The Effects of Sedatives on Tobacco Use Disorder
Phase: PHASE1
Conditions: Tobacco Use Disorder
Sponsor: Wake Forest University Health Sciences

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
 
Clinical Study Protocol 
 
Study Title: 
The effects of sedatives on tobacco use disorder (SED-TUD) 
Protocol Number: 
229077 
NCT Number: 
NCT03813121 
 
Principal Investigator:  
Merideth Addicott PhD 
University of Arkansas for Medical Sciences 
Psychiatry Department 
Telephone: 501-526-2436 
maddicott@uams.edu 
 
Investigator:  
 
Alison Oliveto, PhD 
University of Arkansas for Medical Sciences 
Psychiatry Department 
OlivetoAlison@uams.edu 
 
Study Physician: 
 
Riley Lide, MD 
 
 
 
 
University of Arkansas for Medical Sciences 
Department of Anesthesiology 
 
 
 
 
rlide@uams.edu 
 
Study Coordinator:   
Deborah Hodges 
University of Arkansas for Medical Sciences 
Psychiatry Department 
Telephone: 501-526-8462 
Dhodges@uams.edu 
 
Study location: 
Psychiatry Research Institute  
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 843 
Little Rock, AR 72205 
 
Sponsor: 
University of Arkansas for Medical Sciences 
4301 W. Markham St,  
Little Rock, AR 72205 
 
 
 
 
 
 
 
 
 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
 
 
Table of Contents 
STATEMENT OF COMPLIANCE ........................................................................................................... 1 
1  
PROTOCOL SUMMARY ............................................................................................................... 2 
 1.1  
 
Synopsis ...................................................................................................................... 2 
 1.2 
 
Schema ....................................................................................................................... 4 
 1.3 
 
Schedule of Activities ................................................................................................. 4 
2  
INTRODUCTION .......................................................................................................................... 5 
 2.1 
 
Study Rationale ........................................................................................................... 5 
 2.2 
 
Background ................................................................................................................. 5 
 2.3 
 
Risk/Benefit Assessment ............................................................................................ 6 
  
2.3.1 
 
Known Potential Risks ........................................................................................ 6 
  
2.3.2 
 
Known Potential Benefits ................................................................................... 7 
  
2.3.3 
 
Assessment of Potential Risks and Benefits ....................................................... 7 
3  
OBJECTIVES AND ENDPOINTS ...................................................................................................10 
4  
STUDY DESIGN ..........................................................................................................................10 
 4.1 
 
Overall Design ...........................................................................................................10 
 4.2 
 
Scientific Rationale for Study Design ........................................................................10 
 4.3 
 
Justification for Dose ................................................................................................10 
 4.4 
 
End of Study Definition .............................................................................................10 
5  
STUDY POPLATION ...................................................................................................................11 
 5.1 
 
Inclusion Criteria .......................................................................................................11 
 5.2 
 
Exclusion Criteria ......................................................................................................11 
 5.3 
 
Lifestyle Considerations ...........................................................................................11 
 5.4 
 
Screen Failures .........................................................................................................11 
 5.5 
 
Strategies for Recruitment and Retention ...............................................................12 
6  
STUDY INTERVENTION .............................................................................................................12 
 6.1 
 
Study Intervention(s) Administration .......................................................................12 
  
6.1.1 
 
Study Intervention Description.........................................................................12 
  
6.1.2 
 
Dose and Administration ..................................................................................12 
 6.2 
 
Preparation/Handling/Storage/Accountability ........................................................12 
  
6.2.1 
 
Acquisition and Accountability .........................................................................12 
  
6.2.2 
 
Appearance, Packaging, and Labeling ..............................................................12 
  
6.2.3 
 
Product Storage and Stability ...........................................................................12 
  
6.2.4 
 
Preparation .......................................................................................................13 
 6.3 
 
Measures to Minimize Bias: Randomization and Blinding .......................................13 
 6.4 
 
Study Intervention Compliance ................................................................................13 
 6.5 
 
Concomitant Therapy ...............................................................................................13 
7  
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
  
DISCONTINUATION/WITHDRAWAL .........................................................................................13 
 7.1 
 
Discontinuation of Study Intervention .....................................................................13 
 7.2 
 
Participant Discontinuation/Withdrawal from the Study ........................................13 
 7.3 
 
Study Retention and Lost of Follow-Up ....................................................................13 
8  
STUDY ASSESSMENT AND PROCEDURES..................................................................................13 
 8.1 
 
Efficacy Assessments ................................................................................................13 
 8.2 
 
Safety Assessments ..................................................................................................16 
 8.3 
 
Adverse Events and Serious Adverse Events ............................................................16

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
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8.3.1 
 
Definition of an Adverse Events .......................................................................16 
  
8.3.2 
 
Definition of a Serious Adverse Event ..............................................................16 
  
8.3.3 
 
Classification of an Adverse Event ....................................................................17 
  
8.3.4 
 
Time Period and Frequency for Event Assessment and Follow-Up ..................18 
  
8.3.5 
 
Adverse Event Reporting ..................................................................................18 
  
8.3.6 
 
Serious Adverse Event Reporting .....................................................................19 
  
8.3.7 
 
Reporting Events to Participants ......................................................................19 
  
8.3.8 
 
Events of Special Interest .................................................................................19 
  
8.3.9 
 
Reporting of Pregnancy ....................................................................................19 
 8.4 
 
Unanticipated Problems ...........................................................................................19 
  
8.4.1 
 
Definition of Unanticipated Problems ..............................................................20 
  
8.4.2 
 
Unanticipated Problem Reporting ....................................................................20 
  
8.4.3 
 
Reporting Unanticipated Problems to Participants ..........................................20 
9  
 
STATISTICAL CONSIDERATIONS ........................................................................................20 
 9.1 
 
Statistical Hypotheses ..............................................................................................20 
 9.2 
 
Sample Size Determination ......................................................................................20 
 9.3 
 
Populations for Analyses ..........................................................................................20 
 9.4 
 
Statistical Analyses ...................................................................................................21 
  
9.4.1 
 
General Approach .............................................................................................20 
  
9.4.2 
 
Analysis of the Primary Efficacy Endpoint(s) ....................................................21 
  
9.4.3 
 
Analysis of the Secondary Endpoint(s) .............................................................21 
  
9.4.5 
 
Baseline Description Statistics ..........................................................................21 
  
9.4.6 
 
Planned Interim Analyses .................................................................................21 
  
9.4.7 
 
Sub-group Analyses ..........................................................................................21 
  
9.4.8 
 
Tabulation of Individual Participant Data .........................................................21 
  
9.4.9 
 
Exploratory Analyses ........................................................................................21 
10  
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................22 
 10.1 
 
Regulatory, Ethical, and Study Oversight Considerations ........................................22 
  
10.1.1 
 
Informed Consent Process ................................................................................22 
  
10.1.2 
 
Study Discontinuation and Closure ..................................................................22 
  
10.1.3 
 
Confidentiality and Privacy ...............................................................................23 
  
10.1.4 
 
Future Use of Stored Specimens and Data .......................................................23 
  
10.1.5 
 
Key Roles and Study Governance .....................................................................24 
  
10.1.6 
 
Safety Oversight ................................................................................................24 
  
10.1.7 
 
Clinical Monitoring............................................................................................24 
  
10.1.8 
 
Quality Assurance and Quality Control ............................................................24 
  
10.1.9 
 
Data Handling and Record Keeping ..................................................................24 
  
10.1.10  
Protocol Deviations ..........................................................................................25 
  
10.1.11  
Publication and Data Sharing Policy .................................................................25 
  
10.1.12  
Conflict of Interest Policy ..................................................................................26 
 10.2 
 
Additional Considerations ........................................................................................26 
 10.3 
 
Abbreviations ...........................................................................................................26 
 10.4 
 
Protocol Amendment History ...................................................................................27 
11  
REFERENCES .....................................................................................................................27 
 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
1 
 
 
  
 
Statement of Compliance 
The trial will be carried out in accordance with all applicable regulations (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312). All research personnel have completed 
Human Subjects Protection Training and Good Clinical Practice Training. 
  
I agree to ensure that all staff members involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
Principal Investigator 
 
 
 
Print/Type Name: ________________________________ 
 
 
  
Signed: ________________________________________ 
  
  
 
Date: __________________________________________ 
 
 
 
 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
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1 Protocol Summary 
1.1 Synopsis 
Arkansas ranks third in the nation for cigarette smoking prevalence (25% of the 
population) and ranks second for smoking-attributed cancer mortality (33.5% mortality). There is 
an urgent need to reduce smoking rates in this state. However, even with counseling and 
pharmacotherapy, >70% of smokers relapse within 12 months of a quit attempt. More effective 
interventions for tobacco addiction are sorely needed. A sub-anesthetic dose of ketamine is a 
novel pharmaceutical agent that has shown promising effects in reducing craving and/or 
withdrawal symptoms to cocaine, alcohol, and opioids. However, its effects on tobacco use 
disorder have not yet been tested.  
Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist that 
enhances synaptic plasticity in the prefrontal cortex and subcortical brain areas. Glutamatergic 
function is altered in depressed patients and a single sub-anesthetic dose of ketamine (0.5 
mg/kg) has also been shown to rapidly (within 24 hours) reduce depressive symptoms. 
Ketamine’s enhancement of synaptic plasticity may underlie ketamine’s antidepressant effects. 
Similar to depression, symptoms of substance use disorders may be related to reduced synaptic 
plasticity in the prefrontal cortex. Ketamine may be altering brain mechanisms common to both 
depression and drug use since the time course and pattern of ketamine’s effects are similar to 
both disorders. Extensive research in animal models suggests that chronic drug use and the 
diminished ability to control drug seeking arises from a dysregulation in synaptic glutamate 
transmission by non-synaptic glial glutamate (i.e., a loss of glutamate homeostasis) at synapses 
connecting the prefrontal cortex to the nucleus accumbens. Blocking the NMDA receptor, which 
plays an important role in neuroplasticity, has been shown to disrupt cue-induced drug seeking 
behavior in rats. Among individuals with cocaine use disorder, ketamine has been shown to 
decrease craving and improve motivation to quit using cocaine. In particular, non-treatment 
seeking cocaine users demonstrated decreased craving and an increased preference for money 
over cocaine in a lab-based model of cocaine use administered 28-hours post-ketamine 
infusion; subjects also had reduced ad lib cocaine use over the next several days. Ketamine has 
also been associated with higher abstinence rates among treatment-seeking detoxified heroin 
users. Thus, ketamine holds potential to disrupt craving and motivation for drug use across 
different classes of drug use disorders. Given the broad nature of ketamine’s effects in 
addiction, we hypothesize that it may prove to have effects in nicotine dependence. 
 
