVA at an 
alpha level of 0.05.  
 
Incidence and percentages of concomitant medications and therapies will be displayed by 
concentration and by stage. 
9.0   Interim Analyses 
 
No interim analyses are planned for this study. 
10.0   Timing of Analyses 
 
The study will remain blinded until final database lock, at which point the randomization 
file will be merged by the unblinded Randomization Monitor with the clinical study 
database. The primary efficacy analysis will be conducted after database lock. Changes to 
protocol will not occur after primary analysis.  
11.0   Statistical Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, 
and graphical representations will be performed primarily using SAS (release 9.3 or 
higher) for Windows.  If the use of other software is warranted, the final clinical study 
report will detail what software was used and for what purposes. 
12.0   References 
 
 
 
 
 
 
 
References 
 
1. 
Puetz, T.W., S.D. Youngstedt, and M.P. Herring, Effects of Pharmacotherapy on 
Combat-Related PTSD, Anxiety, and Depression: A Systematic Review and Meta-
Regression Analysis. PLoS One, 2015. 10(5): p. e0126529. 


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2. 
Imel, Z.E., et al., Meta-analysis of dropout in treatments for posttraumatic stress 
disorder. J Consult Clin Psychol, 2013. 81(3): p. 394-404. 
3. 
Senn, S.S., Statistical issues in drug development. Vol. 69. 2008, Chichester, 
England: John Wiley & Sons. 
4. 
Nilsson, M.E., et al., Columbia Suicide Severity Rating Scale Scoring and Data 
Analysis Guide, in CSSRS Scoring Version 2.0. 2013: 
http://www.cssrs.columbia.edu/documents/ScoringandDataAnalysisGuide_Feb20
13.pdf. p. 1-13.