Impact of a Reduced Nicotine Standard on Young Adult Appeal for Menthol and Non-menthol Cigarettes
Phase: NA
Conditions: Cigarette Smoking, Smoking Behaviors
Sponsor: University of Oklahoma

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RESEARCH PROTOCOL OUTLINE
Title of Project: 
Cigarette Smoking in Young Adults (Project ENHANCE)
Principal Investigator:
Amy Cohn, PhD, Department of Pediatrics
NIH Grant Number: R01DA050990-01 
Abstract
The FDA has announced its intention to reduce the nicotine content in cigarettes7 
as a strategy to promote cessation and reduce smoking-related harm.8,9 Notably, a 
low nicotine product standard will apply to all cigarettes on the market, including 
menthol cigarettes, which account for approximately 30% of the cigarettes used 
by smokers.10 Menthol cigarette smoking has increased in young adults (YA; 
defined here as ages 18-26), while non-menthol smoking has decreased in this age 
group,1,2 and the majority of new YA smokers initiate with a menthol cigarette.3 
Additionally, according to recently published data, adults aged 26-34 have shown 
a rapid increase in menthol cigarette use from 2008 – 2019, compared to adults 
ages 18-25, and that menthol use was most common among adults aged 18-25 and 
26-34 years . Experimentation with menthol cigarettes is linked to smoking 
progression,11,12 and greater nicotine dependence relative to non-menthol cigarette 
use.1,4,5 If menthol very low nicotine cigarettes (VLNCs) remain more appealing 
than non-menthol VLNCs, this would indicate that some aspect of menthol 
maintains smoking behavior even in the absence of nicotine. Results will also 
further support FDA’s regulatory authority to ban or restrict the sale of menthol 
cigarettes, in addition to market-wide reductions in nicotine content of cigarettes.  
This study will recruit a sample of 132 “someday/everyday” menthol smokers 
aged 18-34 years to capture smokers early in their smoking trajectory. The study 
will measure reinforcement for smoking experimental (SPECTRUM) menthol and 
non-menthol very low nicotine cigarettes (VLNCs; 0.4mg) and the impact of 
proposed product standards and policy scenarios on tobacco product purchasing 
behavior using a validated Experimental Tobacco Marketplace (ETM).13-16 
Reinforcement across product standards will be assessed using complimentary 
measures with puff topography measures in a controlled laboratory and using 
ecological momentary assessment (EMA). We have received supplemental funds 
to this project from the NIH to add an additional sample of n = 40 sexual and 
gender minority (SGM) smokers. These individuals will complete the same 
protocol. Therefore, a total sample size of 172 YA ages 18-26 and adults aged 26-
34 years “someday/everyday” menthol smokers will be recruited.
Due to the sensitive nature of items included in the inclusion/exclusion criteria, 
screening participants who appear to be eligible for the study will have additional 
screening questions concerning medical history, current mental health status, 
current suicidal ideation, and past 10-year suicide attempts. Those found to have 
medical conditions that would preclude successful completion of the study 
sessions, untreated or worsening mental health concerns, current suicidal ideation, 
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or past 10-year suicide attempt(s) will not be eligible for the study and will be 
withdrawn at baseline. An additional 88 participants will be added to the study 
recruitment analytic sample size goal of 172 YA ages 18-26 and adults aged 26-
34 years to accommodate for participants found ineligible at baseline. Therefore, 
the total enrollment (as defined by The University of Oklahoma Health Sciences 
Center Institutional Review Board) goal will be a maximum of 260 YA ages 18-
26 and adults aged 26-34 years "someday/everyday" menthol smokers.
A.
Specific Aims
Aim 1: Determine the influence of menthol flavoring on smoking reinforcement 
in the context of a reduced nicotine standard in the laboratory. Abstinent smokers 
(> 12 hours) will attend four laboratory visits. Following a 7-day baseline period 
of usual brand smoking at home, smoking session 1 will measure reinforcement 
of one’s usual brand cigarette via ad-libitum smoking, where subjective response 
(satisfaction, craving reduction, psychological reward, sensory effects like throat 
hit), smoking exposure (CO boost), and behavior (number of puffs, puff volume) 
will be measured. Following smoking session 1, participants will then undergo 
two experimental conditions (counterbalanced) in their home environment and the 
lab for 7 days each: (1) 7 days smoking menthol VLNCs; (2) 7 days smoking non-
menthol VLNCs. Participants will be instructed to switch their usual cigarette for 
the assigned cigarette for each 7-day period (allowing for other product use during 
that time without specific instruction to model real world behavior). Each 
condition will be separated by a 7-day wash-out period. On the last day of each 
condition (smoking Visits 2 and 3), participants will smoke the assigned research 
cigarette in the laboratory, and data on subjective response, smoking exposure, 
and behavior will be measured. Hypothesis: Craving reduction and positive 
subjective response will be greater for menthol VLNCs compared to non-menthol 
VLNCs, but lower compared to usual brand. 
Aim 2: Determine the influence of menthol flavoring on smoking reinforcement 
in the context of a reduced nicotine standard in the natural environment. During 
each 7-day period of exposure, participants will complete assessments of cigarette 
and other tobacco use, withdrawal, and subjective response (satisfaction, craving 
reduction, reward, sensory effects) via twice-daily EMA. Hypothesis: Cigarettes 
per day, craving reduction, and positive subjective response will be greater for menthol 
versus non-menthol VLNCs, but lower compared to usual brand. Per previous work, 
ATP use will be greater in both VLNC conditions compared to usual brand. Effects of 
menthol vs non-menthol VLNCs on withdrawal, mood, cigarette compliance, and ATP 
will be compared. 
Aim 3: Determine the influence of a menthol flavor ban on tobacco purchasing 
behavior in the context of a reduced nicotine standard using an ETM. At Visit 5, 
participants will complete two ETMs in the laboratory to model the impact of menthol 
flavoring and nicotine content on cigarette purchasing in the context of all available 
tobacco products currently on the market. ETM 1 will evaluate willingness to purchase 
and smoke non-menthol VLNCs at increasing prices under the scenarios where a 
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nicotine reduction policy is in effect and menthol is banned in combustible cigarettes. 
ETM 2 will evaluate willingness to purchase and smoke menthol vs non-menthol 
VLNCs at increasing prices under the scenario where a nicotine reduction policy is in 
effect but menthol in combustible cigarettes is available. In both ETMs, all ATPs will 
be available in different flavors, including menthol, to simulate the real-world 
marketplace. Hypothesis: In ETM 1, YAs will be more likely to choose an ATP than 
purchase any cigarettes. In ETM 2, YAs will be more likely to purchase menthol 
VLNCs or ATPs than purchase non-menthol VLNCs or no tobacco products. 
Exploratory Aim: Determine the influence of a menthol flavor ban on tobacco 
purchase behavior when menthol is banned in all combustible tobacco products 
(cigarettes, cigars), but is available in non-combustible products (e.g., e-
cigarettes). 
The proposed research design is unlike existing research, as it combines rigorous, 
controlled laboratory paradigms of smoking response with “real-world” 
measurements of the same to determine the relative impact of menthol 
characteristics and nicotine on cigarette smoking in YAs, a vulnerable group of 
tobacco users, and adults aged 26-34, who also have high rates of menthol 
cigarette use.  Beyond informing policy, this proposal will validate a new set of 
measures to be used in future studies to evaluate the potential impact of tobacco 
policies (e.g., a ban on all flavors) on YA cigarette and alternative tobacco use 
behavior.
B.
Background and Significance
Menthol cigarette smoking is linked to initiation and progression in young adults 
(YAs). Although the US Food and Drug Administration (FDA) banned 
characterizing flavors in cigarettes, menthol cigarettes are still available to 
consumers. The FDA has recently released an Advanced Notice of Proposed Rule 
Making (ANPRM) seeking comment on the role of menthol, with the potential for 
menthol to be limited or banned in some or all tobacco products. Recent studies 
show that menthol cigarette smoking has increased in young adults (YAs; defined 
here as ages 18-25) and adults aged 26-341, while non-menthol smoking has 
decreased in this age group.1,2 Further, national data show that the majority of new 
YA smokers initiate with a menthol cigarette3 and that menthol cigarettes are the 
most popular flavored tobacco product used by YAs and adults aged 26-34.17,18 
Menthol flavoring has been hypothesized to mask the harshness of inhaled 
cigarette smoke,19,20 making it easier for new users to initiate smoking.21,22 This 
likely enhances their appeal and increases curiosity and experimentation with 
smoking. Experimentation with menthol cigarettes is linked to progression to 
regular smoking and greater nicotine dependence compared to experimentation 
with non-menthol cigarettes.1,4,5 
Very low nicotine cigarettes (VLNCs) may improve public health. The FDA has 
announced its intention to set product standards to reduce the nicotine content in 
cigarettes available in the US to a minimally addictive or non-addictive level7 as a 
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strategy to promote smoking cessation and consequently reduce smoking-related 
harm among adult smokers.8,9 This regulatory action may also deter initiation and 
uptake of cigarettes by reducing their overall appeal to younger users.23 Previous 
clinical trials, including work conducted by our own study team, report reductions 
in cigarettes per day , biomarkers of toxicant exposure, and increases in smoking 
quit attempts among adult and adolescent smokers24-29 using very low nicotine 
cigarettes. Notably, a low nicotine product standard will apply to all available 
cigarettes on the market; including menthol cigarettes, which account for 
approximately 30% of the cigarettes used by smokers in general. However, all 
clinical trials of reduced or very low nicotine cigarettes (VLNC) thus far have 
modeled a scenario in which menthol cigarettes are still on the market. 
Evaluations of VLNCs in younger smokers who prefer menthol, under the policy 
scenario where menthol is not available, are needed to demonstrate that FDA’s 
proposed product standard will have the intended benefit on public health, and 
deter initiation and uptake.11,30,31
Gaps and limitations in the literature. Although reducing nicotine is likely to 
reduce smoking in established smokers, it is not known how a menthol ban may 
interact with a low-nicotine product standard to alter smoking behavior in 
inexperienced smokers who prefer menthol cigarettes. Thus, a key unanswered 
question is whether menthol sustains or increases the reinforcing properties of 
cigarette smoking despite a low-nicotine product standard. If smoking VLNCs 
compared to normal nicotine cigarettes (NNCs), regardless of flavor type 
significantly reduces appeal and use of cigarettes, then FDA’s implementation of 
market-wide reductions in cigarette nicotine content could be an effective means 
to reduce initiation and progression of cigarette use among younger users - 
specifically those who prefer smoking menthol cigarettes - without the need for a 
menthol ban. However, if menthol VLNCs remain more reinforcing and appealing 
than non-menthol VLNCs, this would indicate that some aspect of menthol 
maintains smoking behavior even in the absence of nicotine, and further supports 
FDA’s regulatory authority to ban or limit menthol in cigarettes, in addition to 
market-wide reductions in nicotine content of cigarettes. 
Understanding the abuse liability of menthol VLNCs in young adults and adults 
who have high rates of menthol cigarette smoking. The subjective appeal and 
reinforcing effects of smoking are important indicators of the neurobiological 
systems that underlie addiction and abuse liability,32 and have been shown to 
motivate subsequent smoking. While controlled investigations have examined the 
differential reinforcing effects of smoking VLNCs vs NNCs, 24-29 the majority 
have focused on established adults smokers but omitted  YA new smokers, and 
few, if any, have specifically examined differential appeal for smoking menthol 
vs non-menthol VLNCs.6 This is particularly noteworthy given the highly 
appealing nature of menthol cigarettes as a “starter product” for YAs and tobacco 
company literature suggesting high curiosity and appeal for flavors in this age 
group.22 Further, recent evidence shows that menthol cigarette smoking has 
increased in popularity in adults ages 26-34. Notably, Co-I Cassidy and 
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colleagues24 found significantly greater reduction in positive effects of using 
VLNCs among YA smokers compared to older adult smokers, suggesting that a 
reduced nicotine standard could reduce smoking reinforcement in this vulnerable 
population. However, this study did not examine whether menthol VLNCs remain 
more appealing than non-menthol VLNCs. Establishing a link between menthol 
cigarette appeal and the nicotine content of those cigarettes in younger users is 
crucial for determining the abuse liability of menthol VLNCs and the effects of 
banning menthol in addition to reducing nicotine in cigarettes on population 
health. 
Drawing on the Dual-Reinforcement Model of Smoking as the scientific premise 
to understand the effects of a menthol ban on a reduced nicotine standard,33 this 
study uses a multi-method design to measure appeal/reinforcement and abuse 
liability of menthol vs non-menthol VLNCs that addresses prior studies’ 
methodological limitations and will inform FDA regulation of tobacco products. 
We will recruit 172 menthol smoking YAs and adults aged 26-34 who started 
smoking regularly (“somedays/everyday”) < 6-months ago, and assess 
appeal/reinforcement to smoking SPECTRUM menthol and non-menthol VLNCs 
(0.4mg/g) and the impact of smoking appeal/reinforcement on tobacco purchasing 
behavior using a validated Experimental Tobacco Marketplace (ETM) task.13-16 
The ETM will allow us to anticipate how smokers will respond to new product 
standards and policies after experimenting with these products: one in which 
nicotine in cigarettes is reduced; and one in which nicotine in cigarettes is reduced 
and menthol is banned. Appeal/reinforcement will be assessed via complementary 
measurement paradigms: one in the laboratory using puff topography measures 
and the other in the natural environment, using ecological momentary assessment 
(EMA). 
An additional 88 participants will be added to the study recruitment analytic 
sample size goal of 172 YA ages 18-26 and adults aged 26-34 years to 
accommodate for participants found ineligible at baseline. Therefore, the total 
enrollment (as defined by The University of Oklahoma Health Sciences Center 
Institutional Review Board) goal will be a maximum of 260 YA ages 18-26 and 
adults aged 26-34 years "someday/everyday" menthol smokers.
After smoking their preferred/usual brand in their home environment for 7-days 
(baseline period) and then in the laboratory ad libitum, participants will undergo 
two experimental conditions of smoking menthol and non-menthol VLNC 
SPECTRUM cigarettes (order of administration will be counterbalanced) in their 
home environment for 7 days each and then in the lab. The two experimental 
conditions will be separated by a 7-day wash-out period, where they will be asked 
to smoke their usual brand, as usual. On the last day of each experimental 
condition, 12-hour abstinent participants will smoke the assigned research 
cigarette in the laboratory, and data on toxicant exposure (i.e., boost in exhaled 
carbon monoxide), appeal/reinforcement (i.e., subjective response), and smoking 
topography measures will be collected. During each 7-day period of exposure and 
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take home use of SPECTRUM cigarettes, participants will be instructed to switch 
their usual brand cigarette for the assigned study cigarette and will provide daily 
data on cigarette use, withdrawal, craving, alternative tobacco use, and subjective 
response to smoking via two random EMA prompts per day. We will allow for 
other tobacco product use during the 7-day take home period without specific 
instruction to align with real-world scenarios, as these products will exist on the 
market even if a menthol ban and/or a reduced nicotine standard are enacted. We 
will examine differences in alternative tobacco product use by study condition in 
exploratory analyses. 
