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)
Phase: PHASE2
Conditions: Posttraumatic Stress Disorder
Sponsor: Multidisciplinary Association for Psychedelic Studies

 
 
 
 
 
 
 
 
 
 
 
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 
 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  7 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  8 of 76 
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.  
 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  9 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  10 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  11 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  12 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  13 of 76 
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.  
 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  14 of 76 
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.  
 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  15 of 76 
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.  
 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  16 of 76 
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.   
 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  17 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  18 of 76 
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. 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  19 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  20 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  21 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  22 of 76 
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 

MAPS Study MJP-1 
  
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  23 of 76 
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.  

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  24 of 76 
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
 
 
 
 
 
 
 
 
 
 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  25 of 76 
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

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  26 of 76 
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
 
 
 
 
 
 
 
 
 
 
 
 
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 Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  27 of 76 
Figure 1: Summary of Events 
 
 
 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  28 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  29 of 76 
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. 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  30 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  31 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  32 of 76 
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. 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  33 of 76 
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. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  34 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  35 of 76 
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. 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  36 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  37 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  38 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  39 of 76 
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. 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  40 of 76 
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
 
 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  41 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  42 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  43 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  44 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  45 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  46 of 76 
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]. 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  47 of 76 
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.  

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  48 of 76 
 
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: 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  49 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  50 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  51 of 76 
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. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  52 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  53 of 76 
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. 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  54 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  55 of 76 
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.  
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  56 of 76 
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.  
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  57 of 76 
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 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  58 of 76 
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. 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  59 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  60 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  61 of 76 
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.  
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  62 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  63 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  64 of 76 
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 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  65 of 76 
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. 
 
