Validation of the Drug Impaired Driving Scenario (DIDS) on the CRCDS-miniSim: Evaluating Sensitivity to the Effects of Cannabis and Alprazolam
Phase: PHASE1
Conditions: Driving Behavior, Driving Under the Influence
Sponsor: Timothy L. Brown

 
 
 
 
1. 
TITLE PAGE 
VALIDATION OF THE DRUG IMPAIRED DRIVING 
SCENARIO (DIDS) ON THE CRCDS-MINISIM: 
EVALUATING SENSITIVITY TO THE EFFECTS OF 
CANNABIS AND ALPRAZOLAM 
PROTOCOL 
 
NCT04970342 
 
Study Drug 
Cannabis 
 
 
Sponsor 
National Highway Transportation Safety Administration 
(NHTSA) 
Date of Original Protocol 
Version 2.0, 1June2021 
Date of Amendment 
12July2021 

  
 
2 
 
2. 
SYNOPSIS 
Name of Sponsor: 
National Highway Transportation Safety Administration (hereafter referred to as NHTSA) 
Name of Study Drug: 
Cannabis 
Name of Active Ingredient: Bulk cannabis (6.18% THC/ <0.025% CBD) in a 500mg dose providing 
30.9 mg THC  
Title of Study:  
Validation of the Drug Impaired Driving Scenario (DIDS) On the CRCDS-Mini-Sim: Evaluating 
Sensitivity To The Effects of Cannabis and Alprazolam Protocol  
Number of Sites and Study Location: This study will take place at 1 site in the US. NADS, 
University of Iowa, Iowa City, IA. 
Phase of Development: 1 
Planned Duration of Participation: Approximately 42 days, including up to 14 days for Screening, 
2 days in each of 3 treatment periods, each separated by at least a 7-day washout period, and a follow-
up phone call approximately 7 days after discharge from the final dosing period 
Objectives: 
Primary:  
The primary objective of this study is to validate the Drug Impaired Driving Scenario (DIDS) using 
the CRCDS-2 driving simulator, by assessing the acute effects of cannabis relative to placebo on 
simulated driving performance. Assay sensitivity will be demonstrated by the significant effect of 
alprazolam 0.75 mg on driving and cognitive endpoints. Other:  
• 
A secondary objective to assess the effects of cannabis on cognitive and psychomotor 
functioning relative to placebo  
• 
Another objective is to evaluate the potential relationship between cannabis blood 
concentration and driving performance endpoints 
Endpoints:  
Key Endpoint:  
• 
Standard Deviation of Lateral Position (SDLP) 
Other Key Endpoints:  
• 
Driving Performance Endpoints 
o Lane exceedance; including number, maximum duration, and area of exceedance 
o Excessive speed count 
o Average speed and speed deviation 
o Excessive Ay (cornering speed threshold exceeded) and Total Crashes 
o Divided Attention: Correct Responses, Omission Errors, Commission Errors, 
Reaction Time, Standard Deviation of Reaction Time 
o Traffic light violations 

  
 
3 
 
o Gap decision making performance 
o Response to Crash Likely Events 
o Attention to mirrors task 
o Working memory task 
o Coherence 
• 
CogScreen Symbol Digit Coding Test 
o Number of correct responses 
o Response Accuracy 
o Standard deviation of reaction time 
• 
CogScreen Symbol Digit Coding – Immediate Recall 
o Immediate recall accuracy 
• 
CogScreen Symbol Digit Coding – Delayed Recall 
o Delayed recall accuracy 
• 
CogScreen Visual Sequence Comparison Test 
o Response speed 
o Response Accuracy 
o Standard deviation of reaction time 
• 
CogScreen Divided Attention Test 
o Response speed 
o Number of premature responses 
o Response accuracy 
o Lapses 
o Multitasking scores 
• 
CogScreen Matching To Sample Test 
o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• 
CogScreen Pathfinder Number 
o Response speed 
o Response accuracy 
o Response coordination 
• 
CogScreen Shifting Attention Test 
o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• 
CogScreen Dual Task Test 
o Tracking errors 
o Number of boundary hits 
o Previous number response speed 
o Previous number response accuracy 

  
 
4 
 
o Previous number standard deviation of reaction time 
o Multitasking scores 
• 
Test of Variables of Attention (TOVA) 
o Response time variability (by quarter and overall) 
o Response speed (by quarter and overall) 
o Commission errors (by quarter and overall) 
o Omission errors (by quarter and overall) 
• 
Self-reported readiness to drive (“Right now do you feel safe to drive?” [Yes/No]) 
• 
VAS to assess subject’s motivation and self-appraisal of their driving performance 
• 
Other self-report measures 
 
Other:  
• 
Changes from baseline in vital signs, clinical laboratory data, ECG parameters, and suicidal 
ideation and behavior using the Columbia Suicide Severity Rating Scale (C-SSRS) 
• 
Relationship between blood concentration of THC and SDLP or other driving or cognition 
endpoints 
Study Description:  
This randomized, double-blind, active- and placebo-controlled, 3-arm, 3-period crossover study is 
designed to validate the DIDS scenarios using the CRCDS-2 driving simulator by assessing the acute 
effects of cannabis relative to placebo on simulated driving performance. Assay sensitivity will be 
demonstrated by the significant effect of alprazolam 0.75 mg on driving and cognitive endpoints.  
 
Following a screening/training period of up to 14 days, eligible subjects will be admitted to NADS on 
Day 1 of Period 1. Baseline performance for cognitive testing will be obtained and subjects will 
practice the CRCDS2-MiniSim driving simulator, then they will be taken to a supervised off-site 
residential facility from the end of Day 1 procedures until the start of procedures on Day 2. Subjects 
will be randomized 1:1:1 into one of 6 treatment sequences as shown in the table below on Day 1. 
Study drug will be administered by inhalation on Day 2 (first subject dosed at approximately 08:40); 
precise timing is relative, as subject dosing will be staggered/offset to accommodate staffing and 
subject flow. Blood samples for pharmacokinetic analysis will be drawn pre-dose and again 40 
minutes post-dose and 3.25 hours post-dose. Symbol Digit Coding (SDC), Pathfinder Number (PFN), 
Readiness to Drive Question, and the Karolinska Sleepiness Scale (KSS) will be administered 
approximately 30 minutes post-dose. Driving assessments will begin approximately 45 minutes 
following dosing (i.e., at approximately 09:25). Driving performance will be assessed via the 
approximate 1-hour Drug Impaired Driving Scenario (DIDS), on the CRCDS2-MiniSim driving 
simulator, comprised of suburban, urban and highway driving tasks. The scenario includes challenges 
designed to assess lane position control, speed control, safety awareness and responsivity, driving-
related decision making, multitasking, and vigilance. Immediately after completing the driving 
simulation, subjects will be administered the visual analog scales, or VAS, followed by the cognitive 
test battery (SDC, Visual Sequence Comparison [VSC], Divided Attention Test – Dual [DAT-Dual], 
PFN, SDC Delayed Recall [SDCDR], Shifting Attention Test – Instruction, Matching to Sample 
[MTS], Dual Task Test – Combined [DT Combined], and Test of Variables of Attention [TOVA]). At 
approximately 3.5 hours post-dose the cognitive test battery (i.e., SDC, VSC, DAT-Dual, PFN, 
SDCDR, SAT Instruction, MTS, DT Combined, TOVA) and self-report measures will be repeated.  
 

  
 
5 
 
Subjects will undergo initial driving simulator training and practice during the Screening period and 
will complete a practice drive on Day 1 of each treatment period.  
 
Subjects will be discharged from NADS on the afternoon of Day 2 of each period approximately 5.33 
hours post-dose, provided they are medically stable for discharge in the opinion of the Investigator 
based on the criteria established by the medical monitor. The subject will not be able to drive 
themselves home and will have transportation arranged. 
 
After a washout of at least 7 days and no more than 10 days between administration of the last dose in 
one period and administration of the first dose in the next period, subjects will be readmitted to 
NADS on Day 1 of Period 2 and receive study drug according to the assigned treatment schedule. All 
study assessments will remain the same as in Period 1. The same process will be repeated for Period 
3.  
 
Seven days (±2 days) after discharge from Period 3, subjects will receive a follow-up/end-of-study 
phone call from the site to evaluate the presence of any AEs and collect any new concomitant 
medication/procedure information. 
 
Figure 1. Study Design 
 
The schedule of assessments is provided in Table 1.  
 
The following regimens will be assessed: 
• 
Treatment A: cannabis (inhaled) 
• 
Treatment B: alprazolam 0.75 mg PO 
• 
Treatment C: placebo PO  
• 
Subjects receive 1 tablet of alprazolam and/or matched placebo 40 minutes prior to 
administration of inhaled cannabis/or matching placebo on Day 2 of each treatment period.  

  
 
6 
 
 
Treatment Sequences 
Sequence 
1 
2 
3 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
A 
C 
6 
C 
B 
A 
Number of Subjects (planned):  Approximately 12 subjects will be randomized and dosed to target 
6 - 8 subjects completing the 3 treatments. Efforts will be made to randomize an approximately equal 
number of subjects by gender. Efforts will be made to randomize an approximately equal number of 
“low frequency” users (1-10 uses per month) and “high frequency” users (>20 uses per month). 
Eligibility Criteria:  
Inclusion 
1. Subject understands and provides written informed consent prior to the initiation of any 
protocol-specific procedures.  
2. Subject is able to comprehend and willing to comply with the requirements of the protocol. 
3. Subject is a healthy male or female, 19 to 45 years of age, inclusive, at Screening.  
4. Subject has a regular sleep pattern (usual bedtime between 21:00 and 00:00). 
5. Subject has Score <10 on Epworth Sleepiness Scale at Screening. 
6. Subject is able to reliably perform study assessments at Screening (On practice drive, SDLP 
no higher than 1 standard deviation greater than the mean for normal healthy adults 
completing the practice scenario; subject exhibits ≥ 11 instances of lane exceedance; or 
subject has fewer than 7 correct hits on the Divided Attention task; CogScreen SDC Correct 
no less than 1 standard deviation below the mean for healthy adults); demonstrates the ability 
to understand task instructions at Screening; and is physically (e.g., adequate manual 
dexterity, vision, and hearing) and cognitively capable of performing study tasks at 
Screening. 
7. Subject possesses (and is willing to provide) a valid driver’s license and is an active driver 
(minimum of approximately 3,000 miles per year for the previous 3 years). 
8. Subject is determined to be (by self-report) either an infrequent user of cannabis (i.e., 1-10 
uses per month) or a frequent user of cannabis (i.e., >20 uses per month) over the preceding 
90 days.  

  
 
7 
 
9. Subject is willing to abstain from cannabis use (other than study drug) beginning 7 days prior 
to admission for the first treatment period (Day 1) until discharge from the facility on Day 2 
of period 3. 
10. Female subjects must meet one of the following criteria: 1) If of childbearing potential, 
female subjects agree to use two contraceptive regimens or remain abstinent during the study; 
or 2) if of non-childbearing potential, female subjects should be surgically sterile or in a 
menopausal state. 
Exclusion 
11. Subject has a significant history and/or presence of hepatic, renal, cardiovascular, pulmonary, 
neurological, psychiatric, gastrointestinal, hematological, immunologic, ophthalmologic, 
metabolic, or oncological disease, or any other medical issue that would, in the opinion of the 
Investigator, present undue risk for the subject in the study.  
12. Subject has a history of suicidal behavior within 24 months of Screening, has answered YES 
to questions 3, 4, or 5 on the C-SSRS at Screening or at any clinic admission, or is currently 
at risk of suicide in the opinion of an Investigator.  
13. Subject has a recent history (within 6 months prior to Screening) of substance use disorder 
(including alcohol) (as judged by the Investigator) or regularly consumes >2 alcoholic 
drinks/day during the last 3 months prior to Screening (1 alcoholic drink is approximately 
equivalent to: beer [284 mL], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]). 
Subjects who consume up to 3 drinks per day but less than 14 drinks per week may be 
enrolled at the discretion of the Investigator.  
14. Subject demonstrates simulator sickness questionnaire scores which are indicative of 
simulator sickness as defined in the driving simulation operations manual.  
15. Subject regularly consumes excessive amounts of caffeine, defined as greater than 6 servings 
(1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other 
caffeinated beverages per day.  
16. Subject smokes more than 10 cigarettes or e-cigarettes, or 3 cigars or pipes per day, or is 
unable to refrain from smoking during study visits. 
17. Subject has been exposed to an investigational drug or device within the 30 days, or 
5 half-lives (if known), whichever is longer, prior to Screening.  
18. Subject has used a prescription or over-the-counter medication known to cause sedation 
within 7 days prior to Admission for Period 1 and is unwilling or unable to refrain from 
sedating medication use during study participation.  
19. Subject has used any benzodiazepine, barbiturate, or GABAA modulator (e.g., eszopiclone, 
zopiclone, zaleplon, and zolpidem) within 28 days prior to Admission for Period 1 or is 
unwilling or unable to refrain from medication use during study participation. 
20. Subject has a history of hepatitis B surface antigen, hepatitis C antibodies, or human 
immunodeficiency virus (HIV) antibodies 1 or 2.  
21. Subject is pregnant or breastfeeding at Screening or any clinic admission or will attempt to 
become pregnant at any time during study participation.  
22. Subject has a clinically significant abnormal finding on 6-lead electrocardiogram (ECG) at 
Screening or at any clinic admission. The ECG may be repeated once for confirmatory 
purposes if initial values obtained exceed the limits specified.  
23. Subject has a positive urine test for drugs of abuse (other than tetrahydrocannabinol [THC]) 
or has a BrAC >0.0 at Screening or any admission.  
24. Subject has any clinically significant abnormal physical examination finding at Screening or 
any clinic admission.  