This proposal will obtain preliminary data on the effect of a single sub-anesthetic 
ketamine infusion on cigarette craving and smoking behavior as well as measuring its 
tolerability, and acceptability. This single-blind, placebo-controlled, randomized clinical trial will 
test 12 non-treatment seeking smokers with a single intravenous infusion of ketamine (0.5 
mg/kg) or placebo. Before and 24-hours after the infusion, smokers will undergo lab-based 
measures of cigarette craving and smoking latency and will also complete diaries of cigarettes 
smoked per day for 7 days before, and 7 days after, the infusion. Physical and subjective effects 
and adverse effects will be closely monitored throughout. Previous research suggests that 
ketamine will produce transient effects on craving and drug use behavior, with effects peaking 
24-72 hours after infusion (Dakwar et al., 2017). 
 
Aim 1. Determine the preliminary safety, tolerability, and acceptability of ketamine. 
Outcomes include physiology (pulse oximetry, vital signs), drug effects, side effects, and 
symptoms of depression. We hypothesize that relative to placebo, a ketamine infusion will be 
comparably safe, well tolerated, and acceptable to smokers. 
 
Aim 2. Determine the effects of ketamine on cigarette craving, smoking latency, and 
smoking frequency. Outcomes include urge to smoke, nicotine withdrawal symptoms, mood, 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
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latency to smoke in a smoking lapse analog task (pre- and post-infusion), and daily smoking 
frequency. We hypothesize that relative to placebo and baseline, ketamine will reduce craving, 
nicotine withdrawal, improve mood, increase the latency to smoke, and decrease the number of 
cigarettes smoked per day. 
 
This pilot study is necessary to estimate the effect size to support future, in depth R01 
research. Future research will compare ketamine to other psychoactive agents, including other 
NMDA receptor antagonists, determine optimal dosing strategies, estimate the duration of 
ketamine effects. Ultimately, this work could impact the field of tobacco addiction research by 
providing evidence of an innovative pharmacologic mechanism that promotes smoking 
cessation. 
 
Study population: Up to 20 adult male and female otherwise healthy tobacco smokers from the 
Little Rock area will sign informed consent and be assessed for eligibility to participate until 12 
(6 ketamine and 6 placebo) have been admitted and complete the study. 
 
Phase: The overarching aim of this study is to assess its feasibility as a phase I/II study. 
 
Description of sites/facilities enrolling participants: The study will be performed at the 
Psychiatric Research Institute (PRI) at the University of Arkansas for Medical Sciences (UAMS). 
PRI is a five-story, approximately 100,000 square foot state-of-the-art facility that incorporates 
inpatient and outpatient facilities, including 40 inpatient beds, research, clinical, educational and 
administrative space. It is connected to the main hospital at which emergency care can also be 
received. Two inpatient floors have 24-hr clinical coverage and research-certified nurses to 
provide back-up coverage for research protocols on the floor. The 4th floor where screening 
occurs includes two exam rooms, a nursing station and a clinical laboratory for processing 
samples and specimen storage. Medical backup is provided by the UAMS Psychiatric Research 
Institute, which has dedicated facilities for inpatient studies and the medical/psychiatric 
expertise to care for the subjects.  
Health screenings will be conducted on the 4th floor of PRI. The drug infusion session 
will be completed in one of four bays in the UAMS PRI Procedures Suite on the 6th floor of PRI. 
The PRI Procedures Suite is the location for electroconvulsive therapy treatments and ketamine 
infusions. Medical staff members have access to both a MECTA and Thymatron machines. 
Philips vital sign machines incorporated with wireless technology to sync with the patient's 
electronic medical record. With over 1,300 sq ft, the Suite has a separate waiting area for 
patients and families, a prep area with four bays, a treatment room, and a separate recovery 
area with 5 bays. The infusion room has a physiologic monitor that will capture continuous pulse 
oximetry, heart rate, and electrocardiography, and intermittent non-invasive blood pressure 
measurements. Wall mounted oxygen, suction, and equipment to deliver positive pressure 
ventilation is available at the bedside. A crash cart and additional supplies are available.  
 
Description of study intervention: This is a single-blind clinical trial and the study intervention 
(ketamine or placebo) will occur on 1 day. Participants will have previously completed eligibility 
screening. On the infusion day, they will report to the PRI, undergo pre-anesthesia physical 
evaluation, and receive a 20-minute infusion of ketamine (0.5 mg/kg) or placebo. Assessments 
of vital signs and dissociative state will be obtained every 15 min for 1 hour, then 1 hour later 
(hour 2). Self-reported drug effects, side effects, and subjective mood and tobacco withdrawal 
symptoms will be obtained at hour 2. 
 
Study Duration: The duration of the study is anticipated to be approximately 2 years. 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
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Participant Duration: The eligibility screening, study days, infusion day, and follow-up visit will 
be spread out across 4-6 weeks.  
 
1.2 Schema:  
Prior to enrollment: obtain informed consent, screen for inclusion/exclusion criteria, and physical 
exam. Eligible subjects then randomized to drug condition and complete 7-day smoking diary 
 
Study Day 1: first smoking analogue task and subjective self-report measures 
 
Study Day 2: drug infusion session and safety/tolerability assessments 
 
Study Day 3: second smoking analogue task and subjective self-report measures, complete 7-
day smoking diary 
 
Follow-up lab visit (about 8-days post infusion) 
  
1.3 Schedule of Activities:  
 
Procedures 
Screening 
(Day 1) 
1st Study visit 
(Day 8 to 14) 
2nd Study visit  
(Day 15 to 21) 
drug infusion 
3rd Study visit  
(Day 16 to 22) 
4th Study visit  
(Day 24 to 29) 
Informed Consent 
x 
 
 
 
 
Demographics 
x 
 
 
 
 
Employment history 
x 
 
 
 
 
MINI Psychiatric 
interview 
x 
 
 
 
 
Drug use history 
questionnaire 
x 
 
 
 
 
Smoking history 
questionnaire 
x 
 
 
 
 
FTND 
x 
 
 
 
 
Urinalysis 
x 
 
 
 
 
Pregnancy test 
x 
 
x 
 
 
Vitals 
x 
x 
x 
x 
x 
Serum analysis 
x 
 
 
 
 
ECG 
x 
 
 
 
 
Height 
x 
 
 
 
 
Weight 
x 
 
 
 
 
Breath CO 
x 
x 
x 
x 
x 
BrAC 
x 
x 
x 
x 
x 
7-day smoking diary 
& CESD 
x 
 
 
x 
 
QSU 
 
x 
x 
x 
 
PANAS 
 
x 
x 
x 
x 
MNWS 
 
x 
x 
x 
 
Smoking lapse 
analog task 
 
x 
 
x 
 
Drug infusion 
 
 
x 
 
 
CADSS 
 
 
x 
 
 
DEQ 
 
 
x 
 
 
SEQ 
 
 
x 
 
x 
Physiological 
monitoring 
 
 
x 
 
 
 
2 Introduction 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
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2.1 Study Rationale 
This proposal will obtain preliminary data on the feasibility, safety and tolerability of sub-
anesthetic ketamine infusion in cigarette smokers. In addition, the impact of ketamine on 
reducing the severity of withdrawal symptoms and smoking behavior will be explored. This 
innovative proposal is justified by a large body of preclinical and clinical data supporting 
ketamine's potential utility and the significance of the research is high due to the need for more 
effective interventions for tobacco use disorder. 
 