 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  66 of 76 
16.0 References  
 
1. 
Mithoefer, M.C., et al., The safety and efficacy of {+/-}3,4-
methylenedioxymethamphetamine-assisted psychotherapy in subjects with 
chronic, treatment-resistant posttraumatic stress disorder: the first randomized 
controlled pilot study. J Psychopharmacol, 2011. 25(4): p. 439-52. 
2. 
Mithoefer, M.C., et al., Durability of improvement in post-traumatic stress 
disorder symptoms and absence of harmful effects or drug dependency after 3,4-
methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-
term follow-up study. J Psychopharmacol, 2013. 27(1): p. 28-39. 
3. 
Oehen, P., et al., A randomized, controlled pilot study of MDMA (+/- 3,4-
Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of 
resistant, chronic Post-Traumatic Stress Disorder (PTSD). J Psychopharmacol, 
2013. 27(1): p. 40-52. 
4. 
Bonn-Miller, M.O., K.A. Babson, and R. Vandrey, Using cannabis to help you 
sleep: heightened frequency of medical cannabis use among those with PTSD. 
Drug Alcohol Depend, 2014. 136: p. 162-5. 
5. 
Procon.org. 23 Legal Medical Marijuana States and DC; Medical Marijuana - 
Procon.org. 2014  [cited 2014 December 9, 2014]; Available from: 
http://medicalmarijuana.procon.org/view.resource.php?resourceID=000881. 
6. 
Medical Cannabis Numbers as of August 18, 2010. 2010, New Mexico 
Department of Health Medical Cannabis Program: 
http://nmhealth.org/IDB/medicalcannabis/Medical%20Cannabis%20Numbers%2
0as%20of%208-18-10.pdf. 
7. 
Bonn-Miller, M.O., et al., Self-reported cannabis use characteristics, patterns and 
helpfulness among medical cannabis users. Am J Drug Alcohol Abuse, 2014. 
40(1): p. 23-30. 
8. 
Bonn-Miller, M.O., A.H. Harris, and J.A. Trafton, Prevalence of cannabis use 
disorder diagnoses among veterans in 2002, 2008, and 2009. Psychol Serv, 2012. 
9(4): p. 404-16. 
9. 
Kessler, R.C., et al., Lifetime prevalence and age-of-onset distributions of DSM-
IV disorders in the National Comorbidity Survey Replication. Arch Gen 
Psychiatry, 2005. 62(6): p. 593-602. 
10. 
Resnick, H.S., et al., Prevalence of civilian trauma and posttraumatic stress 
disorder in a representative national sample of women. J Consult Clin Psychol, 
1993. 61(6): p. 984-91. 
11. 
Brunello, N., et al., Posttraumatic stress disorder: diagnosis and epidemiology, 
comorbidity and social consequences, biology and treatment. 
Neuropsychobiology, 2001. 43(3): p. 150-62. 
12. 
Norris, F.H., et al., Epidemiology of trauma and posttraumatic stress disorder in 
Mexico. J Abnorm Psychol, 2003. 112(4): p. 646-56. 
13. 
Perkonigg, A., et al., Traumatic events and post-traumatic stress disorder in the 
community: prevalence, risk factors and comorbidity. Acta Psychiatr Scand, 
2000. 101(1): p. 46-59. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  67 of 76 
14. 
Sareen, J., et al., Disability and poor quality of life associated with comorbid 
anxiety disorders and physical conditions. Arch Intern Med, 2006. 166(19): p. 
2109-16. 
15. 
Zlotnick, C., et al., Epidemiology of trauma, post-traumatic stress disorder 
(PTSD) and co-morbid disorders in Chile. Psychol Med, 2006. 36(11): p. 1523-
33. 
16. 
Hoge, C.W., et al., Combat duty in Iraq and Afghanistan, mental health problems, 
and barriers to care. N Engl J Med, 2004. 351(1): p. 13-22. 
17. 
Tanielian, T.L., L. Jaycox, and Rand Corporation., Invisible wounds of war : 
psychological and cognitive injuries, their consequences, and services to assist 
recovery. 2008, Santa Monica, CA: RAND. xliii, 453 p. 
18. 
Statement Of Jon A. Wooditch Acting Inspector General Department Of Veterans 
Affairs, in Committee On Veterans' Affairs Subcommittee On Disability 
Assistance And Memorial Affairs. 2005: Washington, DC. 
19. 
de Jong, J.T., I.H. Komproe, and M. Van Ommeren, Common mental disorders in 
postconflict settings. Lancet, 2003. 361(9375): p. 2128-30. 
20. 
Thabet, A.A. and P. Vostanis, Post-traumatic stress reactions in children of war. 
J Child Psychol Psychiatry, 1999. 40(3): p. 385-91. 