At the conclusion of the laboratory and take-home phases, participants will 
complete two ETMs in the laboratory. The ETM will assess reinforcing value of 
the study cigarettes smoked by the degree to which they are willing to pay for 
these study cigarettes at increasing prices, when all other available tobacco 
products on the market are offered at a fixed price. Participants will be shown a 
virtual “marketplace” of combustible and non-combustible tobacco products and 
will be given the option to make purchases of, and take home, the products they 
would like to use for the week, under two policy scenarios: (1) where menthol and 
non-menthol VLNCs, but no NNCs or usual brand cigarettes are available in the 
marketplace, thus modeling a reduced nicotine standard and no menthol ban (on 
combustible cigarettes); and (2) where non-menthol VLNCs are available, but 
menthol VLNCs and NNCs or usual brand cigarettes are not available; thus 
modeling a reduced nicotine standard with a menthol ban on combustible 
cigarettes. Participants will receive account balances approximately equal to the 
money they would spend on a week’s worth of tobacco. In both ETMs, all 
alternative tobacco products will be available in menthol and other flavors that are 
popular. They can purchase as many or few tobacco products as their account 
balance allow, including no tobacco products; they can ‘save’ unspent spends. 
Thus we are able to model the possibility of switching and quitting behavior in 
response to a nicotine and menthol ban product standard. Participants will be re-
contacted 30-days after the ETM visit to assess whether smoking and other 
tobacco use has returned to baseline levels, and cessation services will be offered.
Due to restrictions on in-person sessions because of COVID-19, virtual sessions 
will be offered. See section Protocol Modifications in Response to COVID-19 
below for more detail. 
This proposal will answer important policy relevant questions about the ways in 
which menthol smokers could be influenced by FDAs regulatory actions to bring 
VLNCs to the market AND ban menthol in combustible cigarettes. If smoking 
menthol VLNCs translates into greater appeal and cigarette consumption relative 
to smoking non-menthol VLNCs in YAs and adults aged 26-34 who are new to 
smoking, this provides further evidence that menthol in cigarettes, even with low 
levels of nicotine, could be a public health hazard. This would support FDA’s 
authority to take additional regulatory actions toward the distribution, 
manufacture, or marketing of menthol to improve public health. These actions 
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could include extending the flavored cigarette ban to cigarettes (distribution), 
restricting menthol cigarette sales to adult-only venues (distribution), limiting the 
amount of menthol allowed in cigarettes (manufacture), and reducing menthol 
appeal through public health campaigns or warnings (marketing). 
Conceptual Framework and Scientific Premise. 
The scientific premise for this study relies on Dual-Reinforcement Model of 
Smoking.34 According to this model, nicotine has two key effects on reinforced 
behavior: (1) nicotine acts as a primary (unconditioned reinforcer) that can 
support the establishment of associated stimuli as conditioned reinforcers, and (2) 
nicotine enhances the effectiveness and reward value of non-nicotine reinforcers 
directly, through non-associative mechanisms.  The latter is exemplified by 
studies in which nicotine, administered in a manner unrelated to any cues or 
behavior, increases operant responding for both unconditioned and conditioned 
reinforcers.35-38  As applied to the current study, this model proposes that menthol 
smoking is a function of menthol acting as a conditioned reinforcer, as a 
consequence of its association with nicotine (and possibly other primary 
reinforcers, e.g., sweeteners) and because nicotine may further enhance the 
conditioned reinforcing effects of menthol.  
Tobacco companies have long manipulated the sensory characteristics of 
cigarettes, including menthol, to encourage smoking.39-44 Menthol adds a pleasant 
minty flavor to tobacco and it also imparts a cooling and anesthetic sensation in 
the mouth and throat, masking the harshness of inhaled cigarette smoke.12 The 
conditioned reinforcing effects of the sensory aspects of smoking and nicotine 
delivery, when paired with the pleasurable taste and sensory effects of menthol 
(e.g., throat grab) enhances the rewarding effects of smoking (conditioned 
reinforcer).32,33 This pairing between nicotine delivery and menthol likely 
strengthens the learned association between smoking and reward, beyond nicotine 
alone. As such, even low doses of nicotine paired with menthol could maintain 
the potency and reinforcing value of smoking because menthol is naturally 
pleasant, or because menthol has become a conditioned reinforcer that will 
perpetuate smoking behavior even in the absence of nicotine. If this were the case, 
it could mean that FDA’s attempts to reduce nicotine in cigarettes may have little 
impact on reducing appeal to smoke if menthol is not also targeted. This has not 
yet been examined.
Our hypotheses about the subjective appeal /reinforcing value of menthol and the 
effects of this appeal/reinforcement on response to smoking VLNCs in YAs and 
adults aged 26-34 are based on the Dual-Reinforcement Model of Smoking and 
on research in this age group that shows the following. (1) YAs score particularly 
high on self-report measures of hedonism (i.e., motivated by a strong desire to 
engage in pleasure-seeking and reward-enhancing behavior) - a central factor of 
our theoretical model – and hedonism in this age group is correlated with and 
predicts future health-risk behaviors, including tobacco use.45-48 (2) Our own 
analysis of data from the PATH study, which shows that youth and YAs who 
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initiate smoking with a menthol cigarette are more likely to report a pleasant first 
smoking experience;49 and this pleasant first smoking experience is associated 
with increased odds of reporting past 30-day cigarette smoking and past 30-day 
use of non-cigarette tobacco products.49 (3) Literature reviews of tobacco 
company documents reporting that menthol cigarette marketing campaigns and 
tobacco companies continue to target consumers, particularly younger ones, with 
themes of freshness, coolness, crispness and cleanliness,22,44,50-52 all positive 
sensory aspects that were used by YA menthol smokers to describe menthol 
smoking in a recent qualitative study.49,53 and (4) recent evidence showing a rapid 
increase in menthol cigarette smoking among adult smokers ages 26-34. Thus, we 
hypothesize that YAs will show higher levels of appeal and reinforcement for 
menthol vs non-menthol VLNCs, both in the laboratory and via EMA, and 
appeal/reinforcement for menthol will be linked to purchase behavior on the 
ETM. Findings from this previous research and our theoretical model provided 
the foundation for our methodology and design.
A.3. Complementary Measurements of Cigarette Appeal/Reinforcement
Laboratory Assessment – Absolute Appeal/Reinforcement. Laboratory studies 
provide a great deal of efficiency and internal control, allowing for causal 
inference of exposure to toxins in tobacco smoke and acute subjective response to 
smoking as a function of how a cigarette is smoked (e.g., puff volume, duration of 
smoking, number of puffs), information that cannot be captured through 
subjective self-report. Assessing cigarette smoking in the laboratory allows for the 
detailed and precise measurement of a range of puffing behavior (e.g., puff 
volume, inter-puff-interval) in responses to different cigarette types; product 
factors on which tobacco companies capitalize.22,44,50,54 Previous research shows 
that smoking behavior in the laboratory predicts changes in plasma nicotine and 
exhaled CO, and differences in subjective assessments of the tobacco product 
being measured, including studies of VLNCs.44,54-57  These laboratory studies 
have led to an understanding of the craving reduction and satisfaction differences 
across menthol and non-menthol cigarettes and the thresholds of menthol and 
nicotine on subjective responses to cigarette smoking.56,58-64 
Ecological Momentary Assessment (EMA) – Subjective Appeal. EMA allows for 
similar causal sequencing of behavior measured in the tightly controlled 
laboratory setting, but in the smoker’s natural environment. EMA has several 
advantages over survey data collection methods65: (1) data are recorded in “real 
time” and in the natural environment, enhancing external validity; (2) data are 
time-stamped, maintaining sequencing of behavior; and (3) individual as well as 
group-level behaviors can be examined with greater precision than one-time 
assessments or longitudinal assessments that are taken weeks, months, or years 
apart.66 There are discrepancies between EMA reports of substance use behavior 
and retrospective reports of the same events, indicating that data revealed through 
EMA are qualitatively different than what is collected through traditional 
retrospective reports,66-68 and would add significant value to our understanding of 
processes related to appeal and abuse liability of cigarette smoking in YAs and 
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adults aged 26-34, beyond what we already know.69 EMA provides a unique 
method to examine the effect of subjective appeal in the natural vs laboratory 
environment and the variability in ratings of appeal across cigarette type (menthol 
vs non-menthol), situations, and days. In this proposal, we will use a well-
validated smart-phone based EMA application,70-74 in which participants read 
assessment items displayed on their mobile phone screen and touch the screen to 
select answers. The PI is using this application in her ongoing R01 with YAs. 
Behavioral Economic Assessment – Relative Appeal/Reinforcement. Behavioral 
economic theory assumes that appeal, or reinforcing value for drugs is best 
measured by examining the degree of resource allocation towards drugs, and the 
extent to which consumption is sensitive to contingencies, such as price, 
availability, and/or degree of effort to obtain that drug.75,76 One recent study by 
our team’s Co-I, Dr. Cassidy, showed that adolescent smokers who used VLNC 
cigarettes following overnight abstinence demonstrated reduced behavioral 
economic demand for VLNCs relative to their usual brand.25  In this proposal, we 
use a well-validated ETM,75,77-81 which systematically manipulates the availability 
and characteristics of tobacco products that align with different policy scenarios. 
By doing so, the ETM allows for estimation of the relative impact of these 
characteristics on decision-making (e.g., desire to purchase and use the product 
with the specific characteristics) as a method of determining how these stimuli 
impact user appeal and thus reinforcing value. The ETM simulates real-world 
experiences, in which users are simultaneously exposed to multiple available 
tobacco products and can “control” their cigarette consumption by changing their 
use patterns (e.g., switching to non-cigarette products, quitting) if, for example, 
menthol flavoring and/or NNCs were to be restricted.82,83 The ETM used in the 
current proposal allows us to measure the choice of one reinforcer (e.g., menthol 
VLNCs) as a function of the presence of alternative(s) (e.g., non-menthol 
VLNCs), thus having direct policy implications.84-88 Further, in our ETM tasks, 
participants are given the option not purchase any of the available tobacco 
products, thus allowing us to model quitting behavior in response to product 
standards. The underlying assumption of the ETM is that participants are willing 
to pay more for one commodity (e.g., menthol VLNCs) versus alternative 
commodities (all other tobacco products on the market) if they perceive that 
commodity to be more appealing/reinforcing.88,89
C.
Preliminary Studies/Progress Report  
C.1. Relevant Experience and Preliminary Data. This study builds on our 
expertise and ongoing work in EMA, menthol cigarette smoking in YAs, and 
assessment of VLNC appeal in the laboratory and via behavioral economic 
paradigms with adults and adolescents. The Principal Investigator (PI), Dr. Amy 
Cohn is an Associate Professor in the Department of Pediatrics at the University 
of Oklahoma Health Sciences Center and the Oklahoma Tobacco Research Center 
(OTRC). She is an expert in the assessment of mechanisms underlying appeal for 
flavored tobacco products using laboratory and EMA paradigms, and has nearly a 
decade of experience recruiting YAs for longitudinal and observational studies of 
tobacco and other substance use behavior. She has been PI of three NIH/FDA 
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grants on flavored tobacco product use in YAs that have informed the current 
proposal; the most recent of which is a currently funded NIDA/FDA R01 that 
uses both laboratory and EMA methodologies to examine appeal for menthol and 
non-menthol NNC smoking in YA new initiates to smoking. The current R01 
proposal is a natural extension of the PI’s ongoing R01, as it seeks to examine 
menthol’s appeal on smoking under several proposed policy scenarios, which the 
PI’s current R01 does not.  
Dr. Rachel Cassidy (Co-Investigator) is Assistant Professor at the Center for 
Alcohol and Addiction Studies at Brown University. She has wide-ranging 
experience in smoking topography of nicotine and tobacco products, as well as 
measuring subjective response to smoking VLNCs in youth (ages 15-19). Her 
ongoing R01 investigates the impact of nicotine reduction on youth use of 
cigarettes and alternative tobacco products, and uses laboratory, EMA, and ETM 
assessments to determine whether and how nicotine reduction may lead youth to 
change their tobacco use behavior. Dr. Eric Donny (Co-Investigator) is Professor 
of Physiology and Pharmacology at the Wake Forest School of Medicine. His 
work focuses on understanding how nicotine functions as a reinforcer of tobacco 
use behavior. With a wealth of expertise in the proposal’s content area and 
methods, Dr. Donny will help guide the methodology and analyses to ensure 
comparability with existing clinical trials of VLNCs and assist the team in 
applying the research findings to inform FDA’s proposed policy to reduce 
nicotine in cigarettes. Dr. Rachel Denlinger-Apte (Co-Investigator) is an Assistant 
Professor in Wake Forest College of Medicine and specialized in ETM paradigms 
to assess tobacco product choices under different policy scenarios. Preliminary 
research performed by our team has informed the central questions addressed in 
this proposal and decisions about recruitment, methods, measures, and analytic 
strategies. Our experience is bolstered by the track records of our consultants Drs. 
Andrea Villanti and Dorothy Hatsukami who are experts in correlates and 
consequences of menthol cigarette smoking in youth and YAs and measurement 
of responses to VLNCs using laboratory methods, respectively. 
Dr. Cohn has extensive experience conducting NIH-funded EMA studies 
measuring tobacco and substance use behavior in adults and YAs, with protocols 
comprising 2 to 4 weeks of daily monitoring periods.111,112  She has been 
successful at recruiting participants for these studies, which have included YA 
smokers. The PI’s recently completed R21 of marijuana and tobacco co-use in 
YAs, used thrice-daily EMA for 28-days and showed an average EMA 
compliance rate of ~70%. 
Co-I Donny and Consultant Hatsukami have managed and conducted numerous 
human longitudinal laboratory studies evaluating the physiological and subjective 
effects associated with smoking VLNCs in adults. Co-I Cassidy has conducted 
several studies of the effects of VLNC use on adolescent smoking 
behavior.24,25,117 Her recent work shows that following overnight abstinence 
(using similar abstinence criteria as those proposed here), adolescent daily 
smokers (ages 15-19, N=50) who smoked one cigarette of varying nicotine 
content (15.8, 5.2, 1.3, and 0.4 mg/g of tobacco) in the laboratory rated higher 
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nicotine content cigarettes as resulting in greater reductions in craving and greater 
increases in both positive and negative subjective evaluations.24 This study 
demonstrates that, acutely, VLNCs reduce craving in adolescents as in adults, and 
are subjectively less satisfying than higher-nicotine cigarettes. Dr. Cassidy is also 
PI of an ongoing trial investigating the effects of 3-week use of VLNC vs. NNC 
cigarettes on smoking behavior, toxicant exposure, risk perceptions, and 
compensatory smoking in adolescent daily smokers (K01 CA189300). Data 
collection for this trial is ongoing. Taken together, these studies underscore the 
team’s expertise conducting human laboratory studies of response to VLNCs 
across the age continuum.58-63 Many have included the same outcome measures as 
those proposed in the current study. 
