Vaping THC From Electronic Cigarettes: a Novel Evaluation of Intake and Pharmacokinetics
Phase: PHASE3
Conditions: Marijuana Dependence
Sponsor: University of California, San Francisco

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Vaping THC: a Novel Evaluation of Intake and Pharmacokinetics 
 
R01: DA039264 
UCSF IRB #: 18-24854 
Clinical Trials.gov #: NCT02955329 
 
 
Manual of Procedures (MOP) 
NEAL BENOWITZ, M.D. (PI) 
GIDEON ST. HELEN, Ph.D. (CO-I) 
PEYTON JACOB, Ph.D. (CO-I) 
October 2018 

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TABLE OF CONTENTS 
Vaping THC: a Novel Evaluation of Intake and Pharmacokinetics ............................................... 1 
TABLE OF CONTENTS ................................................................................................................ 2 
INVESTIGATORS, PERSONNEL, CONTACT INFORMATION ................................................... 4 
1 
INTRODUCTION AND STUDY DESIGN ............................................................................... 5 
1.1 
Background .......................................................................................................................... 5 
1.2 
RESEARCH QUESTIONS ................................................................................................. 6 
1.3 
SPECFIC AIMS/OBJECTIVES ............................................................................................ 6 
1.4 
STUDY DESIGN ................................................................................................................ 6 
1.5 
ELIGIBILITY ........................................................................................................................ 7 
1.6 
ID AND RANDOMIZATION .............................................................................................. 10 
1.7 
PARTICIPANT WITHDRAWAL ........................................................................................ 10 
2 
STUDY TIMELINE ............................................................................................................... 11 
2.1 
VISIT SCHEDULE & WINDOWS OF ASSESSMENTS .................................................... 11 
3 
STUDY VISITS AND PROCEDURES ................................................................................. 11 
3.1 
REDCap Questionnaire .................................................................................................... 11 
3.2 
Phone Evaluation & Confirmation .................................................................................... 12 
3.3 
SCREENING VISIT PROCEDURES ................................................................................ 13 
3.3 
ORIENTATION ................................................................................................................. 15 
3.4 
PHARMACOKINETIC STUDY: Outpatient Visits ............................................................. 16 
3.4.1   Protocol for Outpatient Study .................................................................................... 16 
3.4.1(a) Marijuana preparation ............................................................................................. 16 
3.4.1(b) Hospital Admission Protocol ................................................................................... 16 
3.4.1 (c) Outpatient Study Protocol ...................................................................................... 17 
3.4.2 Protocol for gas trap .................................................................................................. 20 
3.4.3 Timing of Blood Collection ........................................................................................ 20 
3.4.4 Timing of Saliva Collection ........................................................................................ 21 
3.4.5 Timing of Urine Collection ......................................................................................... 21 
3.4.6 Sample Assays ......................................................................................................... 22 
4. 5B PAPERWORK AND PREPARATION FOR OUTPATIENT STUDY .................................. 22 
5 
ADVERSE EVENTS & PROTOCOL DEVIATIONS ............................................................. 23 
5.1 
SAFETY MONITORING ................................................................................................... 23 

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5.2 
DEFINITION OF ADVERSE EVENTS ............................................................................. 23 
5.3 
REPORTING ADVERSE EVENTS .................................................................................. 25 
5.4 
PROTOCOL DEVIATIONS AND VIOLATIONS ............................................................... 26 
6 
DATA COLLECTION AND MANAGEMENT ........................................................................ 26 
6.1 
DATA COLLECTION FORMS .......................................................................................... 26 
6.2 
DATA ENTRY, STORAGE, AND ANALYSIS ................................................................... 27 
6.3 
DATA ANALYSIS ............................................................................................................. 27 
7 
DUTIES AND RESPONSIBILITIES OF STAFF ................................................................... 28 
7.1 
PRINCIPAL INVESTIGATOR .......................................................................................... 28 
7.2 
Study Doctor ................................................................................................................... 28 
7.2 
CO-INVESTIGATORS ..................................................................................................... 28 
7.3 
PROJECT MANAGER ..................................................................................................... 28 
7.4 
CLINICAL RESEARCH COORDINATOR ........................................................................ 28 
8 
STUDY MANAGEMENT ...................................................................................................... 28 
8.1 
PRE-STUDY DOCUMENTATION .................................................................................... 28 
8.2 
INSTITUTIONAL REVIEW BOARD APPROVAL ............................................................. 29 
8.3 
INFORMED CONSENT.................................................................................................... 29 
8.4 
CHANGES IN PROTOCOL .............................................................................................. 29 
9 PROTECTION OF HUMAN SUBJECTS ............................................................................... 29 
9.1 PROTECTION AGAINST RISKS .......................................................................................... 29 
10 REFERENCES ...................................................................................................................... 30 

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INVESTIGATORS, PERSONNEL, CONTACT INFORMATION 
 
Neal Benowitz, MD 
Principal Investigator 
neal.benowitz@ucsf.edu 
415-206-8324 
 
Gideon St. Helen, PhD 
Co-Investigator 
gideon.sthelen@ucsf.edu 
415-476-8982 
 
Peyton Jacob III, PhD 
Co-Investigator 
Peyton.Jacob@ucsf.edu 
 
 
Neal Benowitz, MD 
Study Doctor 
neal.benowitz@ucsf.edu 
415-206-8324 
 
Natalie Nardone, PhD 
Project Manager 
natalie.nardone@ucsf.edu 
415-514-1450 
 
Nickole Criner 
Clinical Research Coordinator 
nickole.criner@ucsf.edu 
415-530-8020 

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1 
INTRODUCTION AND STUDY DESIGN 
 
1.1 Background 
 
Electronic cigarettes for nicotine delivery 
Electronic cigarettes (e-cigarettes) have proliferated at a rapid rate since their 
introduction into the US market in 2007 and their use as a form of nicotine delivery 
far outpaced the science base (1, 2). Important questions revolved around their 
abuse liability and safety. Although the design of these devices continues to evolve, 
we 
have 
previously 
described 
nicotine 
intake, 
systemic 
retention, 
pharmacokinetics, and effects, as well as vaping behavior and self-administration 
of e-cigarettes (3, 4). We showed that e-cigarettes deliver as much nicotine from 
15 puffs as a typical tobacco cigarette (~1 mg), most of which is systemically 
retained, and the shape of the plasma nicotine concentration-time curve is also 
similar to tobacco cigarettes, except that the maximum plasma nicotine 
concentration is, on average, lower for e-cigarettes. During ad libitum access, e- 
cigarettes were vaped intermittently in groups of 2-5 puffs or single puffs such that 
plasma nicotine levels rose gradually and peaked at the end of the 90-minute 
session. This differs from the rapid increase in plasma nicotine observed during 
controlled use of e-cigarettes or during tobacco cigarette smoking. Taken together, 
these results indicate that e-cigarettes have the potential to produce and sustain 
nicotine addiction but their use and abuse liability may differ from tobacco cigarette. 
 
Electronic cigarettes are NOT restricted to nicotine 
Marijuana is the most widely used illicit drug (5). While marijuana has traditionally 
been combusted, currently vaping of either loose leaf marijuana or other forms of 
・-9-tetrahydrocannabinol (THC) oil has been increasing (6). The latest national 
data show that 7.6% of current marijuana users (past 30 days) and 9.9% of ever 
marijuana users (lifetime) administered THC through a vaporizer or electronic 
device (6) (the study did not differentiate between vaporizers and electronic 
devices like e-cigarettes). The prevalence of vaped marijuana or THC is higher 
among younger adults. Prevalence of vaped marijuana/THC among 18-24 and 25- 
34 year-old ever marijuana users was 19.3% and 16.3%, respectively, compared 
to 8.8% for 35-49 year-olds and 5.7% for those 50 years and over (6). A recent 
study also showed high rates of cannabis vaping using e-cigarettes among high 
school students (18.0% among ever e-cigarette users) (7). 
Combined effects of tobacco and marijuana. 

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The combined inhalation of tobacco and marijuana is common. Smoking of 
marijuana in a cigar wrapping (a blunt) is very popular among adolescents and 
young adults, particularly in the African American population. Smoking of a 
combination of tobacco and marijuana in cigarette form is also common, 
particularly in Europe (8) (9). Since both marijuana and tobacco are consumed by 
vaping, it is likely that vaping of both products will also soon become common. Very 
little is known about the pharmacology and safety of simultaneous intake of nicotine 
and THC from vaping. 
1.2 RESEARCH QUESTIONS 
To understand THC pharmacology and safety of cannabis vaping, including the 
pharmacology and safety of co-administration of nicotine and THC. 
 