21. 
Weine, S.M., et al., Psychiatric consequences of "ethnic cleansing": clinical 
assessments and trauma testimonies of newly resettled Bosnian refugees. Am J 
Psychiatry, 1995. 152(4): p. 536-42. 
22. 
Kessler, R.C., et al., Prevalence, severity, and comorbidity of 12-month DSM-IV 
disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry, 
2005. 62(6): p. 617-27. 
23. 
Breslau, N. and G.C. Davis, Posttraumatic stress disorder in an urban population 
of young adults: risk factors for chronicity. Am J Psychiatry, 1992. 149(5): p. 
671-5. 
24. 
Breslau, N., The epidemiology of posttraumatic stress disorder: what is the extent 
of the problem? J Clin Psychiatry, 2001. 62 Suppl 17: p. 16-22. 
25. 
Frayne, S.M., et al., Burden of medical illness in women with depression and 
posttraumatic stress disorder. Arch Intern Med, 2004. 164(12): p. 1306-12. 
26. 
Foa, E.B., et al., Effective Treatments for PTSD, Practice Guidelines from the 
International Society for Traumatic Stress Studies. Second ed. 2009, New York, 
NY: Guilford Press. 
27. 
Benedek, D.M., et al. Guideline watch (March 2009): Practice guideline for the 
treatment of patients with acute stress disorder and posttraumatic stress disorder. 
Psychiatry Online, 2009. 
28. 
Foa, E.B., et al., A comparison of exposure therapy, stress inoculation training, 
and their combination for reducing posttraumatic stress disorder in female 
assault victims. J Consult Clin Psychol, 1999. 67(2): p. 194-200. 
29. 
Resick, P.A. and M.K. Schnicke, Cognitive processing therapy for sexual assault 
victims. J Consult Clin Psychol, 1992. 60(5): p. 748-56. 
30. 
van der Kolk, B.A., et al., Fluoxetine in posttraumatic stress disorder. J Clin 
Psychiatry, 1994. 55(12): p. 517-22. 
31. 
Brady, K., et al., Efficacy and safety of sertraline treatment of posttraumatic 
stress disorder: a randomized controlled trial. JAMA, 2000. 283(14): p. 1837-44. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  68 of 76 
32. 
American Psychiatric, A., Diagnostic and Statistical Manual of Mental Disorders  
(DSM IV): 4th Edition. 4th ed. 1994, Washington, DC: American Psychiatric 
Publishing. 
33. 
Jordan, R.G., T.V. Nunley, and R.R. COOK, Symptom exaggeration in a PTSD 
inpatient population: Response set or claim for compensation. J Trauma Stress, 
1992. 5: p. 633-642. 
34. 
Smith, D.W. and B.C. Frueh, Compensation seeking, comorbidity, and apparent 
exaggeration of PTSD symptoms among Vietnam combat veterans. . 
Psychological Assessment, 1996. 8: p. 3-6. 
35. 
Calhoun, P.S., et al., Drug use and validity of substance use self-reports in 
veterans seeking help for posttraumatic stress disorder. J Consult Clin Psychol, 
2000. 68(5): p. 923-7. 
36. 
Schlicker, E. and M. Kathmann, Modulation of transmitter release via 
presynaptic cannabinoid receptors. Trends Pharmacol Sci, 2001. 22(11): p. 565-
72. 
37. 
Greer, G.R., C.S. Grob, and A.L. Halberstadt, PTSD symptom reports of patients 
evaluated for the New Mexico Medical Cannabis Program. J Psychoactive Drugs, 
2014. 46(1): p. 73-7. 
38. 
Passie, T., et al., Mitigation of post-traumatic stress symptoms by Cannabis resin: 
a review of the clinical and neurobiological evidence. Drug Test Anal, 2012. 4(7-
8): p. 649-59. 
39. 
Roitman, P., et al., Preliminary, open-label, pilot study of add-on oral Delta9-
tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin Drug 
Investig, 2014. 34(8): p. 587-91. 
40. 
Cougle, J.R., et al., Posttraumatic stress disorder and cannabis use in a nationally 
representative sample. Psychol Addict Behav, 2011. 25(3): p. 554-8. 
41. 
Chhatwal, J.P. and K.J. Ressler, Modulation of fear and anxiety by the 
endogenous cannabinoid system. CNS Spectr, 2007. 12(3): p. 211-20. 
42. 
Pistis, M., et al., Cannabinoids modulate neuronal firing in the rat basolateral 
amygdala: evidence for CB1- and non-CB1-mediated actions. 
Neuropharmacology, 2004. 46(1): p. 115-25. 
43. 
Hajos, N. and T.F. Freund, Pharmacological separation of cannabinoid sensitive 