  
 
8 
 
25. Subject participates in night shift work. 
26. Subject has traveled across ≥1 time zone in the 2 weeks prior to Admission for Period 1 or is 
expected to travel across ≥1 time zone during the study. 
27. Subject is investigative site personnel or their immediate families (spouse, parent, child, or 
sibling whether biological or legally adopted). 
Study Drug Dosage and Mode of Administration: Cannabis will be administered by inhalation.  
Reference Therapy, Dosage and Mode of Administration:  
Alprazolam (active comparator) at a dose of 0.75 mg will be administered orally. 
Cannabis matching placebo will be administered by inhalation. 
Alprazolam matched placebo will be administered orally. 
Duration of Treatment:  
Subjects will receive 1 500 mg dose of cannabis active on Day 2 of one of the three periods. 
Subjects will receive 1 dose of alprazolam 0.75 mg active on Day 2 of one of the three periods. 
Subjects will receive placebo in all treatments. 
Subjects will not receive active cannabis and alprazolam during the same period. 
Statistical Methods:  
A statistical analysis plan (SAP) will provide a detailed description of the analyses to be performed in 
the study. The SAP will be finalized and approved prior to database lock. Any deviations from or 
changes to the SAP following database lock will be described in detail in the clinical study report. 
Analysis Sets 
Randomized Set: All subjects who are randomized 
Full Analysis Set (FAS): all randomized and treated subjects that have at least one primary efficacy 
measure (SDLP) in any treatment period.  
Safety Set (SS) will include all subjects administered at least one dose of any study drug. 
PK Set will include subjects in the Safety Set who have at least one collected blood sample from 
which a valid blood concentration can be measured. 
Primary analysis 
The FAS will be used for the primary analysis.  
The comparison of primary interest is cannabis versus placebo (Day 2) as a function of frequency of 
self-reported cannabis use. The statistical significance of alprazolam versus placebo (p<0.05) 
comparison for SDLP is considered only to validate the experiment as having the ability to detect 
effects (i.e., assay sensitivity).  
Formal statistical tests (when performed) will be 2-sided and tested at the alpha=0.05 level of 
significance.  
Secondary Analyses 
The FAS will be used for secondary analyses.  
Safety Analyses 
Safety and tolerability of cannabis will be assessed by the incidence of TEAEs, and by changes from 
baseline in vital signs, ECG parameters, and suicidal ideation and behavior using the C-SSRS.  
Safety data will be listed by subject and summarized by treatment. All safety summaries will be 
performed on the SS. 
PK Analyses 

  
 
9 
 
The potential relationship between THC blood concentration and SDLP or other driving or cognition 
endpoints will be examined using regression techniques. 
 

 
 
10 
 
Table 1: 
Schedule of Assessments 
 
Screening 
Double-Blind Treatment 
Periods 1 through 3a 
Event 
Day -14 to -1 
Day 1 
(Admission) 
Day 
2 
Follow-
up /or 
ET 
(phone)b 
Informed consent 
X 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
Epworth Sleepiness Scale 
X 
 
 
 
Body weight/height/BMIc 
X 
 
 
 
Physical examinationd (full) 
X 
 
 
 
Physical examinationd (brief) 
 
X 
 
 
HIV and hepatitis screen 
X 
 
 
 
Urine drug & breathalyzer alcohol 
screen 
X 
X 
 
 
Vital signse 
X 
X 
 
 
C-SSRSf 
X 
 
 
 
6-lead ECG 
X 
 
 
 
Randomization 
 
Xg 
 
 
Screen and Familiarize DIDS on 
CRCDS2-MiniSim 
X 
(Day -14 to -3) 
 
 
 
Simulator Sickness Questionnaire 
X 
(Day -14 to -3) 
 
 
 
Screen on CogScreen Battery and 
TOVAh 
X 
(Day -14 to -3) 
 
 
 
Practice CogScreen, TOVA, and DIDS 
on CRCDS2-MiniSimi 
 
X 
 
 

 
 
11 
 
 
 
3a Subjects will be admitted to NADS on Day 1 of each treatment period and then housed at the supervised off site residential facility under NADS staff 
supervision between the end of procedures on Day 1 and start of procedures on Day 2. Each treatment period will be separated by a washout of at least 7 days 
and no more than 10 days between administration of the last dose in one period and administration of the first dose in the next period. 
Error! No bookmark name given. In the event of Early Termination, efforts should be made to obtain the safety assessments indicated for the day of discharge (Day 2). 
c Height and weight will be measured at Screening only. 
d A symptom-directed physical examination may be conducted at any time as needed. 
e Vital signs will include blood pressure, heart rate, respiratory rate, pulse oximetry, and temporal temperature (°F). Heart rate and blood pressure to be collected 
in supine position after the subject has been resting for approximately 3 minutes.  
f The “Baseline/Screening” C-SSRS form will be completed at Screening 
g Subjects will be randomized to a treatment sequence on Day 1 of Period 1. 
i Subjects will complete a training and practice CogScreen session at Screening and will complete a practice CogScreen Session in the afternoon on Day 1. 
Subjects will complete a practice drive on the CRCDS2 at Screening and will also complete the practice drive on the afternoon of Day 1. 
Administer study drugj 
 
 
X 
 
Blood PK collectionk 
 
 
X 
 
CogScreen SubtestsError! Reference source 
not found., l  
 
 
X 
 
TOVA l 
 
 
X 
 
TBD Self-Report Scales 
 
 
X 
 
Self-perceived safety to drive 
questionError! Reference source not found. 
 
 
X 
 
Drug Impaired Driving ScenarioError! 
Reference source not found. 
 
 
X 
 
VASm 
 
 
X 
 
Dischargen 
 
 
X 
 
Phone call  
 
 
 
X 
Adverse events/SAEs 
Ongoing from the time of consent throughout the duration of study 
participation 
Prior/concomitant medicationso 
X 
CRCDS2 = Cognitive Research Corporation Driving Simulator-2nd Edition; C-SSRS = Columbia Suicide Severity 
Rating Scale; DIDS = Drug Impaired Driving Scenario; ECG = electrocardiogram; ET = early termination; HIV = 
Human immunodeficiency virus; PK = pharmacokinetic, SAE = Serious adverse event; VAS = Visual Analog Scale 

 
 
12 
 
Error! Reference source not found. Oral (PO) study drug (alprazolam or placebo) will be administered approximately 40 minutes prior to Inhaled study drug (cannabis or 
placebo) according to the treatment sequence assigned at Period 1. 
k Three separate blood samples for PK analysis will be collected; the samples will be collected pre-dose on Day 2, at.40 minutes (±5 minutes) post-dose (PPP-
001) on Days 2 and at 3.25 hours (±5 minutes) post-dose on Day 2. 
Error! Reference source not found. Symbol Digit Coding, Pathfinder Number, KSS, and self-perception question will be completed prior to driving assessments. The KSS 
will also be administered pre-dose (cannabis). 
Error! Reference source not found. CRCDS2-MiniSim drive to be completed in the morning of Day 2 starting approximately 45 minutes following dosing of cannabis. 
Upon completion of the drive subjects will complete the cognitive test battery and self-report questionnaires. 
m Visual analog scales to assess subject’s motivation and self-appraisal of their driving performance immediately upon completion of the driving assessment. 
   The cognitive test battery and self-report questionnaires will be repeated at approximately 3.5 hours post-dose (cannabis). 
n Subjects will be discharged upon completion of Day 2 assessments if deemed medically stable for discharge by the Investigator. 
o Medications taken within 30 days of Screening and for the duration of the study will be recorded. 
 
 
 
 

13 
 
 
13 
 
 
  
 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................2 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
LIST OF TABLES .........................................................................................................................16 
LIST OF FIGURES .......................................................................................................................16 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Study Rationale ...........................................................................................................20 
5.2. 
Dose Rationale ............................................................................................................22 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
6.1. 
Study Objective ..........................................................................................................23 
6.2. 
Endpoints ....................................................................................................................23 
6.2.1. 
Key Endpoints ............................................................................................................23 
6.2.2. 
Other Key Endpoints ..................................................................................................23 
6.2.3. 
Additional Endpoint(s) ...............................................................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Study Design ..................................................................................................26 
7.2. 
Number of Subjects ....................................................................................................27 
7.3. 
Treatment Assignment ................................................................................................27 
7.4. 
Criteria for Study Termination ...................................................................................28 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
8.1. 
Subject Inclusion Criteria ...........................................................................................29 
8.2. 
Subject Exclusion Criteria ..........................................................................................29 
8.3. 
Subject Withdrawal Criteria .......................................................................................31 
9. 
TREATMENT OF SUBJECTS ..................................................................................32 
9.1. 
Study Drugs ................................................................................................................32 
9.2. 
Meal Timing in Relation to Study Drug Administration and Driving 
Simulations .................................................................................................................32 
9.3. 
Prior Medications, Concomitant Medications, and Restrictions ................................32 
9.3.1. 
Prior and Concomitant Medications and/or Supplements ..........................................32 

14 
 
 
14 
 
 
  
 
9.3.2. 
Prohibited Medications ...............................................................................................33 
9.3.3. 
Other Restrictions .......................................................................................................33 
9.4. 
Treatment Adherence ..................................................................................................33 
9.5. 
Randomization and Blinding ......................................................................................33 
9.5.1. 
Emergency Identification of Study Drug ....................................................................34 
9.6. 
Subject Compensation ................................................................................................34 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................35 
10.1. 
Description of Study Drugs ........................................................................................35 
10.2. 
Study Drug Packaging and Labeling ..........................................................................35 
10.3. 
Study Drug Storage .....................................................................................................35 
10.4. 
Study Drug Preparation ..............................................................................................35 
10.5. 
Study Drug Administration.........................................................................................35 
10.6. 
Study Drug Accountability, Handling, and Disposal .................................................36 
11. 
PHARMACODYNAMIC AND PHARMACOKINETIC ASSESSMENTS ............37 
11.1. 
Pharmacodynamic Assessments .................................................................................37 
11.1.1. 
DIDS Driving Scenario on the CRCDS2-MiniSim ....................................................37 
11.1.2. 
CogScreen Cognitive Test Battery .............................................................................37 
11.1.2.1. 
Digit Symbol Substitution Test (CogScreen Symbol Digit Coding) ..........................37 
11.1.2.2. 
CogScreen Visual Sequence Comparison Test ...........................................................37 
11.1.2.3. 
CogScreen Divided Attention Test .............................................................................37 
11.1.2.4. 
CogScreen Matching to Sample Test .........................................................................37 
11.1.2.5. 
CogScreen Pathfinder Number Test ...........................................................................38 
11.1.2.6. 
CogScreen Shifting Attention Test .............................................................................38 
11.1.3. 
CogScreen Dual Task Test .........................................................................................38 
11.1.4. 
Test of Variables of Attention ....................................................................................38 
11.1.5. 
Karolinska Sleepiness Scale .......................................................................................38 
11.1.6. 
Self-perceived Safety to Drive Question ....................................................................38 
11.1.7. 
Visual Analog Scales to Assess Subjects’ Self-appraisal and Motivation .................39 
11.2. 
Pharmacokinetic Assessments ....................................................................................39 
11.2.1. 
Blood Sample Collection ............................................................................................39 
11.2.2. 
Sample Analysis .........................................................................................................39 
12. 
ASSESSMENT OF SAFETY .....................................................................................40 
12.1.1. 
Demography and Medical History ..............................................................................40 

15 
 
 
15 
 
 
  
