Effects of Heated Tobacco Product Flavor on Tobacco Use Behavior and Abuse Liability Among Menthol Cigarette Smokers
Phase: NA
Conditions: Tobacco Use
Sponsor: Virginia Commonwealth University

Official Title:  
The Abuse Liability of a Novel Heated Tobacco Product (IQOS) and Its Feasibility as a 
Menthol Cigarette Substitute 
 
 
NCT Number: NCT05499377 
 
Document Date: Jan 26, 2023 
 
 
 

1. Objectives:  
This project’s objective is to determine if menthol cigarette smokers will substitute with a modified 
risk tobacco product (an HTP known as “IQOS”) and whether the availability of a menthol-flavored 
HTP is important for substitution behaviors in this population. The overarching hypothesis is that, 
relative to own brand menthol cigarettes (OB), IQOS-menthol’s abuse liability profile will differ 
less than IQOS-tobacco’s, suggesting that menthol smokers will be more likely to substitute an 
HTP for combustible cigarettes when a menthol-flavored HTP option is available. The specific 
aims of our study are to: 
Aim 1. Assess IQOS’ abuse liability among menthol smokers in a clinical lab setting. In 
clinical lab sessions, participants will complete standard controlled product use episodes 
(10 puffs, 30-sec inter-puff interval) with OB (baseline) and IQOS (intervention). Blood will 
be sampled to assess nicotine/menthol delivery, puff duration and volume will be 
measured to assess use behavior, and subjective effects (e.g., cigarette craving) and the 
Experimental Tobacco Marketplace (ETM) task will assess IQOS’ substitutability for OB. 
H1A: Nicotine delivery will be lower for IQOS-tobacco than IQOS-menthol, but both will 
deliver less nicotine than OB menthol cigarettes. H1B: Puff duration will be greater for 
IQOS-menthol than IQOS-tobacco. H1C: IQOS-menthol will reduce craving for cigarettes 
more completely than IQOS-tobacco. H1D: The cross-price elasticity of IQOS with respect 
to own-brand menthol cigarettes will be higher in a market with access to both IQOS-
menthol and IQOS-tobacco than it will be in a market with access only to IQOS-tobacco. 
H1E: IQOS-menthol will deliver more menthol than IQOS-tobacco, but both will deliver 
less menthol than OB menthol cigarettes.   
Aim 2. Measure tobacco use patterns across IQOS flavor availability conditions to assess 
clinical lab result validity.  During 7-day naturalistic evaluation outside of the clinical lab, 
participants will respond to daily Ecological Momentary Assessment (EMA) prompts by 
reporting OB and IQOS use.  H2A: Those in the IQOS-menthol condition will have a larger 
percentage reduction in average daily cigarettes consumed per day (Tues-Thurs) from 
the baseline to the intervention week, than those in the IQOS-tobacco condition. H2B: 
IQOS use/day higher during the intervention week (Tues-Thurs) will be higher in the 
IQOS-menthol condition compared to the IQOS-tobacco condition. H2C: Those with 
access to IQOS-menthol will replace a greater percentage of their total tobacco product 
consumption (cigarettes + IQOS) with IQOS products during the intervention week (Tues-
Thurs) than will those with access to IQOS-tobacco.  
Hypothesis H1A, H1D, and H2A constitute primary outcomes. All other hypothesis represent 
secondary outcomes.  
 
Primary Study Endpoints: 
Aim 1: For sub-hypothesis A, the outcome is the baseline-adjusted plasma nicotine 
concentration following a 10-puff directed bout with the participant’s randomly assigned 
IQOS product on Friday of the intervention week. For sub-hypothesis B, the outcome is 
the average duration of the puffs taken during the 10-puff directed puffing bout with the 
participant’s randomly assigned IQOS product on Friday of the intervention week. For 
sub-hypothesis C, the outcome will be the degree of cigarette craving suppression from 
before to after the directed puffing bout with the participant’s randomly assigned IQOS 
product on Friday of the intervention week. Sub-hypothesis D will consider differences in 
IQOS’ cross-price-elasticity obtained during the ETM performed on Friday of the 
intervention week between those with access to IQOS-M and IQOS-T and those with 

access to IQOS-T only. Sub-hypothesis E will compare the baseline-adjusted plasma 
menthol-glucuronide following a 10-puff directed bout between IQOS-M and IQOS-T 
groups on Friday of the intervention week.   
 