Dr. Denlinger-Apte recently completed a NIDA-funded grant (R36DA045183) 
that incorporates the ETM into a multi-session laboratory study to determine what 
alternative tobacco or nicotine products adult menthol cigarette smokers would 
purchase under conditions simulating a menthol cigarette ban. 
Research Design and Methods (What, When, How, Where)
1. Identify sources of research material in the form of biospecimens, records 
and/or data from interaction with participants.
Data will be acquired through self-report questionnaires, biochemical 
measures (expired carbon monoxide), laboratory smoking procedures, and 
laboratory choice procedures (ETM). Biochemical measures will be collected 
for research purposes only: exhaled carbon monoxide levels, measured with a 
smokerlyzer machine, either handheld or iCO (Covita) that can be connected 
to a smartphone.
2.
 Describe study design, including sequence and timing of study 
procedures. Distinguish research procedures from those that are routine 
care. Provide a flow diagram or timetable.
C.4 Overview and Experimental Design. This study will take place in the 
laboratory at the Health Promotion Research Center (HPRC), which is 
specifically designed for the observation and measurement of tobacco use 
behavior (virtual sessions will be offered due to COVID-19). After a pre-
screen/baseline session, participants will abstain from cigarette smoking and other 
nicotine for > 12-hours (CO-verified ≤6 ppm or >50% reduction in CO from 
baseline, per Dr. Cassidy’s research with adolescents) prior to each of three 
laboratory smoking visits (scheduled around the same time of day). Participants 
will also be asked to refrain from using caffeine for an hour before each in person 
visit. For these visits, they will smoke their usual brand cigarette, one menthol 
SPECTRUM VLNC, and one non-menthol SPECTRUM VLNC (order of 
SPECTRUM cigarette smoking will be counterbalanced), and complete measures 
of subjective response (e.g., smoking satisfaction, craving reduction, 
psychological reward, sensory effects like throat hit), smoking exposure (CO 
boost), and behavior (topography: number of puffs, total time smoked). At the 
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fifth and final in-person visit, participants will return to the laboratory to complete 
two Experimental Tobacco Marketplace (ETM) tasks (more detail below). This 
proposal’s abstinence requirement is being used in the PI’s ongoing R01 and was 
chosen because it controls for recent smoking exposure, produces optimal levels 
of smoking motivation that are sensitive to the experimental manipulations,64,66,158 
and prevents greater attrition and non-compliance relative to more prolonged 
periods.157 The laboratory assessment protocol will follow procedures developed 
and executed in past research studies by the team members. We expect a 20% 
attrition rate over the four visits, based on the team’s experience with laboratory 
protocols lasting a similar length of time and the PI’s work with YAs.9  We expect 
a final analytic sample size of n = 138. 
The figure below is a diagram of the study visits and procedures. 
Consent
After a brief screening over the phone, individuals will be provided with a 
description of the study and procedures. Those who are qualified and interested 
will be scheduled for a pre-screen/ baseline session.  Upon arrival to the baseline 
session, a member of the research team will review the informed consent with 
eligible participants to ensure he or she understands the material covered. 
Participants will be given ample opportunity to read the consent and have any 
questions related to the consent, the study, or participation answered by the 
research team member. The participant will have the option to decline 
participation or withdraw from the study at any time. Individuals will be given as 
much time as they need to make a decision about participation. If the individual 
decides to participate, s/he will be given the opportunity to sign the consent and 
the research team member will sign as a witness. The participant will be given a 
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copy of the consent form to keep for his or her records. After completing 
informed consent, a trained member of the research team will verify age and 
negative pregnancy status (for female participants) before administering the 
medical history questionnaire and intention to quit smoking log, the Patient 
Health Questionnaire-9 and the MINI suicidal scale. A licensed clinician will 
be available or on-call for the mental screenings should a person report suicidal 
risk.
 Participants will attend five visits to the laboratory and then complete a follow-up 
assessment 30-days after their last study visit (either in person or remotely) to 
assess return to baseline smoking and other tobacco use, reactivity (e.g., behavior 
change) to EMA surveys, complete a third ETM, and will be provided cessation 
referrals. For each of the in-person smoking sessions (V2-V4), participants will be 
asked to abstain from nicotine or other tobacco use for a minimum of 12-hours. 
During all smoking sessions, participants will provide a breath sample to 
determine expired carbon monoxide (CO) level to measure smoking exposure, 
and will complete measurements of smoking topography (puff duration, puff 
volume, inter-puff interval) through a topography machine for each of three 
sessions. The baseline session will include the informed consent process 
described above, filling out questionnaires about basic demographic information, 
health history, smoking patterns and history, and attitudes about tobacco use. 
After smoking their preferred/usual brand in their home environment for 7-days 
(baseline period) and then in the laboratory ad libitum, participants will undergo 
two experimental conditions of smoking SPECTRUM menthol and non-menthol 
very low nicotine cigarettes (VLNCs) (order of administration counterbalanced) 
in their home environment for 7 days and then in the lab ad libitum. The 
experimental phases of smoking research VLNCs will be separated by a 7-day 
wash-out period, where participants will be asked to resume the same amount of 
smoking as the baseline period. On the last day of each experimental condition, 
12-hour abstinent participants will smoke the assigned research cigarette in the 
laboratory, where data on toxicant exposure (i.e., boost in exhaled carbon 
monoxide) and smoking topography measures will be collected. Participants will 
also complete questionnaires about smoking urges, withdrawal, mood, and 
subjective effects of smoking (satisfaction, psychological reward, sensory effects) 
immediately before and after smoking a cigarette at each visit. Participants will be 
compensated $35 for the baseline session or $25 if they are deemed ineligible. 
Participants will be compensated $45 for laboratory smoking sessions 2-4 if they 
are eligible and $50 for session 5. Participants can receive a $20 bonus incentive 
if they schedule and attend the first study session with 5 business days of 
completing the phone screener. 
During each 7-day take-home period of smoking SPECTRUM cigarettes, 
participants will be instructed to switch their usual brand cigarette for the assigned 
research cigarette and will provide daily data on cigarette use, withdrawal, 
smoking urge, other tobacco use, and subjective response to smoking via twice 
daily EMA, as well as other factors related to tobacco use. 
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Protocol Modifications in Response to COVID-19
To prioritize the participants’ and the study team’s health, the sequence of study 
requirements may vary due to COVID-19, rules and guidelines set by authorities 
at the National, Local, or University level.  This may mean that the in-person 
study visits may become virtual (e.g. online video calls) visits. Per our other IRB 
approved protocols (10581, 10974), the consent and baseline survey will be 
collected electronically if a participant chooses virtual sessions. Age will be 
verified before participants engage in their first smoking session if they complete 
the study remotely/virtually. 
COVID-19 accommodations for measuring smoking behavior and expired 
carbon monoxide: Remote topography will be used to allow ambulatory smoking 
behavior to be recorded remotely from the participant’s, if a session is completed 
remotely/virtually due to COVID-19. The unit will record time, puff duration, volume 
of smoke inhaled and pressure drops and calculate averages and standard deviations. 
By using this device, the study will be able to collect smoking topography remotely. 
Additionally, pregnancy tests will be sent to female participants for exclusion 
confirmation prior to virtual smoking sessions. 
Participants will also be provided a smartphone compatible portable carbon 
monoxide (CO) monitor (iCO Smokerlyzer) and asked to complete iCOs reading 
of expired CO to verify smoking status at the beginning of each virtual smoking 
session (≤6ppm or >50% reduction in CO from baseline) and exhaled CO 
(exposure) following smoking. Participants will be prompted to connect the iCO 
device to the study smartphone at the beginning of each study session. They will 
follow step-by-step instructions to complete the iCO test provided on the 
smartphone app, and can be assisted by the study staff member during the video 
call to ensure the device is used correctly. Results of these tests will be date and 
time stamped. Each participant will be provided their own iCO Smokerlyzer free 
of charge. This iCO procedure has been approved for use in several other 
OUHSC IRB-approved studies.  
Research Cigarettes. We will use combustible SPECTRUM research cigarettes 
available through the NIDA Drug Supply Program.  The VLNC non-menthol and 
menthol cigarettes will both be 0.4 mg nicotine/g tobacco. These nicotine levels were 
chosen because prior studies have shown that there is a significant reduction in 
cigarettes smoked per day and biomarkers of nicotine exposure compared to normal 
nicotine content cigarettes at this level. Further, it has been proposed that the maximum 
allowable nicotine content of cigarettes by FDA will be roughly equivalent to this 
level.2 The application to obtain research cigarettes from NIDA will be initiated once 
the OUHSC IRB has approved the study protocol, as a copy of the Institutional Review 
Board letter is required as part of this application process. 
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Pre-Screening/Baseline Session (V1): 
Following a telephone screen, potentially eligible participants will attend a pre-
screen/baseline session either in-person or remotely to confirm eligibility. After 
completing informed consent, participants will verify age, participants will be 
asked when they smoked their last cigarette, a baseline carbon monoxide 
measurement will be taken, and female participants will be asked to verify 
negative pregnancy status. Participants will then complete a medical history 
questionnaire, and asked about intentions to quit smoking, mental health with the 
Patient Health Questionnaire-9, and suicide risk using the MINI Suicide 
screening before eligibility can be confirmed. Eligibility determination will be 
made by the RA based on the inclusion/exclusion criteria. If the participant is 
deemed initially eligible, the Baseline session will immediately begin. Eligibility 
criteria will be reviewed by the PI (and the medical monitor, if necessary), to 
confirm final eligibility for the study, prior to Visit 2.  If the participant is eligible 
after Visit 1 screening procedures, the first baseline session will begin 
immediately. Participants who are ineligible will be paid $25 and will not 
complete the baseline procedures. The RA will make the initial determination of 
eligibility; final eligibility will be confirmed by the PI (and medical monitor if 
necessary), prior to Visit 2. Eligible participants will move on to complete the 
baseline surveys, which is a battery of questionnaires assessing baseline 
characteristics. After these assessments, the EMA application will be loaded onto 
the participant’s phone or a study-provided phone (at their choosing) and 
participants will be given a 10-15 minute training, as per the PIs previous EMA 
studies, on how to use the EMA platform. For 7-days following V1, participants 
will smoke their usual brand cigarette in their home environment, as per usual, 
and measurements of cigarettes per day, craving, symptoms of nicotine 
withdrawal, subjective response, and alternative tobacco use will be assessed 
twice daily via EMA. 
Smoking Session 1 (V2): Usual Brand Smoking. At the end of the 7-day 
baseline period of usual brand smoking, > 12-hour abstinent smokers (expired CO 
≤ 6ppm) or >50% reduction in CO from baseline, per Co-I Dr. Cassidy’s 
research)24 will return to the laboratory to assess absolute reinforcing value 
(ARV) of their usual brand cigarette by having participants smoke one of their 
usual brand cigarettes (ad libitum) through a transducer-based smoking 
topography data collection device. The instrument records puff volume, duration 
and velocity and inter-puff interval for each puff and their aggregate averages. 
These puff topography measures are useful indices of smoke exposure and are 
sensitive to differences in smoking behavior that may occur between different 
cigarette flavoring types.59,61,124 Puff topography measures will be used to 
examine whether increased puff volume, duration, and lower inter-puff interval 
differ across cigarettes as a measure of compensation. Prior to smoking 
participants will be asked when they smoked their last cigarette. Immediately 
before and after smoking the following measurements will be taken: heart rate and 
blood pressure will be assessed (heart rate, but not blood pressure, will be 
collected for remote sessions), and exhaled carbon monoxide (CO boost). 
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Subjective response to smoking (craving reduction, psychological reward, 
satisfaction, sensory effects) using the Modified Cigarette Evaluation 
Questionnaire (mCEQ138-140) in addition to the Nicotine Drug Effects 
Questionnaire (N-DEQ), the Duke Sensory Questionnaire (DSQ), and the 
Minnesota Nicotine Withdrawal Scale (MNWS) will be measured immediately 
after smoking. Exhaled CO will be collected via a Smokerlyzer CO detector 
(Bedfont Scientific LTD), and measured in ppm immediately before and 10 
minutes after smoking. CO boost has been used in previous studies141,142,143  to 
index smoke exposure, and will be calculated as the difference between pre- and 
post-smoking levels. 
At the end of V2, participants will receive the first set of assigned research 
cigarettes and will be asked to smoke those cigarettes in their home environment 
for 7 days; starting on the day after V2 The ordering of flavor of the research 
VLNCs to be smoked (menthol and non-menthol) will be counterbalanced and 
assigned prior to Visit 2 (Individuals who complete the session remotely will be 
scheduled for a pick-up date to get the VLNCs1). During each 7-day period of 
exposure, participants will be instructed to switch their usual brand cigarette for 
the assigned research cigarette and will provide daily data on smoking quantity, 
craving, withdrawal, subjective response, and alternative tobacco product use via 
twice daily EMA surveys. We will allow for other tobacco product use without 
specific instruction to align with the real-world scenario, as these products will 
exist on the market even if a menthol ban and/or a reduced nicotine standard are 
enacted.  Given the high prevalence of dual and poly-tobacco use in this age 
group, we will examine change in alternative tobacco product use between 
conditions as a secondary outcome in exploratory analyses, per Co-I Cassidy’s 
and Donny’s previous work. Participants will have a 7-day period wash-out 
period of return to smoking as usual (own brand of cigarette) between the 
experimental conditions. 
 
Smoking Sessions 2 and 3 (Visits 3 and 4): Research Cigarettes.  Study Visits 
3 and 4 (V3-V4) will be identical to each other.  Participants will return to the 
laboratory for V3 and V4 at the end of each 7-day period of using the assigned 
research cigarette in their home environment, and smoke that assigned research 
cigarette in the laboratory . At each visit, participants will be asked to abstain 
from cigarette smoking or other nicotine for > 12 hours (verified by expired CO ≤ 
6ppm or >50% reduction in CO from baseline, per Dr. Cassidy’s research. 