 
12.1.2. 
Weight and Height ......................................................................................................40 
12.1.3. 
Physical Examination .................................................................................................40 
12.1.4. 
Vital Signs ..................................................................................................................40 
12.1.5. 
Electrocardiogram (ECG) ...........................................................................................40 
12.1.5.1. 
Drugs of Abuse and Alcohol ......................................................................................40 
12.1.5.2. 
Pregnancy Screen ........................................................................................................41 
12.1.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................41 
12.2. 
Adverse Events and Serious Adverse Events .............................................................41 
12.2.1. 
Adverse Event Definitions ..........................................................................................41 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................41 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................42 
12.2.2. 
Relationship to Study Drug ........................................................................................42 
12.2.3. 
Recording Adverse Events .........................................................................................43 
12.2.4. 
Reporting Serious Adverse Events .............................................................................43 
12.3. 
Pregnancy ...................................................................................................................44 
12.4. 
Overdose .....................................................................................................................44 
13. 
STATISTICS ..............................................................................................................45 
13.1. 
Data Analysis Sets ......................................................................................................45 
13.2. 
Handling of Missing Data ...........................................................................................45 
13.3. 
General Considerations ...............................................................................................45 
13.4. 
Demographics and Baseline Characteristics ...............................................................45 
13.5. 
Pharmacodynamic Analyses .......................................................................................45 
13.6. 
Safety Analyses ..........................................................................................................48 
13.6.1. 
Adverse Events ...........................................................................................................48 
13.6.2. 
Physical Examinations ................................................................................................48 
13.6.3. 
Vital Signs ..................................................................................................................49 
13.6.4. 
6-Lead Electrocardiogram ..........................................................................................49 
13.6.5. 
Prior and Concomitant Medications ...........................................................................49 
13.6.6. 
Columbia Suicide Severity Rating Scale ....................................................................49 
13.7. 
Pharmacokinetic Analyses ..........................................................................................49 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................50 
14.1. 
Audits and Inspections ................................................................................................50 
14.2. 
Ethics Committee ........................................................................................................50 

16 
 
 
16 
 
 
  
 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................51 
16. 
ETHICS ......................................................................................................................52 
16.1. 
Ethics Review .............................................................................................................52 
16.2. 
Ethical Conduct of the Study ......................................................................................52 
16.3. 
Written Informed Consent ..........................................................................................52 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................53 
17.1. 
Inspection of Records .................................................................................................53 
17.2. 
Retention of Records ..................................................................................................53 
18. 
PUBLICATION POLICY ..........................................................................................54 
19. 
LIST OF REFERENCES ............................................................................................55 
APPENDIX A. AMOUNT OF BLOOD DRAWN PER STUDY VISIT ...................................59 
APPENDIX B. DAILY SCHEDULE OF ACTIVITIES PER PERIOD ....................................60 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................10 
Table 2: 
Abbreviations and Definitions of Terms ....................................................................17 
Table 3: 
Treatment Sequences ..................................................................................................28 
Table 4: 
Treatments Administered ............................................................................................32 
 
LIST OF FIGURES 
Figure 1. Study Design ....................................................................................................................5 
 

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
adverse event 
Ay 
cornering speed threshold exceeded 
BAC 
blood alcohol concentration 
BMI 
body mass index 
CBD 
Cannabidiol 
CNS 
central nervous system 
CPT 
continuous performance test 
CRCDS2 
Cognitive Research Corporation Driving Simulator 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DIDS 
Drug Impaired Driving Scenario 
DAT 
Divided Attention Test 
DTT 
Dual Task Test 
EC 
ethics committee 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GABAA 
γ aminobutyric acid-gated chloride channel 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
KSS 
Karolinska Sleepiness Scale 

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Abbreviation 
Definition 
MTS 
Matching To Sample 
MMRM 
mixed model for repeated measures 
NADS 
National Advanced Driving Simulator 
NHTSA 
National Highway Transportation Safety Administration 
PFN 
Pathfinder Number 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PO 
by mouth 
QA 
quality assurance 
QC 
quality control 
QTcF 
QT corrected according to Fridericia’s formula 
qAM 
each morning 
SAE 
serious adverse event 
SDC 
Symbol Digit Coding 
SAT 
Shifting Attention Test 
SDLP 
Standard Deviation of Lateral Position 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TOVA 
Test of Variables of Attention 
THC 
Tetrahydrocannabinol 
WHO 
World Health Organization 
VAS 
visual analog scale 
VSC 
Visual Sequence Comparison 

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5. 
INTRODUCTION 
Following recommendations from the National Transportation Safety Board (NTSB) that the 
U.S. Department of Transportation (DOT) establish a list of approved medications and classes of 
medications that may be used safely when operating a vehicle (NTSB, 2000 as cited in Kay and 
Loga, 2011) the National Highway Traffic Safety Administration (NHTSA) released its Drugs 
and Human Performance Fact Sheets (Cooper & Logan, 2004, as cited in Kay and Logan 2011) 
representing the current scientific knowledge in the area of drugs and human performance for 16 
substances. However, studies determining effects on performance and on driving reflect myriad 
study methodologies. Similar efforts by the National Institute on Drug Abuse (NIDA, 2007 as 
cited in Kay and Logan, 2011) and by the European Union to produce lists characterizing the 
impairing effects of drugs yielded similarly fraught issues regarding the inability to generalize 
results secondary to methodological differences across studies. Subsequently, NHTSA convened 
an expert panel in 2008 and 2009 (Kay and Logan, 2011) with the goal of determining whether a 
list of drugs could be developed indicating which drugs or classes of drugs may pose a risk to 
driving.  
 
Kay and Logan (2011) reported that the panel agreed that a limited number of drugs generally 
pose a low risk to driving when taken according to approved prescribing information under 
appropriate medical oversight. However, the panel also recognized that even among drugs 
generally considered safe for driving, adverse reactions and interactions may occur that could 
impair driving performance. The panel was of the opinion that some specific drugs and drug 
classes are clearly impairing, including sedatives, hypnotics, sedating antihistamines, narcotic 
analgesics, hallucinogens, antipsychotics, and muscle relaxants, even at therapeutic or sub-
therapeutic doses. Furthermore, the panel noted that a potent barrier to categorizing drugs with 
respect to driving impairment risk is “lack of a common, standardized protocol for assessing the 
impairing potential of drugs,” (Kay and Logan, 2011, p. 7). That is, there is recognition of the 
need for a structured, standardized protocol to assess the driving impairment risk of drugs, as 
current systematic reviews reveal inconsistencies in methodology, failures to address 
inconsistencies relative to dosing, time since dosing, subject characteristics and pattern of use, 
and the use of non-standardized testing methodologies.  
 
As a result, a tiered assessment protocol was proposed, including the following tiers: I) 
pharmacology/toxicology review to identify drugs likely to impair driving; II) epidemiological 
review to identify the relative risk of impairment for drugs/drug classes based on comparison to 
control populations or by culpability assessment; and III) standard behavioral assessment (Kay 
and Logan, 2011). Tiers I and II identify the drugs most likely to impair driving, leading to the 
activation of Tier III. The current study is designed as a structured, standardized approach based 
on the Essential Driving Ability Domains (EDAD) Model described in Kay and Logan (2011) in 
order to validate a standardized protocol to evaluate drug impaired driving.  
 
Bulk cannabis was chosen as the study drug given its known chemical properties and range of 
cannabis THC concentrations. This source of cannabis has been used for a series of NHTSA and 
NIDA sponsored driving studies conducted at NADS (Brown et al., 2019; Brown et al., 2020; 
Hartman, Anizan, Jang, Brown, Yun…Huestis, 2015; Hartman et al., 2015a; Hartman et al., 
2015b; Hartman et al., 2016; Hartman, Brown, Milavetz, Spurgin, Pierce…Huestis, 2015; 

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Hartman, Jang, Spurgin, Yun, Gorelick…Huestis, February 2015; Miller et al., 2020; Smith et 
al., November 2018).  
5.1. 
Study Rationale 
 
SELECTION OF CANNABIS FOR VALIDATION OF ASSESSMENT METHODOLOGY: As 
the legal atmosphere surrounding cannabis use continues to evolve, the potential for increased 
usage among drivers raises questions regarding its effects on driving ability. Epidemiological 
studies have examined the relationship between cannabis use and motor vehicle crash risk, injury 
risk, and fatal crash risk. Cannabis tends to be the most common illicit substance present in 
injured drivers (Legrand et al., 2013; Brubacher et al., 2016) and the second only to alcohol as 
the most common recreational substance among injured drivers (ibid). While the presence of 
cannabis in injured drivers in Italy occurred to a lesser extent than did the presence of cocaine 
and benzodiazepines (Siliquini et al., 2007), another study found individuals aged 35 – 54 years 
who reported using cannabis within the past year had significantly greater odds of reporting 
having been in a motor vehicle collision (Mann et al., 2010). Cannabis use has been shown to be 
associated with self-reported instances of road rage, driving mistakes, and accident risk in 
Pakistani truck drivers (Mir et al., 2012). 
 
Methodological and design differences and limitations notwithstanding, the majority of case-
controlled studies show an increase in motor vehicle crashes (MVC) for drivers under the 
influence of cannabis (DeBalzoa et al., 2018; Kuypers et al., 2012; Jamt et al., 2018; Li et al., 
2013; Baldock & Lindsay, 2015; Chihuri & Chen, 2017). Of two case-controlled studies that did 
not find an increase in crash risk, one found an association between cannabis use and unsafe 
driving (Dubois et al., 2015) while the other study reported inconclusive results for the effect of 
cannabis when used in isolation (Steinemann et al., 2018). DeBalzoa et al. (2018) found a high 
degree of association between cannabis use and collisions resulting in driver injuries yet 
concluded that risk of serious injury and fatal injury for individuals testing positive for cannabis 
alone was relatively low. Contradictory findings have been reported for the role of cannabis 
(alone) in fatal crashes (Gjerde et al., 2011; Chihuri & Chen, 2017; Martin et al., 2017).  
 
Experimental research investigating the effects of cannabis on driving have been conducted with 
over-the-road and simulated driving tests. There has been little consistency in the methodology 
applied across researchers and generally a lack of replication. Investigators have studied drivers 
with markedly different characteristics which likely interact with the effect of the drug (e.g., 
patterns of substance use, prior driving experience, and age). Published studies also show a wide 
range of doses and delivery systems and generally fail to show an association between exposure 
and serum THC. Furthermore, driving simulator studies have not been conducted using anything 
approaching a standard set of driving challenges or tasks.  
 
In spite of these methodological issues, there is general agreement that cannabis increases 
weaving. However, the relationship between cannabis exposure and magnitude of weaving 
remains to be determined. The impact of cannabis on lane crossings has been inconsistent. 
Cannabis (without concomitant alcohol consumption) generally results in slower driving speeds 
and greater headway distances in nighttime conditions. With respect to neurocognitive testing, 
cannabis has consistently been shown to impact performance under multitasking conditions.  

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SELECTION OF ALPRAZOLAM FOR USE AS ACTIVE COMPARATOR: Alprazolam is the 
most frequently prescribed benzodiazepine for treating panic disorder and anxiety disorders 
(RxList, 2005 as cited in Leufkens et al., 2007). The cognitive and psychomotor effects of 
alprazolam have been well-documented in older studies (Verster and Volker, 2004b as cited in 
Leufkens et al., 2007; Bertz et al., 1997 as cited in Leufkens et al., 2007; Ellinwood et al., 1985 
as cited in Leukens et al., 2007; Greenblatt et al., 1988 as cited in Leufkens et al., 2007; Kroboth 
et al., 1998 as cited in Leufkens et al., 2007; Rickels, 2004 as cited in Leufkens et al., 2007; 
Scavone et al., 1992 as cited in Leufkens et al., 2007; Smith et al., 1984 as cited in Leufkens et 
al., 2007; Subhan et al., 1986 as cited in Leufkens et al., 2007; Vermeeren et al., 1995 as cited in 
Leufkens et al., 2007; Verster et al., 2002 as cited in Leufkens et al., 2007). While limited in 
number, results from the more recent studies available reveal that alprazolam has an adverse 
impact on driving performance. The most consistent findings are increased weaving (Leufkens et 
al., 2007; Stone et al., 2015; Brown et al., 2018; CRC data on file 2019 and 2020; Verster et al., 
2002), increased lane departures (Sone et al., 2015; Brown et al., 2018; CRC data on file 2019 
and 2020; Pearlman et al., 2020; Verster et al., 2002), and poor speed maintenance (Brown et al., 
2018; Pearlman et al., 2020; CRC data on file 2017, 2019, and 2020; Verster et al., 2002). 
Additional safety endpoints show increased collision risk and failure to adjust speed in corners 
(CRC data on file 2017, 2019, 2020; Verster et al., 2002).  
With regards to neurocognitive functioning, alprazolam has been shown to impair immediate and 
delayed recall of word lists (Leufkens et al., 2007; Reissig et al., 2014; Hindmarch et al., 2005; 
Snyder et al., 2005), impair tracking ability (Hindmarch et al., 2005; Leufkens et al., 2007; 
Verster et al., 2002), slow reaction times (Leufkens et al., 2007; Stone et al., 2015; Reissig et al., 
2014; Hindmarch et al., 2005; CRC data on file 2017, 2019, 2020), and adversely affect 
information processing speed (Reissig et al., 2014; Hindmarch et al., 2005; CRC data on file 
2017 and 2019; Pearlman et al., 2020). 
 