1.3 SPECFIC AIMS/OBJECTIVES 
1. To characterize Δ9-tetrahydrocannabinol (THC) delivery, systemic exposure, 
and effects from vaping THC-containing cannabis leaf alone or cigarette 
tobacco alone, or the combination of cannabis and tobacco. 
 
2. To assess sympathetic nervous system (SNS) stimulating and subjective SNS- 
related effects of THC alone compared to nicotine (tobacco) alone or combined 
to THC and nicotine co-administration. 
 
3. To assess emissions of THC, terpenes, and other compounds from electronic 
THC delivery devices. 
 
1.4 STUDY DESIGN 
 
1.4.1 
Design Summary 
The study is designed as a within-subjects single-blinded crossover study. 
Fourteen smokers of tobacco cigarettes and cannabis will switch between three 
conditions, namely: (a) vaping cannabis leaf, (b) vaping tobacco containing 
nicotine and (c) vaping a combination of cannabis leaf and tobacco containing 
nicotine. All participants will vape each product with the PAX loose-leaf 
vaporizer. 
PAX vaporizers will be purchased by the study team. The cannabis leaf will be 
obtained through the National Institute on Drug Abuse Drug Supply Program. 
The tobacco containing nicotine, used in conditions (b) and (c) will come from 
commercially available Marlboro brand cigarettes. The same amount of cannabis 
or tobacco will be used in all conditions. 

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The study will be conducted during three outpatient visits separated by at least 
48 hours. The order of treatment (cannabis leaf, tobacco with nicotine, cannabis 
leaf & tobacco with nicotine) will be counterbalanced between subjects. Subjects 
will be blinded to the content of the vaporizer on the study day but will be told 
during screening that they will vape cannabis alone, tobacco alone, and cannabis 
plus tobacco with nicotine. 
1.4.2 
Number of Subjects 
A total of 14 subjects will be enrolled in this study over a period of about 6 
months. The anticipated accrual rate is approximately 2-4 subjects per month. 
1.4.3 
Study Timeline 
 Study application was submitted to the Institutional Review Board (IRB): 
pending 
 IRB Approval date: June 14, 2018 
 Other approvals: 
o Research Advisory Panel of California: Approved 
o Schedule 1 license from the US DEA: Received 
o Investigational New Drug Application: Approved 
 
1.5 
ELIGIBILITY 
All individuals interested in participating and who meet the inclusion/exclusion 
criteria will be invited to be part of the study. Inclusion criteria for participants to be 
enrolled are described below. Eligibility will be assessed by the Clinical Research 
Coordinator beginning an eligibility checklist at the time of the online survey. This 
checklist will be updated during the phone screen and finally after the in-person 
screening visit. 
 
1.5.1 Inclusion Criteria 
o Age ≥21 years ≤ 70 years 
o Regular user of combustible tobacco cigarettes (at least 1 cigarette weekly) 
o Regular user of cannabis in any form administered through the pulmonary 
route (smoking and/or vaping) at least once a week. 
o Positive for THC on screening toxicology test 
o Willing to abstain from tobacco smoking and all other combustible products 
(ex: cigars) for 12 hours prior to each outpatient hospital admission. 
o Willing to abstain from smoking/ingesting cannabis for 12 hours prior to each 
outpatient hospital admission. 

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o Willing to abstain from using any kind of nicotine products for 12 hours prior to 
each outpatient hospital admission (ex: electronic cigarettes, nicotine 
replacement therapy). 
o Saliva cotinine ≥ 30 ng/mL and/or NicAlert of 6 
o Healthy (based on limited physical examination and medical history collected 
during screening) 
o Heart rate < 105 BPM 
o Systolic Blood Pressure < 160 and > 90 [considered out of range if both 
machine and manual readings are above/below these thresholds] 
o Diastolic Blood Pressure < 100 and > 50 [considered out of range if both 
machine and manual readings are above/below these thresholds] 
o Body Mass Index ≤ 38.0 
o Women of child-bearing potential must use an acceptable contraceptive 
during the study 
1.5.2 Exclusion Criteria 
o Any congenital or acquired immunologic disorders due to the following: 
o Human immunodeficiency virus [HIV] infection 
o Congenital immune deficiency syndromes 
o Chronic diseases (diabetes mellitus, cancer, emphysema, or cardiac 
failure) 
o Intensive Care Unit care 
o Malnutrition 
o Immunosuppressive therapy of another disease process (e.g., 
radiation, cytotoxic chemotherapy, anti-graft rejection medication, 
corticosteroids, monoclonal antibodies directed against a specific 
component of the immune system) 
o Medical (The following unstable medical conditions): 
o Heart disease 
o Seizures or history of seizure disorder 
o Cancer 
o Thyroid disease (okay if controlled with medication) 
o Diabetes 
o Hepatitis B or C or Liver disease 
o Glaucoma 
o Kidney disease or urinary retention 
o History of stroke 
o An ulcer in the past year 
o Active use of an inhaler for Asthma or COPD 
o History of traumatic brain injury with current sequelae 
o History of paranoia after marijuana use 

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o Psychiatric conditions 
o Current or past schizophrenia, and/or current or past bipolar disorder 
o Major Depression (current or within the past year) 
o Major Personality Disorder 
o Participants with current or past minor or moderate depression and/or 
anxiety disorders will be reviewed by the study physician and considered 
for inclusion 
o History of psychiatric hospitalizations are not exclusionary, but study 
participation will be determined as per study physician's approval 
o Drug/Alcohol Dependence 
o Alcohol or illicit drug dependence within the past 12 months with the 
exception of those who have recently completed an alcohol/drug 
treatment program and are currently abstaining from drug and alcohol 
o Positive toxicology test for illicit drugs at the screening visit (THC & 
prescribed medications okay) 
o Opioid Replacement therapy (including methadone, buprenorphine) 
o Scoring a 7 or higher total sum score on the Severity of Dependence 
Scale for cannabis use. 
o Psychiatric medications 
o Current regular use of any psychiatric medications with the exception of 
SSRIs and SNRIs and current evaluation by the study physician that the 
participant is otherwise healthy, stable, and able to participate. 
o Other Medications 
o Use of medications that are inducers of nicotine metabolizing enzyme 
CYP2A6 (Example: rifampicin, carbamazepine, phenobarbital, and other 
anticonvulsant drugs). 
o Concurrent use of nicotine-containing medications 
o Any stimulant medications (example: Adderall) generally given for ADHD 
treatment 
o Use of sympatholytic medications for cardiovascular conditions including 
hypertension (Example: beta and alpha-blockers) 
o Other/Misc. Chronic Health Conditions 
o Oral thrush 
o Fainting (within the last 30 days) 
o Other “life threatening illnesses” as per study physician's 
discretion 
o Use of Other Tobacco Products (OTP); any of the following products in 
combination more than 15 times in the past month 
o smokeless tobacco 
o pipes 
o cigars 

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o Pregnancy 
o Pregnancy (self-reported and urine pregnancy test) 
o Breastfeeding (determined by self-report) 
o Concurrent participation in another clinical trial 
o Inability to communicate in English 
o Planning to quit smoking or cannabis use within the next 60 days 
 
1.6 ID AND RANDOMIZATION 
 
1.6.1 Study ID Assignment 
Subject IDs will be assigned as follows: XXXX-YYY, where XXXX is the CTSI CRS 
Study Number and YYY is assigned sequentially once a subject consents to the study 
during the Screening Visit, starting with XXXX001. Plasma samples and inpatient 
questionnaire labels will be labeled as follows: XXXX-#-YYY, where # is the study day 
(1 for day 1, 2 for day 2, 3 for day 3). 
 
1.6.2 Subject assignment to conditions 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Study 
Day 1 
C 
T 
C+T 
C 
T 
C+T 
C 
T 
C+T 
C 
T 
C+T 
C 
T 
Study 
Day 2 
T 
C+T 
C 
T 
C+T 
C 
T 
C+T 
C 
T 
C+T 
C 
T 
C+T 
Study 
Day 3 
C+T 
C 
T 
C+T 
C 
T 
C+T 
C 
T 
C+T 
C 
T 
C+T 
C 
*Where, C is cannabis leaf; T is tobacco cigarettes; C+T is cannabis leaf + tobacco 
cigarettes. Order of enrolled subjects will be counterbalanced; order is assigned at 
admission. 
 