2.2 Background and Significance 
Arkansas ranks third in the nation for cigarette smoking prevalence (25% of the 
population) and ranks second for smoking-attributed cancer mortality (33.5% mortality) (Lortet-
Tieulent et al., 2016; Nguyen and Ma, 2016). There is an urgent need to reduce smoking rates 
in this state. However, even with counseling and pharmacotherapy, >70% of smokers relapse 
within 12 months of a quit attempt (Ferguson et al., 2005). More effective interventions for 
tobacco addiction are sorely needed. A sub-anesthetic dose of ketamine is a novel 
pharmaceutical agent that has shown promising effects in cocaine, alcohol, and opioid use 
disorders (Jones et al., 2018). However, its effects on tobacco use disorder have not yet been 
tested.  
Ketamine is a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist primarily 
used as an anesthetic agent. Sub-anesthetic doses of ketamine (0.5 mg/kg) have shown 
effectiveness in alleviating treatment-resistant depression in clinically depressed populations 
(Mathew et al., 2012). The antidepressant effect peaks 24-72 hours post infusion (Iadarola et 
al., 2015) and has been attributed to the modulation of glutamate signaling and the promotion of 
synaptic plasticity in the prefrontal cortex (Mathew et al., 2012; Murrough et al., 2017). Similar to 
depression, substance use disorders are associated with increased affective stress and 
impaired motivation for change. These symptoms, in addition to heightened sensitivity to drug 
cues, may be related to disrupted synaptic plasticity in the prefrontal cortex (Goldstein and 
Volkow, 2002; Kalivas, 2008).  
Extensive research in animal models suggests that chronic drug use and the diminished 
ability to control drug seeking arises from a dysregulation in synaptic glutamate transmission by 
non-synaptic glial glutamate (i.e., a loss of glutamate homeostasis) at synapses connecting the 
prefrontal cortex to the nucleus accumbens (Kalivas, 2009). This dysregulation contributes to 
lasting drug-induced changes in synaptic plasticity and dendritic spine morphology. For 
instance, during the development of drug addiction, long-term depression and long-term 
potentiation changes in glutamate-mediated synaptic communication between prefrontal and 
limbic brain regions may attenuate the salience of nondrug reinforcers (e.g., money) while 
enhancing drug-seeking and drug cue reactivity. Drugs that restore glutamate homeostasis may 
reset these drug-induced changes and interfere with drug-seeking behavior (Kalivas, 2009). 
Indeed, blocking the NMDA receptor, which plays an important role in neuroplasticity, has been 
shown to disrupt cue-induced drug seeking behavior in rats (Bespalov et al., 2000). Among 
individuals with cocaine use disorder, sub-anesthetic doses of ketamine have been shown to 
decrease craving and improve motivation to quit using cocaine (Dakwar et al., 2014). In 
particular, non-treatment seeking cocaine users demonstrated decreased craving and an 
increased preference for money over cocaine in a lab-based model of cocaine use administered 
28-hours post-ketamine infusion; subjects also had reduced ad lib cocaine use over the next 
several days (Dakwar et al., 2017). Ketamine has also been associated with higher abstinence 
rates among treatment-seeking detoxified heroin users (Krupitsky et al., 2002). Thus, ketamine 
holds potential to disrupt craving and motivation for drug use across different classes of drug 
use disorders. 
This project is innovative because ketamine has a distinctly different mechanism of 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
6 
 
action than current FDA-approved medications for tobacco withdrawal. Current 
pharmacotherapies for tobacco addiction include nicotine replacement therapy (a full nAChR 
agonist), varenicline (a partial nAChR agonist), and bupropion (a norepinephrine-dopamine 
reuptake inhibitor and nAChR antagonist) (Slemmer et al., 2000). These drugs essentially 
“substitute” for nicotine, reducing symptoms of nicotine withdrawal and the reinforcing effects of 
nicotine. While they are about 2x as effective as placebo in promoting tobacco cessation, 
abstinence rates are typically below 25% among smokers in clinical trials of these medications 
(Eisenberg et al., 2008). Most problematically, these pharmacotherapies do not adequately 
diminish cravings and the urge to smoke. In contrast, ketamine blocks the NMDA receptor and 
has shown potential to disrupt or diminish cravings and the motivation for drug use across 
several drug classes, suggesting it may be altering the reinforcement process itself. This project 
will help guide future research on this and other agents that target these neural mechanisms 
and will have implications for new pharmacotherapies. 
The goal of this proposal is to obtain preliminary data on the effects of sub-anesthetic 
ketamine infusion on cigarette craving and smoking behavior, as well as data on the tolerability 
and acceptability of the infusion. This small, exploratory phase I/II trial is necessary to justify a 
larger, more thorough R01 investigation. More research is needed on ketamine’s mechanism of 
action and its effects on tobacco use. Future research will compare ketamine to other 
psychoactive agents, including other NMDA receptor antagonists, determine optimal dosing 
strategies, and estimate the duration of ketamine effects. Ultimately, this work could impact the 
field of tobacco addiction research by providing evidence of an innovative pharmacologic 
mechanism that promotes smoking cessation. 
 
2.3 Risk/Benefit Assessment 
2.3.1 Known Potential Risks 
1. Loss of Confidentiality. There is a risk attendant to the confidentiality of medical records, 
psychological data, drug use history, and self-report data.  
 
2. Ketamine. The dose of ketamine to be administered is below the threshold for anesthesia. 
Common side effects of ketamine include changes in respiration, heart rate and blood pressure, 
muscle tremors, diplopia and nystagmus, decreased hunger, nausea, vomiting, pleasant or 
unpleasant dream-like states, vivid imagery, hallucinations, confusion, excitement, irrational 
behavior, and anesthesia. Finally, ketamine may produce adverse psychotropic effects that 
could also exacerbate tobacco withdrawal symptoms. All participants will be clinically monitored 
according to the American Society of Anesthesiology Standards for Basic Anesthetic Monitoring 
during infusion of study drug, pulse oximetry, and electrocardiography, and intermittent non-
invasive ocillometric blood pressure measurement. Body temperature will be recorded prior to 
infusion and prior to release. Following completion of the study drug infusion, study personnel 
will complete and document periodic assessment of oxygen saturation, and level of 
consciousness at least once every 15 minutes for the first hour of recovery, in addition to 
variables collected specifically for the purposes of the research protocol. 
Although ketamine abuse is very context dependent, being almost entirely confined to 
clubs and large music parties (De Luca et al., 2012), risks associated with abuse liability of 
ketamine cannot be ruled out. The abuse liability of ketamine will be measured by assessing 
drug liking, perceived potency, and desire to take this drug again (Carter and Griffiths, 2009). 
 
3. Intravenous (IV) line/Infusion Procedure. Angiocatheter insertion can cause pain and result in 
a hematoma. Intravenous line infiltration may cause pain. Participants will be offered comfort 
measures and observation for rare but serious consequences (e.g., compartment syndrome). 
 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
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4. Blood Drawing. Subjects will have approximately 20 cubic centimeters (cc) of blood drawn 
during eligibility screening. Blood drawing can cause some pain and result in a hematoma. 
 
5. Symptoms of Tobacco Withdrawal. Participants will be asked to refrain from smoking for up to 
10 hours on 2 occasions during the study. They may begin to experience withdrawal symptoms 
in this amount of time. Symptoms may include tobacco craving, loss of concentration, negative 
mood, headache, drowsiness, trouble sleeping, increased appetite, and dry mouth. 
 
6. Nonspecific Risks. Other risks from the rating scales are not beyond usual clinical 
procedures. Confidentiality of these results are specifically protected by Federal laws, and all 
records will be identified by code number only, with the master file kept under lock by the PI or 
data manager.      
 
2.3.2 Known Potential Benefits 
The information gained in this study can assist us in developing more effective strategies for 
treating tobacco use disorder, which ultimately would be of great benefit to society. 
 
2.3.3 Assessment of Potential Risks and Benefits 
2.3.3.1 Adequacy of Procedures to Minimize Risks 
1. Subject Recruitment and Consent Procedures. Tobacco-dependent volunteers will be 
recruited via flyers, newspaper, word of mouth, internet, and ARresearch.org. A research staff 
member experienced in obtaining informed consent will interview subjects to determine interest 
in participating in this trial. Aspects of the study procedures, risks, and potential benefits will be 
explained, and any questions will be answered. The subject will be asked questions to ensure 
an adequate understanding of the study and encouraged to read through the consent form a 
second time. The subject is asked to read aloud a section of informed consent to ensure that 
s/he can read (if the person is illiterate, a witness will be found to be present for the entire 
informed-consent process). If the subject indicates any hesitation about signing the consent 
form, s/he will be encouraged to leave with the consent form to consider the matter at leisure. If 
a subject indicates a desire to sign the consent form, both the participant and staff member will 
sign the form. The staff member will document that the informed-consent process occurred and 
whether the person's questions were addressed to his/her satisfaction. If at any time the subject 
exhibits intoxication, sedation, over-agitation, or some form of inattentiveness, the consenting 
process will be stopped and the interview rescheduled. After obtaining written informed consent 
for participation in the study and completing all screening procedures, a study physician will 
review all medical and psychiatric data prior to admitting the subject and beginning medication. 
 
2.3.3.2 Protections Against Risk 
1. Our inclusion and exclusion criteria will be applied by experienced professionals, who will be 
carefully trained and monitored in order to accept only appropriate subjects into the study. Thus, 
effective screening will exclude subjects who would be placed at a greater risk. Risk level is 
determined by the medical and psychiatric history, drug use history, the physical examination, 
and the laboratory studies done prior to beginning this research protocol. 
 