PURPOSE OF PRESENT STUDY: The primary purpose of the current study is to establish a 
standardized protocol for assessing drug impaired driving. Validation of this methodology is to 
be accomplished with a study using cannabis, alprazolam, and matching placebo. As part of this 
research effort, investigators have worked to identify the driving tasks and cognitive abilities 
found to be most vulnerable to the impairing effects of cannabis. In addition, an effort was made 
to identify the subject characteristics associated with increased vulnerability to the impairing 
effects of cannabis. Worked was conducted to develop a methodology for determining when 
drivers are safe to resume driving after drug exposure. The current study is designed to test these 
hypotheses.  
Simulated driving will be performed using an updated version of Cognitive Research 
Corporation’s Driving Simulator (CRCDS2 MiniSim). The prior version of this simulator has 
been used in dozens of driving studies submitted for regulatory review. Driving performance will 
be assessed using an approximate 1-hour Drug Impaired Driving Scenario (DIDS), comprised of 
suburban, urban and highway driving tasks. The scenarios include challenges designed to assess 
lane position control, speed control, safety awareness and responsivity, driving-related decision 
making, multitasking, and vigilance. These domains correspond to the Essential Driving Ability 

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Domains described by Kay and Logan (2011). In addition, cognitive functions associated with 
driving performance and self-report measures will also be administered.  
Consistent with the principles outlined in the FDA Guidance for Industry (2017), this study 
includes both a positive (active) and placebo control condition. The study is designed to assess 
the duration of drug effects. Readiness to resume driving will be assessed using both self-report 
and objective testing. Subjects will include regular (daily) users and weekly users of cannabis. 
The intent is to assess the impact of pattern of drug use on driving performance. A cross-over 
study design will be utilized to maximize statistical power.  
Cannabis will be administered once in the morning on Day 2. Effects on driving and cognition 
will be assessed from 30 to 45 minutes after dosing. Cognitive and self-report measures will be 
repeated approximately 3.5 hours post-dose to assess residual effect. There will be a one-week 
washout between treatment periods. Subjects will be instructed to refrain from drug use for 7 
days prior to treatment period 1 and to continue to abstain from (non-study) drug use for the 
duration of the trial.  
Alprazolam was selected as the active comparator and to further validate the CRCDS-2 and the 
DIDS scenario. The negative effect of Alprazolam on driving performance has been 
demonstrated in both on-the-road and simulated driving studies (Pearlman et al., 2019; CRC, 
data on file; Leufkens 2009; Leufkens & Vermeeren 2014; Mets 2011; Simen 2015; Verster 
2011). Additionally, as alprazolam is the most commonly prescribed psychotropic in the U.S., 
use of the drug remains a concern for traffic safety.  
5.2. 
Dose Rationale 
One dose of cannabis will be evaluated in this study:  
• Bulk cannabis (6.18% THC/ <0.025% CBD) in a 500mg dose providing 30.9 mg THC 
administered by inhalation via vaporization on Day 2 in each of 3 treatment periods 
This dose was selected based on comparability of THC concentrations with a currently in 
development medicinal cannabis medication, PPP001 (Tetra Bio-Pharma Inc), that provides 26.6 
mg THC. Prior research conducted by the research team also demonstrates tolerability of THC 
concentrations of this level (6-7% THC in a 500mg vaporized dose). 
The active comparator, alprazolam, will be administered at a dose of 0.75 on Day 2, based on 
previous demonstration of impaired performance on the driving simulator test following 
administration of a single oral dose at this level (CRC, data on file). 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Study Objective 
The primary objective of this study is to validate the DIDS scenarios using the CRCDS-2 driving 
simulator, by assessing the acute effects of cannabis relative to placebo on simulated driving 
performance. Assay sensitivity will be demonstrated by the significant effect of alprazolam 0.75 
mg on driving and cognitive endpoints. A secondary objective of the study is to assess the effects 
of cannabis on cognitive and psychomotor functioning relative to placebo. Another objective of 
this study is to evaluate the potential relationship between THC blood concentration and driving 
performance endpoints.  
6.2. 
Endpoints 
6.2.1. 
Key Endpoints 
A key driving performance endpoint is Standard Deviation of Lateral Position (SDLP) after a 
single dose of cannabis. 
6.2.2. 
Other Key Endpoints 
• Driving Performance Endpoints 
o Lane exceedance; including number, maximum duration, and area of exceedance 
o Excessive speed count 
o Average speed and speed deviation 
o Excessive Ay (cornering speed threshold exceeded) and Total Crashes 
o Divided Attention: Correct Responses, Omission Errors, Commission Errors, 
Reaction Time, Standard Deviation of Reaction Time 
o Traffic light violations 
o Gap decision making performance 
o Response to Crash Likely Events 
o Attention to mirrors task 
o Working memory task 
o Coherence 
• CogScreen Symbol Digit Coding Test 
o Number of correct responses 
o Response Accuracy 
o Standard deviation of reaction time 
• CogScreen Symbol Digit Coding – Immediate Recall 
o Immediate recall accuracy 
• CogScreen Symbol Digit Coding – Delayed Recall 
o Delayed recall accuracy 
• CogScreen Visual Sequence Comparison Test 

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o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• CogScreen Divided Attention Test 
o Response speed 
o Number of premature responses 
o Response accuracy 
o Lapses 
o Multitasking scores 
• CogScreen Matching To Sample Test 
o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• CogScreen Pathfinder Number 
o Response speed 
o Response accuracy 
o Response coordination 
• CogScreen Shifting Attention Test 
o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• CogScreen Dual Task Test 
o Tracking error 
o Number of boundary hits 
o Previous Number response speed 
o Previous Number response accuracy 
o Previous Number standard deviation of reaction time 
o Multitasking scores 
• Test of Variables of Attention (TOVA)  
o Response time variability (by quarter & overall)  
o Response speed (by quarter & overall) 
o Commission errors (by quarter & overall) 
o Omission errors (by quarter & overall) 
• Self-reported readiness to drive (“Right now do you feel safe to drive?” [Yes/No]) 
• VAS to assess participant’s motivation and self-appraisal of their driving performance 
• Other self-report measures 

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6.2.3. 
Additional Endpoint(s) 
Other endpoints of this study are: 
• Changes from baseline in vital signs, clinical laboratory data, ECG parameters, and 
suicidal ideation and behavior using the Columbia Suicide Severity Rating Scale (C-
SSRS) 
• Relationship between blood concentration of THC and SDLP or other driving or 
cognition endpoints 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, double-blind, active- and placebo-controlled, 3-arm, 3-period crossover 
study to assess the effects of cannabis on simulated driving performance and related cognitive 
functions in healthy male and female adult cannabis users. The study design is provided in 
Figure 1. The schedule of assessments is provided in Table 1.  
 
Following a screening/training period of up to 14 days, eligible participants will be admitted to 
NADS on Day 1 of Period 1. Baseline performance for cognitive testing will be obtained and 
subjects will practice the CRCDS2-MiniSim driving simulator. Participants will be randomized 
1:1:1 into one of 6 treatment sequences as shown in Table 4. Study drug will be administered by 
inhalation on Day 2 with the alprazolam dosing approximately 40 minutes prior to the cannabis 
dosing (the first cannabis dose will occur at approximately 8:40); precise timing is relative, as 
subject dosing will be staggered/offset to accommodate staffing and subject flow. Blood samples 
for pharmacokinetic analysis will be drawn pre-dose and again 40 minutes post-dose and 3.25 
hours post-dose. Symbol Digit Coding (SDC), Pathfinder Number (PFN), Readiness to Drive 
Question, and the Karolinska Sleepiness Scale (KSS) will be administered approximately 30 
minutes post-dose. A baseline KSS will also be administered prior to dosing. Driving 
assessments will begin approximately 45 minutes following dosing. Driving performance will be 
assessed via the approximate 1-hour Drug Impaired Driving Scenario (DIDS), on the CRCDS2-
MiniSim driving simulator, comprised of suburban, urban and highway driving tasks. The 
scenario includes challenges designed to assess lane position control, speed control, safety 
awareness and responsivity, driving-related decision making, multitasking, and vigilance. 
Immediately after completing the driving simulation, subjects will be administered the visual 
analog scales, or VAS, followed by the cognitive test battery (SDC, Visual Sequence 
Comparison [VSC], Divided Attention Test – Dual [DAT-Dual], PFN, SDC Delayed Recall 
[SDCDR], Shifting Attention Test – Instruction [SAT-Instruction], MTS, Dual Task Test – 
Combined [DAT – Combined], and TOVA). At approximately 3.5 hours post-dose the cognitive 
test battery (i.e., SDC, VSC, DAT-Dual, PFN, SDCDR, SAT – Instruction, MTS, DTT – 
Combined, TOVA) and self-report measures will be repeated. 
 
Subjects will undergo initial driving simulator training and practice during the Screening period 
and will complete a practice drive on Day 1 of each treatment period.  
 
Subjects will be discharged from NADS on the afternoon of Day 2 of each treatment period 
approximately 5.33 hours post-dose, provided they are medically stable for discharge in the 
opinion of the Investigator. The subject will not be able to drive themselves home and will have 
transportation arranged. 
 
After a washout of at least 7 days, but no more than 10 days, between administration of the last 
dose in one period and administration of the first dose in the next period, subjects will be 
readmitted to NADS on Day 1 of Period 2 and receive study drug according to the assigned 

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treatment schedule. All study assessments will remain the same as in Period 1. The same process 
will be repeated for Period 3.  
 
Seven days (±2 days) after discharge from Period 3, subjects will receive a follow-up/end-of-
study phone call from the site to evaluate the presence of any AEs and collect any new 
concomitant medication/procedure information. 
 
The schedule of assessments is provided in Table 1. The following regimens will be assessed: 
• Cannabis (inhaled) on Day 2 
• Alprazolam 0.75mg on Day 2 
• Placebo on Day 2 
Subjects will receive 0.75mg of alprazolam (over-encapsulated) or matching placebo capsule 40 
minutes prior to administration of inhaled cannabis or matching placebo inhalation/vaporizer on 
Day 2 of each Treatment Period. Matched placebo tablets and/or vaporizers will be administered 
as necessary to maintain the blind across the 3 treatment regimens. 
7.2. 
Number of Subjects 
Approximately 12 subjects will be randomized and dosed. Efforts will be made to randomize an 
approximately equal number of male and female subjects. Efforts will be made to randomize an 
approximately equal number of “low frequency users” (i.e., 1 – 10 uses of cannabis per month) 
and “high frequency users” (i.e., > 20 uses of cannabis per month).  
7.3. 
Treatment Assignment 
Subjects will be randomized into one of 6 treatment sequences (Table 3). 
 
 

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Table 3: 
Treatment Sequences 
Sequence 
Treatment Period 
1 
2 
3 
1 
A 
B 
C 
2 
B 
C 
A 
3 
C 
A 
B 
4 
A 
C 
B 
5 
B 
A 
C 
6 
C 
B 
A 
Treatment A: Cannabis on Day 2  
Treatment B: Alprazolam 0.75mg on Day 2  
Treatment C: Placebo on Day 2  
Note: Matched placebo capsule or vaporizers will be administered as necessary to maintain the blind across the 3 
treatments. 
7.4. 
Criteria for Study Termination 
NHTSA may terminate this study or any portion of the study at any time for safety reasons 
including the occurrence of AEs or other findings suggesting unacceptable risk to subjects, or for 
administrative reasons. In the event of study termination, NHTSA will provide written 
notification to the Investigator. The investigational site must promptly notify its ethics committee 
and initiate withdrawal procedures for subjects.  