receptors on hippocampal excitatory and inhibitory fibers. Neuropharmacology, 
2002. 43(4): p. 503-10. 
44. 
Neumeister, A., et al., Elevated brain cannabinoid CB1 receptor availability in 
post-traumatic stress disorder: a positron emission tomography study. Mol 
Psychiatry, 2013. 18(9): p. 1034-40. 
45. 
Patel, S. and C.J. Hillard, Adaptations in endocannabinoid signaling in response 
to repeated homotypic stress: a novel mechanism for stress habituation. Eur J 
Neurosci, 2008. 27(11): p. 2821-9. 
46. 
Arevalo, C., R. de Miguel, and R. Hernandez-Tristan, Cannabinoid effects on 
anxiety-related behaviours and hypothalamic neurotransmitters. Pharmacol 
Biochem Behav, 2001. 70(1): p. 123-31. 
47. 
Navarro, M., et al., Acute administration of the CB1 cannabinoid receptor 
antagonist SR 141716A induces anxiety-like responses in the rat. Neuroreport, 
1997. 8(2): p. 491-6. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  69 of 76 
48. 
Beinfeld, M.C. and K. Connolly, Activation of CB1 cannabinoid receptors in rat 
hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible 
mechanism contributing to the spatial memory defects produced by cannabinoids. 
Neurosci Lett, 2001. 301(1): p. 69-71. 
49. 
Katona, I., et al., Presynaptically located CB1 cannabinoid receptors regulate 
GABA release from axon terminals of specific hippocampal interneurons. J 
Neurosci, 1999. 19(11): p. 4544-58. 
50. 
Marsicano, G. and B. Lutz, Expression of the cannabinoid receptor CB1 in 
distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci, 
1999. 11(12): p. 4213-25. 
51. 
Onaivi, E.S., M.R. Green, and B.R. Martin, Pharmacological characterization of 
cannabinoids in the elevated plus maze. J Pharmacol Exp Ther, 1990. 253(3): p. 
1002-9. 
52. 
Houser, S.J., et al., Dynorphin B and spinal analgesia: induction of 
antinociception by the cannabinoids CP55,940, Delta(9)-THC and anandamide. 
Brain Res, 2000. 857(1-2): p. 337-42. 
53. 
Pugh, G., Jr., et al., Involvement of dynorphin B in the antinociceptive effects of 
the cannabinoid CP55,940 in the spinal cord. J Pharmacol Exp Ther, 1997. 
281(2): p. 730-7. 
54. 
Zimmer, A., et al., Absence of delta -9-tetrahydrocannabinol dysphoric effects in 
dynorphin-deficient mice. J Neurosci, 2001. 21(23): p. 9499-505. 
55. 
Berrendero, F. and R. Maldonado, Involvement of the opioid system in the 
anxiolytic-like effects induced by Delta(9)-tetrahydrocannabinol. 
Psychopharmacology (Berl), 2002. 163(1): p. 111-7. 
56. 
Marin, S., et al., Involvement of the kappa-opioid receptor in the anxiogenic-like 
effect of CP 55,940 in male rats. Pharmacol Biochem Behav, 2003. 74(3): p. 649-
56. 
57. 
Marsicano, G., et al., The endogenous cannabinoid system controls extinction of 
aversive memories. Nature, 2002. 418(6897): p. 530-4. 
58. 
Kuhnert, S., C. Meyer, and M. Koch, Involvement of cannabinoid receptors in the 
amygdala and prefrontal cortex of rats in fear learning, consolidation, retrieval 
and extinction. Behav Brain Res, 2013. 250: p. 274-84. 
59. 
Ganon-Elazar, E. and I. Akirav, Cannabinoids and traumatic stress modulation of 
contextual fear extinction and GR expression in the amygdala-hippocampal-
prefrontal circuit. Psychoneuroendocrinology, 2013. 38(9): p. 1675-87. 
60. 
Fraser, G.A., The use of a synthetic cannabinoid in the management of treatment-
resistant nightmares in posttraumatic stress disorder (PTSD). CNS Neurosci 
Ther, 2009. 15(1): p. 84-8. 
61. 
Berger, W., et al., Pharmacologic alternatives to antidepressants in posttraumatic 
stress disorder: a systematic review. Prog Neuropsychopharmacol Biol 
Psychiatry, 2009. 33(2): p. 169-80. 
62. 
Zanelati, T.V., et al., Antidepressant-like effects of cannabidiol in mice: possible 
involvement of 5-HT1A receptors. Br J Pharmacol, 2010. 159(1): p. 122-8. 
63. 
Cameron, C., D. Watson, and J. Robinson, Use of a synthetic cannabinoid in a 
correctional population for posttraumatic stress disorder-related insomnia and 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  70 of 76 
nightmares, chronic pain, harm reduction, and other indications: a retrospective 