1.7 PARTICIPANT WITHDRAWAL 
 
1.7.1 Dropouts and compensation 
If a participant declares they are no longer interested in completing the study, they will 
be considered a “dropout.” If the participant decides to stop participating in the study 
prior to outpatient admission for study day 1, they will only receive compensation for the 
Screening Visit (i.e. $30). 
• 
Complete study day 1: $100 
• 
Complete study day 2: $100 
• 
Complete study day 3: $100 
• 
For complying with all study procedures including attending the orientation visit, 
abstaining from tobacco cigarettes, nicotine products, and marijuana use 12 

Page 11 of 30 
 
hours prior to Study Days 1, 2 and 3, subjects will be given an additional $120 
bonus ($40 each day). 
• 
Total possible compensation is $450. 
 
1.7.2 Lost to Follow Up 
If a participant is unable to be contacted and does not respond to calls from the Clinical 
Research Coordinator (up to three unsuccessful phone contact attempts), he/she will be 
considered “lost to follow-up” (LTFU). Before a participant is considered LTFU, every 
effort will be made to contact him/her. After being considered LTFU no further outreach 
will be conducted. If a formerly LTFU participant re-contacts the CRC outside a given 
study window, participant will be rescheduled for screening. 
2 
STUDY TIMELINE 
 
2.1 
VISIT SCHEDULE & WINDOWS OF ASSESSMENTS 
 
Assessment Point 
Maximum Time from REDCap Questionnaire 
Screen 
REDCap Questionnaire 
 
In-Person Screening Visit 
14 days from REDCap questionnaire 
Orientation 
45 days* (~1 month from in-person screening) 
Study Day 1 
47 days 
Study Day 2 
49 days 
Study Day 3 
51 days 
*In-person screening may be repeated if this window is exceeded. 
 
3 
STUDY VISITS AND PROCEDURES 
 
3.1 
REDCap Questionnaire 
Interested participants will fill out a short (10-minute) survey on REDCap. The 
CRC will complete an eligibility checklist, beginning at the time of this online 
survey. This checklist will be labeled first by the REDCap ID and later by the Study 
ID after consent & assignment. The Clinical Research Coordinator (CRC) will then 
determine if the participant is eligible to attend a Screening Visit based on above 
inclusion/exclusion criteria. 

3.2 
Phone Evaluation & Confirmation 
3.2.1 Phone Evaluation Scripts 
Various items related to eligibility must be confirmed by the CRC during a 
phone conversation. 
If preliminarily eligible, the CRC will contact the participant by phone and ask 
them the following questions: 
 
Script: “Okay, I am going to ask you various questions about your medical 
history. This will help us determine if you are a good match for our study. Do I 
have your consent to ask these questions?” 
 
“1) Have you ever been diagnosed with or told you have any of the following 
disorders? I’ll read a list aloud and you at the end, just let me know yes or no.” 
a) Human immunodeficiency virus infection (or HIV/AIDS) 
b) Congenital immune deficiency syndromes 
c) Chronic diseases, such as diabetes mellitus, cancer, emphysema, or 
heart failure? 
*If yes to a-c, participant is ineligible. End the phone screen. 
2) “Have you ever acquired a disorder from any of the following?” 
a) Being in Intensive Care Unit (ICU) care 
b) Malnutrition 
c) Immunosuppressive therapy (examples of these may be radiation, 
cytotoxic chemotherapy, anti-graft rejection medication, corticosteroids, 
monoclonal antibodies directed against a specific component of the 
immune system) 
*If yes to a-c, participant is ineligible. End the phone screen. 
3) “Have you ever experienced a traumatic brain injury, or currently experiencing 
any symptoms resulting from a head injury?” 
*If yes, participant is ineligible. End the phone screen. 
 
4) “Do you have a history of feeling paranoid after using marijuana” 
*if yes, participant is ineligible. End the phone screen. 
5) Do you currently take any medications? 
*If a psychiatric medication is a non-SSRI or SNRI, or participant is on 
anticonvulsants, nicotine replacement therapy, stimulant medication, opioid 
replacement therapy or beta-blockers, participants is ineligible. 
*Review any other questionable medications with the PI/Study Doctor. 
 
6) Are you willing to abstain from tobacco smoking, smoking any other tobacco 
products 
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Page 13 of 30 
 
(like cigars, cigarillos, blunts, splits & other) from smoking or ingesting and 
cannabis or 
marijuana products, and from using nicotine products of any kind (like e- 
cigarettes, or nicotine gum, patch, lozenge, inhaler) for 12 hours before each of 
your study days? 
*If no, ineligible. 
 
7) If female, for the duration of this study, are you willing to use an acceptable 
method of birth control if you have sexual intercourse with a man? Acceptable 
methods are barrier methods, hormonal methods, or implantation devices. 
Please let me know, yes or no. *If no, ineligible. 
 
8) If participants indicate they are in a drug treatment program & further 
clarification is needed, “I saw you indicated that you are in a drug treatment 
program. Can you let me know what that is for? Did you complete it or are you 
currently in the program” 
*If recently completed a program, they are eligible. If still in the program, 
ineligible. 
 
If still eligible after those questions, a Screening Visit appointment should be 
scheduled immediately. 
 
 
 
3.2.2  Scheduling Script 
 
 V-PAX Phone Screen & Consent Conversation  
   
 
If preliminarily eligible based on the REDCap report, contact the participant by 
 
phone and ask them the following questions using the script:  
 
 
Study Team: Good afternoon, may I please speak with [name]? 
 
    If the Person is not available: Thank the person who answered and say goodbye. 
               If the Person is available: First confirm that you are speaking to the correct person. 
 
    Study Team: This is [name] calling from the UCSF Tobacco Research Center. I am a  
    coordinator working with Dr. Benowitz’s research group. 
 
    Is this an Ok time for you to speak? 
    If the Person says “No” or “I’m not sure” 
 
Study Team: Okay. [Ask if you can schedule another time to talk. If the person is not 
sure or seems hesitant, thank him/her and say goodbye.] 
 

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If the Person says “Yes” 
 
Study Team: Great. I wanted to talk with you about a new study for tobacco cigarette and 
cannabis smokers who are willing to vape cannabis, tobacco and a combination of the 
two using the PAX loose leaf vaporizer. You may remember you filled out a 
questionnaire online to be considered for this study. You indicated that you were 
interested in learning more.  
 
If the Person says “No” or “I’m not sure” 
 
Study Team: No problem. I just wanted to make sure you had the opportunity to learn 
about any study we have at the UCSF Tobacco Research Center. Thank you for your 
time. 
 
If the Person says “Yes” 
 
Study Team: Study Team: This new study is looking at the safety and addictiveness of 
orally vaping cannabis (THC) and nicotine. This study consists of 5 visits across about 14 
days. First, there is a 45 minute screening visit at our research center, to make sure you are 
a good match for our study. Then you will return for a 30 min orientation visit the day before 
your first study visit. For each outpatient study visit, you will be admitted for 8 hours in the 
hospital starting at 7am and will be discharged from our hospital research ward at ZSFG at 
3pm. Each of your 3 outpatient study visits will involve blood draws, urine collections, pulse 
monitoring (heart rate) & questionnaires.  
 
 
That’s the purpose and procedures for our study. Can I answer any questions? (if yes,  
answer questions; if no continue…)  
 
Okay, the first step is for me to ask you some questions to see if you are a good match for  
the study. This can take about 20 minutes. Do you have the time right now to speak with  
me? Do I have your consent to ask these questions?”   
 
Update the Eligibility Checklist as you ask the questions. 
 
Study Team: (if no) “Okay, well it seems like this study may not be the best fit for you,  
which is totally fine. Would you like us to keep your name down for other studies as they  
come up?”  
 
(If yes, continue)  
 
Study Team: “Okay, so we reviewed the purpose and procedures of this study. I’d like to let  
you know that research is 100% voluntary and you can choose at any time not to  
participate.”  
 
“I’d like to review some risks with you 

Page 15 of 30 
 
 
 
We will be collecting blood so there is a risk of pain, swelling, bruising, or infection at the  
draw site. Some people experience feelings of paranoia after smoking marijuana, so we will  
dismiss you from the study if you develop feelings of paranoia. Study procedures may be  
inconvenient and tedious. For example you will befilling out many forms, spending time in  
the hospital, providing specimens, etc. We will also ask you to abstain from tobacco  
cigarette use, so you may feel uncomfortable, irritable, restless or have difficulty  
concentrating due to possible nicotine withdrawal. Nicotine withdrawal may also result in  
headaches, nausea, fatigue, or changes in mood. We will also be measuring  
your blood pressure and it may feel uncomfortable depending on the tightness of the cuff.  
And finally, we will be collecting personal information from you, so there is a risk of breach  
of confidentiality. However, we will do our best to keep your confidentiality. There may be  
undiscovered drug toxicity associated with the use of cannabis, that can put you at risk for 
unknown effects. There may be long-term effects associated with the use of cannabis that  
are currently unknown to the scientific community. 
 