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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Qualified subjects will meet all of the following criteria: 
1. Subject understands and provides written informed consent prior to the initiation of any 
protocol-specific procedures.  
2. Subject is able to comprehend and willing to comply with the requirements of the 
protocol. 
3. Subject is a healthy male or female adult, 19 to 45 years of age, inclusive, at Screening.  
4. Subject has a regular sleep pattern (usual bedtime between 21:00 and 00:00). 
5. Subject has Score <10 on Epworth Sleepiness Scale at Screening. 
6. Subject is able to reliably perform study assessments at Screening (On practice drive, 
SDLP no higher than 1 standard deviation greater than the mean for normal healthy 
adults completing the practice scenario; subject exhibits ≥ 11 instances of lane 
exceedance; or subject has fewer than 7 correct hits on the Divided Attention task; 
CogScreen SDC Correct no less than 1 standard deviation below the mean for healthy 
adults); demonstrates the ability to understand task instructions at Screening; and is 
physically (e.g., adequate manual dexterity, vision, and hearing) and cognitively capable 
of performing study tasks at Screening. 
7. Subject possesses (and is willing to provide) a valid driver’s license and is an active 
driver (minimum of approximately 3,000 miles per year for the previous 3 years). 
8. Subject is determined to be (by self-report) either an infrequent user of cannabis (i.e., 1-
10 uses per month) or a frequent user of cannabis (i.e., >20 uses per month) over the 
preceding 90 days. 
9. Subject is willing to abstain from cannabis use (other than study drug) beginning 7 days 
prior to admission for the first treatment period (Day 1) until discharge from the facility 
on Day 2 of period 3. 
10. Female subjects must meet one of the following criteria: 1) If of childbearing potential, 
female subjects agree to use two contraceptive regimens or remain abstinent during the 
study; or 2) if of non-childbearing potential, female subjects should be surgically sterile 
or in a menopausal state. 
8.2. 
Subject Exclusion Criteria 
Subjects who meet any of the following criteria are disqualified from participation in this study: 
1. Subject has a significant history and/or presence of hepatic, renal, cardiovascular, 
pulmonary, neurological, psychiatric, gastrointestinal, hematological, immunologic, 

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ophthalmologic, metabolic, or oncological disease, or any other medical issue that would, 
in the opinion of the Investigator, present undue risk for the subject in the study.  
2. Subject has a history of suicidal behavior within 24 months of Screening, has answered 
YES to questions 3, 4, or 5 on the C-SSRS at Screening or at any clinic admission, or is 
currently at risk of suicide in the opinion of an Investigator.  
3. Subject has a recent history (within 6 months prior to Screening) of substance use 
disorder (including alcohol) (as judged by the Investigator) or regularly consumes >2 
alcoholic drinks/day during the last 3 months prior to Screening (1 alcoholic drink is 
approximately equivalent to: beer [284 mL], wine [125 mL/4 ounces], or distilled spirits 
[25 mL/1 ounce]). Subjects who consume 3 drinks per day but less than 14 drinks per 
week may be enrolled at the discretion of the Investigator.  
4. Subject demonstrates simulator sickness questionnaire scores which are indicative of 
simulator sickness as defined in the driving simulation operations manual.  
5. Subject regularly consumes excessive amounts of caffeine, defined as greater than 6 
servings of coffee, tea, cola, or other caffeinated beverages per day.  
6. Subject smokes more than 10 cigarettes or e-cigarettes, or 3 cigars or pipes per day, or is 
unable to refrain from smoking during study visits. 
7. Subject has been exposed to an investigational drug or device within the 30 days, or 
5 half-lives (if known), whichever is longer, prior to Screening.  
8. Subject has used a prescription or over-the-counter medication known to cause sedation 
within 7 days prior to Admission for Period 1 and is unwilling or unable to refrain from 
sedating medication use during study participation.  
9. Subject has used any benzodiazepine, barbiturate, or GABAA modulator (e.g., 
eszopiclone, zopiclone, zaleplon, and zolpidem) within 28 days prior to Admission for 
Period 1 or is unwilling or unable to refrain from medication use during study 
participation. 
10. Subject has a history of hepatitis B surface antigen, hepatitis C antibodies, or human 
immunodeficiency virus (HIV) antibodies 1 or 2.  
11. Subject is pregnant or breastfeeding at Screening or any clinic admission or will attempt 
to become pregnant at any time during study participation.  
12. Subject has a clinically significant abnormal finding on 6-lead electrocardiogram (ECG) 
at Screening or at any clinic admission. The ECG may be repeated once for confirmatory 
purposes if initial values obtained exceed the limits specified.  
13. Subject has a positive urine test for drugs of abuse (other than tetrahydrocannabinol 
[THC]) or BrAC > 0.0 at Screening or any admission.  
14. Subject has any clinically significant abnormal physical examination finding at Screening 
or any clinic admission.  
15. Subject participates in night shift work. 
16. Subject has traveled across ≥1 time zone in the 2 weeks prior to Admission for Period 1 
or is expected to travel across ≥1 time zone during the study. 
17. Subject is investigative site personnel or their immediate families (spouse, parent, child, 
or sibling whether biological or legally adopted). 
 

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8.3. 
Subject Withdrawal Criteria 
Subjects may withdraw from the study at any time for any reason. The Investigator may 
withdraw a subject from the study for any of the following reasons: 
• The subject is unwilling or unable to adhere to the protocol 
• The subject experiences an intolerable AE 
• Other medical or safety reason, at the discretion of the Investigator and/or the 
Medical Monitor 
If a subject is persistently noncompliant, the Investigator should discuss with the Sponsor the 
potential withdrawal of the subject. Any reasons for unwillingness or inability to adhere to the 
protocol must be recorded in the subject’s eCRF, including: 
• missed visits; 
• interruptions in the schedule of study drug administration and/or assessments; 
• non-permitted medications (Section 9.3.2); 
• violation of other restrictions (Section 9.3.3). 
Subjects who withdraw from the study due to an AE, regardless of Investigator-determined 
causality, should be followed until the event is resolved, considered stable, or the Investigator 
determines the event is no longer clinically significant.  
Subjects who withdraw from the study for any reason should have an early termination (ET) 
visit/phone call and the follow up phone call should take place as scheduled. The Investigator 
must notify the Sponsor when a subject withdraws from the study for any reason. The reason 
must be recorded in the subject’s case report form. A subject will be deemed lost to follow-up 
after attempts at contacting the subject have been unsuccessful. 

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9. 
TREATMENT OF SUBJECTS 
9.1. 
Study Drugs 
Cannabis will be administered via vaporizer for an inhaled dose of 30.9mg THC on Day 2 during 
Treatment Period A. Alprazolam tablets at a dose of 0.75mg will be administered orally in 
Treatment Period B approximately 40 minutes earlier on Day 2. Matching placebo (i.e., inhaled 
via vaporizer or tablets, dependent on Treatment Period) will be administered during Treatment 
Period C. Subjects will receive active or matched placebo each morning during each Treatment 
Period. Placebo will be administered as necessary to maintain the blind across the 3 periods. 
Dosing for each treatment is outlined in Table 4.  
Table 4: 
Treatments Administered 
Treatment 
Study Drug 
Day 2 
A 
Cannabis 
30.9mg THC 
B 
Alprazolam 
0.75mg 
C 
Placebo 
Placebo 
9.2. 
Meal Timing in Relation to Study Drug Administration and Driving 
Simulations 
From the time of admission on Day 1 until discharge on Day 2 of each treatment period, subjects 
will consume only food and beverages that are provided to them by the staff at the clinical site. 
Meals (e.g., breakfast, lunch, dinner, and evening snack) will be provided to the subjects while in 
the supervised off-site residential facility.  
On the morning of testing, subjects will eat a low-fat breakfast. The breakfast menu will include 
non-caffeinated breakfast foods and beverages. A single serving of caffeinated beverage may be 
consumed prior to 6 am. Breakfast will be provided prior to the cognitive testing and driving 
simulation. 
All other meals and snacks during inpatient periods will be provided according to standard 
procedures while at the supervised off-site residential facility. 
9.3. 
Prior Medications, Concomitant Medications, and Restrictions 
9.3.1. 
Prior and Concomitant Medications and/or Supplements 
All medications (prescription and non-prescription, and herbal medications/natural health 
products) taken by subjects during the 30 days prior to Screening until the completion of the 
follow-up phone call will be recorded. The reported medications will be reviewed and evaluated 
by the Investigator to determine if they affect a subject’s eligibility or continued participation in 
the study.  

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Subjects are permitted to take hormonal contraceptives, hormone replacement therapy, and 
acetaminophen (up to 2 grams per day) during the study. On a case-by-case basis, the 
Investigator is permitted to allow the use of concomitant medications to treat an AE. Wherever 
possible, the Investigator should obtain approval from the Sponsor’s Medical Monitor prior to 
administering the medication.  
9.3.2. 
Prohibited Medications 
Prohibited medications include the following: 
• any prescription or over-the-counter medication known to cause sedation within 7 days 
prior to admission for Period 1 and throughout study participation; 
• any benzodiazepine, barbiturate, or GABAA modulator (e.g., eszopiclone, zopiclone, 
zaleplon, and zolpidem) within 28 days prior to Admission for Period 1 and throughout 
study participation; 
• exposure to investigational drugs or devices within the 30 days, or 5 half-lives (if known), 
whichever is longer, prior to Screening and throughout study participation. 
9.3.3. 
Other Restrictions 
Subjects are restricted from the following: 
• smoking during the study visits; 
• Caffeinated beverages will be restricted to no more than 3 servings per day, one 
caffeinated beverage is allowed no later than 6am on study visit day; 
• consumption of > 2 alcoholic beverages per day; 
• use of drugs of abuse, other than marijuana/THC-containing products, that would result 
in a positive urine test at any clinic admission; 
• use of cannabis products (other than study drug) beginning 7 days prior to admission for 
Period 1 through study completion; 
• traveling across ≥1 time zone from 2 weeks prior to Admission for Period 1 and through 
study completion; 
• female subjects are restricted from breastfeeding from Screening and through study 
completion. 
9.4. 
Treatment Adherence 
All study drug doses will be administered by staff at NADS. The date and time of study drug 
administration will be recorded. Any reasons for non-adherence will also be documented. 
9.5. 
Randomization and Blinding 
This is a randomized, double-blind, active- and placebo-controlled study. On Day 1 of Period 1, 
subjects will be randomized 1:1:1 into one of 6 treatment sequences ( 
 

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Table 3). The active and placebo treatments are identical in appearance within each group and 
matched placebo will be administered as necessary to maintain the blind (Table 4). 
The allocation to treatment sequence will be based on a randomization schedule generated by 
blinded study personnel. The randomization schedule will be kept strictly confidential, accessible 
only to authorized personnel until the time of unblinding. A copy of each randomization 
schedule will be held by the Study Pharmacist.  
9.5.1. 
Emergency Identification of Study Drug 
During the study, the blind is to be broken by the Investigator only when the safety of a subject is 
at risk and the treatment plan is dependent on the study drug received. All circumstances 
surrounding an early unblinding must be clearly documented in the source records.  
In all cases where the study drug allocation for a subject is unblinded, pertinent information 
(including the reason for unblinding) must be documented in the subject’s records and in the 
CRF. If the subject’s or study center personnel’s data have been unblinded, the subject will be 
permanently discontinued from the study. 
9.6. 
Subject Compensation 
Subjects will be compensated for their time and effort. Subjects who complete all study 
procedures successfully will receive up to $1100. For subjects that do not complete, prorated 
compensation will be provided as show below. For each study visit, there will be an incentive for 
completing one of the drives safely in the time allowed. This incentive compensation is $25 per 
visit. 
 
 
Base 
Incentive 
Max Total 
Screening 
$50 
 
 
$50 
Visit 1  
$275 $25 
 
$300 
Visit 2  
$300 $25 
 
$325 
Visit 3  
$400 $25 
 
$425 
Total Base Pay 
 
 
$1025 
Max Total Compensation  
 
$1100 
 
Additionally, subjects will not be permitted to drive themselves after the study visits and must 
procure their own transportation. Based on historical costs, subjects will be reimbursed $35 per 
trip to cover the expenses of a taxi or rideshare. 