2. Although ketamine abuse is almost entirely confined to clubs and large music parties (De 
Luca et al., 2012), we will minimize risk of subsequent ketamine abuse after discharge by not 
informing participants of the actual drugs being studied. Study participants will receive a list of 
drugs that they could receive and their potential side effects (e.g., placebo, midazolam, 
ketamine) along with a statement that they will receive 1 of the drugs listed and no drug that is 
not on the list. Participants will be able to be informed of the actual drugs received once the 

SED-TUD IRB Number 229077 version 9, 3/2/21 
 
 
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entire study has been completed, if they desire, to increase the time interval between having the 
drug-induced experience and knowing the actual drug. Not knowing exactly what drug they 
received minimizes the risk that participants will seek more ketamine immediately after the 
study. This also minimizes the risk that participants who have recently completed the study will 
share information about their ketamine experience with other prospective participants, who may 
desire to enter the study because they are seeking ketamine. This strategy has been used 
successfully in other studies to reduce risk of subsequent drug use following study participation. 
This study procedure has also been approved by the IRB in prior protocols that also had an 
IND, including IRB #29123, 57184, 104881, and 110528 (also #135883 that did not have an 
IND), with the FDA not having issues with this strategy for these protocols. Participants will also 
be asked about their drug use, including ketamine and other club drugs, at screening and follow 
up interviews to determine whether an increase in use of these kinds of agents occurred. 
Finally, data on drug liking and desire to use this drug again (Carter and Griffiths, 2009) will be 
obtained after the infusion. 
 
Another justifications for the midazolam sham condition and the use of deception prior to 
drug administration is the problem of drug discrimination. Although participants are blinded to 
the drug condition, participants will easily discern whether they received active drug (ketamine) 
versus placebo, which can influence their subsequent mood and smoking behavior if they are 
under the belief that the active drug may affect these outcomes. Smoking behavior and mood 
are subjective and easily influenced by expectation. Many ketamine studies use an “active 
placebo”, such as midazolam, to avoid this limitation (in fact, the use of an active placebo during 
ketamine research is strongly recommended (Aan Het Rot et al., 2012). While an active placebo 
is not being used in this small pilot study, we may be able to minimize this confound by using 
the midazolam sham (an active placebo will be used in future studies). 
 
3. All participants will be asked to not eat solid food for 7 hours prior to the infusion. 
Consumption of clear liquids will be permitted until the start of the infusion.  
 
4. Participants will be monitored according to the American Society of Anesthesiology 
Standards for Basic Anesthetic Monitoring (American Society of Anesthesiologists Task Force 
on Sedation and Analgesia by Non-Anesthesiologists 2002, Standards and Practice Parameters 
Committee, 2011) with ketamine being administered by the study anesthesiologist. The 
anesthesiologist will perform a brief pre-anesthesia evaluation to ensure the person can safely 
undergo ketamine infusion, remain available to periodically evaluate the patient and intervene 
as needed to diagnose or treat any serious physiologic derangements during infusion, and be 
available by pager if any issues arise thereafter. The close monitoring of objective and 
subjective drug effects by direct observation, interviewing, and self-ratings will allow objective 
evaluation of the effects of ketamine. If at any point during the study adverse reactions are 
severe enough to warrant physician intervention, the subject will be removed from the study. If 
the subject drops out of the study, treatment referrals will be offered. 
 
To ensure that participants return home safely after release, participants will be shuttled 
to and from the hospital by another driver on the ketamine infusion day. If the participant cannot 
arrange for their own transportation, a taxi will shuttle them to and from the hospital.  
 
5. The experimental procedure will be completed in one of the ketamine infusion rooms in the 
UAMS PRI Ketamine Infusion Suite with at least an LPN-level research nurse present during the 
session. The infusion suite has a physiologic monitor that will capture continuous pulse 
oximetry, heart rate, and electrocardiography, and intermittent non-invasive blood pressure 
measurements. Wall mounted oxygen, suction, and equipment to deliver positive pressure 
ventilation are available at the bedside. A crash cart and additional supplies are also available. 

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The room contains full resuscitation equipment under the direct observation of an 
anesthesiologist certified by the American Board of Anesthesiology. Treatment of cardiac 
arrhythmia will depend on the particular dysrhythmia and physiologic response, and may range 
from continued observation by Dr. Lide to defibrillation. Management of respiratory depression 
will depend on the level of sedation, oxygenation, and ventilatory response, and may range from 
reminders to the patient to breathe, to supplemental oxygen, to facemask ventilation. Other 
adverse events will be treated in accordance with standard medical practice. See Miller’s 
Anesthesia, 8th edition, for details. Participants will be discharged from the infusion suite based 
on criteria in the UAMS Practice Document: Interventional Service Line – Patient Discharge 
NR.CP.5.45 approved December 6, 2017. 
6. We will follow use the following recommended criteria for ketamine discontinuation (Murrough 
et al., 2013): 
1- In the event that three consecutive vital signs measurements (over 15 minutes) are 
consistently above the heart rate and BP limits (greater than 110 beats per minute and 
170/100), then the study infusion will be discontinued. 
2- In the event that the patient becomes sedated to the point that he/she is unresponsive 
to verbal commands or there is complete or partial airway obstruction, the study infusion will be 
discontinued. Should either of these problems occur, the anesthesiologist will treat the patient 
according to standard protocols. The patient would then be transferred to the post-anesthesia 
care unit or an intensive-care unit bed, as necessary for further observation and treatment. 
3- In the event that the peripheral oxygen saturation is <95% over a 5-minute interval, 
the anesthesiologist has the option of supplementing oxygen. If oxygen saturation does not 
increase to 95% or greater with intervention, the infusion is discontinued, and further therapy is 
administered by the anesthesiologist. 
 
7.     Based on current recommendations by the manufacturer, pregnant women will be 
excluded by history and urine pregnancy test. Women capable of becoming pregnant will be 
asked to use effective birth control in order to participate and to inform the study physician if 
their birth control plans change after being accepted into the study.   
 
8.    Confidentiality will be protected by having all research records identified by code number 
only. A Certificate of Confidentiality will be obtained from the Department of Health and Human 
Services when the protocol is approved by the IRB and will be submitted to the IRB prior to 
subject enrollment. 
 
9.  If one participant experiences a study-related serious adverse event, the investigative team 
will review the data to determine whether the protocol needs to be modified or the trial stopped. 
 
10.  All personnel involved in this project will undergo triennial training in protection of human 
subjects and Good Clinical Practice. 
 
2.3.3.3 Assessment of Potential Risks and Benefits 
1. Potential Benefits. The risks associated with this study include the effects of the study 
medication, infusion, and tobacco withdrawal symptoms. In addition, subjects will have the 
inconvenience of participating in the study. Benefits offsetting these risks include that subjects 
will undergo a medical evaluation. The information gained in this study can assist us in 
developing more effective strategies for treating tobacco use disorder, which ultimately would be 
of great benefit to society. We believe that the benefits more than justify the risks of participating 
in this study.  
 

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2. Importance of Knowledge to be Gained. Despite several years of research on treating 
tobacco use disorder, prevalence is still high and current strategies are limited by high relapse 
rates. Moreover, effective strategies for treating tobacco use disorder still need to be identified. 
Thus, it is of vital importance to examine novel strategies for treating this condition. Examining 
ketamine infusion as a potential treatment strategy for reducing addiction is important because 
(1) the pharmacology of ketamine makes it a good candidate for reducing addiction, (2) 
ketamine infusion has been well tolerated and can be done on an outpatient basis, and (3) data 
from human and nonhuman studies support the use of ketamine. The findings of this study may 
support future studies that shed light on the efficacy of this medication as well as provide 
support for further development of ketamine as a pharmacotherapy for tobacco use. 
 
3 Objectives and Endpoints 
This proposal will obtain preliminary data on the effect of a single sub-anesthetic ketamine 
infusion on cigarette craving and smoking behavior as well as measuring its tolerability, and 
acceptability. This single-blind, placebo-controlled, randomized clinical trial will test 12 non-
treatment seeking smokers with a single intravenous infusion of ketamine (0.5 mg/kg) or 
placebo. Before and 24-hours after the infusion, smokers will undergo lab-based measures of 
cigarette craving and smoking latency and will also complete diaries of cigarettes smoked per 
day for 7 days before, and 7 days after, the infusion. Physical and subjective effects and 
adverse effects will be closely monitored throughout. 
 
Aim 1. Determine the preliminary safety, tolerability, and acceptability of ketamine. 
Outcomes include physiology (pulse oximetry, vital signs), drug effects, side effects, and 
symptoms of depression. We hypothesize that relative to placebo, a ketamine infusion will be 
comparably safe, well tolerated, and acceptable to smokers. 
 
Aim 2. Determine the effects of ketamine on cigarette craving, smoking latency, and 
smoking frequency. Outcomes include urge to smoke, nicotine withdrawal symptoms, mood, 
latency to smoke in a smoking lapse analog task (pre- and post-infusion), and daily smoking 
frequency. We hypothesize that relative to placebo and baseline, ketamine will reduce craving, 
nicotine withdrawal, improve mood, increase the latency to smoke, and decrease the number of 
cigarettes smoked per day. 
 
4 Study Design 
4.1 Overall Design 
This study has a mixed, within- and between-groups design. Non-treatment seeking smokers 
will be randomized into a ketamine or a placebo group. After the screening session, subjects will 
complete a 7-day smoking diary. Then complete the first study day in which a smoking analog 
task will be administered. On the second study day, the drug infusion will occur, followed by the 
third study day 24 hours after the infusion. Participants will complete a second 7-day smoking 
diary, then return to the lab for a follow-up visit.  
 