Can I answer any questions about risks?  
 
Okay, let’s talk about the benefits. There are no direct benefits to you, but you will be  
helping us learn about how safe and addictive it can it is to vape cannabis and nicotine,  
which has great potential benefit to other smokers like you.  
 
Here are some important reminders: You will be asked to abstain from any type of cannabis  
use from 6pm (approximately 12 hours) prior to each hospital admission. This cannabis use  
includes smoking cannabis, vaping cannabis, edibles, THC concentrates, etc. You will also  
be asked to abstain from recreational drug use from the time of orientation until the study is  
completed. You will be asked to abstain from the use of other tobacco products that include  
cannabis for approximately 12 hours prior to each hospital admission. This includes blunts  
and spliffs. You will be asked to abstain from using any type of tobacco and nicotine  
products from 6pm (approximately 12 hours) prior to each hospital admission. This nicotine  
use includes cigarettes, e-cigarettes, smokeless tobacco, pipes, cigars and cigarillos.  
 
Please note that there are no guest are permitted at the hospital. This is to protect  
everyone’s confidentiality.  
 
We will also be compensating you for your time and effort – if you complete all parts of the 
study, you will receive a total of $450 via check. You will fill out a check request after you  
complete each portion of the study and it is estimated to take 4-6 weeks to receive it.  
 
Can I answer any other questions? (if yes, answer) (if no proceed)  
 
Okay, can I ask you a few questions? 
 
Do you remember – how long does this study last? (about 14 days) Do you remember – 
how many visits will you have? (5 visits) 
 

Page 16 of 30 
 
What are some risks you may experience? (discomfort, bruising, mood changes, breach of  
confidentiality, etc)  
 
Do you think you are interested in seeing if you are a match for the study?  
(if yes) “Great! I am going to send you a powerpoint presentation via your email. Please look  
it over – it describes in great detail more information about the study. I will also send you the  
consent form – please take time to read it over and review carefully. If you agree to  
participate, you will be prompted to sign the form.  
 
I can schedule you for the next phase of screening – this is the 45 minute screening visit I  
mentioned to you. When would be a good time for you to come in for that? 
(proceed with scheduling visit)  
 
Okay, very important before you come in…  
After you sign the consent form and about 24 hours before your visit, I will send you a  
survey link to your email. It’s important that you complete this survey before you come in,  
otherwise you will need to complete it in person and the visit will take longer than 45  
minutes.  
 
At the screening visit we will first review a HIPPA form. This is another important form for  
you to sign related to the study and your health information privacy. We will then have you  
fill out a medical history form and we will conduct a quick interview and collect your basic  
vitals and a saliva sample. At this visit, you will also need to provide a urine sample for a  
drug test and a pregnancy test, if applicable.  The drug test must be positive for THC and  
negative for all other drugs. If your positive for any drugs other than marijuana it will result in  
an automatic dismissal without payment. There will also be a breath measurement to   
assess your tobacco cigarette smoking status. If this measurement shows you are not a  
smoker, we will dismiss you without payment. If you pass these tests and complete the  
screening visit we will compensate you with a $30 check, which will reach  
your home within 4-6 weeks.  
 
For this visit, please bring in your photo ID to verify your name and age. If you are currently  
taking any medications, please bring the bottle or a copy of your prescription, so we can  
verify any medications you are taking. If you need to reschedule your study visit, we will give  
you one option to reschedule, so please make sure you pick a time that works with your  
schedule. 
 
Any other questions? 
(if no) GREAT! I will send you a confirmation email which will include the PowerPoint  
summary and consent form. Please do not hesitate to contact me with any questions. 
 
3.2.3  Email Confirmation 
 
Participants will receive a confirmation email upon scheduling their screening visit. 
 
Hi [participant name], 

Page 17 of 30 
 
Thank you for your interest in helping us with our Vaping Tobacco and Cannabis Study. 
 
This email is to remind you that you are now scheduled to come in for your visit on [DAY,  
DATE at TIME].Our center is located at Zuckerberg San Francisco General (1001 Potrero  
Ave) in Building 100 on the 2nd floor. The directions are as follows: Turn onto 22nd Street  
from Potrero Avenue towards the brick ZSFG buildings. Continue on 22nd Street and you  
will see Carr Auditorium at your 3rd right. Walk through the parking lot and enter Building  
100 through the grey door. You will see signs directing you to UCSF Tobacco Research  
Center. 
 
Please ring the door bell to notify us that you are here. We do ask that you don’t bring any  
guests with you since our center cannot accommodate unscheduled visitors. 
 
Please remember to bring with you: 
- 
A valid Photo ID 
- 
Your prescription medication bottles, if you have any 
- 
A pack of your cigarettes to confirm your brand usage 
To note: 
- 
Be prepared to provide urine for a drug test. 
- 
The screening visit will take around 45 minutes. 
- 
You will be compensated $30 for your visit via mailed check, which can take up to 4-6 
weeks to reach you after your visit, as long as our test shows you are a smoker of 
tobacco cigarettes. 
 
Please feel free to email us if you have any questions or need to reschedule  
(tobaccocoord@ucsf.edu). Thank you again for your help and we look forward to seeing 
you! 
 
3.3 SCREENING VISIT PROCEDURES 
Subjects will undergo a 45 min Screening Visit to obtain and determine their 
enrollment eligibility. During this visit, participants will complete a basic physical 
assessment (height, weight, heart rate, blood pressure, expired carbon 
monoxide, urine drug test, and pregnancy test (if applicable), saliva collection, 
and questionnaires: the Severity of Dependence Scale, THC use history and a 
standard screening packet asking demographics, health history and other 
product use. 
 
The CRC will determine initial eligibility via basic physical assessment, toxicology 
screen, and inclusion/exclusion criteria. In the event of a positive toxicology test 
(except marijuana), subject will be dismissed immediately without payment and 
the remainder of the screening visit measures will not be completed. Participants 
who fail the pregnancy test, blood pressure test, or BMI assessment will be paid 
and dismissed. Clinical Research Coordinator should follow the Tobacco 
Research Center Pregnancy Test SOP for communicating results with the 
participant. Participants who indicate an exclusionary medication that they 

Page 18 of 30 
 
neglected to report during the initial REDCap survey, will be dismissed without

Page 19 of 30 
 
payment. In all cases of early dismissal, any collection of biosamples will be      
discarded. 
 
Upon determination of preliminary eligibility, the participant’s saliva sample will 
be delivered to the lab for analysis. Participants must have saliva cotinine levels 
≥ 30 ng/mL to be considered eligible for enrollment. NicAlert tests will be used to 
verify cotinine in cases when saliva cotinine samples are not able to be run 
quickly. 
 
3.2.4 Consent Process 
Upon initiation of the Screening Visit, CRC will initiate the Informed Consent 
process. The participant will be asked to read the first line of the consent form 
aloud to ensure reading ability. The CRC will instruct the participant to read each 
page of the consent document. Participants will be asked to refrain from signing 
the consent form until CRC returns to discuss consenting document specifics. 
CRC will leave the room for 10 minutes to allow subject to read the consent form. 
After 10 minutes, CRC will return, answer any questions, and present a brief 
PowerPoint presentation highlighting important aspects of the consent document. 
The CRC will ask the participant if they have any questions, and will ask them 
questions to verify understanding. Consent will be obtained via participant’s and 
CRC’s signature at the conclusion of the PowerPoint presentation. Two original 
consent documents will be signed by both the participant and the CRC. One is to 
be filed and stored in the participant’s folder, another is to be given to the 
Hospital research ward for their records. The CRC will make a copy of one of 
those consent documents and give to the participants for his/her records. CRC 
should present participant with a copy of their Bill of Rights as a research 
participant at UCSF. Participant will also be presented with the HIPAA 
authorization form to sign after an explanation of what it entails. The HIPPA form 
must have “entire medical record” checked off in Section B, information 
pertaining to drug & alcohol abuse checked off in Section C, and the optional 
activities of banking samples checked off & initialed in Section G. 
3.2.5 Forms for Data Collection 
During recruitment participants will complete the following below. 
1. REDCAP Online Screen 
2. Phone Screen Evaluation 
 