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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drugs 
Dried bulk cannabis plant material obtained from the NIDA Drug Supply Program will be used 
for this protocol. The active cannabis contains 6.18% THC and the placebo cannabis contains no 
detectable THC or CBD. Cannabis will be inhaled using a Volcano® Digit Vaporizer device. 
Each subject will be administered a dose of cannabis as described in Section 9.1.  
Alprazolam tablets will be sourced by the pharmacy at the clinical site through commercial 
suppliers. Each subject will be administered a dose of 0.75mg as described in Section 9.1. 
Alprazolam tablets will be over-encapsulated.  
Placebo capsules contain only the excipients listed for the active alprazolam capsule.  
10.2. 
Study Drug Packaging and Labeling 
Bulk cannabis received from the Research Triangle Institute via the NIDA Drug Supply Program 
will be maintained with appropriate labeling.  
Alprazolam tablets will have commercial packaging and labeling. 
Each container of study drug will be clearly labeled with study-specific information meeting all 
applicable regulatory requirements. 
10.3. 
Study Drug Storage 
Upon receipt of the medication, an investigator, or the responsible pharmacist or designee, will 
inspect the medication and acknowledge receipt in accordance with the study-specific process.  
Cannabis should be stored frozen (-15 to -25°C) by the site and humidified at room temperature 
for 18-48 hours prior to administration. Alprazolam should be stored per the package insert 
requirements. The study medication may not be used for any purpose other than the present 
study.  
The Investigator or a designee will be responsible for ensuring appropriate storage, 
compounding, dispensing, inventory, and accountability of all clinical supplies. An accurate, 
timely record of the disposition of all clinical supplies must be maintained.  
10.4. 
Study Drug Preparation 
The study drug will be dispensed or administered according to applicable standard operating 
procedures. Once dispensed, study drug may not be relabeled or reassigned for use by other 
subjects. 
10.5. 
Study Drug Administration 
A cued-puff procedure will be used to standardize the administration of cannabis. Dried bulk 
cannabis plant material obtained from the NIDA Drug Supply Program is ground (via herb 
mill/grinder provided by Volcano® manufacturer) and 500 mg is heated to a temperature of 
210°C by the hot air generator to vaporize THC (Hazekamp, 2010; Pomahacova et al., 2009). 
The vapor is collected in a plastic balloon with a one-way valve. This valve shuts when removed 

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from the Volcano® device, preventing the escape of vapor. A mouthpiece is attached to the valve 
and allows for subject-controlled inhalation of the cannabis vapor. Each session utilizes a new 
balloon to ensure hygienic administration. The Volcano® Digit Vaporizer is operated according 
to the manufacturer’s specifications. 
Subjects will be trained to the Foltin Puff Procedure (Foltin, Brady & Fischman, 1986; Wilsey et 
al., 2013), which includes the following steps: “get ready” (5 seconds), “inhale” (5 seconds), “hold 
vapor in lungs” (10 seconds), and “exhale and wait” (40 seconds). The subject repeatedly inhales 
the vapor over 10 minutes. Subjects will be instructed to inhale at their capacity; that means 
without any dizziness, nausea, vomiting, panic, or difficulty breathing.  
All study treatments will be administered following consumption of breakfast as outlined in 
Section 9.2. 
10.6. 
Study Drug Accountability, Handling, and Disposal 
The study drug provided is for use only as directed in this protocol. The Investigator or a 
designee must keep a record of all study drug received, used, and returned/discarded. It must be 
clear from the records what study drug each subject received on each dosing day. 
NHTSA or designee will be permitted access to the study supplies at any time with appropriate 
notice during or after completion of the study to perform drug accountability reconciliation. 
The Investigator, pharmacist, or qualified designee is responsible for drug accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition 
records). 
After the study is completed, all unused study medication must be returned as directed or 
destroyed on site per the site’s SOPs.  

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11. 
PHARMACODYNAMIC AND PHARMACOKINETIC 
ASSESSMENTS 
All PD and PK assessments will be performed at the visits and time points outlined in the 
Schedule of Assessments (Table 1). The time of study drug administration will be considered as 
time zero.  
11.1. 
Pharmacodynamic Assessments 
11.1.1. 
DIDS Driving Scenario on the CRCDS2-MiniSim  
This study employs the Drug Impaired Driving Scenario (DIDS) comprised of suburban, urban, 
and highway driving tasks. The scenario includes challenges designed to assess lane position 
control, speed control, safety awareness and responsivity, driving-related decision making, 
multitasking, and vigilance. Data will be captured in electronic format. Details are provided in 
the Cognitive Research Corporation Driving Simulation Testing Operations Manual. 
11.1.2. 
CogScreen Cognitive Test Battery 
The CogScreen computer-based cognitive test battery will be administered by trained and 
certified study center personnel. Subjects enter responses by tapping a stylus on an LCD 
touchscreen monitor. Details are provided in the CogScreen® Examiner Manual, CogScreen 
LLC. 
11.1.2.1. Digit Symbol Substitution Test (CogScreen Symbol Digit Coding) 
Symbol Digit Coding (SDC) is a computer analogue of the conventional digit 
symbol-substitution task found in the revised Wechsler Adult Intelligence Scale (WAIS-R, 1981) 
Digit Symbol subtest. SDC will be used in this study to measure attention, visual scanning, 
working memory, and speed of information processing. Immediate and delayed recall for the 
digit-symbol pairs will also be assessed. 
11.1.2.2. CogScreen Visual Sequence Comparison Test 
The CogScreen Visual Sequence Comparison Test (VSC) will be used in this study to measure 
visual attention, working memory, visual-sequential processing, and visual-perceptual speed.  
11.1.2.3. CogScreen Divided Attention Test 
The CogScreen Divided Attention Test (DAT) will be used in this study to measure visual 
monitoring, choice visual reaction time, impulsivity, divided attention, working memory, verbal-
sequential processing, visual-perceptual speed, and capacity for multitasking. 
 
11.1.2.4. CogScreen Matching to Sample Test 
The CogScreen Matching to Sample Test (MTS) will be used in the study to measure visual 
perceptual speed, spatial processing, and visual working memory. 

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11.1.2.5. CogScreen Pathfinder Number Test 
The CogScreen Pathfinder Number Test (PFN) will be used to measure number sequencing 
skills, immediate memory, motor coordination, visual scanning.   
11.1.2.6. CogScreen Shifting Attention Test 
The CogScreen Shifting Attention Test (SAT) will be used to measure sustained attention, 
vulnerability to response interference, working memory, application of novel rules, visual 
scanning, and choice visual reaction time.  
11.1.3. 
CogScreen Dual Task Test  
The CogScreen Dual Task Test (DTT) will be used to measure visual-motor tracking, divided 
attention, and working memory. 
11.1.4. 
Test of Variables of Attention  
The Test of Variables of Attention (TOVA) will be used in this study to measure visual 
vigilance.  The TOVA provides measures of response consistency, speed of response, 
impulsivity, and focus.  
The TOVA will be administered by trained study center personnel. Subjects will perform the test 
by interacting with an electronic monitor screen. Details are provided in the TOVA Manual.  
11.1.5. 
Karolinska Sleepiness Scale  
The KSS (Akerstedt and Gillberg 1990; Akerstedt 2014) will be used to assess subjective level 
of sleepiness. This is a subject self-reported measure of situational sleepiness and provides an 
assessment of alertness/sleepiness at a particular point of time. Subjects will rate their sleepiness 
level using a 9-point categorical Likert-type scale with the following anchors: 
 
(1) “extremely alert” 
 
(2) “very alert” 
 
(3) “alert 
 
(4) “rather alert” 
 
(5) “neither alert nor sleepy” 
 
(6) “some signs of sleepiness” 
 
(7) “sleepy, but no effort to keep awake” 
 
(8) “sleepy, some effort to keep awake” 
 
(9) “very sleepy, great effort to keep awake, fighting sleep” 
11.1.6. 
Self-perceived Safety to Drive Question 
Prior to driving, the subject will be asked a simple question as to whether they feel safe to drive 
(“Right now do you feel safe to drive?”). Subject will answer “yes” or “no”.  

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11.1.7. 
Visual Analog Scales to Assess Subjects’ Self-appraisal and Motivation 
Visual analog scales will be performed to assess a subject’s self-appraisal of driving performance 
and motivation to drive one’s best. Immediately after completing the driving simulation (DIDS), 
subjects will assess their own performance and their level of motivation to perform at their best 
during the DIDS. 
Subjects will respond to 2 questions: 
1. 
How well do you think you drove for the last 60 minutes? 
2. 
How motivated did you feel to drive at your best during the last 60 minutes of driving? 
Subjects will record their response to each question by drawing a vertical line on a 100-mm 
horizontal, linear VAS printed on paper or administered electronically. For the self-assessment of 
driving performance, 1 end of the line is marked “Not Satisfactory” and the other end of the line 
is marked “Satisfactory”. For the motivation item, 1 end of the line is marked “Not Motivated” 
and the other end is marked “Motivated”. Scores on the 100-mm linear scale will be measured to 
the nearest millimeter from the left with a ruler or recorded by the electronic system.  
11.2. 
Pharmacokinetic Assessments 
11.2.1. 
Blood Sample Collection 
Separate PK blood samples will be collected and processed for analysis of THC and alprazolam 
blood concentrations. Three separate samples will be collected: pre-dose, at 40 minutes (± 5 
minutes) post-dose on Day 2, and at 3.25 hours (± 5 minutes) post-dose on Day 2. Additional 
details regarding the collection and processing of PK samples will be provided in a separate PK 
manual. 
Blood will be collected and stored into labeled sample containers until analysis. These samples 
(whole blood) will be refrigerated at NADS until transported to the Iowa DCI Crime Lab for 
analysis. The Iowa DCI Crime Lab will discard extra blood, using at least one aliquot for 
analysis and one aliquot for backup. The backup sample will be maintained at -70°C until study 
close and then discarded. 
Blood volumes required for PK sampling are available in Appendix A. 
11.2.2. 
Sample Analysis 
Bioanalysis of blood samples for the determination of THC concentrations will be conducted 
utilizing a validated LC-MS/MS method. 

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12. 
ASSESSMENT OF SAFETY 
12.1.1. 
Demography and Medical History 
Demographic characteristics (age, race, sex, and ethnicity) and a full medical history will be 
documented. The Epworth Sleepiness Scale will be conducted at Screening to ensure subjects 
have no recent history of sleep disorder. 
12.1.2. 
Weight and Height 
Height, weight, and BMI will be measured and documented as outlined in Table 1. 
12.1.3. 
Physical Examination 
Physical examinations will be conducted to assess the subject’s overall health and physical 
condition. A full or brief physical examination will be completed at the times outlined in Table 1. 
A full physical examination will include assessment of general appearance, head, eyes, ears, nose 
and throat (HEENT), neck/thyroid/lymphatic, cardiovascular, respiratory, gastrointestinal, and 
neurological systems, musculoskeletal/extremities, and skin. A brief physical examination will 
include assessment of general appearance, cardiovascular, respiratory, gastrointestinal, and 
neurological systems. Unscheduled symptom-directed physical examinations may also be 
conducted per Investigator’s discretion. Whenever possible, the same individual should perform 
all physical examinations for a given subject.  
Any abnormality in physical examinations will be interpreted by an Investigator as abnormal, not 
clinically significant (NCS); or abnormal, clinically significant (CS) in source documents.  
12.1.4. 
Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, pulse oximetry, and temporal 
temperature (°F). Heart rate and blood pressure will be collected in the supine position after the 
subject has been resting for approximately 3 minutes.  
All abnormal vital signs will be interpreted by the Investigator or designee as abnormal NCS, or 
abnormal CS in source documents.  
12.1.5. 
Electrocardiogram (ECG) 
Six-lead ECGs will be performed after the subject has been resting in a supine position for at 
least 5 minutes. The ECG variables will include ventricular heart rate and the PR, QRS, QT, and 
QTcF intervals.  
All abnormal ECGs will be interpreted by the Investigator as abnormal NCS, or abnormal CS in 
source documents. The standard intervals, any rhythm abnormalities, and the Investigator 
interpretation will be noted on the eCRF. 
12.1.5.1. Drugs of Abuse and Alcohol 
A urine drug screen will be conducted for the assessment of selected drugs of abuse 
(amphetamines, barbiturates, benzodiazepines, THC, cocaine, methadone, phencyclidine, 
opiates, 3,4-methylenedioxy-methamphetamine (MDMA), and oxycodone). A breathalyzer 
alcohol screen will be conducted. 