4.2 Scientific Rationale for Study Design 
The design of this study is modeled after Dakwar et al (Dakwar et al., 2017). In this previous 
study, non-treatment seeking cocaine dependent participants (aged 21-55) underwent lab-
based measures of cocaine self-administration before and 24-hours after an intravenous 
ketamine infusion (0.71 mg/kg) or an active placebo, midazolam (0.025 mg/kg). The results 
showed ketamine decreased cocaine self-administration and craving in lab-based measures. 
There was also a slight reduction in cocaine use outside the lab that lasted for a few days. The 
goal of this study is to translate this work for tobacco use disorder. 

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4.3 Justification for Dose 
Ketamine will be infused in order to control for variability in bioavailability of the agent. The 0.5 
mg/kg dose of ketamine has been infused previously for opioid withdrawal (Jovaisa et al., 2006), 
is already being used clinically to treat depression at UAMS and is well-tolerated. If findings are 
positive, future studies will determine the optimal dosing and/or administration method. 
 
4.4 End of Study Definition 
A participant is considered to have completed the entire study if he or she has completed 
activities through the follow-up lab visit. 
 
5 Study Population 
5.1 Inclusion Criteria 
Up to 20 male and female cigarette smokers will sign informed consent and be assessed for 
eligibility to participate until 12 have completed the study. 
 
1) between the ages of 21 and 55 
2) smoke ≥ 5 cigarettes/day of a brand delivering ≥ 0.5 mg nicotine  
3) smoked ≥ 2 years 
4) afternoon expired CO concentrations ≥ 10 ppm or morning urinary NicAlert ≥ 100 ng/ml (note: 
both will be measured at screening regardless of the time of day) 
5) negative urine drug screen for illicit drugs (except for THC) and negative breath alcohol 
concentration 
6) do not plan to change smoking behavior within the next 90 days 
 
5.2 Exclusion Criteria 
1) have an unstable medical condition or stable medical condition that would interact with study 
medications or participation, including chronic pulmonary disease, coronary artery disease, 
current brain tumor, current increased intracranial pressure or impaired consciousness 
2) history of serious head trauma or neurological disorder (e.g., seizure disorder) 
3) have any of the following: hypertension (i.e., systolic >140 mm Hg and/or diastolic >90 mm 
Hg on three separate measures; systolic >170 or diastolic > 110 on any occasion), liver function 
tests >3 times normal, Blood Urea Nitrogen and Creatinine outside normal range; ECG 
(electrocardiogram) abnormalities including but not limited to: bradycardia (<55 beats per 
minute); prolonged QTc interval (>450 msec); Wolff-Parkinson White syndrome; wide complex 
tachycardia; 2nd degree, Mobitz type II heart block; 3rd degree heart block; left or right bundle 
branch block; pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic) 
4) meet DSM-5 criteria for psychosis, schizophrenia, major depressive disorder, or bipolar 
disorder 
5) current substance abuse/dependence other than nicotine 
6) use of psychoactive medications or other drugs that would interact with study drug 
7) use of cannabis/THC >4 days/week 
8) current use of smokeless tobacco, nicotine replacement therapy, bupropion, or varenicline 
9) history of regular use of ketamine for nonmedical purposes 
10) among females, pregnancy or breastfeeding 
11) Body Mass Index > 40 
 
5.3 Lifestyle Considerations 
NA 
 

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5.4 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently entered in the study. This refers to participants who have signed a consent 
form but do not meet eligibility criteria during the screening session. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and 
to respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) 
because of a questionable laboratory finding may be rescreened upon subsequent follow up 
and resolution of the issue as documented by a local physician. Rescreened participants will be 
assigned the same participant number as for the initial screening. 
 
5.5 Strategies for Recruitment and Retention 
Subjects will be recruited from the community via flyers, newspaper, word of mouth, and 
internet. Approximately 25% of Arkansas smoke tobacco. We should easily be able to recruit 
approximately 1-2 participants per month to stay on schedule. 
 
6 Study Intervention 
6.1 Study Intervention Administration 
6.1.1 Study Intervention Description  
Participants will be randomized to receive either ketamine or placebo on the drug infusion day. 
 
6.1.2 Dosing and Administration 
Ketamine is a schedule III anesthetic. The 0.5 mg/kg dose is already being used clinically to 
treat depression at UAMS and is well-tolerated. Sub-dissociative doses (<1 mg/kg) of ketamine 
have also been administered to pain patients in the ED with minimal adverse side effects and an 
efficacy similar to that of opioids (Pourmand et al., 2017). Participants with body mass index ≥ 
30 may receive a dose using their calculated ideal body weight and not actual body weight, per 
the recommendation of the study physician and/or pharmacist. 
 
On the infusion day, subjects will receive an infusion of ketamine (0.5 mg/kg). 100 mg of 
ketamine will be prepared in NS 100 ml IVPB (I mg/ml concentration). All study participants will 
receive a 22-gauge angiocatheter inserted intravenously by the study anesthesiologist and 
connected to standard intravenous tubing and a 1000 ml bag of crystalloid solution (Lactated 
Ringers or Plasma-Lyte). The infusion will be administered by infusion pump at a rate of 125 
mL/hour. Study drug will be infused intravenously by pump over 20 minutes, the standard 
procedure for ketamine infusion for depressed patients at UAMS.  
 
6.2 Preparation/Handling/Storage/Accountability 
6.2.1 Acquisition and Accountability 
The UAMS Research Pharmacy will purchase, store medication supplies, prepare all 
medications and be in charge of drug accountability and blinding. For purposes of ketamine 
dose preparation, the participant's body weight measured on the screening visit will be used. 
When dispensed from the pharmacy, medication will be stored in a separate container in the 
medication room cabinet behind the nurse's station on the inpatient floor until administration 
time. All medication administration will occur under observation by research/medical staff to 
ensure compliance with medication procedures. Unused medications will be returned to the 
research pharmacy typically within 24-48 hours for destruction.  
 
6.2.2 Appearance, Packaging, and Labeling 

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Ketamine is formulated from the manufacturer as a slightly acidic sterile solution for intravenous 
infusion. We will prepare ketamine 100mg in NS 100ml IVPB (1mg/ml concentration).   
 
6.2.3 Product Storage and Stability 
See package inserts for relevant information. 
 
6.2.4 Preparation 
The appropriate doses of Ketamine will be compounded per protocol by the UAMS research 
pharmacy and provided to study staff based on physician’s prescription in appropriately labeled 
sterile IVPB containers.  
 
6.3 Measures to Minimize Bias: Randomization and Blinding.  
Subjects will be blind to infusion medication. They will be given a list of drugs, including 
ketamine, and told that one of the drugs listed will be administered. 
 
6.4 Study Intervention Compliance 
The infusion will be administered by the study physician anesthesiologist to ensure medication 
is infused according to the protocol. Timing of medication administrations will be documented on 
a study checklist. 
 
6.5 Concomitant Therapy 
NA 
 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal 
 
7.1 Discontinuation of Study Intervention 
NA 
 
7.2 Participant Discontinuation/Withdrawal from the Study 
Participants choosing not to take the study medication or not following study or unit procedures 
will be discharged from the study. Participants have a right to withdraw from the study at any 
time. 
 
7.3 Study Retention and Lost to Follow-Up 
In previous studies, we have implemented procedures to successfully recruit, enroll, and ensure 
the safety of subject populations.  
 
Participants will receive no payment for the phone screening and in-person eligibility screening. 
Participants will be compensated $20 for completing the two 7-day smoking diaries ($10/diary), 
$178 for the smoking analog study days ($75 for participation, up to $14 for not smoking during 
the analog task), $100 for the drug infusion study day, and $10 for the follow-up lab visit. They 
will receive a $100 bonus for completing all aspects of the study. The maximum amount of 
compensation will be $408. 
 
Staff will also obtain contact information from subjects and a reliable contact for sending up to 
three reminders of the appointment by phone and documenting these attempts in the 
participant's research record. 
 
8 Study Assessments and Procedures 
8.1.1 Efficacy Assessments 

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Assessment of Eligibility. Participants will undergo a comprehensive evaluation, including 
physical, psychiatric and routine laboratory studies (CBC, basic metabolic panel, urinalysis, 
ECG). These assessments must occur within 30 days of intake procedures. A physician will 
review laboratory data and ECG prior to study day 1. Women of childbearing potential will have 
a urine pregnancy test at initial assessment and prior to ketamine infusion. 
 
Study Entry. Table 1 outlines the study timeline. Prospective participants will call the study 
telephone number and be given a brief description of the study and answer some questions 
regarding eligibility. Individuals who are interested in the study and meet basic inclusion criteria 
will be invited to a full screening session.  
The screening interview will be conducted by a research staff member and take 
approximately 2-3 hours to explain the study, obtain informed consent, conduct informal 
interviews for mental health (i.e., to rule out major psychiatric illness) and other drug use 
disorders, collect vitals (blood pressure and heart rate), conduct drug urinalysis and urine 
pregnancy test for women, collect smoking history and medical history, review information in the 
phone screen. The research staff member will have a bachelor’s degree and at least 2 years 
research experience or another equivalent combination of education and research. The ECG 
and blood draw will be performed by a research nurse. A blood evaluation will be performed 
(basic metabolic panel, CBC—these and any other laboratory test mentioned in this protocol will 
be outsourced to Quest Diagnostics and/or Redwood Laboratories). The study physician will 
review the results of the screening and determine eligibility. 
 