At Screening participants will complete the following below. 
The Screening Packet consists of the following forms: 
3. Personal Data Form 

Page 20 of 30 
 
4. Demographic Information 
5. Nicotine/Tobacco Product Use Form 
6. Electronic Cigarette or E-Cigarette History 
7. Penn State E-Cigarette Dependence Index 
8. E-Cigarette Use Assessment 
9. Smoking History Screening Form [Cigarettes] 
10. Alcohol Use 
11. Non-medical Drug Use 
12. Medical History 
13. Physiological Assessment Form 
14. Center for Epidemiological Studies Depression Scale (CES-D) 
15. Fagerström Test for Nicotine Dependence (FTND) 
 
Participants will also complete: 
16. THC History Questionnaire 
17. Severity of Dependence Scale (SDS) 
 
The outpatient questionnaires consist of the following forms: 
1. Marijuana Cravings Questionnaire- Short Form (MCQ-SF) 
2. Positive Affect Negative Affect Schedule (PANAS) 
3. Minnesota Nicotine Withdrawal Scale (MNWS) 
4. Modified Cigarette Evaluation Questionnaire (mCEQ) 
5. Drug Effect Questionnaire (DEQ-5) 
 
 
3.3 
ORIENTATION 
Subjects will be asked to come back to the UCSF Tobacco Research Center for 
an Orientation Visit at least 48 hours before Study Day 1. This visit will take 
approximately 30 - 45 minutes. The following will happen during the Orientation 
Visit: 
• 
A urine sample will be collected and saved. 
• 
Participants will be asked to not use marijuana or marijuana-containing 
products for 12-hours prior to each study visit. 
• 
Participants will be asked to not use tobacco cigarettes or nicotine- 
containing products for 12-hours prior to each study visit. 
• 
Participants will be asked to not use any recreational drugs from that point 
until the study is completed. 
• 
Study procedures will be reviewed with the participants, who will do 
practice sessions of outpatient questionnaires and gas trap procedure. 

Page 21 of 30 
 
3.4 
PHARMACOKINETIC STUDY: Outpatient Visits 
 
3.4.2 Protocol for Outpatient Study 
3.4.1(a) Marijuana preparation 
Cannabis leaf material (11.7% THC) obtained from NIDA will be stored frozen in a 
locked room in the Zuckerberg San Francisco General Hospital Pharmacy. When a 
participant is randomized, the pharmacy will dispense of 250 mg of cannabis (this 
includes a back-up supply of 125 mg). All cannabis will then be stored in the freezer 
compartment of the medication refrigerator in the medication room of the Clinical 
Research Services Ward 5B. 
 
Cannabis material to be used by a study participant will be humidified 24-36 hours 
before use. Using a petri dish placed at the bottom of the desiccator, 2 centrifuge tubes, 
each filled with sodium chloride solution, will be emptied into the dish. Cannabis 
cigarettes will be placed on the desiccator platform and maintained at room temperature 
overnight, which is expected to raise the moisture of the cannabis cigarettes by 3 to 5%. 
Cannabis material will be used within one hour after removal from the humidifier. 
 
3.4.1(b) Hospital Admission Protocol 
 
Before arrival to the hospital, the study co-I or CRC will meet the participant to 
collect a urine sample for drug testing. Only when it is confirmed that the 
participant is negative for all drugs other than cannabis, will we admit him/her on 
the research ward. 
 
Upon arrival at the research ward, the following procedures will occur: 
1. Nurses will ask the participant when they last smoked, vaped, or used 
THC. 
 If the participant smoked cigarettes or vaped e-cigarettes after 10pm 
the night before either admission, they will be dismissed from the 
study. 
2. An expired CO test will be administered. If their CO reading is greater 
than or equal to 5 ppm, they will either be dismissed from the study or 
procedures will be delayed depending on PI discretion. 
3. A pregnancy test will be administered to female participants. If the 
pregnancy test is positive, they will be dismissed from the study. 
4. If the participant is female, the pregnancy test will also serve as the voided 
urine. If the participant is male, they will provide urine sample for discard. 

Page 22 of 30 
 
 
3.4.1 (c) Outpatient Study Protocol 
Samples Time 
Activity 
STUDY DAY 1 (same procedures as Study Days 2 & 3) 
 
 
 
 
 
 
~7 AM 
• 
Nurses will measure and record the room temperature. 
• 
Subject arrives at about 7 AM 
• 
Nurses will ask the participant when they last smoked, vaped 
and used marijuana 
• 
Expired CO measured: If <5 ppm, then admit; if ≥ 5 ppm, then 
dismiss 
• 
Urine pregnancy test and drug toxicology test (if applicable), 
positive result then dismiss (if female this can the voided urine) 
• 
If male, participant voids urine, the discards 
• 
Subject’s personal e-cigarette and other tobacco products are 
taken away at admission 
• 
No product until 8:30 AM 
 
 
~7:30 
• 
Participant rests and eats a light breakfast, may drink 
decaffeinated coffee or tea 
• 
Liquids (water) will be given in preparation for urine sample 
 
 
 
Pre-STANDARDIZED Cannabis Vaping (pre-SVC) 
 
 
US#1 
(Urine 
sample) 
 
 
PAX device filled with 125 mg of grounded cannabis leaf 
containing about 12% THC by the study team and weighed 
using microbalance 
NOTE: The order of the first condition will not be the same 
between subjects. The order here is shown for the first 
participant. 
BS#1 
(blood 
sample) 
 
 
~8:20 
• 
After resting (before IV catheter insertion), baseline urine 
sample will be collected 
• 
IV placed (plastic catheter in vein of forearm) 
 
  
Baseline Questionnaire Packet # 1, after IV placement  
• 
Weigh PAX device containing cannabis before vaping 
• 
BLOOD sample #1 (Pre-EC1) collected before standardized 
session 
• 
BLOOD sample, catecholamines 
• 
Blood sample should be taken just before first standardized 
session; ~8:20 AM 
 
 
BASELINE Heart Rate, by pulse oximeter, baseline skin 
temperature, baseline core body temperature 
 

Page 23 of 30 
 
 
 
 
SCV 
 
 
 
~8:40- 
8:45 
C STANDARDIZED SESSION (Standardized Cannabis Vaping) 
-One (1) 5 second puff every 45 seconds for a maximum of 3 
puffs with each puff followed by a 10 second breath hold. 
 
• 
PAX will be turned on and allowed to pre-heat at temperature 
setting #2, which heats at about 193 °C. 
• 
Subjects will be voice-prompted (taped or in-person by CRC) 
• 
Gas trap procedures will be conducted (See Section 3.5.2) 
• 
The PAX device will be collected for weighing. 
2-min 
BS#2 
 
~8:47 
2-MIN Post-SCV; Blood Sample #2 
 
• 
BLOOD sample #2 collected after the SCV session 
• 
Heart Rate 
 
 
 
5-min 
BS#3 
 
 
 
~8:50 
5-MIN POST-SCV; Blood Sample #3 and Questionnaire 
Packet #2 
• 
BLOOD sample #3 (5-min after last puff) 
• 
BLOOD sample, catecholamines 
• 
5-min HEART RATE, 5-min SKIN TEMPERATURE TEST, Core 
body temperature 
• 
Questionnaire packet between 5-min and 15-min blood sample. 
CRC will administer. 
 