Additionally, prior to smoking participants will be asked when they smoked their 
last cigarette.).24 Before smoking the assigned research cigarette, participants will 
complete a cigarette purchase task (CPT), a behavioral economics-based 
measure of cigarette reinforcement, which assesses hypothetical demand for 
cigarettes across a range of prices, and a cross-price elasticity purchase task, 
which assesses hypothetical demand for experimental cigarettes at increasing 
prices of an individual’s preferred brand of cigarettes. Participants will also 
complete a perceived health risk survey for the study cigarettes, a predicted 
behavior questionnaire, an expected utility questionnaire, the American 
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Thoracic Society Questionnaire, and heart rate and blood pressure will be taken 
before smoking. They will smoke one assigned research cigarette ad libitum at 
each visit. Puff topography, subjective response, heart rate and blood pressure, 
and CO boost will be collected. After smoking, participants will complete the 
Modified Cigarette Evaluation Questionnaire (mCEQ138-140), the Nicotine 
Drug Effects Questionnaire (N-DEQ), the Duke Sensory Questionnaire 
(DSQ), and the Minnesota Nicotine Withdrawal Scale (MNWS). At the 
conclusion of visit 4, participants will be asked to participate in a brief assessment 
to query about satisfaction with and reactivity to the daily EMA survey (post-lab 
and post-EMA reactivity questionnaire).
EXPERIMENTAL TOBACCO MARKETPLACE (ETM)
C.6. Laboratory Visit 5 (V5) and ETM Procedure. Participants will complete 
the ATSQ, mFTQ, MNWS, and QSU after which two separate ETM3-6 tasks 
(counterbalanced) will be administered at the conclusion of the laboratory and 
take home trials (V5) to >12 hour abstinent participants. In the tasks, participants 
will be shown an online virtual ‘marketplace’ of cigarettes and all combustible 
and non-combustible tobacco products that are available on the market. 
Participants will be instructed to complete the task as if they were purchasing the 
products from a retailer, and told to make purchases of cigarettes and/or 
alternative tobacco products that they would take home and use for the week. The 
price of cigarettes will increase over eight trials ($0.12, $0.25, $0.50, $1.00, 
$2.00, $4.00, $8.00, and $16.00 per cigarette). The prices of alternative products 
available on the market will remain fixed, and will reflect the average cost of 
these products in Oklahoma. The first iteration of the task (ETM 1) will assess 
participant’s willingness to purchase non-menthol VLNCs at increasing prices, 
where no other types of cigarettes will be available (e.g., menthol NNCs; menthol 
VLNCs); this will model a scenario where a nicotine reduction policy is in effect 
and menthol in combustible cigarettes is banned. Findings from ETM 1 will 
inform FDA whether the presence of menthol-containing tobacco products, 
beyond cigarettes, leads to significant changes in combustible and non-
combustible product use. The second iteration of the task (ETM 2) will assess 
participant’s willingness to purchase menthol VLNCs at increasing prices, where 
non-menthol VLNCs are available but no other cigarette types (e.g., NNCs) are 
available; this will model a nicotine reduction policy without a menthol ban. The 
prices for non-menthol VLNCs in ETM 1 and menthol VLNCs in ETM 2 will be 
presented at increasing prices. All alternative tobacco products presented in the 
ETMs will be available in different flavors, including menthol, to simulate the 
real-world marketplace. 
Participants will receive account balances approximately equal to the money they 
spend on tobacco in one week. They will be instructed that they can ‘save’ 
unspent money, and purchase as many or few tobacco products as their account 
balance allows, including no tobacco products at all. Results of the ETM will not 
be actualized – meaning the ETM will be hypothetical and they will not receive 
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the products in their account. Real-world brands of each product type will be 
presented in the ETM and chosen from those with the highest grossing product 
sales at the time of funding. The ETM tasks will serve as a controlled assessment 
of tobacco decision-making processes (e.g., alternative product use behavior) to 
be compared with patterns of product use generated from laboratory and EMA 
assessment in the field. 
Participants can complete the ETMs in person or remotely, online.  
The following images of tobacco/nicotine products will be shown in the ETM:
a) SPECTRUM Study cigarettes menthol OR non-menthol flavors, depending on 
the ETM;
b) Little cigars
c) Cigarillos 
d) E-cigarettes (e.g., cigarette-like systems such as Juul and tank-like systems 
such as NJOY prefilled tanks)
e) Snus;
f) Conventional smokeless tobacco products
g) Non-prescription medicinal nicotine (e.g., 2mg and 4mg nicotine gum; 7, 14 
and 21 mg nicotine patch) menthol and regular flavors
h) Large Cigars
i) Hookah/shisha
j) Tobacco free nicotine pouches
30-DAY FOLLOW-UP
A month (30-days) after the final study visit, participants will complete the 
smoking stages of change, mFTQ, and ATSQ before completing a third ETM in 
which will assess appeal for non-menthol VLNCs in the scenario where menthol 
is restricted in all combustible tobacco products. Thus, the only product in which 
menthol would be available in ETM 3 is e-cigarettes. After that, participants will 
complete a brief survey indicating whether smoking and other tobacco use has 
returned to baseline levels (End of Study Questionnaire). This 30-day follow-up 
will be offered face-to-face or remotely. at the participant’s preference. They will 
also be provided cessation referrals. 
C.4.e. Research Cigarette Compliance. Co-I’s Cassidy and Donny, and 
Consultant Hatsukami all have extensive experience measuring and analyzing the 
impact of noncompliance with research cigarettes in similar trials,26,144 and their 
expertise will help ensure that non-compliance is mitigated and controlled to the 
best extent possible using the following methods. (1) Compliance with research 
cigarettes has been demonstrated to increase when incentives are provided for 
using them. This incentive will be a payment made at each in-person session. To 
reduce distribution, hoarding, and/or overconsumption, participants will also 
receive a nominal payment for returning unused cigarettes ($0.25/cigarette up to 
$20 maximum per participant).  Participants will be instructed to return all unused 
cigarettes and empty cigarette packs to the laboratory each week.  At each study 
visit, participants will also be asked to bring all used study and non-study 
cigarette butts that they have smoked for the past 7 days. They will be given 
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plastic bags labeled with their study ID number and calendar dates; a single 
plastic bag will be used to collect the butts for a single day. The payment schedule 
for returning research cigarettes (smoked or unsmoked) at each in-person visit (in 
the form of used butts) is as follows: 75-100%, $7; 50-74% returned, $5; 25-49% 
returned, $2.50; and 0-24% returned, $0. Participants can receive $1 for each 
returned empty pack, up to $5 maximum. The team has used this strategy to 
incentivize product accountability in other studies with success. Honesty of 
reporting will also be encouraged throughout the study. We will examine 
concordance between EMA reports of cigarettes per day and number of cigarettes 
returned to verify compliance. (2) Unfortunately, as participants’ usual brand 
cigarettes will exist in the real world, noncompliance can be an issue in all such 
studies of this kind.145 However, noncompliance can be used as an index of 
dissatisfaction with reduced-nicotine cigarettes.146 Differences in noncompliance 
across research cigarette conditions will be examined in exploratory analyses in 
an effort to inform the application of a reduced nicotine product standard and a 
menthol cigarette ban to age groups that prefer menthol cigarettes.
C.4.f. Research Cigarette Distribution and Accountability.  Participants will 
be given enough cigarettes to accommodate usual smoking patterns until the next 
visit in 7 days (125% of their baseline cigarettes per day, based on the team’s 
previous work). At V2, participants will report the number of cigarettes smoked 
per day. Based on this number, staff will calculate the number of SPECTRUM 
cigarettes needed to provide the participant for each 7-day experimental period (# 
of own cigs smoked per day x 125% x 7 days). At each in-person visit, research 
staff will complete a ‘Product Accountability Log’ with participants to record 
used and unused cigarettes.  Any discrepancies in the product dispensed versus 
product returned will be discussed and recorded in the log.  Participants will be 
surveyed about desire to quit smoking at each in-person visit. If they endorse that 
they wish to quit, they will be asked if they still want to receive research 
cigarettes. If they do not, no study cigarettes will be dispensed and the participant 
will be retained in the study with no penalty and will continue to complete all 
subsequent EMAs, the ETM, and the 30-day follow-up. Changes in desire to quit 
and actual quitting behavior will be examined as an outcome in exploratory 
analyses, where sample size allows. In her ongoing R01, Co-I Cassidy dispenses 
research cigarettes in this manner to 15-19-year-old daily smokers with approvals 
from the FDA and her institutional IRB. 
Measures Descriptions
Participants will complete validated measures from the PhenX Toolkit and the 
team members’ published studies. The following domains will be assessed in the 
baseline survey: (1) demographics; (2) Tobacco use patterns (age at first use; 
nicotine dependence (time-to-first use and mFTQ),145-146 cigarettes per day; 
alternative tobacco product use; motivation to quit and quit history; peer tobacco 
use; tobacco marketing/media exposure133-136; and weekly tobacco expenditure; 
(3) Self-reported appeal of menthol cigarettes; (4) Harm perceptions of 
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menthol/non-menthol cigarettes; (5) Knowledge and attitudes about nicotine and 
VLNCs; (6) self-reported skin color; (7) cultural identification and experiences of 
discrimination; (8) delayed discounting, and (9) factors associated with tobacco 
use (stress, alcohol, marijuana, drug use). Positive and negative characteristics of 
cigarette smoking will be measured.137 Positive characteristics will include: 
satisfying, fun, exciting, interesting, smell good, taste good, friends would like, 
stimulating, good with a drink, sophisticated, mature, and mild. Negative 
characteristics of appeal will include: hard to quit, cause cancer, dangerous, bad 
breath, stupid, addictive, make me cough, harsh, and make me nauseated. 
Because of the high prevalence of menthol cigarette smoking among 
Black/African-American smokers, multiple dimensions of skin color will also be 
assessed objectively using a dermaspectrometer,7 which is a non-invasive tool that 
measures that amount of melanin in the skin.  Dermaspectrometer skin assessment 
will be taken one time, either during a study visit, or at a curb-side pickup or 
dropoff, if the study is taken remotely. 
Respiratory symptoms will be assessed using the American Thoracic Society 
Questionnaire (ATSQ)8. Participants report the frequency of experiencing each 
of 8 respiratory symptoms (e.g., morning cough, wheezing, shortness of breath 
when walking). 
Safety: Pregnancy tests will be performed for all female participants prior to 
engaging in a smoking session. The suicide subscale from the Mini International 
Neuropsychiatric Interview (MINI)9 will be used to evaluate suicide risk. A 
licensed clinical practitioner will be available to conduct the mental health 
assessment (see section F). CO level will be obtained at every session to evaluate 
level of exposure to smoke; a large increase in CO can be a reason for 
withdrawing a participant from the study. The Patient Health Questionnaire 9-
item version (PHQ-9)10, 11 is a widely used and validated 9-item questionnaire 
assessing depressive symptoms in the past 2 weeks. This measure will be used for 
sample description given the high co-occurrence of smoking and depression and 
will be used to screen out individuals with moderately severe and severe 
depression. Brief Medical History assesses physical and emotional health to 
establish eligibility for participation. In subsequent, sessions, the Health Changes 
Questionnaire asks whether the participant experienced any changes in his/her 
physical or emotional health since their last visit, including whether they have 
visited the doctor, the hospital, or whether they have had a change in any of their 
medications. Any endorsement of a negative health change will be tracked as an 
adverse event. The Adverse Events Questionnaire asks about adverse events 
experienced since the last visit. 
Past 7-day tobacco use will be measured in two different ways. First, at V2 (as 
part of the cigarette distribution and accountability log) past 7-day tobacco use 
will be comprehensively assessed using a Timeline Follow-Back (TLFB) 
technique, a reliable calendar-assisted interview validated for estimating daily use 
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of tobacco and other substances.12-14 The TLFB will determine: # cigarettes per 
day; and frequency and quantity of use of all other tobacco products at baseline to 
determine the number of cigarettes to be dispensed for the experimental 
conditions. The 7-day Tobacco Use Questionnaire will be administered at 
VLNC2 pick-up (between Visits 3 and 4), where there is a 7-day wash-out period 
and will ask about past 7-day menthol and non-menthol cigarette smoking, 
frequency of use of other tobacco products, quit attempts in the past 7-days, and 
use of other tobacco products to quit.
Before smoking the assigned research cigarette, participants will complete a 
cigarette purchase task (CPT), a behavioral economics-based measure of 
cigarette reinforcement, which assesses hypothetical demand for cigarettes across 
a range of prices, and a cross-price elasticity purchase task, which assesses 
hypothetical demand for experimental cigarettes at increasing prices of an 
individual’s preferred brand of cigarettes. Participants will also complete 
assessment of nicotine withdrawal and craving prior to smoking using the 
Minnesota Nicotine Withdrawal Scale (MNWS)15 and the Questionnaire on 
Smoking Urges16. Heart rate and blood pressure will be taken before smoking 
(some measurements may not be taken if sessions are completed remotely). After 
smoking, participants will complete assessments of subjective response to 
smoking with the modified Cigarette Evaluation Questionnaire (mCEQ), the 
Duke Sensory Questionnaire (DSQ), and the Nicotine Drug Effects 
Questionnaire (NDEQ). Participants will also complete the MNWS again. 
The Predicted Behavior Questionnaire will be asked at the beginning of Visits 3 
and 4, prior to when the VLNC is smoked. It asks participants to indicate their 
intentions to use cigarettes and other tobacco products when cigarettes have lower 
nicotine content and come menthol or non-menthol flavor. The Expected Utility 
Questionnaire will also be administered at Visits 3 and 4, before participants 
smoke. This questionnaire asks the degree to which participants would use the 
study cigarettes they just smoked for the past week (menthol or non-menthol) 
would help them quitting, be less dangerous than smoking, give up tobacco use, 
smoker fewer cigarettes, etc. 
Participants will report their perceptions of the health risks associated with both 
their usual brand and their study cigarette brand using the Perceived Health 
Risks Assessment.17
ECOLOGICAL MOMENTARY ASSESSMENT (EMA)
C.5 EMA Procedure. Participants will record cigarette smoking and alternative 
tobacco use, craving, symptoms of withdrawal, and subjective ratings (e.g., 
satisfaction, reward, craving reduction, physical sensations like throat hit) 
associated with smoking the most recent cigarette in response to 2 random 
prompts to their phone each day. We will use a mobile EMA application, in which 
participants answer a set of survey questions on their cell phone by selecting 
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responses on their mobile phone screen. Dr. Cohn is currently using this EMA 
platform in her ongoing R01 with YAs, and it has been used it in many prior 
studies of smoking behavior.71,73,74 The selected monitoring schedule was driven 
by the study aims, and will allow us to capture a random sample of smoking 
episodes and to characterize variation in smoking reinforcement, craving, and 
withdrawal within-days and across days.147,148 Asking participants to record every 
smoking episode would be too burdensome and could result in substantial 
attrition. To ensure we capture smoking episodes for smokers who may be 
exclusively stimulus-based (e.g., morning only, evening only),149 we will use an 
adaptive random prompting schedule that is programmed to coincide with the 
participant’s sleep-wake cycle (e.g., time they wake up, time they go to bed), 
which will be collected at baseline. 