evaluation. J Clin Psychopharmacol, 2014. 34(5): p. 559-64. 
64. 
Jetly, R., et al., The efficacy of nabilone, a synthetic cannabinoid, in the treatment 
of PTSD-associated nightmares: A preliminary randomized, double-blind, 
placebo-controlled cross-over design study. Psychoneuroendocrinology, 2014. 
65. 
Bhattacharyya, S., et al., Opposite effects of delta-9-tetrahydrocannabinol and 
cannabidiol on human brain function and psychopathology. 
Neuropsychopharmacology, 2010. 35(3): p. 764-74. 
66. 
Crippa, J.A., et al., Cannabis and anxiety: a critical review of the evidence. Hum 
Psychopharmacol, 2009. 24(7): p. 515-23. 
67. 
Morgan, C.J., et al., Impact of cannabidiol on the acute memory and 
psychotomimetic effects of smoked cannabis: naturalistic study. Br J Psychiatry, 
2010. 197: p. 285-90. 
68. 
Fusar-Poli, P., et al., Distinct effects of {delta}9-tetrahydrocannabinol and 
cannabidiol on neural activation during emotional processing. Arch Gen 
Psychiatry, 2009. 66(1): p. 95-105. 
69. 
Rauch, S.L., et al., Exaggerated amygdala response to masked facial stimuli in 
posttraumatic stress disorder: a functional MRI study. Biol Psychiatry, 2000. 
47(9): p. 769-76. 
70. 
Eraly, S.A., et al., Assessment of plasma C-reactive protein as a biomarker of 
posttraumatic stress disorder risk. JAMA Psychiatry, 2014. 71(4): p. 423-31. 
71. 
Tucker, P., et al., Neuroimmune and cortisol changes in selective serotonin 
reuptake inhibitor and placebo treatment of chronic posttraumatic stress 
disorder. Biol Psychiatry, 2004. 56(2): p. 121-8. 
72. 
Newton, T.L., et al., Interleukin-6 and soluble interleukin-6 receptor levels in 
posttraumatic stress disorder: associations with lifetime diagnostic status and 
psychological context. Biol Psychol, 2014. 99: p. 150-9. 
73. 
Tursich, M., et al., Association of trauma exposure with proinflammatory activity: 
a transdiagnostic meta-analysis. Transl Psychiatry, 2014. 4: p. e413. 
74. 
Gill, J.M., et al., Women in recovery from PTSD have similar inflammation and 
quality of life as non-traumatized controls. J Psychosom Res, 2013. 74(4): p. 301-
6. 
75. 
Mechoulam, R., et al., Cannabidiol--recent advances. Chem Biodivers, 2007. 
4(8): p. 1678-92. 
76. 
Rajavashisth, T.B., et al., Decreased prevalence of diabetes in marijuana users: 
cross-sectional data from the National Health and Nutrition Examination Survey 
(NHANES) III. BMJ Open, 2012. 2: p. e000494. 
77. 
Huestis, M.A., A. Barnes, and M.L. Smith, Estimating the time of last cannabis 
use from plasma delta9-tetrahydrocannabinol and 11-nor-9-carboxy-delta9-
tetrahydrocannabinol concentrations. Clin Chem, 2005. 51(12): p. 2289-95. 
78. 
Weathers, F.W., et al., The Clinician-Administered PTSD Scale for DSM-5 
(CAPS-5). 2013, Washington DC: National Center for PTSD. 
79. 
American Psychiatric Association, Diagnostic and statistical manual of mental 
disorders : DSM-5. 5th ed. 2013, Washington, D.C.: American Psychiatric 
Association. xliv, 947 p. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  71 of 76 
80. 
Weathers, F.W., et al., The PTSD Checklist for DSM-5 (PCL-5). National Center 
for PTSD, 2013. 
81. 
Watson, D., et al., Development and validation of the Inventory of Depression and 
Anxiety Symptoms (IDAS). Psychol Assess, 2007. 19(3): p. 253-68. 
82. 
Watson, D., et al., Further validation of the IDAS: evidence of convergent, 
discriminant, criterion, and incremental validity. Psychol Assess, 2008. 20(3): p. 
248-59. 
83. 
Morin, C.M., Insomnia: psychological assessment and management. 1993, New 
York, NY: Guilford Press. 
84. 
Bastien, C.H., A. Vallieres, and C.M. Morin, Validation of the Insomnia Severity 
Index as an outcome measure for insomnia research. Sleep Med, 2001. 2(4): p. 
297-307. 
85. 
Morin, C.M., et al., The Insomnia Severity Index: psychometric indicators to 
detect insomnia cases and evaluate treatment response. Sleep, 2011. 34(5): p. 
601-8. 
86. 
Yang, M., et al., Interpreting score differences in the Insomnia Severity Index: 