Aim 2: The primary EMA outcome (H2A) is the percentage reduction in average daily 
consumption of cigarettes (Tues-Thurs) from the baseline to the intervention week (e.g., 
10 cigs/day in baseline week to 2 cigs/day in intervention week = 80% reduction). The 
outcome for H2B is the average daily number of IQOS HeatSticks used on Tues-Thurs of 
the intervention week. The outcome for H2C is the percentage of average daily 
consumption of tobacco products (cigarettes + IQOS) consumed during the intervention 
week (Tues-Thurs) that are IQOS HeatSticks.  
 
2. Overview of Design. Once enrolled, eligible participants will complete a two-arm, 
parallel group, 14-day clinical lab study (Aim 1) of IQOS that includes naturalistic 
assessment (Aim 2; see Table 1). First, participants will complete a 7-day 
positive-control, own-brand (OB) menthol cigarette baseline. Then, for the 
second 7-day period, participants will be randomized (1:1 allocation; stratified by 
gender (Male vs Female) and race (African American/Black vs non-African 
American/Black) to receive either IQOS-M or IQOS-T and instructed to attempt to 
use their assigned product as a complete cigarette substitute. The baseline and 
intervention weeks will feature clinical lab sessions (Monday and Friday) and 
daily naturalistic use assessments.  
 
3. Participants. A total of 50 community volunteers who currently use menthol 
cigarettes will be randomized in this study (25 per condition; randomization will 
stratify across gender (Male vs Female) and race (African American/Black vs 
non-African American/Black).  
Inclusion Criteria  
o Healthy adults (aged 21 and older)  
o Smoke at least 5 cigarettes per day for at least 1 year (i.e., established, 
daily smokers) 
o Regular cigarette brand is flavored to taste like menthol or mint  
o Exhaled Carbon Monoxide (CO) reading of > 5 PPM at in-person 
screening, as well as a  'positive' cotinine cassette result, to verify smoking 
status/nicotine use at the in-person screening. 
o Report no intention to quit smoking in the next 3 months  
o Participants must be willing to provide informed consent and abstain from 
nicotine/tobacco for ≥8 hours prior to each lab session.  
o Participants must have access to a computer/smartphone and be willing to 
receive and respond to daily surveys 
o Able to read and write in English  
 
 
Exclusion Criteria  
o Daily use of any tobacco products other than cigarettes  
o Self-reported history of unstable or significant medical conditions in the 
past 12 months. These include: uncontrolled high blood pressure (via self-

report or observed at screening; BP must be less than 160/100 at screening), 
heart-related conditions (e.g., recent heart attack/stroke, coronary heart 
disease), severe immune system disorders (e.g., HIV/AIDS, multiple sclerosis), 
respiratory disorders (e.g., COPD, asthma), kidney diseases, liver diseases (e.g., 
cirrhosis), or seizures.  
▪ Individuals with other self-reported current, diagnosed medical 
conditions (e.g., diabetes, thyroid disease, lyme disease) will be 
considered for exclusion after consultation with the PI and medical 
monitor. Participants with any medical condition/medication that may 
affect participant safety, study outcomes, or biomarker data will be 
excluded based on these consultations. 
o Individuals with current, diagnosed, psychiatric conditions that are 
uncontrolled will be excluded. A controlled psychiatric illness is defined as one 
where the individual is taking medication and/or receiving other treatment (e.g., 
psychotherapy). In addition, individuals who have been to the ER and/or been 
hospitalized for a psychiatric condition in the past year will be excluded. 
o Cannabis use >15 days, alcohol use >25 days, and any other illicit drug 
use (e.g. cocaine, opioids, etc.) in the past 30 days. 
o Women will be excluded if they test positive for pregnancy (by urinalysis) 
or self-report breastfeeding.  
 