Participants will be able to directly access the EMA survey upon receiving a 
prompt (vibration or “ping”) to their phone by touching the screen. EMA entries 
are expected to last ~5 minutes (based on response times in prior studies 
conducted by the PI),111,113 will be date- and time-stamped, and recorded 
immediately. To enhance compliance, we will provide detailed training on EMA 
and monetary incentives (see section 2.5. Recruitment and Retention Plan for 
more detail on monetary incentives). Pre-paid phones or reimbursement for 
cellular service will be provided (at the participant’s choosing). Pre-paid phones 
will be labeled “government property”. At the 30-day follow-up, participants will 
complete a brief survey of satisfaction with and reactivity to EMA and another 
ETM where they will select VLNCs when menthol is banned in all combustible 
tobacco products, including cigarettes, hookah, little cigars, etc., but not banned in 
e-cigarettes.
C.5.b. EMA Measures. EMA measurements will parallel the constructs used in 
the laboratory assessments (e.g., craving, subjective response) and have 
established psychometric properties.66,68,111,150-154 Subjective ratings will be 
queried using items from the mCEQ, which has been pilot tested for EMA 
deployment by the PI and is being deployed via EMA for her ongoing R01. 
Questions will also assess the use of alternative tobacco products since the 
previous assessment, characterizing flavors (e.g., fruit, chocolate), use of usual 
brand cigarettes, craving, withdrawal, and factors associated with smoking (life 
events, mood, peer use, alcohol, other drug use) that have been used in prior EMA 
studies by the PI and others. To minimize response burden, EMA will prompt 
use-relevant probes via skip patterns.  Missed EMA assessments will be 
retrospectively assessed by phone or online via a REDCap survey. 
Following are the standard procedures that have been adopted for 
OUM/OUHSC for all studies that will be facilitated in-person and would be 
utilized for this study in response to COVID-19. 
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PROCEDURE: 
1. Employees will comply with all OUHSC COVID related policies and procedures 
as currently exist and as are revised in the future.
2. Efforts will be made to minimize face-to-face time with participants. When 
possible, consents will be sent to participants at their homes and reviewed by 
phone or zoom, as available.  Additional items, including pregnancy tests, will 
also be shipped to the home, and reviewed over phone or zoom, when possible.
3. During scheduling, participants will be asked to wear a mask, if they have one 
available, to their appointments. For participants who do not have access to a face 
mask, one will be provided. They will also be asked the questions from the 
OUM/OUHSC COVID19 Questionnaire (see attached in “Other Documents”). 
4. If the patient is symptomatic or has known direct contact with a person with 
COVID-19 they will not be able to attend a study session and will be asked to 
consult with their PCP prior to re-scheduling the visit. 
5. Participants will be instructed to call from their vehicle upon arrival for their 
appointment to prevent participants from congregating in the waiting room. They 
will also be verbally asked if any of their answers from the COVID-19 
questionnaire have changed since their original completion. If the patient is 
symptomatic or has known direct contact with a person with COVID-19 they will 
be asked to reschedule their appointment.
6. If a room is not available, the participant will wait in their car and the study 
coordinator will call them once space is available. We will make every effort to 
ensure that the assigned research room will be available by spacing apart study 
sessions. 
7. Participants will have their temperature taken using a contactless thermometer 
prior to entering the facility. If the temperature is above at or above 100.0°F they 
will not be seen and will be advised to contact their PCP for further assistance.
8. Participants will not be allowed to have a second individual accompany them or 
wait in the waiting room unless previously approved for special circumstances by 
study staff. 
9. Upon entering research rooms, proper hand hygiene will be executed by study 
staff and participants. Study staff will be gloved for any touch-related interactions 
with the participant. Hand sanitizer will be available for participant use as well.
10. Staff will wear proper PPE at all times.
11. To reduce viral transmission, study staff will be seated in a separate room from 
the research participant during the visit. Communication with the participant will 
occur by video and audio connection between the staff “control room” and the 
participant’s research room.  These sessions will not be recorded. All participants 
will be placed in a negative pressure room that is specifically designed to circulate 
the air outside of the room every 10 minutes; thus reducing exposure to viral 
droplets. 
12. To reduce viral transmission during and between shifts and following interaction 
with participants, all spaces will have available cleaning products containing 70% 
ethanol to disinfect surfaces, door knobs, and equipment surfaces frequently, 
between each research participant, and at the beginning and end of a shift and 
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before and after each participant.  Common equipment in shared areas will be 
disinfected with 70% ethanol prior to and after each use. 
3. Duration and number of study visits required.
Participants will be involved in the study for approximately 2 months. There will 
be 5 in-person study visits (or virtual sessions) and a total of 21 days of daily 
monitoring of cigarette smoking behavior. There will be a 30-day follow-up after 
visit 5, that will be conducted either in person or over the telephone. 
4. Describe blinding, including justification for blinding or not blinding the 
trial.  
We considered blinding participants to the nicotine content in the research cigarettes to 
minimize the possibility that perceptions of these cigarettes may impact ratings of 
appeal/reinforcement and use behavior (e.g., compensatory behavior). We ultimately 
chose not blind participants so that we could model real-world conditions in which 
participants would be aware of the nicotine content of the cigarettes they smoke. Dr. 
Hatsukami, our consultant, is taking this same approach (e.g., not blinding participants) 
in a pilot study conducted as part of her U54. While we know about responses to 
VLNCs in a blinded scenario, findings from our study will be one of the first to inform 
VLNC work in an un-blinded scenario with young people. 
5. Include justification for inclusion of a placebo or non-treatment group.
N/A. This is not a treatment study.
6. Describe what happens to participants receiving therapy when study ends 
or if their participation in the study ends prematurely.
N/A. This is not a treatment study. 
7. Indicate where the procedures will be completed. 
All participant recruitment, enrollment and testing will occur at the research 
laboratory of the TSET Health Promotion Research Center (HPRC) in Oklahoma 
City, OK. HPRC has conducted smoking research for the past 5 years. 
8. Indicate whether clinically relevant research results, including individual 
research results, will be disclosed to participants. If so, under what 
conditions?
Females will be asked to take a pregnancy test at each in-person (or virtual) 
session prior to smoking, to determine eligibility. If a woman is pregnant, she will 
be given the results of her test immediately. If the session is completed remotely, 
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pregnancy tests will be provided to the participant before the session (mailed or 
curb-side pick-up) and pregnancy will be confirmed prior to beginning a smoking 
session.
9.
Identifiers might be removed and the de-identified information may be 
used for future research without additional informed consent from the subject.
D.
Biospecimens
Biospecimens will be collected prospectively. Biospecimens to be collected will 
be expired breath analysis of carbon monoxide level to determine smoking 
recency. This is a non-invasive procedure conducted by blowing air through a 
Smokerlyzer tube. We are also collecting pregnancy tests prior to each smoking 
visit, to determine study eligibility. Pregnancy tests will be discarded and not 
kept. All biospecimen data collection will be de-identified and associated only 
with a unique ID number. The participant’s biospecimens (even if identifiers are 
removed) will not be used for commercial profit. The research will not include 
whole genome sequencing (i.e., sequencing of a human germline or somatic 
specimen with the intent to generate the genome or exome sequence of that 
specimen). 
E.
Banking/Repository/Database
All data collected during the study will be retained for future use in tobacco and 
nicotine research. Data will be stored electronically on a secure password server 
that can only be accessed by approved study personnel. Only data, no samples, 
will be stored.  
F.
Inclusion / Exclusion Criteria
1.
Inclusion criteria for participants will include:
a.
Ages 18 to 34;
b. Smoke cigarettes “somedays” or “everyday” for at least the past 3-months; 
c.
A strong preference for menthol cigarettes (i.e., smoke menthol >80% of 
the time)124;  
d. Ability to read English at an 8th grade level or higher; and
e.
No immediate plans to quit smoking.
2.
Exclusion criteria for participants will include:
a.
Current use of nicotine replacement therapy (NRT); 
b. Pregnant, planning to become pregnant, or currently breastfeeding (verified 
by pregnancy test at each study visit/virtual smoking session); 
c.
Past or current self-reported clinically significant heart disease or 
hypertension, or other smoking-related disease (by history) that preclude 
successful study completion;
d. Serious psychiatric disorder, as evidenced by any of the following
i. Ever schizophrenia, schizoaffective disorder, or bipolar disorder;
ii. Psychiatric hospitalization in the past year;
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iii. Suicidal ideation in the past month or any past year suicide attempt
1. Suicidal ideation determined by the MINI suicide subscale 
(Questions 1-3)
2. Any suicide attempts in the past 10 years (MINI suicide 
subscales Questions 5 and 6)
iv. Suicidal intent and plan (MINI suicide subscale Question 4)
v. PHQ-9 score of 15 or higher, indicating moderately severe 
depression, if participant also indicates suicidal intent or worsening 
depression in the past 3-months. Scores of 20 or higher, indicating 
severe depression will be excluded.
vi. Worsening symptoms of depression or anxiety in the past 3-
months (as determined by Medical History Questionnaire).
If a participant indicates that he/she currently has suicidal ideation 
during the baseline or any future session, the Suicide Risk SOP 
protocol will be followed in which a Licensed Clinician will be 
contacted immediately (if that clinician is not already conducting 
the assessment). Participants will speak with the clinician in 
person, over the phone (or via Zoom) and the clinician will 
determine the appropriate action to take to keep the participant 
safe. See Suicide Risk SOP for more detail. This SOP follows the 
same protocol outlined in the OUHSC Tobacco Treatment 
Research Program (TTRP) and has been approved by the OUHSC 
IRB.
e.
Inability to abstain from nicotine/tobacco products and caffeine prior to 
study visits;
f.
Strong preference for non-menthol cigarettes (smoke non-menthol > 80% 
of the time)124
All participants will need to provide an ID that indicates their age in order to 
participate. If a participant is enrolled remotely, participants will be asked to 
email a picture of their ID to the study email, or show an image of their ID to 
study personnel via a Zoom session so it can be verified prior to being enrolled in 
the study. Eligible participants will not have immediate plans to quit smoking, and 
will be “someday” or “everyday” smokers for at least the last 3 months, thus the 
laboratory and take home smoking will confer no additional risks beyond their 
usual smoking. We will exclude individuals who report immediate plans to quit 
smoking or who are currently trying to quit smoking at the screener and baseline, 
as we do not wish to impede any active quit attempt. We will assess desire to quit 
smoking at screening and each laboratory visit, and any indication of a desire to 
quit will result in ineligibility from the laboratory phase of the study if a 
participant chooses not to continue using the study cigarettes. Participants who 
choose not to use the study cigarettes will be allowed to remain in the study and 
complete the remaining study assessments if they desire. Individuals will be 
provided tobacco cessation resources upon request or at the end of the study (if 
not provided earlier). We will exclude participants who indicate suicidal ideation 
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as the potential to undergo nicotine withdrawal may exacerbate symptoms of 
depression. All female participants will be tested for pregnancy at each smoking 
visit or session. If a participant becomes pregnant during the study, she will be 
withdrawn from the study. Individuals will be provided referrals for treatment, 
where needed or desired, and at the 30-day follow-up. Males and females of any 
ethnic or racial group are eligible to participate in the study if they meet 
inclusion/exclusion criteria.
The suicide subscale from the Mini International Neuropsychiatric Interview 
(MINI; Sheehan et al., 2010) will be used to evaluate suicide risk.  A licensed 
clinical practitioner will be on call should a participant endorse suicidal ideation, 
intent, or plan. If a participant indicates that he/she currently has suicidal ideation 
during the first or any future session, the Suicide Risk SOP will be followed in 
which a Licensed Clinician will be contacted immediately, and the participant will 
speak with the clinician over the phone, in person,  or via Zoom. The licensed 
clinician will determine the appropriate action to take to keep the participant safe.
G.
Gender/Minority/Pediatric Inclusion for Research
The research will not focus on any particular racial or ethnic group. All 
participants will be between the ages of 18 and34 due to the aims of the study. We 
expect the racial/ethnic composition of our sample will reflect the composition of 
the populations from which they are drawn. If eligible, participants will be enrolled 
without regard to gender or racial/ethnic background. Oklahoma City is diverse, with a 
population that is 15% African American and 17% Hispanic or Latino, according to 
2018 census data. We will try to recruit a sample that is 50% female so that we can 
examine sex as a moderator of study outcomes. 
H.
Recruitment and Enrollment
1.
Describe the plans for recruitment.
Recruitment will take place through the Oklahoma Tobacco Research Center (OTRC), 
now called the TSET Health Promotion Research Center (HPRC), in Oklahoma City, 
OK, using methods that have been used in previous laboratory studies at HPRC: local 
newspapers (including at local colleges/universities), online (e.g., Craigslist, Facebook, 
Instagram, Snapchat), community flyers, snowball techniques, , through mass email at 
the University of Oklahoma (mass email reaches all undergraduate students, > 
20k), and a database of interested callers from prior studies. These strategies have been 
successful at recruiting smokers across the age spectrum for a variety of studies 
conducted by the team members. Oklahoma City greatly facilitates the successful 
recruitment of YAs given its close proximity (<10-20 miles) to several colleges and 
universities, such as the University of Oklahoma, University of Central Oklahoma, 
Rose State College, Oklahoma City Community College, Francis Tuttle Technology 
Center, and Oklahoma State University. 
Social media recruitment occurs through work with Trialfacts and BuildClinical. 
Trialfacts and BuildClinical will assist with recruitment by designing and 
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managing targeted, GCP-compliant, IRB approved advertising.  Potential 
participants who express an interest will click on a Trialfacts- or BuildClinical-
generated ad and will be taken to a custom landing page created by Trialfacts or 
BuildClinical. These landing pages will offer a brief description of the study that is 
designed to convert interest into engagement. After clicking on a Trialfacts ad, 
participants will review the Trialfacts Consent to continue (attached as part of the 
Trialfacts pre-screener) and will only be able to provide their contact information 
and continue with the Trialfacts pre-screener if they select “Yes” in response to 
“Are you willing to continue.” Individuals who select “No” will not continue with 
the prescreener. Participants who click on a BuildClinical ad will be presented with 
a pre-screening form that they will complete which includes contact information so 
a research technician can contact the potential participant for additional screening.
Update about the impact of Tobacco 21 regulation on study recruitment
Because of the new Tobacco 21 regulations at the state and federal level, 
individuals under the age of 21 are currently not allowed to purchase tobacco 
products. The Governor of Oklahoma signed a bill into law (SB319) in April 2021. 
This new law went into effect November 1, 2021 and allows IRB-approved studies 
to "furnish" tobacco products to individuals ages 18 to 20. As a result, individuals 
ages 18 to 20 can be enrolled in the study and we are legally allowed to dispense 
cigarettes to individuals aged 18-20.  
2.
Describe the consent procedures to be followed 
Participants will provide verbal or electronic consent if they are screened over the 
phone or online, respectively.  Verbal consent will be obtained for participants 
completing the telephone screener. Prior to beginning the telephone screener, 
participants will be told (a) their research data provided on the telephone screen 
will be confidential and coded only with a unique identifier; (b) their personally 
identifiable information will be encrypted and can be accessed only by approved 
study personnel; and (c) there is a possible risk of loss of confidentiality although 
the risk is considered low given that research data will be de-identified.  