~8:55 
 10-min HEART RATE 
 
• 
Questionnaire packet #3 
 
15-min 
BS#4 
 
 
~9:00 
15-MIN POST-SCV; Blood Sample #4 
 
• 
BLOOD sample #4 (15-min after last puff) 
• 
15-min HEART RATE, 15-min SKIN TEMPERATURE TEST, 
Core body temperature 
• 
Questionnaire packet #4 
 
~9:05 
20-min HEART RATE 
 
• 
Questionnaire packet #5 
 
~9:10 
25-min HEART RATE 
 
• 
Questionnaire packet #6 
30-min 
BS#5 
 
~9:15 
30-MIN POST-SCV; Blood Sample #5 
 
• 
BLOOD sample #5 (30-min after last puff) 
• 
30-min HEART RATE, 30-min SKIN TEMPERATURE TEST, 
Core body temperature 
45-min 
BS#6 
~9:30 
45-MIN POST-SCV; Blood Sample #6 
 
• 
BLOOD sample #6 (45-min after last puff) 
55-min 
~9:40 
• 
Questionnaire packet #7 
 
~9:45 
60-MIN POST-SCV; Blood Sample #7 
 
 

Page 24 of 30 
 
1-h 
BS#7 
 
• 
BLOOD sample #7 (1-h after last puff) 
• 
1-h HEART RATE, 1-h SKIN TEMPERATURE TEST, Core 
body temperature 
85-min 
~10:00 • 
Questionnaire packet #8 
90-min 
BS#8 
~10:15  90-min POST-SCV; Blood Sample #8 
 
• 
BLOOD sample #8 (90-min after last puff) 
• 
90-min HEART RATE, 90-min SKIN TEMPERATURE TEST, 
Core body temperature 
 
2-h 
BS#9 
 
~10:45 
120-MIN POST-SCV; Blood Sample #9 
 
• 
BLOOD sample #9 (120 min after last puff from THC1) 
• 
2-h HEART RATE, 2-h SKIN TEMPERATURE TEST, Core 
body temperature 
 
 
3-h 
BS#1 
0 
 
 
~11:45 
180-MIN POST-SCV; Blood Sample #10 
 
• 
BLOOD sample #10 (180 min after last puff) 
• 
3-h HEART RATE, 3-h SKIN TEMPERATURE TEST, Core 
body temperature 
• 
Light lunch at noon 
 
 
6-h 
BS#1 
1 
 
 
~14:45 
360-MIN POST-SCV; Blood Sample #11 and Questionnaire 
Packet #4 
 
• 
BLOOD sample #11 (2 h after last puff) 
• 
6-h HEART RATE, 6-h SKIN TEMPERATURE TEST, Core 
body temperature 
• 
Nurses will administer Questionnaire Packet #9 
6-h 
US#2 
~14:55 
6-h URINE SAMPLE (6-h post SVC) 
 
End of Study Day 1 
Collect all of subjects’ products. 
Before each discharge, participants will be evaluated by the study physician and 
administered the Drug Effects Questionnaire. Participants who drive to the 
research ward, must report a zero “0” on the VAS of drug effects before discharge. 
If participants took public transportation to the hospital, they must score a 50 or 
less on the VAS of drug effects. 
Discharge with the following instructions: 
1. Abstain from smoking marijuana or using marijuana products 12 hours prior to your 
next admission. 
2. Abstain from tobacco products and any nicotine products 12 hours prior to your 
next admission. 
3. Arrive at hospital at 7:00 AM on scheduled second visit. 

Page 25 of 30 
 
Repeat all procedures above for Study Day 2 with the alternate product “T” (tobacco 
containing nicotine) and the following standardized vaping: One (1) 5 second puff every 
45 seconds for a maximum of 3 puffs with each puff followed by a 10 second breath 
hold. PAX will be filled with 125 mg of tobacco from American Spirit Blue cigarettes. 
Repeat all procedures above for Study Day 3 with the alternate product “C+T” (125 mg of 
cannabis leaf + 125 mg of tobacco containing nicotine from American Spirit Blue 
cigarettes) and the following standardized vaping: One (1) 5 second puff every 45 
seconds for a maximum of 3 puffs with each puff followed by a 10-second breath 
hold. 
Abbreviations: BS = blood sample; C=cannabis leaf; SCV=standardized cannabis 
vaping 
UX = Urine sample at screening visit, U0=Urine sample at orientation, US=Urine sample 
 
3.4.2 Protocol for gas trap 
1) Install a new 47 mm EPM 2000 Whatman filter into the filter cassette. 
2) Insert a new clean mouthpiece in the inlet of the filter cassette 
3) Connect the filter to the pump and adjust the flow rate through the filter to 10-15 
LPM. 
4) Have the subject exhale into the mouthpiece with the vacuum pump on. 
5) After the 3-puffs, remove the filter to a silanized 16X125 mm glass extraction 
tube. 
6) Transport the container to the Clinical Pharmacology Lab Room 105. 
 
3.4.3 Timing of Blood Collection 
Blood 
Spec 
# 
 
Event 
Time 
of 
day 
Nic/Cot 
[6 ml] 
THC 
[6 
ml] 
Catecholamines 
[6 ml] 
Total 
VOLUME 
drawn 
 
Notes 
STUDY DAYS  1, 2 & 3 
B1 
Pre- 
SVC 
8:20 
6 
6 
6 
18 
6ml green 
top 
Hemogard 
tube for all 
B2 
2-min 
post 
SVC 
8:47 
6 
6 
 
12 
 
B3 
5-min 
post 
SVC 
 
8:50 
6 
6 
6 
18 
 

Page 26 of 30 
 
B4 
15-min 
post 
SVC 
9:00 
6 
6 
 
12 
 
B5 
30-min 
post 
SVC 
9:15 
6 
6 
 
12 
 
B6 
45-min 
post 
SVC 
9:30 
6 
6 
 
12 
 
B7 
60-min 
post 
SVC 
9:45 
6 
6 
 
12 
 
B8 
90-min 
post 
SVC 
10:15 
6 
6 
 
12 
 
B9 
120- 
min 
post 
SVC 
10:45 
6 
6 
 
12 
 
B10 
180- 
min 
post 
SVC 
11:45 
6 
6 
 
12 
 
B11 
360- 
min 
post 
SVC 
14:45 
6 
6 
 
12 
 
 
 
3.4.4 Timing of Saliva Collection 
Saliva 
Spec 
# 
 
Event 
Time 
of 
day 
 
COT 
 
Notes 
S-0 
Screening visit 
N/A 
5 mL collected 
Cotinine testing 
 
 
3.4.5 Timing of Urine Collection 
Urine 
Spec 
# 
 
Event 
Time 
of 
day 
Total 
VOLUME 
Collected (mL) 
 
Notes 

Page 27 of 30 
 
UX 
Screening visit 
N/A 
~50 
Toxicology and pregnancy 
test; remaining discarded 
U0 
Orientation 
N/A 
~50 
Baseline urine sample 
collected 
U1, 
U3 & 
U5 
Pre-EC1 loading 
7:00 
~50 
Days 1, 2 & 3 
U2, 
U4 & 
U6 
Post 6-h THC1 
loading 
 
14:55 
 
~50 
 
Days 1, 2 & 3 
 
3.4.6 Sample Assays 
• 
Plasma: nicotine, cotinine, 3-Hydroxicotinine (3HC) 
• 
Urine: total nicotine metabolites (nicotine equivalents), NNAL, catecholamines, 
mercapturic acid, biomarkers of acrolein and propylene oxide, and other volatile 
organic compounds (VOCs). 
 
4. 5B PAPERWORK AND PREPARATION FOR OUTPATIENT STUDY 
• 
Admission Request Form 
o Use the current template for this form 
o Participant, date of admission (night before) 
o Address/phone number/DOB/SSN 
o Sent via PHI secure email (This is done after confirmation of the hospital 
and participant that this is the correct date) (Re-submit with updated 
date as needed) 
• 
Coversheet 
o Use the current template for this form 
o Participant name and study ID on top as 
a label. 
o Edit date of admission and date of drop- 
off 
o General info about the study prepped on a per patient basis during 
admission 
• 
Flow Sheet (one long continuous document) 
o Template existing & Study Staff and 5B review this at study initiation 
o Update this with e-cig brands/liquid info 
o Explain on the flow sheet the hospital will put PHI on this, we copy 
without PHI and file 
• 
Outpatient Form 
o Make copy to 5B and we have the original in our chart 
• MD Orders 

Page 28 of 30 
 
o Pre-signed 
o Name on the top corner and name/date IN PENCIL 
• Admit PE 
o Name IN PENCIL at the top 
o Fill out by Sara/Delia at the time of the visit 
• Adverse Event Form 
o Initialed if none occurred 
• Setup 
o Should be done within 3 days before the admission and given to 5B within 
a day of the admission if possible. 
o Documents should be given to 5B in the order above 
o Paper clipped and given to them 
o 5B will make/use labels 
o Questionnaire Packet, organized and clipped by day 
o Consent form (there will be 3 signed at screening). The original for 5B 
will go in the set-up. 
 
• At completion, CRC will copy de-identified: 
o 
Flowsheet 
o 
MD Orders 
o 
Admit PE 
o 
Discharge Sheet 
o 
AE Form (we take the original) 
 
 
5 
ADVERSE EVENTS & PROTOCOL DEVIATIONS 
 
5.1 SAFETY MONITORING 
During the outpatient stay, subjects will be monitored by the Clinical Research 
Coordinator and 5B staff who will directly contact the study physician in case of 
any subsequent adverse events. If the subjects experience serious adverse 
effects, the research staff will evaluate this with them and decide if they should be 
withdrawn from this study. 
 