Experimental Procedures. This study has a mixed, within- and between-groups design. Non-
treatment seeking smokers will be consented, screened for eligibility, and randomized into a 
ketamine (n = 6) or placebo (n = 6) group (single-blind). Subjects will be told they may receive 
ketamine, midazolam, or placebo (to minimize drug expectations; only ketamine or placebo will 
actually be administered). After the screening session, eligible subjects will complete a 7-day 
smoking diary at home. Then, they will be asked to abstain from smoking for 10 hours (to induce 
withdrawal symptoms) and arrive for their first study day to complete the first smoking lapse 
analog task. After this study day, they may resume ad lib smoking before the second study day, 
when subjects will arrive and undergo a pre-anesthesia evaluation, followed by an intravenous 
administration of either ketamine or placebo. This procedure will last 2 hours. At the end of 
these 2 hours, they will complete self-report mood questionnaires and be released. They will be 
asked to abstain from smoking for 10 hours before the third study day visit, which begins on the 
following day- when the effects of ketamine on mood are thought to peak. Subjects will undergo 
a second smoking lapse analog task. They may resume ad lib smoking and they will be given a 
second 7-day smoking diary to begin the following day. This diary will be returned in 1 week at a 
follow-up lab visit, where participants’ vitals will be measured, and any side effects and adverse 
events experienced since the drug infusion will be reported. See Table 1. 
 
8.1.2 Dependent Measures 
1 Self-report Measures of Tobacco Use. All subjects will complete a Smoking History 
Questionnaire and the Fagerström Test of Nicotine Dependence (FTND)(Heatherton et al., 
1991) at screening. These measures will be used to screen subjects and characterize 
individual’s smoking behavior.  
 
2 Tobacco Use and Abstinence Biomarkers. Expired-air CO will be measured using a handheld 
monitor (Vitalograph, Lenexa, KS). Urinary cotinine concentrations will be measured with 
NicAlertTM strips (Nymox Pharmaceutical Corp, Canada). These biomarkers will verify smoking 
status at screening.  

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3 Smoking Diary. Subjects will be provided with a questionnaire to log the number of cigarettes 
smoked each day for 7 days. The first smoking diary will be recorded after the screening 
session and before the first study day. The second smoking diary will be recorded after the third 
study day. 
 
4 Physiological Monitoring. All participants will be clinically monitored according to the American 
Society of Anesthesiology Standards for Basic Anesthetic Monitoring during infusion of study 
drug, including continuous assessment (i.e., every 5 min) of pulse oximetry, and 
electrocardiography, and intermittent non-invasive ocillometric blood pressure measurement. 
After infusion, these measures will be documented every 15 min for the first hour, then after 1 
more hour.  
 
5 Study Drug. Ketamine is a schedule III anesthetic. Participants will undergo pre-infusion 
assessments including a medical history and physical examination, application of physiologic 
monitors (including pulse oximetry, non-invasive ocillometric blood pressure measurement) and 
insertion of the IV line. Normal saline infusion at 125 mL/min will begin and pre-session 
research assessments will be completed. 100 mg of ketamine will be prepared in NS 100 ml 
IVPB (I mg/ml concentration). All study participants will receive a 20-gauge angiocatheter 
inserted intravenously and connected to a 1000 mL bag of crystalloid solution. The infusion will 
be administered by infusion pump at a rate of 125 mL/hour. Study drug will be infused 
intravenously by pump over 20 minutes, the standard procedure for ketamine infusion for 
depressed patients at UAMS. The placebo will be the crystalloid solution alone. Subjects will be 
blind to the contents of the infusion. Participants will remain in the Ketamine Infusion Suite for at 
least 2 hours under observation of a nurse before being released. 
 
6 Safety and Tolerability Measures. Clinician Administered Dissociated States Scale (CADSS) 
measures perceptual alterations that the subject may experience during the infusion session 
(Bremner et al., 1998). Drug Effects Questionnaire (DEQ) consists of scales rated from 0 (not at 
all) to 10 (extremely) e.g., "do you feel a drug effect?". Side Effects Questionnaire (SEQ) 
consists of scales rated from 0 (not at all) to 10 (extremely) of aversive side effects associated 
with ketamine and other drugs (e.g., nausea, headache, feeling faint, blurred vision). The 
CADSS will be administered throughout the drug infusion. The DEQ and SEQ will be 
administered at the end of the 2-hour study medication session. 
 
7 Subjective Mood Measures. The 10-item Tiffany Questionnaire of Smoking Urges-Brief 
(QSU (Cox et al., 2001)) measures urges to smoke in response to positive or negative 
reinforcement (visual analog scale, range 1–100). The 21-item Positive and Negative Affect 
Schedule (PANAS (Watson et al., 1988)) measures current emotional state for positive and 
negative moods (Likert scale, range 1-5). The 8-item Minnesota Nicotine Withdrawal Scale 
(MNWS (Hughes and Hatsukami, 1986)) measures symptoms of nicotine withdrawal. The QSU, 
PANAS, and MNWS will be administered at screening, before and after the drug infusion, and 
before and after the smoking lapse analog tasks. Since ketamine may affect symptoms of 
depression, the 20-item Center for Epidemiologic Studies Depression Scale (CESD (Beekman 
et al., 1997)) will be included on day 7 of the smoking diary to assess depression symptoms 
over the previous week. 
 
8 Smoking Lapse Analog Task. The smoking lapse analog task is a lab-based model of real-
world lapse during a quit attempt (McKee, 2009). This task measures the relative value of a 
drug (cigarette) vs a nondrug (money) reward, and it is appropriate for testing the effects of 

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ketamine on drug craving and drug-taking behavior. Participants will be seated in a smoking-
permitted room. Set on a table in front of them will be a pack of their preferred brand of 
cigarettes, a lighter, and an ashtray. Participants are instructed they can initiate smoking at any 
time over the next 50 min, but for each 5 min they delay smoking, they would earn $1 (total of 
$0 to $10 based on how long they delay). They will be instructed that the session will end in 50 
min regardless of whether they choose to smoke, but they can smoke 1 cigarette within this 
time. Immediately following the 50 min session is a 60 min period of ad lib smoking, where 
participants will be provided with a $4 “tab” which they can save or use to smoke additional 
cigarettes (up to 8 cigarettes) at $0.50 each. The time at which participants choose to smoke is 
the primary dependent variable (range 0–50min). 
 
Table 1 
• Consent and eligibility screening 
• 7-day smoking diary (CESD on day 7) 
• First Study Day (10 hours abstinent) 
• Subjective mood (QSU, PANAS, & MNWS) 
• 2hr - Smoking lapse analog task 
• Subjective mood (QSU, PANAS, & MNWS) 
• Second Study Day  
• Subjective mood (QSU, PANAS, & MNWS) 
• Pre-anesthesia evaluation 
• 0hr – Ketamine or Placebo infusion 
• .25hr – Physiological monitoring & CADSS 
• .5hr – Physiological monitoring & CADSS 
• .75hr – Physiological monitoring & CADSS 
• 1hr – Physiological monitoring & CADSS 
• 2hr– Physiological monitoring & CADSS 
• Drug side-effects (DEQ & SEQ) 
• Subjective mood (QSU, PANAS, & MNWS) 
• Third Study Day (10 hours abstinent) 
• Subjective mood (QSU, PANAS, & MNWS) 
• 2hr - Smoking lapse analog task 
• Subjective mood (QSU, PANAS, & MNWS) 
• 7-day smoking diary (CESD on day 7) 
• Follow-up lab visit (SEQ & PANAS) 
 
8.1.3 Milestones.  
 
We will train staff and develop procedures during month 1, enroll 1-2 subject/month into the 
study proper during months 2—12, allowing for holidays and staff vacations. All study 
procedures and follow-up visits will be completed by month 12. Data analyses, manuscript 
preparation and final report will be completed by Month 15. These data, if positive, will be used 
to support an R21 or R01 submission to comprehensively test the effects of ketamine infusion 
on tobacco use disorder. 
 
8.2 Safety Assessments 
Participants will be encouraged to report the occurrence of untoward effects. Participants will be 
asked whether they are experiencing any symptoms and, if so, a symptoms form will be 
completed. All symptoms will be monitored until resolution. 
 

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8.3 Adverse Events and Serious Adverse Events 
8.3.1 Definition of an Adverse Event 
Adverse event means any untoward occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related. Specifically, adverse event refers to 
any new untoward occurrence that had not been experienced previously by a participant OR an 
occurrence that has been experienced previously be the participant (e.g., pre-existing condition) 
that is greater in severity and/or duration than previously. 
 
8.3.2 Definition of a Serious Adverse Event 
An adverse event (AE) 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, a 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 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the participant 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. 
 
8.3.3 Classification of an Adverse Event 
8.3.3.1 Severity of Event 
All AEs will be assessed by the study physician and Principal Investigator using the following 
guidelines to describe severity: 
 
Mild — Events require minimal or no treatment and do not interfere with the participant's 
daily activities. 
 
Moderate — Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
 
Severe — Events interrupt a participant's usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.   
8.3.3.2 Relationship to Study Intervention 
All AEs will have their relationship to study intervention assessed by the study physician who 
examines and evaluates the participant based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below: 
 
 
Definitely Related — There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
 
 
Probably Related — There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time after administration of the study intervention, 

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is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
 
 
Potentially Related — There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant's clinical 
condition, other concomitant events). Although an AE may rate only as "possibly related" 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to "probably related" or "definitely related", as appropriate. 
 
 
Unlikely to be related — A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant's clinical 
condition, other concomitant treatments). 
 
 
Not Related — The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
 
8.3.3.3 Expectedness 
The study physicians will be responsible for determining whether an AE is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study intervention. 
 