Eligible participants who complete the study in person will provide written 
consent in person immediately before their first laboratory visit begins. This will 
take place in our lab. We will go over every section of the consent document with 
the participant, then ask if he or she has any other questions before signing. Each 
participant will be allowed time to read the consent document and ask questions 
before any data are collected. A copy of the consent form will be given to the 
participant. 
Per our other IRB approved protocols (10581, 10974), the consent can be 
collected electronically in the event that sessions are completed virtually due to 
COVID-19. To provide consent electronically, participants will be sent a link to 
the eIC via REDCap.  REDCap has a feature which allows for version control, 
automatic time and date stamp, and electronic signature (using a fingertip, 
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computer mouse, or stylus on a tablet screen). To ensure that the eIC is presented 
appropriately and that subjects will have enough time to dedicate to the eIC 
process, an eligible and interested participant will be told by a study personnel, at 
the end of the phone screening session, approximately how long the consent 
review process will take and will review with them the information that will be in 
the eIC.  The eIC will record the timestamp of participant’s acceptance or 
declination and a copy of the signed eIC will be sent to the participant via email. 
No personal information, other than the participant’s name, will be collected in 
the eIC.  
Participants will be reminded that their participation is voluntary. Additionally, 
they will be reminded that they are allowed to discontinue participation in the 
study at any time, without any loss of benefits or other negative consequences. 
Participants will be given ample opportunity to read the consent and have any 
questions related to the consent, the study, or participation answered by the 
research team member. The participant will have the option to decline 
participation or withdraw from the study at any time. Individuals will be given as 
much time as they need to make a decision about participation. If the individual 
decides to participate, s/he will be given the opportunity to sign the consent and 
the research team member will sign as a witness. The participant will be given a 
copy of the consent form to keep for his or her records. All research team 
members will complete an approved course on the protection of human subjects 
and be trained on how to clearly describe study procedures and the obtain 
informed consent process.
Compensation
We will use several strategies to encourage completion of the study by providing 
participants: 1) a calendar of their appointments throughout the study; 2) reminder 
calls, emails, and/or texts the day prior to a scheduled session; 3) monetary 
incentives at each visit; and 4) a completion bonus.
All participants will be reimbursed for their participation via cash or reloadable 
gift card, at their preference. Participants will receive $35 for completing the 
baseline session. Participants will receive $45 for completing each in-person 
laboratory smoking visit (Visits 2-4) and $50 for the completing the final in-
person ETM session (Visit 5). Participants who attend the baseline session but are 
determined ineligible during that session will receive $25. Eligible participants 
who schedule and attend their first visit within 5 business days of completing the 
telephone screener will receive a $20 bonus.
Participants will be compensated for completing the daily surveys as follows: they 
will receive $1 for each completed EMA survey (totaling $42), a $10 bonus each 
week of EMA for completing all EMA surveys in that one week period (totaling 
$30), and a $45 bonus if they complete 85% of EMA surveys over the courses of 
three weeks. There will be a brief 30-day follow-up to assess whether smoking 
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and other tobacco use has returned to baseline levels. This 30-day follow-up 
survey will also include a post-EMA survey to assess reactivity, or behavior 
change to daily monitoring; for which they will be paid $45. Participants who 
refer an individual who is eligible and who signs informed consent to participate 
will receive a $20 referral bonus (limited to one per participant) and those who 
complete all phases of the study will be eligible for a $70 bonus. 
Per previous studies conducted by the study team’s Co-Investigators with adults 
and adolescents using very low nicotine cigarettes, participants will receive a 
nominal incentive for returning unused cigarettes, to ensure that participants to 
not hoard, stockpile, or share cigarettes with others. The compensation schedule 
for returning unused cigarettes is $0.25 per cigarette, up to $20 per participant; 
and $1 for returning empty packs, for up to $5 per participant. For returning used 
and unused cigarettes at Visits 2 and 3, participants will be compensated as 
follows: 75-100% returned, $7; 50-74% returned, $5; 25-49% returned, $2.50; 
and 0-24% returned, $0. 
Participants will receive $10 for travel for each in person visit (@ 4 visits) or $10 
for each curbside pick-up/drop-off of study materials, for a total of up to $40. 
Curbside pick-up/drop-off can be at the HPRC laboratory location or at another 
public (e.g. coffee shop, restaurant, convenience store, or shopping center) agreed 
upon location. Total possible compensation will be $571. Participants are 
compensated for returning used cigarettes so that we can accurately track and 
account for used study cigarettes and unused study cigarettes. Participants will be 
asked to provide their social security number, their residency status (permanent 
residents must provide a copy of their green card if applicable), and whether they 
are a University of Oklahoma employee for tax reporting purposes. Participants 
who are not U.S. Citizens or permanent residents or individuals who are 
unwilling/unable to provide their residency status, social security number, and 
whether they are a University of Oklahoma employee will be excluded due to the 
inability to receive study compensation according to the University of Oklahoma 
Administrative Policy Part 500 Section 557.
Table  of Compensation Schedule. 
EVENT
AMOUNT
                                                      Laboratory Visit 
Visit 1 (Pre-Screen/Baseline session)
$35
Visit 2
$45
Visit 3
$45
Visit 4
$45
Visit 5 (Experimental Tobacco Marketplace)
$ 50
Bonus for eligible referral
$20
Bonus for scheduling and attending first visit within 5 days of 
phone screening
$20
                                                              EMA
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Call completion (*42 calls)
$1/call ($42 total)
Bonus for completing all calls each week (* 3 weeks)
$10/week ($30 total)
Bonus for completing 85% of calls for 3 weeks
$45
Total possible EMA
$117
Research Cigarette Compliance
Returned used cigarettes
$7 maximum/week @ 2 weeks
Returned unused cigarettes ($0.25/cigarette)
$20 maximum/participant
Returned empty packs ($1/pack)
$5 maximum/participant 
Total possible cigarette compliance
$14 + $20 + $5 = $39 
                                                          30-Day Follow-up
30-day Follow-Up + ETM 3
$45
Travel for In Person or Curbside Pick-up/Drop-Off
$10 for each in person visit/curbside pick-up/drop-off of study 
materials @ 4 visits
$40 maximum/participant 
Bonus for completing all phases
$ 70
Maximum Total
$ 571
To enhance retention in all phases of the study, due to higher than anticipated 
loss-to-follow-up, we will offer a bonus of missed incentive amounts to 
participants who are hard-to-reach or schedule. With this bonus, participants will 
be eligible to receive missed compensation opportunities, if they complete 
remaining in-person study sessions and/or surveys. Missed opportunities may 
include the bonus for scheduling and attending the first visit within 5 days of 
phone screening ($20), the eligible referral bonus ($20), bonuses for completing 
all EMA surveys each week ($30 maximum) even if they miss some surveys, 
bonus for completing 85% of EMA surveys for 3 weeks ($45) even if they miss 
some surveys, and the bonus for completing all phases of the study ($70). 
Enhancement bonuses will be separated into $20 increments to encourage a 
participant to attend any remaining session(s) they have not completed. After the 
final in person session is complete, the participant will be eligible for all 
remaining compensation amount not already claimed, up to the maximum of 
$571, even if they may not have met the full criteria. Thus, we calculate their 
maximum bonus amount allotted to participant, and give it to them in $20 
increments (per number of sessions attended). When they complete the final 
in-person visit, they are eligible for all remaining bonus/compensation to get 
the maximum amount ($571).
Participants have the option to receive payment via Amazon Gift Card code or 
reimbursable gift card (Greenphire ClinCard). The university has a Business 
Associate Agreement with Greenphire. All participants who complete the 
baseline/pre-screen session remotely will only be paid with Amazon gift card 
code, to reduce costs associated with mailing a ClinCard to individuals who may 
not be eligible after the pre-screen session.  To set up ClinCard payments, 
Greenphire is provided the name, birthdate, and address of the participant. 
Greenphire does not have access to any research data. Participants who report a 
lost or stolen ClinCard will be given one replacement at no cost to them. The 
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replacement card will be linked to the existing account and the previous card will 
be deactivated. Participants who lose a second ClinCard will be given instructions 
to contact Greenphire to request a replacement card for a $7 fee at their own 
expense.  They may also choose Amazon gift card code for future reimbursement, 
at no cost to them.  
3.
Describe the location where consent is most likely to take place 
Consent will take place at the TSET Health Promotion Research Center.
4.
Describe provisions for recruiting non-English speaking participants. 
Non-English speaking participants will not be recruited into this study. 
5.
Describe measures to decrease participant coercion.
Several recommended approaches will be used to reduce coercion, including 
allowing participants ample time to review the consent, and using only 
qualified trained research staff to engage in the consent form process. 
Further, participants will be told at the screening and at the time of consent 
that their participant is completely voluntary. They will be reminded at each 
in-person visit, and at the 30-day follow-up that they can decline to answer 
any question and they can withdraw their participation at any time without 
penalty. Individuals will be also told at consent and reminded again at each 
in-person visit that they can decline to continue using the study product at 
any time, and still remain enrolled in the study and undergo the study 
assessments. This will reduce the potential for incentivizing continued 
smoking.
I.
Risks and Benefits
1.
Describe risks and assess their likelihood and severity.
The risks in this study are considered minimal and include (1) subjective 
discomfort from answering questionnaire items or from providing breath samples; 
(2) risk of breach of confidentiality; (3) issues of coercion; (4) discomfort from 
withdrawal (e.g., mild irritability, trouble concentrating) due to abstinence 
requirement or use of VLNCs; (5) the possibility that use of VLNC cigarettes may 
lead to compensatory smoking or use of alternative tobacco products; (6) the 
possibility of perceiving a reduced risk associated with VLNCs and smoking a 
single cigarette in the laboratory. The cigarettes smoked during the course of this 
study will be either the participant’s own brand provided by the participant, or 
SPECTRUM cigarettes, which are issued by the NIDA Drug Supply Program. 
Although smoking is associated with disease, we do not expect the disease risk to 
be significantly greater from smoking the experimental cigarettes. 
Subjective discomfort. The likelihood of experiencing subjective discomfort from 
answering questions is very low and the severity is low, based on our past and 
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current experience using similar protocols and measures with young adults in our 
research studies.  Discomfort from providing breath samples also is low based on 
past experience using these measures as well, as our assessment tool is non-
invasive. 
Breach of confidentiality. The risk of breach of confidentiality is also low, and the 
severity of this risk is low. The procedures used to protect confidentiality, and the 
adequacy of the data safety and monitoring plan is outlined below.  
Coercion. Coercion is a possible risk due to monetary compensation for 
participation; however, the likelihood and severity of this risk is low because the 
compensation is commensurate with time and effort required for this study. 
Further, participants are reminded at the baseline session, during the consent 
process and again at each in-person session that their participation is voluntary 
and that they can decline to use study cigarettes at any time, and remain in the 
study to complete all subsequent assessments. 
Discomfort from withdrawal. The risk of experiencing discomfort from 
withdrawal is moderate and the severity is considered low. Participants will be 
instructed to abstain from cigarette smoking and other nicotine/tobacco use for a 
minimum of 12 hours prior to each in-person study visit. Some participants may 
experience nicotine withdrawal symptoms including irritability, difficulty 
concentrating, restlessness, anxiety, and depressed mood. Nicotine withdrawal 
symptoms can be uncomfortable, but they are not dangerous. Participants will be 
given information about the possibility of nicotine withdrawal symptoms at the 
end of the screening (before they attend the first baseline session) and again 
during the consent process. The likelihood of experiencing withdrawal symptoms 
from using VLNCs is moderate. In the study, participants will be asked to smoke 
VLNC cigarettes for 7-days at a time, and are able to return to smoking as usual 
after that 7-day period, and may experience nicotine withdrawal symptoms such 
as irritability, negative affect, and craving. Participants are not prohibited from 
using other nicotine-containing products, which could reduce these symptoms. 
Compensatory smoking and/or tobacco use. It is possible that compensatory 
smoking or increased use of alternative tobacco products may occur. The 
possibility that use of VLNCs may lead to compensatory smoking is low in this 
study, especially because these cigarettes are not being used over an extended 
period of time. While compensatory smoking with VLNC cigarettes has not been 
observed in adult smokers, it is possible that it may occur in this population. 
However, in Co-Investigator’s Cassidy’s current field trial using VLNC cigarettes 
in adolescents, she has not yet seen significant compensation (N=45 complete); 
therefore, this outcome is unlikely. The potential for an increase in alternative 
tobacco product use is moderate. Young adults will report their cigarette use and 
their use of other tobacco products daily, and their CO levels will be collected at 
each weekly in-person visit; therefore, we will be able to closely monitor the 
extent to which compensatory smoking or tobacco use may be occurring and 
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make changes to the protocol to reduce this as necessary. 
Perceived reduced risk of low nicotine cigarettes. The possibility of perceiving a 
reduced risk of harm with VLNC cigarettes is moderate; the severity of the risk is 
considered low. We will debrief each participant, post-study on the relative and 
absolute risks of all products involved in the study. Finally, use of cigarettes will 
be limited to current smokers with no immediate intentions to quit smoking and 
will present no increased risk of harm than their current smoking status incurs.  
Smoking a single cigarette in the laboratory. Although no exposure to smoking is 
safe, participants will not be exposed to any more risk than the usual risk they 
expose themselves to by choosing to smoke. The laboratory where smoking 
sessions will be completed was constructed with a special ventilation system for 
quickly removing smoke from the experimental rooms to reduce excess smoke 
exposure to participants and researchers. 
2.
Describe procedures for protecting against or minimizing potential risks.
Subjective discomfort. Any distress or subjective discomfort from answering 
questions will be minimized by assurances that participants can refuse to answer 
any particular question that they do not feel comfortable addressing and may 
withdraw at any time without penalty.  To minimize the risk of discomfort from 
providing breath sample, only trained staff will conduct all procedures and, as 
above, emphasize that study participation is voluntary. Participants will be 
debriefed following each session to determine their level of discomfort and will 
have the opportunity to discuss any discomfort with project staff.
Breach of confidentiality. Protection of privacy is of the upmost importance. We 
will implement several practices to ensure privacy protection. 
All paper/pencil participant data will be kept in locked files which are only 
accessible to project staff. 
Publication of results will be in the aggregate with no identification of 
individual respondents. No names will ever appear in data sets. 
Participants will provide responses to a series of questionnaires at each study 
visit. Study records will be collected via a 21 CFR Part 11 compliant 
electronic data capture (EDC) system called REDCap with a unique study ID 
for each participant. REDCap has been approved for use in clinical trial data 
collection by the OUHSC IT. 