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12.1.5.2. Pregnancy Screen 
A urine pregnancy test will be conducted for all women at Screening; thereafter, a urine 
pregnancy test will be conducted for women of child-bearing potential at all subsequent periods. 
12.1.6. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Suicidality will be monitored during the study using the C-SSRS (Posner, 2011). This scale 
consists of a baseline evaluation that assesses the lifetime experience of the subject with respect 
to suicidal ideation and behavior, and a post-baseline evaluation that focuses on suicidality since 
the last study visit. The C-SSRS includes ‘yes’ or ‘no’ responses for assessment of suicidal 
ideation and behavior as well as numeric ratings for severity of ideation, if present (from 1 to 5, 
with 5 being the most severe).  
The “Baseline/Screening” C-SSRS form will be completed at Screening (lifetime history and 
past 24 months). 
12.2. 
Adverse Events and Serious Adverse Events 
12.2.1. 
Adverse Event Definitions 
12.2.1.1. Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product whether or not related to the medicinal (investigational) 
product. In clinical studies, an AE can include an undesirable medical condition occurring at any 
time, including baseline or washout periods, even if no study treatment has been administered. 
A TEAE is defined as an AE with onset after the first administration of any study drug or any 
worsening of a preexisting medical condition/AE with onset after the first administration of any 
study drug and through the follow-up phone call. The term study drug includes any study drug, a 
comparator, or a placebo administered in a clinical trial. 
Laboratory abnormalities and changes from baseline in vital signs and ECGs are considered AEs 
if they result in discontinuation of study treatment, require therapeutic medical intervention or if 
the Investigator considers them to be clinically significant. Any abnormalities that meet the 
criteria for an SAE should be reported in an expedited manner.  
All AEs that occur after any subject has signed the informed consent and throughout the duration 
of the study, whether or not they are related to the study, must be reported to the Medical 
Monitor. 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up by 
the Investigator for as long as medically indicated, but without further recording in the eCRF. 
The Sponsor or its representative retains the right to request additional information for any 
subject with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 

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12.2.1.2. Serious Adverse Event (SAE) 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death; 
• Is immediately life-threatening; 
• Requires in-patient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability or incapacity; 
• Results in a congenital abnormality or birth defect. 
An SAE may also be any other medically important event that, in the opinion of the Investigator 
may jeopardize the subject or may require medical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or convulsions occurring at home that do not require an 
inpatient hospitalization). 
All SAEs that occur after any subject has signed the ICF and throughout the duration of the 
study, whether or not they are related to the study, must be recorded on the SAE report form 
provided by NADS and Acclaro. Any SAE that is ongoing when the subject completes their final 
study visit, will be followed by the Investigator until the event has resolved, stabilized, or 
returned to baseline status. 
A prescheduled or elective procedure or routinely scheduled treatment will not be considered an 
SAE, even if the subject is hospitalized. The site must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study. 
• The condition requiring the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress, in the opinion of an 
Investigator, between the subject’s consent to participate in the study and at the time 
of the procedure or treatment. 
12.2.2. 
Relationship to Study Drug 
The Investigator must make the determination of relationship to the study drug for each AE (not 
related or related). The following definitions should be considered when evaluating the 
relationship of AEs and SAEs to the study drug.  
Not Related 
An AE will be considered “not related” to the use of the study drug if there is not a 
reasonable possibility that the event has been caused by the study drug. Factors 
pointing towards this assessment include but are not limited to the lack of temporal 
relationship between administration of the study drug and the event, the presence 
of biologically implausible relationship between the product and the AE, or the 
presence of a more likely alternative explanation for the AE 

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Related 
An AE will be considered “related” to the use of the study drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation. Factors that point towards this assessment include but are not limited 
to a positive rechallenge, a reasonable temporal sequence between administration 
of the drug and the event, a known response pattern of the suspected drug, 
improvement following discontinuation or dose reduction, a biologically plausible 
relationship between the drug and the AE, or a lack of alternative explanation for 
the AE 
12.2.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be recorded during the study at the 
investigational site. The AE term should be reported in standard medical terminology when 
possible. For each AE, an investigator will evaluate and report the onset (date and time), 
resolution (date and time), intensity, causality, action taken, outcome, and seriousness (if 
applicable), and whether or not it caused the subject to discontinue the study drug or withdraw 
early from the study. 
Intensity will be assessed according to the following scale: 
• Mild: symptom(s) barely noticeable to subject or does not make subject 
uncomfortable; does not influence performance or functioning; prescription drug not 
ordinarily needed for relief of symptom(s) 
• Moderate: symptom(s) of a sufficient severity to make subject uncomfortable; 
performance of daily activity is influenced; subject is able to continue in study; 
treatment (including but not limited to prescription drugs) for symptom(s) may be 
needed 
• Severe: symptom(s) cause severe discomfort; symptoms cause incapacitation or 
significant impact on subject’s daily life; severity may cause cessation of treatment 
with study drug; treatment for symptom(s) may be given and/or subject hospitalized  
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not necessarily be considered serious. 
12.2.4. 
Reporting Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE(s), the study site 
must notify Acclaro or designee within 24 hours of the study site staff becoming aware of the 
SAE(s). The Investigator must complete, sign and date the SAE report form, verify the accuracy 
of the information recorded on the SAE report form with the corresponding source documents, 
and send a copy to Acclaro or designee.  
Additional follow-up information, if required or available, should all be sent to Acclaro or 
designee within 24 hours of receipt on a follow-up SAE report form and placed with the original 
SAE information in the source documents. 

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Serious events occurring after the designated follow-up time for the study, should be reported to 
Acclaro or designee according to the timelines noted above only if the Investigator considers the 
SAE related to study drug.  
Acclaro or designee is responsible for notifying the relevant regulatory authorities of certain 
events. It is the principal investigator’s responsibility to notify the Ethics Committee (EC) of all 
SAEs that occur at his or her site. Investigators will also be notified of all suspected unexpected 
serious adverse reactions (SUSARs) that occur during the clinical study. Each site is responsible 
for notifying its EC of all SUSARs. 
Appropriate personnel at NADS will unblind SUSARs for the purpose of regulatory reporting. 
The PI or designee will submit SUSARs (in blinded or unblinded fashion) to regulatory agencies 
according to local law. 
12.3. 
Pregnancy 
If a female subject becomes pregnant after first administration of study drug, pregnancy 
information must be collected, recorded, and submitted to Acclaro or designee within 24 hours of 
learning of the pregnancy. The female subject’s participation in the study will be terminated. 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that a study drug may 
have interfered with the effectiveness of a contraceptive medication. The status of the pregnancy 
is not followed once participation in the study ends. 
12.4. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
the dose described in protocol. Overdoses are not considered AEs and should not be recorded as 
an AE on the CRF; however, all overdoses must be recorded on an Overdose form and sent to 
the sponsor or designee within 24 hours of the site becoming aware of the overdose. An overdose 
must be reported to the sponsor or designee even if the overdose does not result in an AE. If an 
overdose results in an AE, the AE must be recorded. 

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13. 
STATISTICS 
A separate statistical analysis plan (SAP) will provide a detailed description of the analyses to be 
performed in the study. The SAP will be finalized and approved prior to database lock. Any 
deviations from or changes to the SAP following database lock will be described in detail in the 
clinical study report. 
13.1. 
Data Analysis Sets 
The Randomized Set is defined as all subjects who are randomized. 
The Full Analysis Set (FAS) is defined as all randomized and treated subjects that have at least 
one primary efficacy measure (SDLP) in any treatment period.  
The Safety Set (SS) is defined as all subjects administered at least one dose of any study drug. 
The PK Set is defined as all subjects in the SS who have at least one collected blood sample from 
which a valid blood concentration can be measured. 
13.2. 
Handling of Missing Data 
Every attempt will be made to avoid missing data. All subjects will be used in the analyses, as 
per the analysis populations, using all non-missing data available. No imputation process will be 
used to estimate missing data.  
13.3. 
General Considerations 
Continuous endpoints will be summarized with number (n), mean, standard deviation (SD), 
median, minimum, and maximum. In addition, change from baseline values will be calculated at 
each time point and summarized descriptively. For categorical endpoints, descriptive summaries 
will include counts and percentages.  
All data supporting the development of the summary tables and figures will be listed. 
13.4. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, body weight, height, and 
BMI) will be summarized for the SS as well as the FAS separately. No formal statistical 
comparison between the groups will be performed. 
Medical history will be listed by subject.  
Pregnancy test results and drug/alcohol screens will be listed but not summarized.  
13.5. 
Pharmacodynamic Analyses 
All PD analyses will use the FAS Set. 
The FAS will be used for the primary analysis. Summary statistics will be provided (mean, 
standard deviation, median, minimum, maximum) for each treatment. Figures will be provided 
for the within-subject difference scores by treatment and day as both a histogram and scatter plot. 
Data listings for driving simulator data will be provided. 

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SDLP data will be analyzed using a mixed model for repeated measures (MMRM) with fixed 
effects for sequence, period, and treatment and random effect for subject. A log-transformation 
of SDLP values to obtain normal distribution of data will be considered, if necessary. An 
unstructured covariance structure and Kenward-Roger degrees of freedom will be used. In the 
event an unstructured covariance structure fails to converge, a variance components covariance 
structure will be assumed. In addition to treatment effect, p-values for significance testing of 
period and sequence effects will be provided. Pair-wise comparisons of differences in means and 
two-sided 95% CIs on differences will be provided for all active treatments versus the placebo 
treatment.  
The comparison of primary interest is cannabis versus placebo on Day 2 as a function of 
frequency of self-reported cannabis use. The statistical significance of alprazolam versus placebo 
(p < 0.05) comparison for SDLP is considered only to validate the experiment and having the 
ability to detect effects (i.e., assay sensitivity).  
Formal statistical tests (when performed) will be 2-sided and tested at the alpha=0.05 level of 
significance. Cannabis will be considered non-inferior to placebo if the two-sided upper 95% 
confidence limit on the difference in SDLP between that dose and placebo is less than 4.4 cm, 
and it can be concluded that the effect of cannabis on driving is less than that seen at 0.05% 
BAC, which is a level associated with increased crash risk. No adjustment to alpha levels will be 
made for either the comparison of alprazolam to placebo, or for secondary endpoints or analyses. 
 As a supportive analysis, pair-wise, within-subject differences in SDLP greater than 4.4 cm in 
absolute value will be compared using McNemar test. Furthermore, these pair-wise, within 
subject differences in SDLP will be tested for symmetry about zero (Laska et al., 2012) using the 
maximally selected McNemar test. If there is no significant difference between placebo and 
cannabis and if the distribution of paired differences is symmetrical around zero, it can be 
concluded that cannabis does not impair driving. 
Driving performance, cognitive, and self-report endpoints will be evaluated and presented using 
a mixed model for repeated measures. Lane exceedance will be log-transformed (more 
specifically ln[x+1]) before analyses.  
A data listing for the results will be provided. Summary tables will be presented in the same 
format as the primary output for: 
• Driving Performance Endpoints 
o SDLP 
o Lane exceedance; including number, maximum and duration of exceedance 
o Speed related measures; including speed deviation, average speed, and excessive 
speed count 
o Driving safety measures; including excessive Ay (cornering speed threshold-
exceeded), and total number of collisions 
o Divided attention measures; including correct responses, omission errors, 
commission errors, reaction time, and standard deviation of reaction time 
 

47 
 
 
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• CogScreen SDC Test 
o Number of correct responses 
o Response accuracy 
o Standard deviation of reaction time 
• CogScreen Symbol Digit Coding – Immediate Recall 
o Immediate recall accuracy 
• CogScreen Symbol Digit Coding – Delayed Recall 
o Delayed recall accuracy 
• CogScreen Visual Sequence Comparison Test 
o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• CogScreen Divided Attention Test 
o Response speed 
o Number of premature responses 
o Response accuracy 
o Number of lapses 
o Multitasking scores 
• CogScreen Matching To Sample Test 
o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• CogScreen Pathfinder Number 
o Response speed 
o Response accuracy 
o Response coordination 
• CogScreen Shifting Attention Test 
o Response speed 
o Response accuracy 
o Standard deviation of reaction time 
• CogScreen Dual Task Test  
o Tracking errors 
o Number of boundary hits 
o Previous number response speed 
o Previous number response accuracy 
o Previous number standard deviation of reaction time 
o Multitasking scores 

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• Test of Variables of Attention (TOVA)  
o Response time variability (Total, and Scores per quarter) 
o Response speed (Total, and Scores per quarter) 
o Commission errors (Total, and Scores per quarter) 
o Omission errors (Total, and Scores per quarter) 
• KSS 
• Self-Reported Readiness to Drive  
• VAS to assess subject’s motivation and self-appraisal of their driving performance, 
including readiness to drive and whether the subject feels safe to drive 
For total number of collisions, differences in number of collisions for each pair-wise comparison 
will be provided with their corresponding Wilcoxon Signed Rank p-value. A bar chart will be 
provided pooling total number of collisions by 0, 1, 2, or ≥3 for all treatments. In addition, 
pair-wise treatment comparisons for readiness to drive will be analyzed using McNemar’s test. A 
bar graph for percentage of subjects reporting no safe to drive will be provided by treatment and 
day.  
13.6. 
Safety Analyses 
Safety and tolerability of cannabis will be assessed by the incidence of TEAEs, and by changes 
from baseline in vital signs. 
Safety data will be listed by subject and summarized by treatment. All safety summaries will be 
performed on the SS. 
13.6.1. 
Adverse Events 
AEs will be coded using MedDRA version 22.0 or higher. The analysis of AEs will be based on 
the concept of TEAEs presented by treatment. TEAEs will be summarized by System Organ 
Class (SOC) and preferred term, and by treatment. TEAE summaries will be provided showing 
the number and percentage of subjects who experienced at least one TEAE. In addition, 
summaries will be provided by severity (mild, moderate, or severe) and by causality (related or 
not related) to study drug (see Section 12.3). If more than one TEAE is coded to the same 
preferred term for the same subject within the same treatment period, the subject will be counted 
only once for that preferred term using the most severe occurrence for the summarization by 
severity. 
TEAEs leading to discontinuation of study drug and serious TEAEs including death will also be 
summarized.  
All AEs and SAEs (including those with onset or worsening before the start of study drug) 
through the end of the study will be listed.  
13.6.2. 
Physical Examinations 
Physical examination will be conducted on Day 1 of each period. The occurrence of physical 
examinations (yes/no) and the date of the examination will be listed by subject.  