8.3.4 Time Period and Frequency for Event Assessment and Follow-up 
An LPN or RN-level nurse will ask whether a participant is experiencing any symptoms during 
the infusion day and will record any occurrences on a symptoms form. Symptoms are reviewed 
by the study physician to determine whether the symptom meets the criteria for an AE or SAE.  
All AEs including local and systemic reactions will be captured on the appropriate case 
reporting form. Information to be collected includes event description, time of onset, clinician's 
assessment of severity, relationship to study product, and time of resolution/stabilization of the 
event. All AEs occurring while on study must be documented appropriately regardless of 
relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant's condition 
deteriorates at any time during the study, it will be recorded as an AE. 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as intermittent 
require documentation of onset and duration of each episode. 
Study staff will record all reportable events with start dates occurring any time after 
informed consent is obtained until the follow-up visit (for non-serious AEs) or 30 days (for SAEs) 
after the last day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information until 
resolution or stabilization. At least 3 attempts will be made to follow up with the participant and 
these attempts will be documented. 
 
8.3.5 Adverse Event Reporting 

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Institutional Review Board Reporting 
All AEs not meeting the criteria for an unanticipated problem involving risks to subjects or others 
(UPIRTSO: unanticipated problem involving risks to subjects or other) will be recorded and 
reported to the UAMS IRB at continuing review. 
Copies of each report and documentation of IRB notification and receipt will be kept in 
the Clinical Investigator's binder. 
 
Sponsor Reporting for Drug Studies under an IND 
The Sponsor will be promptly notified of all SAEs that are related to the study intervention and 
unanticipated/unexpected. These SAEs will be reported to the Sponsor using the FDA 
MedWatch 3500A. 
The Sponsor will report events to FDA in accordance with 21CFR312. 
All other AEs and SAEs will be reported to the Sponsor and FDA in the Annual Progress 
Report. 
Deaths that are related to research will be reported to the Sponsor immediately upon 
Investigator notification. A death due to a terminal condition of the research participant would be 
considered anticipated and not related to the research.  
THE SPONSOR WILL REPORT DEATHS TO FDA IN ACCORDANCE WITH 
21CFR312. 
 
8.3.6 Serious Adverse Event Reporting 
Institutional Review Board Reporting 
Only adverse events meeting the UPIRTSO (Unanticipated Problem Involving Risks to Subjects 
or Others) will need to be reported to the UAMS IRB within the required 10 day allotment of 
being notified of the event. UPIRTSO requires that an unanticipated problem meet the following 
qualifications: a) unanticipated or unexpected; b) related to the research; and c) involves new or 
increased risk to the subject(s). All other AEs, including expected SAEs, will be recorded and 
reported to the UAMS IRB at continuing review. 
Copies of each report and documentation of IRB notification and receipt will be kept in 
the Study binders. 
 
Sponsor Reporting for Drug Studies under an IND 
The Sponsor will be promptly notified of all SAEs that are related to the study intervention and 
unanticipated/unexpected. These SAEs will be reported to the Sponsor using the FDA 
MedWatch 3500A. 
The Sponsor will report events to FDA in accordance with 21CFR312. 
All other SAEs will be reported to the Sponsor and FDA in the Annual Progress Report. 
Deaths that are related to research will be reported to the Sponsor immediately upon 
Investigator notification. A death due to a terminal condition of the research participant would be 
considered anticipated and not related to the research.  
THE SPONSOR WILL REPORT DEATHS TO FDA IN ACCORDANCE WITH 
21CFR312. 
 
8.3.7 Reporting Events to Participants 
Subjects will be informed of any new findings that might influence their decision to continue their 
participation in the study. 
 
8.3.8 Events of Special Interest 
NA 
 

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8.3.9 Reporting of Pregnancy 
NA 
 
8.4 Unanticipated Problems 
8.4.1 Definition of Unanticipated Problems 
The Office for Human Research Protections considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
 
Related or possibly related to participation in the research ("possibly related" means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
8.4.2 Unanticipated Problem Reporting 
IRB Reporting 
AEs meeting the UPIRTSO criteria will be reported to the UAMS IRB within the required 10 day 
allotment of being notified of the event.  
 
Sponsor Reporting for Drug Studies Under an IND 
The Sponsor will be promptly notified of all SAEs that are related to the study intervention and 
unanticipated/unexpected. These SAEs will be reported to the Sponsor using the FDA 
MedWatch 3500A. 
The Sponsor will report events to FDA in accordance with 21CFR312. 
Deaths that are related to research will be reported to the Sponsor immediately upon 
Investigator notification. A death due to a terminal condition of the research participant would be 
considered anticipated and not related to the research.  
THE SPONSOR WILL REPORT DEATHS TO FDA IN ACCORDANCE WITH 
21CFR312. 
 
8.4.3 Reporting Unanticipated Problems to Participants 
Active participants will be notified at their next study visit of any changes to study procedures or 
drug information deemed necessary by the investigators upon review of the UPIRTSO. This 
notification will be documented in their study records. Once the IRB has approved the changes, 
including those to the consent form, participants will be invited to consider the changes and sign 
the consent if they choose to continue their participation. 
 
9 Statistical Considerations 
9.1 Statistical Hypotheses 
This is a feasibility study so no hypotheses have been generated at this time. 
9.2 Sample Size Determination 
This is a feasibility/pilot study, so sample size was not determined. 
 
9.3 Populations for Analyses 

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Population for analysis under Specific Aim 1: Those completing all aspects of the study. 
 
Population for analysis under Specific Aim 2: Those completing all aspects of the study. 
 
9.4 Statistical Analyses 
9.4.1 General Approach 
We will use descriptive statistics to characterize baseline characteristics of participants using 
the intent-to-treat sample. 
 
Specific Aim 1. Determine the preliminary safety, tolerability, and acceptability of ketamine. 
Outcomes include physiology measures (pulse oximetry, vital signs), self-report questionnaire 
scores for dissociative state (CADSS), drug effects (DEQ), side effects (SEQ), depressive 
symptoms (CESD), as well as the number, type and severity of adverse events. Physiology 
measures and CADSS will be entered into separate 2 (group) x 6 (time: up to 4hr post infusion) 
repeated-measures ANOVAs. CESD scores will be entered into a 2 (group) x 2 (time: pre/post 
drug infusion). DEQ and SEQ scores will be compared using linear regression, using group as a 
predictor. These analyses are exploratory for the purposes of deriving effect size estimates for 
future grant applications.  
Expected Results: While ketamine is expected to increase dissociative state, we hypothesize 
that relative to placebo, a ketamine infusion will be comparably safe, well tolerated, and 
acceptable to smokers. 
Specific Aim 2. Determine the effects of ketamine on cigarette craving, smoking latency and 
smoking frequency. Outcomes include self-report urge to smoke (QSU), symptoms of nicotine 
withdrawal (MNWS), mood (PANAS), delay to smoke measured in the analog task, and 
cigarettes smoked each day across 7 days pre- and post-study days. Self-report measures will 
be entered into separate 2 (group) x 2 (time: pre/post drug infusion) x 2 (time: pre/post smoking 
lapse analog task) repeated-measures ANOVAs. The time (in min) to smoking the first cigarette 
will be analyzed with a 2 (group) x 2 (time: pre/post drug infusion) repeated-measures ANOVA. 
The number of cigarettes per day will be entered into a 2 (group) x 2 (time: pre/post drug 
infusion) x 7 (time: days) repeated-measures ANOVA. These analyses are exploratory for the 
purposes of deriving effect size estimates for future grant applications. Expected Results: We 
hypothesize that relative to placebo and baseline, ketamine will reduce craving, nicotine 
withdrawal, improve mood, increase the latency to smoke, and decrease the number of 
cigarettes smoked per day. 
9.4.2 Analysis of the Primary Efficacy Endpoints 
NA 
 
9.4.3 Analysis of the Secondary Endpoints 
NA 
 
9.4.4 Safety Analysis 
NA 
 
9.4.5 Baseline Descriptive Statistics 
Groups will be assigned to a drug condition based on their age, sex, race, cigarettes/day and 
nicotine dependence severity in order to balance these demographic variables as much as 
possible between groups. We will compare baseline mood symptoms between the two groups. 

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Any differences that relate to outcomes maybe be included as covariates of no interest in the 
relevant analyses. Exploratory analyses will be conducted using SPSS v24. 
 
9.4.6 Planned Interim Analyses 
No interim analyses are planned. 
 
9.4.7 Sub-group Analyses 
NA 
 
9.4.8 Tabulation of Individual Participant Data 
NA 
 
9.4.9 Exploratory Analyses 
NA 
 
10 Supporting Documentation and Operational Considerations 
10.1 Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Informed Consent Process 
10.1.1.1 Consent/Assent and Other Informational Documents Provided to Participants 
A consent form describing in detail the study intervention, study procedures, and risks is given 
to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. Consent materials include the IRB-approved 
version of the consent form and HIPAA. 
 