Confidentiality will be maintained by numerically coding all data with a 
unique ID number, using a HIPAA compliant electronic data capture 
database (REDCap), and keeping data locked in file drawers or on a secure 
password protected server that can only be accessed by approved study 
personnel. Names and contact information of participants, including when 
collected during the screen, will be kept separate from research data in a 
separate locked drawer or data file on a secure password protected server and 
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can only be accessed by approved study personnel. Only study research 
assistants and the PI will have the information that connects participants' 
names and ID numbers. Participant information will be accessible only to 
research staff, who are pledged to confidentiality and complete training in the 
ethical reporting in any publication. 
The following features are designed to ensure the security of the data of the 
mobile app that will be used for EMA data collection in Phase 2: 1) the data 
stored on the smartphone device are in a SQLite database in a sandbox 
environment, where read/write operations are only available through the 
programming application (i.e., no file or output is readable to end users); 2) a 
unique password (only known to researchers) is required to authenticate the 
current user before data can be manually accessed; 3) the web browser 
application linking the investigator’s computer to the database is on HTTPS 
protocol (SSL certificate with encryption) which will guarantee the data 
transfer from web browser to the backend database is well protected; and, 4) 
the backend database is hosted by Microsoft Azure and the University of 
Oklahoma Health Sciences Center (OUHSC). Azure has been approved by 
OUHSC risk assessment. The only personnel who have access to the Azure 
services are the mHealth developers. Study members have access to 
participant data through specified roles with secure logins and can only 
access data for their own projects. Azure databases are encrypted. Further, 
the data associated with the mobile app is encrypted. Azure uses TDE 
(transparent data encryption) AES_256. The database on the app-related 
phone is encrypted with SQL-Cipher, which also underwent risk assessment 
and was approved for use by OUHSC. The OUHSC SSL certification for 
https encrypts data in transit. They only data that will be downloaded is data 
that can be accessed by the OUHSC research team. Only research team 
personnel with specific roles can log in and download data. These steps will 
ensure the security of EMA data. Software will be downloaded onto each 
study phone so that phones can be remotely wiped if lost or stolen.
All research personnel associated with this study will complete the Human 
Subject Protection Training Program or a training program approved by 
OUHSC.  These are standard procedures used by PI of this application and 
they have been effective in the past. As a result of these practices, it is 
unlikely that any loss of privacy will occur during the course of the study.
A Federal Certificate of Confidentiality is automatically provided by the NIH 
to protect against disclosures or release of data. All research personnel 
associated with this study have completed the Human Subject Protection 
Training Program or a training program approved by OUHSC.
Coercion. Participants will be told at the screening and at the time of consent that 
their participant is completely voluntary. They will be reminded at each in-person 
visit, and at the 30-day follow-up that they can decline to answer any question and 
they can withdraw their participation at any time without penalty. Individuals will 
be also told at consent and reminded again at each in-person visit that they can 
decline to continue using the study product at any time, and still remain enrolled 
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in the study and undergo the study assessments. This will reduce the potential for 
incentivizing continued smoking. All research team members will complete an 
approved course on the protection of human subjects and be trained on how to 
clearly describe study procedures and obtain informed consent.
Discomfort from withdrawal. Participants will be given information about the 
possibility of nicotine withdrawal symptoms during the phone screening and 
again at the consent process. Participants will be told that they have the right to 
drop out of the study at any time. All participants will be informed that smoking 
and combusted tobacco use is dangerous for one’s health, but that the smoking 
involved in the study poses no more harm than their usual smoking exposure. As 
noted above, all participants will be given a list of resources to assist them to quit 
smoking should they be interested and at the completion of the study. 
Compensatory smoking and/or other tobacco use. The risk of compensatory 
smoking or increased use of tobacco products will be minimized by tracking daily 
cigarette and alternative tobacco product consumption assessed via EMA; and 
evidence of CO increase beyond acceptable levels (assessed at each in-person 
visit) will result in withdrawal from the study (see DSMP for further details). To 
minimize the risk of compensatory smoking or increased use of tobacco products, 
participants’ daily smoking will be monitored for any increase as described in 
detail in the DSMP, and participants will be withdrawn if a marked increase in 
smoking or other tobacco use is evident. We note that in a recent trial of VLNC 
cigarettes in which adult smokers were given access to SPECTRUM cigarettes 
including VLNC doses for 6 weeks and expected to smoke only those cigarettes, 
there was no evidence of compensatory smoking, neither as measured by 
cigarettes per day nor by cotinine or toxicant exposure; therefore, we do not 
expect compensation to occur. Similarly, as noted above, in Co-I Cassidy’s 
current field trial of these cigarette doses in adolescents, we have not yet seen 
significant compensation (N=45 complete as of 2/2018); therefore, this outcome 
is unlikely. However, we will monitor indicators of increased smoking and 
alternative tobacco as discussed below and in the DSMP. We will work closely 
with our consultants to determine decision rules regarding removal from the trial 
and/or resumption of usual brand cigarettes based on the number of daily reported 
cigarettes and weekly CO levels to ensure that participants’ risk is not increased.  
Smoking in the laboratory. Smoking a single cigarette in the lab is used to 
measure potential compensatory smoking, an important issue under study.  Risks 
related to cigarette puffing will be minimized by limiting this procedure to only 
one cigarette to and individuals who are smoking “somedays” or “everyday” for > 
the past 3-months who have no desire to quit.  The laboratory where sessions will 
be completed was constructed with a special ventilation system for quickly 
removing smoke from the experimental rooms to reduce excess smoke exposure 
to participants and researchers. 
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According to new federal statutes, individuals under the age of 21 are not legally 
allowed to purchase tobacco products. The PI has discussed the legality of 
providing tobacco products to individuals under the age of 21.  In accordance with 
Oklahoma state bill SB319, we are able to provide cigarettes to individuals ages 
18-20 in the context of an IRB approved study. 
Reduced harm perceptions of VLNCs. The possibility of perceiving a reduced risk 
of harm with VLNC cigarettes is moderate. At the end of the study, app 
participants will be debriefed about the relative and absolute risks of all products 
involved in the study and remind participants that all cigarettes have negative 
health effects.  Participants will also be provided resources to encourage 
cessation.  
3.
Describe potential benefits and importance to the participants and 
others.
The participants may benefit directly through increased understanding of factors 
underlying uptake, appeal, and use of cigarettes or other tobacco products.  This 
study is designed to answer important questions about factors that promote 
tobacco use behavior with the ultimate goal of informing prevention and 
regulatory decisions about menthol cigarettes and other flavored tobacco 
products. Improved regulation could ultimately help deter tobacco use among the 
larger population of young people, thus decreasing overall rates of tobacco-related 
morbidity and mortality, including those that stem from tobacco use and 
dependence.
4. Discuss why risks are reasonable in relation to benefits.
The risks are reasonable in relation to the benefits, as the benefits from 
conducting this study will help inform Food and Drug Administration regulation 
of menthol flavored cigarettes. Menthol cigarette smoking is linked to smoking 
initiation among youth and young adults, greater nicotine dependence compared 
to non-menthol cigarette smoking, and worse smoking cessation outcomes 
compared to those who smoke non-menthol cigarettes. Menthol cigarettes are 
also disproportionately used by minority and vulnerable populations, including 
Black and Hispanic smokers and women. These groups are disproportionately 
targeted by tobacco company marketing and experience worse tobacco use 
outcomes. As such, collecting data that would inform a ban on menthol cigarette 
smoking would significantly improve public health. 
POTENTIAL BENEFITS
The participants may benefit directly through increased understanding of factors 
underlying uptake, appeal, and use of cigarettes or other tobacco products.  This 
study is designed to answer important questions about factors that promote 
tobacco use behavior with the ultimate goal of informing prevention and 
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regulatory decisions about menthol cigarettes and other flavored tobacco 
products. Improved regulation could ultimately help deter tobacco use among the 
larger population of young people, thus decreasing overall rates of tobacco-related 
morbidity and mortality, including those that stem from tobacco use and 
dependence.
J.
Statistical Methods  
1.
Power: All assessment methods of this proposal (laboratory, EMA, ETM) 
are adequately powered to test the primary outcomes of interest. Participants will 
be n = 100 menthol smokers aged 18-34 years. We will over-recruit for n = 132 to 
account for a conservative 20% attrition rate over the course of the study; with an 
estimated final analytic sample size of n = 100. We have specifically accounted 
for potential study drop-outs, un-enrollments due to changes in eligibility or 
AE/SAEs, and those who are lost to follow-up in our estimated 20% attrition rate. 
Attrition rate estimate based on previous studies conducted by Co-Investigators 
Dr. Donny and Dr. Cassidy, and by consultant Dr. Hatsukami. We based our 
sample size on effect sizes calculated from similar studies that tested the effect of 
VLNC cigarettes on adult participants across 6 to 20 weeks of exposure 18, 19. A 
sample size of 100 participants would allow us sufficient power (defined as 0.8) 
to detect differences observed in adult cigarette smokers on the primary outcomes 
of interest. We will also recruit an additional n = 40 SGM menthol smokers aged 
18-34 years with the supplemental funds recently obtained from the NIH. We 
anticipate that 15% of the parent grant sample will endorse being SGM (n = 15), 
based on PI Cohn’s ongoing data collection efforts; thus, leaving a total sample of 
n = 55 SGM respondents (inclusive of the supplemental sample)
2.
Laboratory Analyses (Aim 1)
Primary Outcomes: (a) The relative reinforcing value (RRV) of usual brand 
cigarettes vs menthol VLNCs; (b) RRV of non-menthol VLNCs vs menthol 
VLNCs. RRV will be operationalized as within-subject differences in subjective 
ratings of cigarette appeal/reinforcement (satisfaction, reward, craving reduction, 
physical sensations) during each ad libitum smoking session. Secondary 
Outcomes: (a) CO boost; and (b) puff topography (number of menthol versus non-
menthol cigarette puffs consumed, number of minutes smoked, interval between 
puffs). 
Analysis of covariance will be conducted to examine effects of cigarette type 
(usual brand, menthol VLNC, non-menthol VLNC) on the outcomes of interest, 
controlling for cigarettes per day (CPD), nicotine dependence, race/ethnicity, 
gender, and age of smoking onset as potential covariates. Factors related to study 
drop-out and differences in cigarette compliance will also be examined as 
potential covariates. Exploratory analyses will examine differential reactions to 
usual brand and each research cigarette by race/ethnicity (White, Black, Hispanic, 
Other) and by gender. Significant interactions will be followed up with individual 
contrasts of cell means using Fisher’s Least Significant Difference tests. We will 
examine whether topography differs as a function of in-person versus remote 
session. 
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3.
EMA Analyses (Aim 2)
Primary Outcomes: (a) within-day subjective response (craving reduction, 
satisfaction, psychological reward, physical sensations like throat grab) to the 
most recent cigarette smoked; (b) within-day number of research cigarettes 
smoked per day; (c) within-day number of non-research cigarettes smoked; and 
(d) within-day withdrawal intensity. Secondary Outcomes: (a) within-day use of 
alternative tobacco products; (b) changes over the course of days (creating an 
average change score for each person) for each outcome; (c) number of days 
abstinent from tobacco use. 
Patterns of missing data, compliance, distributional properties of variables, and 
correlations among all measures will be assessed. We will control for potential 
variables related to missing data and utilize multiple imputation methods 
(expectation maximization algorithm).160-163 Analysis will use linear mixed 
modeling with random subjects effects164,165 to assess the main effect of cigarette 
type on the primary and secondary outcomes of interest. Models will use a 
contrast to compare differences between menthol VLNC and non-menthol VLNC 
at the day-level on predictions of the outcome of interest and that outcome of 
interest at time t (e.g., morning) predicting behavior (number of cigarettes, any 
smoking, craving, withdrawal) occurring at a subsequent time point (controlling 
for cigarette consumption from the previous report). Comparison of usual brand 
and the menthol VLNC ratings will also be made to determine the perceived 
similarity of the VLNC to one’s own brand. A sub-group of respondents may 
have fixed (unchanging) ratings of subjective response, craving, cigarettes per 
day, or withdrawal over the course of 7 days, although this is unlikely given the 
team’s previous research. We will examine baseline and daily factors that set “no 
changers” apart from those whose show fluctuations in these factors, and examine 
these as potential covariates in models. Within-person slopes capturing 
associations between cigarette type and the EMA outcome of interest will be 
saved in regression models and used to predict the ETM responses.
4.
ETM Analyses (Aim 3)
Primary Outcomes: (a) consumption of alternative tobacco products (milligrams 
of nicotine for alternative tobacco sources) as a function of cigarette type 
available. Typically, as cigarette price increases, consumption of other tobacco 
products increases.14 Secondary Outcomes: (a) breakpoint: the first price at 
which consumption of the available cigarette is zero; (b) intensity of demand: 
consumption at the lowest price); (c) elasticity of demand: sensitivity of cigarette 
consumption to increases in cost, (d) Omax: maximum expenditure for cigarette 
type available; and (e) Pmax: price at which expenditure is maximized.  
The analyses for the aim using ETM data will examine the predictive validity of 
laboratory and EMA data on the ETM outcomes of interest, separately for each 
cigarette type. Hierarchical linear regression models will predict the ETM 
outcome of interest, controlling for baseline cigarettes per day, nicotine 
dependence, other tobacco use, and relevant demographics in Step 1 and then 
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including the laboratory or EMA-derived slopes of appeal/reinforcement in Step 
2. Models will separately examine the effects of laboratory and EMA 
measurements of appeal/reinforcement on the ETM outcomes of interest. 
5.
Exploratory Analyses
Differences by age (18-24 vs 25-34), sex, race/ethnicity, alternative tobacco 
product use, and ETM flavor and product preference. Menthol cigarettes are 
disproportionately used by women, as well as Black and Hispanic smokers.18,166-
168 As such, sex and race/ethnicity will be examined as moderators of outcomes, 
as sample size permits. This allows us to adhere to NIH guidance examining sex 
as a biological variable. Variation in the use of alternative tobacco products 
during each 7-day take-home phase will be examined as a possible moderator of 
the reinforcing effects of the research cigarette to which participants are assigned, 
as well as an outcome assessment of compensatory tobacco use. Given the 
popularity of menthol cigarette use in adults aged 26-34 years and alternative 
tobacco product use in this age group,17,169-171 flavor preference by product type 
(e-cigarettes, little cigars) will be examined as an exploratory outcome from the 
ETM analyses. 
Laboratory and EMA concordance and predictive utility. We will examine the 
association of laboratory and EMA measurements of appeal/reinforcement and 
determine whether correlations between these measures differ in magnitude by 
menthol vs non-menthol use and by VLNC vs usual brand. A weak or non-
significant correlation could indicate that these paradigms tap into different 
dimensions of reinforcement/appeal. We will also compare the utility of 
laboratory vs EMA outcomes as predictors of ETM outcomes to determine the 
relative contribution of each measurement paradigm. This would advance 
theoretical models and facilitate future research by identifying the most relevant 
aspects of abuse liability that uniquely account for the role of menthol in 
increasing risk for dependence.