These inclusion and exclusion criteria are consistent with those employed by Dr. Barnes’ 
recently awarded clinical trial (R01DA050996 [HM20022060]) and previous studies 
conducted at the VCU Center for the Study of Tobacco Products, including 2 F31 awards 
(F31DA047018 [HM20015258] and F31DA054780 [HM20018418]).   
 
4. Recruitment and Enrollment. Participants will be recruited by institutional 
review board-approved advertisements and by word of mouth. The BHRL and 
CSTP Tobacco User Registries are available to aid recruitment efforts. Interested 
individuals will use the BHRL or CSTP website to complete a screening survey 
online (i.e., “brief pre-screener”) or call the BHRL or CSTP to complete the same 
survey via phone to determine initial eligibility.  
 
5. Consent process. Following documentation of initial eligibility, participants will 
be contacted to confirm their initial interest in the study and invited to an in-
person screening session where consent will be obtained. Prior to the in-person 
session, we will provide all participants with an unsigned copy of the consent 
form for them to review via email. Researchers will be available in-person and via 
email/phone to answer any questions participants may have about the study 
during the consent process. See SmartForm for more detail on the consenting 
process. 
 
6. Study Procedures. 

The study is divided into 3 phases: Screening/Enrollment, Baseline Week (use OB 
menthol cigarettes), and Intervention Week (use randomly-assigned) IQOS product. In 
the Screening/Enrollment phase, participants will complete the CSTP/BHRL registry to 
assess initial eligibility for this study and those deemed potentially eligible will be invited 
to an in-person screening session at the CSTP. At this session, informed consent will be 
obtained, eligibility confirmed, and baseline/demographic information collected. At the 
end of the in-person screening session, all eligible and consenting participants will be 
given an opportunity to take 4 test puffs of the IQOS product (flavor: Tobacco). During 
the baseline and intervention weeks, participants will complete clinical lab sessions (see 
“Aim 1” below) and naturalistic use assessments (see “Aim 2” below). Please note, at 
the start of each in-person activity, participants will answer 4 questions to screen for 
COVID-19 as with the CSTP’s other ongoing projects (all answers must be “no” in order 
to continue). Randomization will occur at the beginning of the first clinical lab session 
(Monday, Baseline week) to allow for the proper ETM to be displayed during all 
subsequent sessions.   
 
Aim 1: During the course of the clinical lab study set forth in Aim 1, participants 
will complete directed puffing bouts (10-puffs, 30 second interpuff interval) with 
either OB (baseline week) or their randomly-assigned IQOS product (intervention 
week). The interpuff interval is defined as the time between the start of 1 puff and 
the beginning of the next (Hiler et al., 2017). This procedure requires 
physiological monitoring of heart rate and blood pressure (sessions will be 
stopped if blood pressure ever exceeds 180/120) and venipuncture and/or 
catheter placement will be completed by Ms. Gaitan, RN. One blood sample (7 
mLs) will taken immediately before and immediately after a standard, controlled 
10-puff directed puffing bout (total of 14 mL per session). A total of 56 mL of 
blood will be sampled for the entire study; this amount of blood sampling will 
occur at 4 sessions over a 12 day period and is less than a standard blood 
donation that is provided in a single sitting (473 mL). Outcome measures include 
changes in plasma nicotine and menthol concentration from pre- to post- puffing 
bout and subjective effects, including cigarette craving suppression as well as the 
direct effects of OB and IQOS. Following this procedure, participants will then 
complete an Experimental Tobacco Marketplace (ETM). In the ETM, participants 
will be asked to make purchasing decisions across an array of tobacco/nicotine 
products, including IQOS and OB, as their OB become increasingly expensive 
(prices will be presented in random order at each session [i.e., the order of price-