using health-related outcomes to define the minimally important difference. Curr 
Med Res Opin, 2009. 25(10): p. 2487-94. 
87. 
Marx, B.P. and E. al., Development of a functional evaluation scale for active 
duty service members and veterans, in International Society for Traumatic Stress 
Studies. 2009: Atlanta, GA. 
88. 
Sobell, M.B., et al., The reliability of a timeline method for assessing normal 
drinker college students' recent drinking history: utility for alcohol research. 
Addict Behav, 1986. 11(2): p. 149-61. 
89. 
Mariani, J.J., et al., Quantification and comparison of marijuana smoking 
practices: blunts, joints, and pipes. Drug Alcohol Depend, 2011. 113(2-3): p. 
249-51. 
90. 
Adamson, S.J., et al., An improved brief measure of cannabis misuse: the 
Cannabis Use Disorders Identification Test-Revised (CUDIT-R). Drug Alcohol 
Depend, 2010. 110(1-2): p. 137-43. 
91. 
Budney, A.J., P.L. Novy, and J.R. Hughes, Marijuana withdrawal among adults 
seeking treatment for marijuana dependence. Addiction, 1999. 94(9): p. 1311-22. 
92. 
Budney, A.J., et al., The time course and significance of cannabis withdrawal. J 
Abnorm Psychol, 2003. 112(3): p. 393-402. 
93. 
Budney, A.J., et al., Comparison of cannabis and tobacco withdrawal: severity 
and contribution to relapse. J Subst Abuse Treat, 2008. 35(4): p. 362-8. 
94. 
Vandrey, R., et al., The dose effects of short-term dronabinol (oral THC) 
maintenance in daily cannabis users. Drug Alcohol Depend, 2013. 128(1-2): p. 
64-70. 
95. 
Vandrey, R., A. Umbricht, and E.C. Strain, Increased blood pressure after abrupt 
cessation of daily cannabis use. J Addict Med, 2011. 5(1): p. 16-20. 
96. 
Vandrey, R.G., et al., A within-subject comparison of withdrawal symptoms 
during abstinence from cannabis, tobacco, and both substances. Drug Alcohol 
Depend, 2008. 92(1-3): p. 48-54. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  72 of 76 
97. 
Posner, K., et al., Columbia Classification Algorithm of Suicide Assessment (C-
CASA): classification of suicidal events in the FDA's pediatric suicidal risk 
analysis of antidepressants. Am J Psychiatry, 2007. 164(7): p. 1035-43. 
98. 
Morean, M.E., et al., The drug effects questionnaire: psychometric support across 
three drug types. Psychopharmacology (Berl), 2013. 227(1): p. 177-92. 
99. 
Weafer, J. and H. de Wit, Inattention, impulsive action, and subjective response to 
D-amphetamine. Drug Alcohol Depend, 2013. 133(1): p. 127-33. 
100. 
Kirkpatrick, M.G., et al., MDMA effects consistent across laboratories. 
Psychopharmacology (Berl), 2014. 
101. 
Beck, A.T. and C.H. Ward, Dreams of depressed patients. Characteristic themes 
in manifest content. Arch Gen Psychiatry, 1961. 5: p. 462-7. 
102. 
Beck, A.T. and R.A. Steer, Internal consistencies of the original and revised Beck 
Depression Inventory. J Clin Psychol, 1984. 40(6): p. 1365-7. 
103. 
Beck, A.T., et al., Comparison of Beck Depression Inventories -IA and -II in 
psychiatric outpatients. J Pers Assess, 1996. 67(3): p. 588-97. 
104. 
First MB, et al., Structured Clinical Interview for DSM-5 - Research Version 
(SCID-5 for DSM-5, Research Version; (SCID-5-RV). 2015, Arlington, VA: 
American Psychiatric Association. 
105. 
Clark, R.C. and D.P. Watson, Cannabis and Natural Cannabis Medicines, in 
Forensics and Science: Marijuana and the Cannabinoids, M.A. ElSohly, Editor. 
2007, Humana Press: Totowa, NJ. p. 1-15. 
106. 
Grinspoon, L., Medical marihuana in a time of prohibition. Int J Drug Policy, 
1999. 10 (2): p. 145-156. 
107. 
Ilan, A.B., et al., Neurophysiological and subjective profile of marijuana with 
varying concentrations of cannabinoids. Behav Pharmacol, 2005. 16(5-6): p. 487-
96. 
108. 
Russo, E. and G.W. Guy, A tale of two cannabinoids: the therapeutic rationale 
for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses, 2006. 
66(2): p. 234-46. 
109. 
Zuardi, A.W., et al., Cannabidiol, a Cannabis sativa constituent, as an 
antipsychotic drug. Braz J Med Biol Res, 2006. 39(4): p. 421-9. 
110. 
Khalsa, J.H., Medical and Health Consequences of Marijuana, in Forensic 