5.2 DEFINITION OF ADVERSE EVENTS 
 
5.2.1 Adverse Event 
An adverse event (also known as an adverse experience) is defined as any 
untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. More specifically, an adverse event can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 

Page 29 of 30 
 
symptom, or disease temporally associated with the use of a drug, without any 
judgment about causality. An adverse event can arise from any use of the drug 
(e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
5.2.2 Adverse Reaction 
An adverse reaction is defined as any adverse event caused by the use of a 
drug. Adverse reactions are a subset of all suspected adverse reactions for 
which there is reason to conclude that the drug caused the event. 
5.2.3 Suspected Adverse Reaction 
A suspected adverse reaction is defined as any adverse event for which there is 
a reasonable possibility that the drug caused the adverse event. For the 
purposes of IND safety reporting, “reasonable possibility” indicates that there is 
evidence to suggest a causal relationship between the drug and the adverse 
event. A suspected adverse reaction implies a lesser degree of certainty about 
causality than an adverse reaction. 
 
5.2.4 Unexpected Adverse Reaction 
An adverse event or suspected adverse reaction is considered unexpected if it is 
not listed in the investigator brochure or package insert(s), or listed in the consent 
form, or is not listed at the specificity or severity that has been observed, or, if an 
investigator brochure is not required or available, is not consistent with the risk 
information described in the general investigational plan or elsewhere in the 
current application. 
“Unexpected,” as used in this definition, also refers to adverse events or 
suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
Adverse events that would be anticipated to occur as part of the disease process 
are considered unexpected for the purposes of reporting because they would not 
be listed in the investigator brochure. For example, a certain number of non-acute 
deaths in a cancer trial would be anticipated as an outcome of the underlying 
disease, but such deaths would generally not be listed as a suspected adverse 
reaction in the investigator brochure. 

Page 30 of 30 
 
5.2.5 Serious Adverse Reaction 
An adverse event or suspected adverse reaction is considered serious if, in the 
view of either the investigator or sponsor, it results in any of the following 
outcomes: 
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life function 
• 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
5.2.6 Life‐threatening Adverse Events 
An adverse event or suspected adverse reaction is considered life-threatening if, 
in the view of either the investigator or sponsor, its occurrence places the patient 
or subject at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
 
5.3 REPORTING ADVERSE EVENTS 
Reporting of serious adverse events will follow the current requirements of the 
Committee on Human Research (CHR). Specifically, the following will be reported 
within five (5) working days of the PI’s awareness, in writing: 
 All serious adverse events associated with the study procedures and/or 
 Any incidents or problems involving the conduct of the study or patient 
participation, including problems with the recruitment and/or consent 
process. The Principal Investigator will provide a discussion of such 
events to the CHR on an annual basis during study renewal. 
 Any incidents or questionable adverse events are discussed at the weekly 
staff meetings with the PI. 

Page 31 of 30 
 
The standard adverse event grading scale will be used to report any potential 
adverse advents from phlebotomy, study drug, or other study procedures: 
 1. Mild AE: did not require treatment 
 2. Moderate AE: resolved with treatment 
 3. Severe AE: resulted in inability to carryon normal activities and required 
profession medical attention 
 4. Life-threatening or disabling AE 
 5. Fatal AE 
 
The supervising study physician will be notified of all grades 2 through 5 AEs. 
Additionally, Dr. Benowitz will be notified of all grades 4 and 5 AEs. 
 
5.4 PROTOCOL DEVIATIONS AND VIOLATIONS 
Protocol deviations are defined as an event that deviates from the defined study 
protocol, but does not pose any risk to the participant or harm to the quality of the 
study data. For example, a follow-up call may be conducted outside of the 
stipulated window, or a section of questions on a questionnaire may be missed 
due to a mistake in branching. Deviations will be recorded on a protocol deviation 
sheet and reviewed and signed by the PI. 
 
Protocol violations are events that deviate from the defined study protocol, but 
put the participant at risk and/or cause harm to the study data. For example, if a 
participant was enrolled in the study but they were under the age of 12 or they 
were enrolled without consent of a parent. Protocol violations will be recorded on 
a protocol violation sheet, reviewed and signed by the PI and reported to the 
CHR. 
 
6 
DATA COLLECTION AND MANAGEMENT 
 
6.1 DATA COLLECTION FORMS 
Data Collection Forms entered by participants include: 
1. Screening packet, except Physiological Assessment Form 
2. REDCap Questionnaire 
3. Research Ward Outpatient Questionnaire Packets 1-10 
 
Data Collection Forms entered by Research Staff: 
1. Physiological Assessment Form of the Screening Packet 
2. Outpatient Product Weight Record 

Page 32 of 30 
 
6.2 DATA ENTRY, STORAGE, AND ANALYSIS 
 
A folder “XXXX ECig THC” on the shared drive utilized by the Clinical 
Pharmacology Lab will be used to store electronic data from this study (where 
XXXX is the CTSI-CRS study number). 
All databases are password protected with the following: XXXXTHC 
1. Information collected from messages in the REDCap questionnaires will be 
entered by CRC in the Call Log database 
2. A record of participants screened and/or enrolled is kept by CRC using the 
Participant Log 
3. Personal data and Demographic data from the Screening Packet are entered 
by the CRC in the Personal Data & Demographics database 
4. Information entered by the participant on the Screening Packet are entered in 
the Screening Database by the CRC 
5. Data collected during the outpatient days, except questionnaire data, are 
entered by CRC in Outpatient Measures 
6. Questionnaire data from the Inpatient days are entered by the CRC in 
Outpatient Questionnaires 
 
6.3 DATA ANALYSIS 
The study is not hypothesis-driven but will provide valuable data to guide future 
research as well as provide needed data on THC delivery and effects from vaping. 
Variables of interest include amount of THC inhaled, amount exhaled, and amount 
retained; pharmacokinetic parameters for THC, 11-OH-THC, and nicotine, the 
psychoactive compounds; heart rate and blood pressure change; and subjective 
effects. 
Delivered and Retained Doses: Delivered THC and nicotine doses are estimated 
as the change in e-cigarette weight × concentration of THC or nicotine in e-liquid. 
The amount of THC or nicotine systemically retained is estimated as delivered 
dose minus amount in gas traps. 
THC, 11-OH-THC, and Nicotine Pharmacokinetics: Pharmacokinetic parameters 
will be estimated from blood THC and 11-OH-THC and plasma nicotine 
concentrations using Phoenix WinNonlin 6.3 (Pharsight Corporation, Mountain 
View, CA). Time to max concentration (Tmax), max concentration (Cmax), and area 
under the blood/plasma concentration-time curves (AUC) will be estimated using a 
non-compartmental model and trapezoidal rule. Cmax, and AUC0∞ will be adjusted 
for baseline nicotine levels. 
Averages and 95% confidence intervals will be computed by e-liquid type (THC 
only or 

Page 33 of 30 
 
THC+nicotine). Although this study is not hypothesis-driven, we will use mixed 
model analysis of variance (ANOVA) to assess differences in these variables 
between e-liquids type. Models will include sex as a covariate. 
 
 
7 
DUTIES AND RESPONSIBILITIES OF STAFF 
 
7.1 PRINCIPAL INVESTIGATOR 
The Principal Investigator is responsible for study design and oversight of 
implementation, data analysis, and manuscript preparation. 
 
7.2 
Study Doctor 
The Study Doctor will hold privileges at the CTSI Ward 5B, and will be on call for any 
serious events that may occur with study participants. They will also be a resource for 
reviewing medical history, medications, eligibility, or any questions that may pertain to 
participant eligibility and safety. In some cases the Study Doctor role may be filled by the 
Study Principal Investigator, Dr. Neal Benowitz. 
 
7.2 CO‐INVESTIGATORS 
The co-principal investigators are responsible for study design and oversight of 
implementation, data analysis, and manuscript preparation, with the assistance of 
the Principal Investigator. 
 
7.3 PROJECT MANAGER 
The Project Manager is responsible for overall functioning of study coordination 
with CHR protocols; monitoring of study budget and coordination with 
departmental administrative personnel; supervision of research associates; 
management of clinic facilities. 
 
7.4 CLINICAL RESEARCH COORDINATOR 
The CRC will oversee study logistics including logging specimens, chart reviews, 
protocol review, consenting, Screening Visit procedures, scheduling, and 
orientation procedures. 
 