trials will be randomly determined for each session, but within a session each 
participant will face the same order of price-trials]). The minimum task time for 
the ETM will be set to 20 minutes (i.e., if a participant finishes all questions in the 
ETM before 20 minutes, they’ll cannot progress to the next portion of the session 
until 20 minutes has elapsed). The primary outcome of interest is the cross-price 
elasticity of demand for IQOS as a function of OB price. Each session will begin 
by obtaining an exhaled Carbon Monoxide breath sample, as will be done in the 
in-person screening session, and asking participants whether they’ve abstained 
from using tobacco or nicotine products in the last 8 hours. Moreover, on the 2 
Friday sessions, participants will complete a short “timeline follow back” 
assessment to report on their usage of cigarettes, IQOS, and other tobacco 
products during the preceding 3-days (Tues-Thurs). A timeline of session 
structure is provided below.  
 
Though every effort will be made to have participants complete the study on the 
prescribed timeline (in-person screening, 2 baseline week visits [Mon, Fri], 2 
intervention week visits [Mon, Fri]), we recognize that things outside the 
participant’s or the researcher’s control could impact completion of the study on 
this schedule. Thus, to handle the event in which a participant misses a session, 
we have devised the following plan. If an in-person screening session is missed, 
that session will be rescheduled at the participant’s convenience. If the 
participant misses 1 of the baseline week visits, we will NOT reschedule the 
missed session – the single baseline visit that was completed will be used as the 
control comparison in statistical analyses. If both baseline visits are completed, 
the Friday results will be used as the control comparison. If a participant misses 
their Monday intervention week visit, we will reschedule for the next Monday on 
which the participant is available and commence the week as normal from that 
point. If a participant misses their Friday intervention week visit, we will 
reschedule for the next business day on which the participant is available. Friday 
intervention week sessions will not be rescheduled such that the “naturalistic” 
use period is any less than 3 full days (i.e., the rescheduled session will occur the 
following week).  
 
 
Aim 2: In addition to the clinical lab sessions, participants will report usage of OB 
and their randomly assigned IQOS product daily by responding to ecological 

momentary assessment (EMA) prompts (text or email) sent each morning of the 
2-week study window. Surveys will be sent at 8 AM each day; if a participant has 
not responded by noon a reminder text/email will also be sent. Outcomes are 
primarily concerned with responses to EMA prompts on Tuesday, Wednesday, 
and Thursday of each week – but prompts will be sent daily to encourage habit 
formation and compliance. Participants will use their OB during the baseline 
week.  
 
On Monday of the intervention week, at the conclusion of the clinical lab session, 
participants will be given an IQOS 2.4 Tobacco Heating System, HeatSticks in 
their randomly-assigned flavor (Fresh Menthol or Regular Tobacco), and brief 
instructions for use (including a handout with accompanying video). Participants 
will be provided with the same number of HeatSticks as cigarettes they reported 
consuming during the baseline week, plus 20% to account for potential product 
loss or increases in use. Participants will be instructed “We are providing you with 
an a heated tobacco product known as IQOS in [condition-specific flavors] over 
the next week to be used as a substitute or complete replacement for your own 
brand cigarettes. We want to understand how you use these specific heated 
tobacco products as well as your own brand cigarettes when they are the only 
products available to you. Therefore, please refrain from using all other 
nicotine/tobacco products and other heated tobacco product flavors for the 
duration of the study. If you use anything else, it is important that you tell us what 
you used. Additionally, please return all of the IQOS product and any unused 
HeatSticks at your lab visit on Friday.” 
 