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13.6.3. 
Vital Signs 
Vital signs will be taken on Day 1 of each period. Vital signs data will be summarized by 
treatment and listed by subjects.  
13.6.4. 
6-Lead Electrocardiogram 
Electrocardiogram will be conducted at screening. Electrocardiogram findings will be listed by 
subject. ECG parameters will be summarized by treatment.  
13.6.5. 
Prior and Concomitant Medications 
Medications will be recorded at each study visit during the study.  
All medications taken within 30 days prior to Screening and through the duration of the study 
will be recorded. Those medications taken prior to the first dose of study drug will be denoted 
“Prior”. Those medications taken prior to the first dose of study drug and continuing beyond the 
first dose of study drug or those medications started at the same time or after the initiation of the 
study drug will be denoted “Concomitant” (i.e., those with a start date on or after the first dose of 
study drug, or those with a start date before the first dose of study drug that are ongoing or with a 
stop date on or after the first dose of study drug).  
Medications will be presented according to whether they are “Prior” or “Concomitant” as 
defined above. If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.  
Details of prior and concomitant medications/procedures will be listed by subject, start date, and 
verbatim term.  
13.6.6. 
Columbia Suicide Severity Rating Scale 
The C-SSRS will be administered at screening. Suicidality data collected on the C-SSRS will be 
summarized and listed for the SS. Listings will include behavior type and/or category for 
Suicidal Ideation and Suicidal Behavior of the C-SSRS.  
13.7. 
Pharmacokinetic Analyses 
The potential relationship between THC blood concentration and SDLP or other driving or 
cognition endpoints will be examined using regression techniques.  
THC and alprazolam concentrations will be listed by subject and summarized by day.  

50 
 
 
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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Audits and Inspections 
Authorized representatives, a regulatory authority, an EC or IRB may visit the site to perform 
audits or inspections, including source data verification. The purpose of a NHTSA audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP) 
guidelines of the International Conference on Harmonization (ICH), and any applicable 
regulatory requirements. The Investigator should contact Acclaro immediately if contacted by a 
regulatory agency about an inspection. 
14.2. 
Ethics Committee 
Acclaro will obtain EC approval for the investigation for this cooperative human subject research 
project that provides coverage for the NADS research effort. NADS will coordinate ceding of 
oversight from the University of Iowa’ Human Subjects Office to Advarra. Initial EC approval, 
and all materials approved by the EC for this study including the subject consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Acclaro may conduct a quality assurance audit. Please see Section 14.1 for more details 
regarding the audit process. 

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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or EC as appropriate.  
The Principal Investigator is responsible for providing the IRB or EC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Acclaro will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or EC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH and GCP guidelines, as well as all 
applicable regulatory requirements. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form. A copy 
of the signed Informed Consent Form must be given to the subject. 
 

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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
Acclaro will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for the period 
outlined in the site contract. If it becomes necessary for Acclaro or the Regulatory Authority to 
review any documentation relating to the study, the Investigator must permit access to such 
records. 

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18. 
PUBLICATION POLICY 
No publication or disclosure of study results will be permitted except as specified in a separate, 
written, agreement between NHTSA, Acclaro, and the Investigator. 
 

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19. 
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Straight-line Simulated Drive to Predict Impairment from Cannabis Intoxication. Traffic Injury 
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alcohol and drug use in injured British Columbia drivers. BMJ Open. 2016; 6(3), 10p. Retrieved from 
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Chihuri, S., Li, G., & Chen, Q. Interaction of marijuana and alcohol on fatal motor vehicle crash risk: a 
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Del Balzoa, G., Gottardoa, R., Mengozzi, S., Dorizzi, R. M., Bortolotti, F., Appolonovac, S., Tagliaroa, F. 
“Positive” urine testing for Cannabis is associated with increased risk of traffic crashes. Journal of 
Pharmaceutical and Biomedical Analysis. 2018; 151, 71–74. 
Dubois, S., Mullen, N., Weaver, B., Bedard, M. The combined effects of alcohol and cannabis on driving: 
Impact on crash risk. Forensic Science International. 2015; 248, 94-100. 
Food and Drug Administration Center for Drug Evaluation and Research. Evaluating Drug Effects on the 
Ability to Operate a Motor Vehicle Guidance for Industry. November 2017. 
Gjerde, H., Normann, P. T., Christophersen, A. S., Samuelsen, S. O., Morland, J. Alcohol, psychoactive 
drugs and fatal road traffic accidents in Norway: A case-control study. Accident Analysis and Prevention. 
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Hartman, R. L., Anizan, S., Jang, M., Brown, T. L., Yun, K., Gorelick, D. A., Milavetz, G., Spurgin, A., 
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Administration with and without Alcohol. Forensic Toxicology. 2015; 1-19. https://doi.org/DOI 
10.1007/s11419-015-0269-6 
Hartman, R. L., Brown, T. L., Milavetz, G., Spurgin, A., Gorelick, D. A., Gaffney, G., & Huestis, M. A.. 
Controlled Cannabis Vaporizer Administration: Blood and Plasma Cannabinoids with and without 
Alcohol. Clinical Chemistry. 2015a; 61(6), 850-869. 
Hartman, R. L., Brown, T. L., Milavetz, G., Spurgin, A., Gorelick, D. A., Gaffney, G., & Huestis, M. A. 
Controlled Vaporized Cannabis, with and without Alcohol: Subjective Effects and Oral Fluid‐Blood 
Cannabinoid Relationships. Drug testing and analysis. Drug Testing and Analysis. 2015b; 
https://doi.org/DOI:10.1002/dta.1839 
Hartman, R. L., Brown, T. L., Milavetz, G., Spurgin, A., Pierce, R., Gorelick, D. A., Gaffney, G., & 
Huestis, M. A. Cannabis Effects on Driving Longitudinal Control With and Without Alcohol. Journal of 
Applied Toxicology. 2016; https://doi.org/10.1002/jat.3295 
Hartman, R. L., Brown, T. L., Milavetz, G., Spurgin, A., Pierce, R. S., Gorelick, D. A., Gaffney, G., & 
Huestis, M. A.. Cannabis Effects on Driving Lateral Control with and without Alcohol. Drug and alcohol 
dependence. 2016; 154, 25-37. 
Hartman, R. L., Jang, M., Spurgin, A., Yun, K., Gorelick, D. A., Milavetz, G., Brown, T. L., Gaffney, G., 
& Huestis, M. A. Cannabinoid Disposition in Oral Fluid after Controlled Cannabis Vaporizer 
Administration. American Academy of Forensic Sciences Annual Conference. February 2015; Orlando, 
FL. 
Hindmarch, I., Trick, L., & Ridout, F. A double-blind, placebo- and positive-internal-controlled 
(alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers. 
Psychopharmacology. 2005; 183, 133-143. 
Jamt, R. E. G., Gjerde, H., Romeo, G., Bogstrand, S. T. Association between alcohol and drug use and 
arrest for driving under the influence after crash involvement in a rural area of Norway: A case-control 
study. BMJ Open. 2018; 9: e023563. doi:10.1136/bmjopen-2018-023563 
Kay GG, Hochadel T, Sicard E, Natarajan KK, Kim NN. Next-day residual effects of flibanserin on 
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Kay, GG and Logan, BK. Drugged driving expert panel report: A consensus protocol for assessing the 
potential of drugs to impair driving (DOT HS 811 438). National Highway Traffic Safety Administration. 
2011. 
Kuypers, K. P. C., Legrand, S.-A., Ramaekers, J. G., Verstraete, A. G. A Case-Control Study Estimating 
Accident Risk for Alcohol, Medicines and Illegal Drugs. PLOS ONE. 2012; 7(8), e43496. 
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Legrand, SA, Silverans, P, de Paepe, P, Buylaert, W, Verstraete, AG. Presence of psychoactive 
substances in injured Belgian drivers. Traffic Injury Prevention. 2013; 14(5), 461-468 
Leufkens TR, Vermeeren A. Zopiclone's residual effects on actual driving performance in a standardized 
test: A pooled analysis of age and sex effects in 4 placebo‐controlled studies. Clinical Therapeutics. 2014; 
36(1), 141–150. 
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psychomotor, and actual driving performance in healthy volunteers after immediate and extended release 
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Neuropsychopharmacology. 2002; 27, 260 – 269. 

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APPENDIX A. AMOUNT OF BLOOD DRAWN PER STUDY VISIT 
 
 
Pharmacokinetic Sampling  
Total 
Day 2 
8 mL x 3 
24 mL 
Total 
24 mL 
24 mL 
 
Blood volumes shown in the table are approximate. At each blood draw, two 4 mL draws will be made for a total of 
8 mL. Additional blood samples may be taken if needed to follow-up on individual subject safety.  
 
 
 

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APPENDIX B. DAILY SCHEDULE OF ACTIVITIES PER PERIOD 
Activity 
Study 
Day 
Location 
Time 
Time Post-Dose 
(Cannabis) 
Admission and Intake 
Day 1 
NADS 
3:00pm 
-17 hours 40 
minutes 
Cognitive Battery 
Practice 
Day 1 
NADS 
3:55pm 
-16 hours 45 
minutes 
CRCDS2 Practice 
Day 1 
NADS 
4:30pm 
-16 hours 10 
minutes 
Transport to supervised 
off-site residential facility  
Day 1 
In transit 
6:00pm 
-14 hours 40 
minutes 
Dinner  
Day 1 
Off-site residential 
facility 
(supervised) 
6:00pm to 
8:00pm 
-14 hours 40 
minutes to -12 
hours 40 
minutes 
Bedtime 
Day 1  
Off-site residential 
facility 
(supervised) 
10:00pm 
-10 hours 40 
minutes 
Awakened 
Day 2 
Off-site residential 
facility 
(supervised) 
5:45am to 
6:00am 
-2 hours 55 
minutes to -2 
hours 40 
minutes 
Breakfast 
Day 2 
Off-site residential 
facility 
(supervised) 
6:30am 
-2 hours 10 
minutes 
Transport to NADS 
Day 2 
In transit 
7:15am 
-1 hour 25 
minutes 
Arrival at NADS 
Day 2 
NADS 
7:30am 
-1 hour 10 
minutes 
Blood Draw & KSS 
Day 2 
NADS 
7:45am 
-55 minutes 
Alprazolam dosing 
Day 2 
NADS 
8:00am 
-40 minutes 
Cannabis dosing 
Day 2 
NADS 
8:40am 
0 

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SDC, PFN, KSS, 
Readiness to Drive 
Question 
Day 2 
NADS 
9:10am 
30 minutes 
Blood Draw 
Day 2 
NADS 
9:20am 
40 minutes 
CRCDS2 
Day 2 
NADS 
9:25/9:30am 
45 minutes 
VAS, SDC, VSC, DAT, 
PFN, SDCDR, SAT, 
MTS, DT, TOVA 
Day 2 
NADS 
10:30am 
1 hour 45 
minutes  
Lunch 
Day 2 
NADS 
11:20 
2 hours 40 
minutes 
Blood Draw 
Day 2 
NADS 
11:55am 
3 hours 15 
minutes  
SDC, VSC, DAT, PFN, 
SDCDR, SAT, MTS, DT, 
TOVA, Self-Report 
Measures 
Day 2 
NADS 
12:10pm 
3 hours 30 
minutes  
Discharge  
Day 2 
NADS 
2:00pm 
5 hours 20 
minutes