Science and Medicine: Marijuana and the Cannabinoids, M.A. ElSohly, Editor. 
2007, Humana Publishing: Totowa, NJ. p. 237-252. 
111. 
Zuurman, L., et al., Biomarkers for the effects of cannabis and THC in healthy 
volunteers. Br J Clin Pharmacol, 2009. 67(1): p. 5-21. 
112. 
Battistella, G., et al., Weed or wheel! FMRI, behavioural, and toxicological 
investigations of how cannabis smoking affects skills necessary for driving. PLoS 
One, 2013. 8(1): p. e52545. 
113. 
Downey, L.A., et al., The effects of cannabis and alcohol on simulated driving: 
Influences of dose and experience. Accid Anal Prev, 2013. 50: p. 879-86. 
114. 
Downey, L.A., et al., Detecting impairment associated with cannabis with and 
without alcohol on the Standardized Field Sobriety Tests. Psychopharmacology 
(Berl), 2012. 224(4): p. 581-9. 
115. 
Sewell, R.A., M. Ranganathan, and D.C. D'Souza, Cannabinoids and psychosis. 
Int Rev Psychiatry, 2009. 21(2): p. 152-62. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  73 of 76 
116. 
Degenhardt, L. and W. Hall, Is cannabis use a contributory cause of psychosis? 
Can J Psychiatry, 2006. 51(9): p. 556-65. 
117. 
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. 
120. 
Bosker, W.M., et al., Psychomotor function in chronic daily Cannabis smokers 
during sustained abstinence. PLoS One, 2013. 8(1): p. e53127. 
121. 
Pope, H.G., Jr., et al., Cognitive measures in long-term cannabis users. J Clin 
Pharmacol, 2002. 42(11 Suppl): p. 41S-47S. 
122. 
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. 
123. 
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. 
124. 
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. 
127. 
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. 
129. 
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 
Prev, 2012. 
130. 
Simpson, H.M., Epidemiology of road accidents involving marijuana. . Alcohol 
Drugs and Driving., 1986. 2: p. 15-30. 
131. 
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, 
1982. 10(1): p. 35-63. 
132. 
Grotenhermen, F., et al., Developing limits for driving under cannabis. Addiction, 
2007. 102(12): p. 1910-7. 
133. 
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. 
134. 
Substance Abuse and Mental Health Services Administration, Results from the 
2013 National Survey on Drug Use and Health: Summary of National Findings , 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  74 of 76 
NSDUH Series H-48. 2014, Substance Abuse and Mental Health Services 
Administration,: Rockville, MD. 
135. 
Anthony, J.C., L.A. Warner, and R.C. Kessler, . Comparative epidemiology of 
dependence on tobacco, alcohol, controlled substances, and inhalents: basic 
findings 
from the National Comorbidity Survey. E. Exp Clin Psychopharmacol, 1994. 2: p. 244-
268. 
136. 
Jones, R.T., Cardiovascular system effects of marijuana. J Clin Pharmacol, 2002. 
42(11 Suppl): p. 58S-63S. 
137. 
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. 
138. 
Charles, R., S. Holt, and N. Kirkham, Myocardial infarction and marijuana. Clin 
Toxicol, 1979. 14(4): p. 433-8. 
139. 
Karabulut, A. and M. Cakmak, ST segment elevation myocardial infarction due to 
slow coronary flow occurring after cannabis consumption. Kardiol Pol, 2010. 
68(11): p. 1266-8. 
140. 
Singh, N.N., et al., Cannabis-related stroke: case series and review of literature. J 
Stroke Cerebrovasc Dis, 2012. 21(7): p. 555-60. 
141. 
Wolff, V., et al., Cannabis-related stroke: myth or reality? Stroke, 2013. 44(2): p. 
558-63. 
142. 
Bloom, J.W., et al., Respiratory effects of non-tobacco cigarettes. Br Med J (Clin 
Res Ed), 1987. 295(6612): p. 1516-8. 
143. 
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. 
144. 
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. 
1606-13. 
145. 
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): 
p. 141-8. 
146. 
Taylor, D.R., et al., A longitudinal study of the effects of tobacco and cannabis 
exposure on lung function in young adults. Addiction, 2002. 97(8): p. 1055-61. 
147. 