10.1.1.2 Consent Procedures and Documentation 
Participants will be recruited via flyers, newspaper, word of mouth, and internet. A research staff 
member experienced in obtaining informed consent will interview subjects to determine interest 
in participating in this trial. Aspects of the study procedures, risks, and potential benefits will be 
explained, and any questions will be answered. The subject will be asked questions to ensure 
an adequate understanding of the study and encouraged to read through the consent form a 
second time. The subject is asked to read aloud a section of informed consent to ensure that 
s/he can read (if the person is illiterate, a witness will be found to be present for the entire 
informed-consent process). If the subject indicates any hesitation about signing the consent 
form, s/he will be encouraged to leave with the consent form to consider the matter at leisure. If 
a subject indicates a desire to sign the consent form, both the participant and staff member will 
sign the form. The staff member will document that the informed-consent process occurred and 
whether the person's questions were addressed to his/her satisfaction. If at any time the subject 
exhibits intoxication, sedation, over-agitation, or some form of inattentiveness, the consenting 
process will be stopped and the interview rescheduled. After obtaining written informed consent 
for participation in the study and completing all screening procedures, a study physician will 
interview the subject and review all medical and psychiatric data prior to admitting the subject 
and beginning medication. 
 
10.1.2 Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigators, and 
applicable regulatory authorities. If the study is prematurely terminated or suspended, the 
Principal Investigator will promptly inform study participants, the IRB, and sponsor and will 

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provide the reason(s) for the termination or suspension. Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
Insufficient compliance to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or FDA. 
 
10.1.3 Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without written consent by the participant. 
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), regulatory agencies or pharmaceutical company supplying 
study product may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant's contact information will be securely stored at the clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
Self-report and observer-report data will be collected using both standardized paper 
forms and forms presented on a computer that will be identified with the participant's study ID. 
The codes that link the name of the participant and study ID will be kept confidential in secured 
cabinets. Paper data will be entered into the computer independently by two different research 
staff trained to perform data entry, and the Principal Investigator or data manager will use a 
verification program to determine and correct any discrepancies based on source data. The 
computer data will be stored on a secure server and downloaded by the Principal Investigator, 
who will then transfer the data from Access to SPSS and check for missing data. The 
computer(s) used to collect data will be kept in a locked office or locked cabinet when not in 
use. 
Blood samples, urine samples and laboratory results will be identified only with subject 
ID. Data will be identified by subject's study ID and entered into the computer independently by 
two different research staff trained to perform data entry, and the PI will employ a verification 
program to determine and correct any discrepancies based on source data.  
 
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 

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civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality 
and privacy to participants 
 
10.1.4 Future Use of Stored Specimens and Data 
Data collected for this study will be analyzed and stored at PRI. No unauthorized individuals will 
have access. No specimens will be obtained for future use. 
 
10.1.5 Key Roles and Study Governance 
Principal Investigator 
Merideth Addicott PhD 
University of Arkansas for Medical Sciences 
Psychiatry Department 
Telephone: 501-526-2436 
maddicott@uams.edu 
 
Study Monitor 
Riley Lide, MD 
University of Arkansas for Medical Sciences 
Department of Anesthesiology 
rlide@uams.edu 
 
10.1.6 Safety Oversight 
Safety oversight of this feasibility study will be by the study investigators. 
 
10.1.7 Clinical Monitoring 
If conducted under an IND, clinical site monitoring will be conducted to ensure that the rights 
and well-being of trial participants are protected, that the reported trial data are accurate, 
complete, and verifiable, and that the conduct of the trial is in compliance with the currently 
approved protocol/amendment(s), and with applicable regulatory requirement(s). 
 
10.1.8 Quality Assurance and Quality Control 
The study team will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site's quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry 
system and data QC checks that will be run on the database will be generated. Any missing 
data or data anomalies will be communicated for clarification/resolution. 
Following written Standard Operating Procedures, if the study is conducted under an 
IND, the monitors will verify that the clinical trial is conducted and data are generated and 
biological specimens are collected, recorded, and reported in compliance with the protocol, and 
applicable regulatory requirements. 
The investigational team will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
 
10.1.9 Data Handling and Record Keeping 
10.1.9.1 Data Collection and Management Responsibilities 

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Data Acquisition, Collection, Transmission, and Entry 
Self-report and observer-report data will be collected using both standardized paper forms and 
forms presented on a computer that will be identified with the participant's study ID. The codes 
that link the name of the participant and study ID will be kept confidential in secured cabinets. 
Paper data will be entered into the computer independently by two different research staff 
trained to perform data entry, and the Principal Investigator (PI) or data manager will use a 
verification program to determine and correct any discrepancies based on source data. The 
computer data will be stored on a secure server and downloaded by the PI or data manager, 
who will then transfer the data from Access to SPSS and check for missing data. The 
computer(s) used to collect data will be kept in a locked office or locked cabinet when not in 
use. 
Blood samples, urine samples and laboratory results will be identified only with subject 
ID. Data will be identified by subject's study ID and entered into the computer independently by 
two different research staff trained to perform data entry, and the PI or data manager will 
employ a verification program to determine and correct any discrepancies based on source 
data. 
 
Procedures in Place to Ensure the Validity and Integrity of the Data 
The research assistant will have at least a bachelor's level education or commensurate 
experience, and the research nurse will be a Registered Nurse, both with previous experience in 
clinical rating and/or interviewing. 
As for training on the scales and tasks, the PI and/or data manager first will give a 
training session on the background of the particular scale and how it is to be completed. Then 
the staff member will observe completion of the assessment by an experienced rater on at least 
three occasions. Afterward, the staff member will complete the assessment in the presence of 
an experienced rater on at least three occasions, with feedback given each time, until the 
supervisor is confident that the person understands the assessment and completes it properly. 
Thereafter, assessments will be checked on a continuous basis for appropriate completion, and 
constructive criticism will be given as necessary.  
Each research staff member will be instructed on the timing of assessments for each 
individual. Checklists will be used to ensure that assessments are obtained at the time 
indicated. The research staff and PI also will review assessments. 
For the computerized assessments, the programs were created in such a way that (1) 
each subject has his/her own template of questionnaires that are prescheduled based on the 
timing of assessments outlined in the protocol, (2) each question must be answered in order to 
go to the next task or question, (3) each answer has a "built in" range of appropriate values 
such that out-of-range answers will not be accepted. The PI will create each subject's template, 
will train research assistants in computer use, and will periodically spot-check to ensure 
research assistants are completing assessments according to proper procedures. The computer 
data will be stored on a secure server and downloaded by the PI, who will then transfer the data 
from Access to SPSS and check for missing data. The computer(s) used to collect data will be 
kept in a locked office when not in use. 
For paper assessments, the research assistant will review the assessments for 
missing/out-of-range values. Paper data will be entered into the computer independently by two 
different research staff trained to perform data entry, and the PI will employ a verification 
program to determine and correct any discrepancies based on source data. If the PI notices 
recurring data entry errors, she will inform the person(s) responsible and retrain them as 
necessary. 

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Prior to statistical analyses, the PI or data manager will check the data for mislabeling, 
missing data, out-of-range data, etc., and will change/correct as appropriate based on source 
data. A master data set will be created with at least two backups.  
 
10.1.9.2 Study Records Retention 
Study documents will be retained for a minimum of 3 years after the study has closed or the 
findings published, whichever is longer. 
 
10.1.10 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, or Standard Operating 
Procedures requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions may be 
developed by the study team and implemented promptly. 
It is the responsibility of the PI to use continuous vigilance to identify and record 
deviations.  All deviations will be addressed in study source documents and sent to the UAMS 
IRB per their policies. The PI is responsible for knowing and adhering to the reviewing IRB 
requirements.  
 
10.1.11 Publication and Data Sharing Policy 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: NIH Public Access Policy, which ensures that the public has access to 
the published results of NIH funded research. It requires scientists to submit final peer-reviewed 
journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon 
acceptance for publication. 
 
10.1.12 Conflict of Interest Policy 
Investigators have no conflicts of interest to disclose. 
 
10.2 Additional Considerations 
N/A 
 
10.3 Abbreviations 
AE 
Adverse event 
BrAC 
Breath Alcohol Content 
BUN 
blood urea nitrogen 
CADSS 
Clinician Administered Dissociated States Scale 
CBC 
complete blood count 
cc 
cubic centimeters 
CESD 
Center for Epidemiologic Studies Depression Scale 
CO 
carbon monoxide 
CONSORT 
Consolidated Standards of Reporting Trials 
DEQ 
Drug Effects Questionnaire 
DSM-5 
Diagnostic and Statistical Manual version 5 
ECG 
electrocardiogram 
FDA 
Food and Drug Administration 
FTND 
Fagerström Test of Nicotine Dependence 
HIPAA 
Health Insurance Portability and Accountability Act 
hr 
hour 
ID 
identification 
IND 
investigational new drug 

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IV 
intravenous 
IVPB 
intravenous piggyback 
LPN 
licensed practical nurse 
mg/kg 
milligrams per kilogram 
mg/ml 
milligram per milliliter 
mm Hg 
millimeters mercury 
MNWS 
Minnesota Nicotine Withdrawal Scale 
NIH 
National Institutes of Health 
NMDA 
N-methyl-D-aspartate 
NS 
normal saline 
PANAS 
Positive and Negative Affect Schedule 
PI 
Principle Investigator 
PRI 
Psychiatric Research Institute 
QC 
quality control 
QSU 
Questionnaire of Smoking Urges 
SAE 
serious adverse event 
SED-TUD 
The effects of sedatives on tobacco use disorder 
SEQ 
Side Effects Questionnaire 
SPSS 
Data analysis software 
UAMS 
University of Arkansas for Medical Sciences 
UPIRTSO 
Unanticipated Problem Involving Risks to Subjects or Others 
 
10.4 Protocol Amendment History 
 
 
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