6. Study Timeline. 
The methodology, sample, sample size, and recruitment were adequately chosen 
to complete analyses for primary and secondary outcomes in the 3-year time-
frame. Months 1-6 will be used for protocol set-up, applying for and obtaining IRB 
approval and then SPECTRUM cigarettes, staff training, and survey development. 
During this protocol set-up phase, we will register the study in ClinicalTrials.gov, 
certify study compliance, and ensure all project personnel complete the Good Clinical 
Practice training (if not already completed). To ensure that data collection is sequences 
with other ongoing studies in the HPRC laboratory and we do not overload study 
personnel with follow-up assessments and EMA data tracking, data collection will 
occur over the course of 22 months (months 7-28), with a recruitment rate of ~6 
participants per month (1-2 a week). This recruitment goal is feasible given the study 
team’s successful recruitment of smokers in past and on-going studies.20-26 Per NIH 
guidelines, the clinical trial will be registered no later than 21 days after the first 
participant enrolls in the study.
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Data cleaning will be ongoing. Development and submission of a protocol manuscript 
will occur at the end of Year 1. Preliminary statistical analyses will begin in Year 2 
(month 13-14) in preparation for an abstract submission to the Tobacco Regulatory 
Science Program (TRSP) annual conference (abstracts typically due in June of each 
year), and a “Rapid Response” abstract submission to the Society for Research on 
Nicotine and Tobacco (SRNT) annual conference (abstracts typically due in December 
of each year). Development and refinement of study codebooks will begin early in 
Year 2 to support these conference submissions. Development of main outcomes 
manuscripts will begin at the end of Year 2 and will be ongoing throughout Year 3 
(months 25-36).  
K.
Data and Safety Monitoring Plan 
The below Data Safety Monitoring Plan has been reviewed and approved by 
officials at NIH/NIDA. 
We will monitor for risks related to cigarette smoking by screening participants 
via self-report for general medical precautions (cardiovascular disease) at baseline 
and each in-person study session. The most likely adverse event (potential for 
nicotine overdose) is anticipated to be rare (< 1%) and mild (nausea, headache) 
and will be handled quickly (i.e., advice to participant to reduce or eliminate 
cigarette use). 
Smoking during pregnancy can lead to miscarriage, preterm delivery, stillbirth, 
birth defects, and other problems. To avoid risks to the participant and fetus, 
female participants will be tested for pregnancy at every smoking visit or session. 
If a participant becomes pregnant during the study, she will be withdrawn from 
the study.
A Randomization and Product Tracking database will be used in REDCap (the 
electronic data capture system) to track participants’ use of menthol and non-
menthol study cigarettes. Randomization of when participants will smoke the 
menthol and non-menthol study cigarette will be deployed and tracked within 
REDCap, and presented by the Project Manager in a weekly CONSORT diagram 
presented at weekly project team meetings.
Process of Adverse Event (AE)/Serious Adverse Event (SAE) collection,
While participating in the trial, adverse events, serious adverse events, and 
changes in medications will be assessed at every study visit and carbon monoxide 
will be obtained. Medical events will typically be identified during the 
administration of the Adverse Events Form and the Health Changes 
Questionnaire. Other events may be identified by spontaneous reports during non-
scheduled assessments. Participants will also be given an emergency number they can 
call if necessary.
No new AE is considered if one or more conditions below are met and the 
description does not otherwise meet the definition of an AE. 
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1) Existing AE already open for reported symptom.
2) Pre-existing condition without increase in severity or frequency of symptoms 
(brief medical history will be updated if not previously reported). 
3) Received preventative or follow-up medical care. 
4) Other (as determined by the PI and medical monitor). 
Serious adverse events (SAEs): Information about all serious adverse events will 
be collected and recorded on a standard Serious Adverse Event Report Form. To 
ensure participant safety, each study-related serious adverse event will also be 
reported to the IRB office within 24 hours and NIDA Program Officer within 72 
hours of learning of its occurrence. A serious adverse event is an undesirable sign, 
symptom or medical condition which: 
1. is fatal or life-threatening 
2. requires or prolongs hospitalization 
3. results in persistent or significant disability/incapacity 
4. constitutes a congenital anomaly or a birth defect 
5. is medically significant, in that it may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed above. 
A hospitalization would not be considered to be a serious adverse event if it was 
elective, pre-planned, or for a pre-existing condition that did not worsen since 
starting the study; or for treatment on an outpatient basis for an event not fulfilling 
any of the definitions of serious given above and not resulting in hospital 
admission. 
Management of AEs/SAEs. 
The medical monitor will review all AEs. A study participant may be 
discontinued from the study if the medical monitor and/or the PI determines it is 
the best decision in order to protect the safety of a participant. In the event that a 
participant either withdraws from the study or the investigator decides to 
discontinue a participant due to an AE/SAE, the participant will have appropriate 
follow-up medical monitoring. The participant experiencing an AE/SAE will be 
followed until the problem resolves, stabilizes, or is clearly unrelated to the study 
cigarettes or procedures. Any AE that remains open will be reviewed and closed 
during the 30-day follow-up phone call. 
For the participant’s protection, participants will be withdrawn immediately 
from the study if any of the following occur: 
1) Cardiovascular disease (CVD) event: Typically includes MI (heart attack), 
PTCA (angioplasty/stenting), bypass surgery, stroke, peripheral vascular disease 
(arterial blockages in arms or legs leading to procedure or surgery). Less common 
CVD problems would be new cardiac arrhythmias (e.g., new atrial fibrillation) or 
new valvular disease (e.g., mitral or aortic regurgitation). 
2) DVT/PE (deep vein thrombosis/pulmonary embolism, i.e., blood clots in the 
venous system). 
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3) Suicide Attempt: A participant will be withdrawn if he/she attempts suicide at 
any time during participation in the study. 
4) Psychiatric Hospitalization: A participant will be withdrawn if he/she is 
hospitalized for psychiatric reasons at any time during participation in the study. 
5) Pregnancy: If a participant indicates she is pregnant or has a positive pregnancy 
test at any session, she will be withdrawn from the study, and this event will 
remain open until delivery. At that time the medical monitor will contact the 
participant to ask a few questions about the baby’s health and will update the open 
‘Adverse Event Form’. 
The following will be monitored and can lead to the participant being 
withdrawn by the PI or Medical Monitor: 
1) Any hospitalization or debilitation in which participation in the study could be 
detrimental to the recovery process. This will be self-reported by the participant 
and will be reviewed by the PI and medical monitor to determine whether 
continued participation in the study is appropriate. 
2) If a participant is behaving in an inappropriate or threatening manner, admits to 
lying about eligibility criteria, including omitting previous medical diagnoses and 
medications, is participating in other smoking research studies that could affect 
the primary outcome measures, does not follow study instructions, etc., then the 
PI can withdraw him/her from the study at her discretion. 
3) Expired breath carbon monoxide increase: A participant will be withdrawn 
from the study if the average of two consecutive CO readings during the same 
visit is 100 ppm or greater. 
4) Following Co-I Cassidy’s protocol with adolescents (aged 15-19), we will 
monitor indicators of increased smoking/tobacco use at each in-person visit, as 
described above. To minimize the risk of compensatory smoking, participants’ 
daily smoking will be monitored via EMA for any increase as described in detail 
above, and participants will be withdrawn if a marked increase in smoking is 
evident. Evidence of marked increase in smoking or tobacco use: A participant 
will be withdrawn from the study if s/he meets the following criteria for two 
consecutive study visits. 

Expired breath carbon monoxide increase: If during a laboratory session 
his/her CO measurement is as follows (based on CO measurement at baseline): 
i. CO is greater than 50 ppm if CO at Baseline (Visit 1) is <20 ppm. 
ii. CO is greater than 60 ppm if CO at Baseline (Visit 1) is 20 – 34 ppm. 
iii. CO is greater than 70 ppm if CO at Baseline (Visit 1) is 35 – 49 ppm. 
iv. CO is greater than 80 ppm if CO at Baseline (Visit 1) is 50 – 64 ppm. 
v. CO is greater than 90 ppm if CO at Baseline (Visit 1) is 65 – 80 ppm
5) At each session, heart rate and blood pressure (or heart rate only if taken remotely) 
will be taken. Individuals who show heart rate and blood pressure out of range will be 
rescheduled. A note will be recorded in REDCap if a participant is rescheduled due to 
out of range score. If a participant shows out of range vitals on two consecutive visits, 
this will be reviewed by the PI and medical monitor to determine whether continued 
participation the study is appropriate. Blood pressure acceptable range: SBP <90 
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or>140mmHg; DBP >90 or<50 mmHg. Heart Rate acceptable range: bpm <49- >100 
bpm.
Desire to Quit Smoking
We will query about desire to quit smoking at screening, each in-person visit (or 
virtual session), and at the follow-up. Those who report a desire to quit smoking 
after study enrollment will be asked if they still want to receive the study cigarettes. 
This is because use of reduced nicotine cigarettes could help reduce craving and 
increase the odds of successful smoking cessation among smokers according to 
findings published by Co-I Cassidy.27  Individuals will also be told at consent and 
reminded again at each in-person visit that they can decline to continue using the study 
cigarettes at any time, and still remain enrolled in the study and undergo the study 
assessments. This will reduce the potential for incentivizing continued smoking. Those 
who do not want to continue receiving the study cigarettes will no longer be dispensed 
study cigarettes and will be retained in the study with no penalty and will continue to 
complete all subsequent EMAs, the ETM, and the 30-day follow-up. Retaining 
individuals who have stopped using the study cigarettes, or who report a desire to quit 
smoking and wish to use VLNCs, are vital to informing the outcomes of the study. All 
participants will be given smoking cessation resources at their request, upon 
completion of the in-person/virtual study visits (Visit 5), and again at the 30-day 
follow-up (in-person or on the phone).
Investigator responsibilities for notification of SAEs are described above. The PI 
will be available for any questions that participants may have about smoking, or 
smoking cessation. Participants will be given contact numbers of the laboratory 
and PI. Any adverse events, breaks of confidentiality, or any other data or safety 
issues that arise will be discussed immediately with the PI (Dr. Cohn). Dr. Cohn, 
or a delegate (Project Manager) will be responsible for completing an Adverse 
Events Form should an event occur. The Adverse Events Form will be reviewed 
by the PI and medical monitor. Dr. Cohn and the medical monitor will gather any 
information needed to investigate the event and to determine subsequent action. 
Any subsequent action will be documented and reported to the OUHSC IRB.
Trial stopping rules
The trial will be stopped if the OUHSC IRB recommends trial discontinuation due 
to SAEs, if the trial is not progressing due to lack of participant recruitment, or if 
advised by the medical monitor.
AE/SAE follow up plan
A participant experiencing an AE/SAE will be followed until the problem 
resolves, stabilizes, or is clearly unrelated to the study cigarettes or procedures. 
Any AE that remains open will be reviewed and closed during the 30-day follow-
up phone call
DSM Plan Administration
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Responsibility for data and safety monitoring
During study sessions, data will be entered in real-time into a laptop or desktop 
computer to REDCap and by participants into the CMS, which is the electronic 
data capture system for the EMA application (which has been approved for use by 
OUHSC). The study PI (Dr. Cohn) will provide a Data Safety and Monitoring 
report to NIDA along with each progress report (annually). The PI will be 
responsible for the oversight of internal monitoring of the participants’ safety and 
data integrity of their project, executing the DSM plan, and complying with the 
reporting requirements to the local IRB, the FDA, and NIDA.
Frequency of DSM
The PI and the research staff will meet weekly throughout the project. During 
these meetings, the team members will evaluate the progress of the trial, review 
data quality, recruitment, retention, and examine other factors that may affect 
study outcomes. The medical monitor will attend these meetings as needed or as 
requested. They will also review the rates of adverse events to determine if there 
are any changes in participant risk. The PI is available to meet outside of the 
scheduled meetings, if concerns regarding a particular participant or another 
problem should arise. The study PI and Co-Investigators, along with the medical 
monitor, will meet monthly to review overall progress, and any recruitment, data 
quality, and safety concerns. Specifically, they will assess enrollment information, 
demographics and characteristics of the participants, the expected versus actual 
recruitment rates, quality assurance or regulatory issues that may have occurred 
during the past month, review a summary of adverse events (AEs) and serious 
adverse events (SAEs), protocol violations, and any actions or changes to the 
protocol. The team members will be available to meet outside of the scheduled 
meetings if concerns regarding any adverse trends or other major problems should 
arise. 
Content of DSM report
The DSM report will be submitted to the NIDA Program Official annually. This 
report will include a brief description of the trial and progress, enrollment 
information, baseline demographics and characteristics of the participants, the 
expected versus actual recruitment rates, retention and disposition of study 
participants (active, completed, terminated/withdrawn), quality assurance or 
regulatory issues that may have occurred during the year, a summary of adverse 
events and SAEs, protocol violations/deviations, any actions or changes to the 
protocol, and any actions by the IRBs.
DSM Board Plan
We have not been informed by or requested by NIH/NIDA that we are required to 
have a DSM Board. 
L.
Data Sharing
All data will be utilized in accordance with the standard reporting procedures for 
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NIH grants and CONSORT (Consolidated Standards of Reporting Trials), an 
evidence-based, minimum set of recommendations for reporting research 
findings. There are organizations outside the OUHSC that may inspect and/or 
copy research records for quality assurance and data analysis. These organizations 
may include the funding organization of this project (University Hospital 
Authority Trust) other regulatory agencies. The FDA/NIH, the OUHSC 
Institutional Review Board, and other University administrative offices may also 
inspect and/or copy research records for these purposes. Outside of these purposes 
where identifiable information may be required by the reviewing regulatory 
agency, all data will be de-identified prior to sharing. Additionally, data may also 
be de-identified and used in aggregate form. All identifiable information will be 
destroyed at the end of the study, unless the participant consents to have their info 
retained in our database so they could be contacted for future studies.  
M. Confidentiality 
Efforts will be made to keep personal information confidential. Participants will 
not be identifiable by name or description in any reports or publications about this 
study. All research data will be identified only with a unique ID and will be kept 
separate from personally identifying information, such as name and contact 
information. Biospecimen data that is collected (breath analysis to determine 
recency of smoking, pregnancy test) will be not be stored. There are organizations 
that may inspect and/or copy research records for quality assurance and data 
analysis. These organizations may include the US Food & Drug Administration 
and other regulatory agencies, the OUHSC Department of Pediatrics. The 
OUHSC Human Research Participant Program office, the OUHSC Institutional 
Review Board, OUHSC Office of Compliance, and other University 
administrative offices may also inspect and/or copy research records for these 
purposes. 
We will remove direct identifiers from data results and assign a code. The key to 
this code will be kept separately and only the researcher and approved study 
personnel for this study will have access to the code. If information is shared with 
another investigator for research purposes, they will not be able to re-identify 
participants.
Study data will be stored for a minimum of 7 years, or as additional analyses are 
needed. 
N.
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