Tashkin, D.P., Smoked marijuana as a cause of lung injury. Monaldi Arch Chest 
Dis, 2005. 63(2): p. 93-100. 
148. 
Hashibe, M., D.E. Ford, and Z.F. Zhang, Marijuana smoking and head and neck 
cancer. J Clin Pharmacol, 2002. 42(11 Suppl): p. 103S-107S. 
149. 
Hashibe, M., et al., Epidemiologic review of marijuana use and cancer risk. 
Alcohol, 2005. 35(3): p. 265-75. 
150. 
Allen, J.H., et al., Cannabinoid hyperemesis: cyclical hyperemesis in association 
with chronic cannabis abuse. Gut, 2004. 53(11): p. 1566-70. 
151. 
Sullivan, S., Cannabinoid hyperemesis. Can J Gastroenterol, 2010. 24(5): p. 284-
5. 
152. 
Gessford, A.K., et al., Marijuana induced hyperemesis: a case report. W V Med 
J, 2012. 108(6): p. 20-2. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  75 of 76 
153. 
Klein, T.W. and C.A. Newton, Therapeutic potential of cannabinoid-based drugs. 
Adv Exp Med Biol, 2007. 601: p. 395-413. 
154. 
Hosking, R.D. and J.P. Zajicek, Therapeutic potential of cannabis in pain 
medicine. Br J Anaesth, 2008. 101(1): p. 59-68. 
155. 
Abrams, D.I., et al., Short-term effects of cannabinoids in patients with HIV-1 
infection: a randomized, placebo-controlled clinical trial. Ann Intern Med, 2003. 
139(4): p. 258-66. 
156. 
Abrams, D.I., et al., Cannabis in painful HIV-associated sensory neuropathy: a 
randomized placebo-controlled trial. Neurology, 2007. 68(7): p. 515-21. 
157. 
Nong, L., et al., Altered cannabinoid receptor mRNA expression in peripheral 
blood mononuclear cells from marijuana smokers. J Neuroimmunol, 2002. 127(1-
2): p. 169-76. 
158. 
Yuan, M., et al., Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine 
balance in activated human T cells. J Neuroimmunol, 2002. 133(1-2): p. 124-31. 
159. 
Bredt, B.M., et al., Short-term effects of cannabinoids on immune phenotype and 
function in HIV-1-infected patients. J Clin Pharmacol, 2002. 42(11 Suppl): p. 
82S-89S. 
160. 
Hegde, M., et al., Seizure exacerbation in two patients with focal epilepsy 
following marijuana cessation. Epilepsy Behav, 2012. 25(4): p. 563-6. 
161. 
Fatma, H., et al., Cannabis: a rare cause of acute pancreatitis. Clin Res Hepatol 
Gastroenterol, 2013. 37(1): p. e24-5. 
162. 
Howaizi, M., et al., Cannabis-induced recurrent acute pancreatitis. Acta 
Gastroenterol Belg, 2012. 75(4): p. 446-7. 
163. 
Rawal, S.Y., D.N. Tatakis, and D.A. Tipton, Periodontal and oral manifestations 
of marijuana use. J Tenn Dent Assoc, 2012. 92(2): p. 26-31; quiz 31-2. 
164. 
Day, N.L., et al., Effect of prenatal marijuana exposure on the cognitive 
development of offspring at age three. Neurotoxicol Teratol, 1994. 16(2): p. 169-
75. 
165. 
Fried, P.A., Prenatal exposure to tobacco and marijuana: effects during 
pregnancy, infancy, and early childhood. Clin Obstet Gynecol, 1993. 36(2): p. 
319-37. 
166. 
Goldschmidt, L., N.L. Day, and G.A. Richardson, Effects of prenatal marijuana 
exposure on child behavior problems at age 10. Neurotoxicol Teratol, 2000. 
22(3): p. 325-36. 
167. 
Kozer, E. and G. Koren, Effects of prenatal exposure to marijuana. Can Fam 
Physician, 2001. 47: p. 263-4. 
168. 
Hathaway, A.D., N. Comeau, and P.G. Erickson, Cannabis normalization and 
stigma: Contemporary practices of moral regulation. Criminology and Criminal 
Justice, 2011. 11(5): p. 451–469. 
169. 
Palamar, J.J., M.V. Kiang, and P.N. Halkitis, Development and psychometric 
evaluation of scales that assess stigma associated with illicit drug users. Subst 
Use Misuse, 2011. 46(12): p. 1457-67. 
170. 
Health Canada, Information for Professionals: (Cannabis, marihuana) and the 
cannabinoids. 2013: Ottawa. 

MAPS Study MJP-1 
 
Amendment 5 Version 1 
US 
 
June 28, 2016 
 
Page  76 of 76 
171. 
Zuurman, L., et al., Pharmacodynamic and pharmacokinetic effects of the 
intravenously administered CB1 receptor agonist Org 28611 in healthy male 
volunteers. J Psychopharmacol, 2009. 23(6): p. 633-44. 
172. 
Watts, B.V., et al., Meta-analysis of the efficacy of treatments for posttraumatic 
stress disorder. J Clin Psychiatry, 2013. 74(6): p. e541-50.