8 
STUDY MANAGEMENT 
 
8.1 PRE‐STUDY DOCUMENTATION 
This study will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); 
consistent with good clinical practice and all applicable regulatory requirements. 

Page 34 of 30 
 
Before initiating this trial, the Investigator will have written and dated approval from 
the Institutional Review Board for the protocol, written informed consent form, 
subject recruitment materials, and any other written information to be provided to 
subjects before any protocol related procedures are performed on any subjects. 
The clinical investigation will not begin until all approvals have been secured. 
 
8.2 INSTITUTIONAL REVIEW BOARD APPROVAL 
The protocol, the proposed informed consent form, and all forms of participant 
information related to the study (e.g. advertisements used to recruit participants) 
will be reviewed and approved by the UCSF CHR (UCSF Institutional Review 
Board). The initial protocol and all protocol amendments must be approved by the 
IRB prior to implementation. 
 
 
8.3 INFORMED CONSENT 
All participants must be provided a consent form describing the study with 
sufficient information for each participant to make an informed decision regarding 
their participation. 
 
 
8.4 CHANGES IN PROTOCOL 
Once the protocol has been approved by the UCSF IRB, any changes to the 
protocol must be documented in the form of an amendment. The amendment must 
be signed by the Investigator and approved by the CHR prior to implementation. 
 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to 
patients, an amendment may be implemented prior to IRB approval. In this 
circumstance, however, the Investigator must then notify the IRB in writing within 
five (5) working days after implementation. 
 
9 PROTECTION OF HUMAN SUBJECTS 
 
9.1 PROTECTION AGAINST RISKS 
All subjects will be under close medical supervision of the CRS staff and study 
doctor. Furthermore, all study procedures will be subject to the approval of UCSF 
IRB. Patient confidentiality will be maintained as carefully as possible. 
Authorization for disclosure of protected health information for research purposes 
will be required in accordance with HIPPA regulations. Patients will be informed 
that all efforts will be made to keep personal information confidential, however, 
absolute confidentiality cannot be guaranteed. Patients will be informed that their 

Page 35 of 30 
 
protected health information may be disclosed if required by law. All of this will be 
presented in the informed consent document and authorization for disclosure form. 
 
 
10 REFERENCES 
 
1. King BA, Patel R, Nguyen K, Dube SR. Trends in awareness and use of 
electronic cigarettes among US adults, 2010-2013. Nicotine Tob Res. 
2015;17(2):219-27. doi: 10.1093/ntr/ntu191. 
2. Arrazola RA, Singh T, Corey CG, Husten CG, Neff LJ, Apelberg BJ, et al. 
Tobacco use among middle and high school students—United States, 2011- 
2014. MMWR. 2015;64(14):381-5. 
3. St.Helen G, Havel C, Dempsey D, Jacob P, 3rd, Benowitz NL. Nicotine delivery, 
retention, and pharmacokinetics from various electronic cigarettes. Addiction. 
2016;111(3):535-44. Epub 2015/10/03. doi: 10.1111/add.13183. PubMed PMID: 
26430813; PubMed Central PMCID: PMC4047652. 
4. St.Helen G, Ross K, Dempsey D, Havel C, Jacob 3rd P, Benowitz N. Nicotine 
delivery and vaping behavior during ad libitum e-cigarette access. Tobacco 
Regulatory Science. 2016;2(3):363-76. 
5. Center for Behavioral Health Statistics and Quality. Behavioral health trends in 
the United States: Results from the 2014 National Survey on Drug Use and 
Health. NSDUH; 2015. 
6. Schauer GL, King BA, Bunnell RE, Promoff G, McAfee TA. Toking, vaping, and 
eating for health or fun: Marijuana use patterns in adults, US, 2014. Am J Prev 
Med. 2016;50(1):1-8. 
7. Morean ME, Kong G, Camenga DR, Cavallo DA, Krishnan-Sarin S. High school 
students’ use of electronic cigarettes to vaporize cannabis. Pediatrics. 
2015;136(4):611-6.Schauer GL, Berg CJ, Kegler MC, Donovan DM, Windle M. 
Differences in tobacco product use among past month adult marijuana users and 
nonusers: findings from the 2003–2012 National Survey on Drug Use and 
Health. Nicotine Tob Res. 2015:ntv093. 
8. Akre C, Michaud PA, Berchtold A, Suris JC. Cannabis and tobacco use: Where 
are the boundaries? A qualitative study on cannabis consumption modes among 
adolescents, Health Education Research , 2010, vol. 25 (pg. 74-82) 
9. Amos A, Wiltshire S, Bostock Y, Haw S, McNeill A. ‘You can’t go without a 
fag…you need it for your hash’—A qualitative exploration of smoking, cannabis 
and young people, Addiction , 2004, vol. 99 (pg. 77-81) 
 
 
 
 
 

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APPENDIX A: DATABASE GUIDE 
 
Screening Visit  
1. Screening Log 
The Screening Log is a list of all participants who came into the 20th street Tobacco Research 
Center or ZSFG location for a screening visit for the V-PAX study.  This log details 
information about each participant as well as the outcome of the visit.  Specifically, the 
Screening Log contains the following information: participant’s name, date of screening 
visit, RedCap ID from the RedCap pre-screening email survey, study ID number, toxicology 
and pregnancy screening results, eligibility status and reason, ethnicity, race, sex, 5B 
status (including whether or not the participant was a no-show)and 5B start and end 
date. 
 Location: t-Drive 
 Folder: 7845 V-PAX 
 Sub-folder 1: Databases 
 Subfolder 2: Logs 
 name: V-PAX Screening Log 
 Password: 7845THC 
2. Saliva Cotinine Screening Log 
The Saliva Screening Log is a list of the cotinine values for participants who came in for a V-
PAX screening visit.   
 Location: s-Drive 
 Folder: Clinical Research 
 Sub-folder 1: Screening Log  
 Subfolder 2: 7845 V-PAX 
 name “7845 V-PAX Saliva Cotinine Screening Log”  
3. Eligible Participant’s Log (only participants deemed eligible at screening) 
The Eligible Participant’s Log is a list of all participants deemed eligible to participate in the 
Crossover study after their screening visit.  This log contains the following information: 
participant’s name, study ID, product assignment number, starting product, MRN number, 
5B admission and discharge date, and notes regarding withdrawals, no-shows and early 
discharges.   Overall, we had 54 eligible participants, and 36 completed participants. 
 Location: t-Drive 
 Folder: 7845 V-PAX 
 Sub-folder 1: Databases 
 Subfolder 2: Logs 
 name: V-PAX Screening Log 
 Password: 7845THC 
 
 
 
 
 

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4. V-PAX Database 
The data collected at the screening visit is located on RedCap under the project titled V-PAX Study Database.  
This project includes the following forms: Participant Summary Form, Screening Eligibility Checklist, 
demographic information, Physiological Assessment, protocol violation, con meds, and adverse events. 
Location: https://redcap.ucsf.edu/redcap_v9.1.13/index.php?pid=21357  
 
5. V-PAX study participant survey Database 
The data collected at the screening visit and study visits 1-3 is located on RedCap under the project titled 
V-PAX study participant survey Database.  This project includes the following forms: demographic 
information, screening packet, SDS, THC Use history questionnaire, NDSS, PS-ECDI, E-WISDOM, E-FTND, 
CES-D, MNWS, M-CES, PANAS, DEQ-5, MCQ-SF, M-SCALE, VAS. 
 
 Location: https://redcap.ucsf.edu/redcap_v9.1.13/index.php?pid=24277  
 
1. Crossover Specimen Log 
The Crossover Specimen Log is a file is a database used to track all of the specimens collected 
during participants’ orientation visit and inpatient study days.  This log contains the 
following information: specimen type, dates and times of specimen collection, date of lab 
sample transfers, and volume/pH of urine specimens. 
a. Location: t-Drive 
b. Folder: 7845 V-PAX 
c. Sub-folder 1: Databases 
d. Subfolder 2: Logs 
e. name: 7845-V-PAX specimen Log 
 
2. Urine Catecholamine Summary 
The plasma Catecholamine Summary contains the catecholamine data from participants 
7845-002-7845-018, including: norepinephrine, epinephrine, and dopamine per volume. 
 Location: t-Drive 
 Location: t-Drive 
 Folder: 7845 V-PAX 
 Sub-folder 1: Databases 
 Subfolder 2: Logs 
 name: 7845-V-PAX specimen Log 
 Information is downloaded from ARUP Labs via email from program manager