7. Measures. Participants will complete the measures in the timeline shown below.  
Study Period 
Pre-
screen 
In-person 
Screening  
Clinical Lab Sessions 
Daily Surveys 
Study Days 
NA 
0 
1, 5, 8, and 12 
1-14 
Demographics 
 X 
X 
  
 
COVID-19 Screening Questionnaire 
 
X 
X 
 
Heart Rate and Blood Pressure 
Monitoring 
 
X 
X 
 
Urine pregnancy and cotinine tests 
 
X 
 
 
Exhaled Carbon Monoxide 
 
X 
X 
 
Tobacco Use History 
 X 
X 
  
 
Drug & Alcohol Use 
 
X 
 
 
Health and Medical History 
  X  
X 
  
 
Reasons for flavored tobacco use 
 
X 
 
 
Contact information 
 
X 
 
 
Cigarette Dependence (PROMIS 4A  
and PSNDI) 
 
X 
 
 
Stage of Change / Quit Confidence 
 
X 
 
 
Test Puffs (4) of IQOS-Tobacco 
 
X 
 
 
 7-day TLFB 
  
 
x 
 
Adverse Events 
 
 
X 
 
3-day Timeline Follow Back 
 
 
X (Days 5 and 12 only) 
 

Product Evaluation Questionnaire 
 
 
X  
 
Subjective Effects Questionnaire  
  
 
X 
 
     Plasma Nicotine and Menthol 
Collection  
  
 
X 
 
Puff Topography  
 
 
X 
 
Experimental Tobacco Marketplace  
 
 
X 
 
Ecological Momentary Assessment 
 
 
 
X 
 
Baseline/Screening and Cigarette/Tobacco Measures: We will assess contact 
information, demographics (e.g., age, gender, race, ethnicity, income, occupation), 
tobacco use history, other drug/alcohol use, and health and medical history including 
health/psychiatric conditions (e.g., Medical History Form used in P50DA036105-Project 
3), reasons for flavored tobacco use (CASEL Flavors Working Group, 2021), cigarette 
dependence (PROMIS 4A; Shadel et al. 2014, Penn State Nicotine Dependence Index 
[PSNDI], Foulds et al., 2015), stages of change/quitting confidence using standardized 
items from PhenX and  national surveys (e.g., PATH; BRFSS; TUS-CPS), and 
items/measures adapted for menthol cigarettes. Additionally, those that attend the in-
person screening but are deemed ineligible because their blood pressure exceeds the 
limits set in the inclusion/exclusion criteria will be given a letter explaining their test result 
and directed to resources that can help them in the management of hypertension.  
 
8. Compensation. Participants will be compensated for their time: $25 for in-
person screening, $2 for each complete EMA assessment (14 total), $50 for each 
of two Monday sessions, and $100 for each of two Friday sessions. Total 
possible compensation for this study amounts to $353. We’ll also reimburse 
participants up to $12/session for parking, if needed.  
 
9. Statistical Analysis Methods and Sample Size/Power. 50 participants will be 
needed to obtain power >0.80 to detect a difference between subjects on the 
plasma nicotine outcome, with alpha<0.05 (G*power 3.1.9.7). The power analysis 
was based on previous studies (Ns ~30) where effect sizes of the main effect of 
condition were large for ETM outcomes (d>1.16), medium for plasma nicotine 
(d>0.76), and large for reduction in average daily number of cigarettes (d>2.66).  
 
Aim 1 Analyses.  
Plasma Nicotine  
The main plasma nicotine outcome was the change in plasma nicotine concentration from 
before the 10-puff bout to after (i.e., nicotine boost) at the final clinical laboratory session (Fri, 
week 2; session 4, study day 12). Plasma nicotine boost was calculated for each participant by 
subtracting their pre-puff plasma nicotine concentration from their post-puff plasma nicotine 
concentration at each session. Mann-Whitney U tests compared the participant-level nicotine 
boost estimates across the IQOS-M and IQOS-T groups (Stata 17).  
Exploratory analyses compared within-group differences in nicotine boost between 
sessions 3 (Mon, week 2; study day 8) and 4 (Fri, week 2; study day 12) using Wilcoxon Signed 
Rank tests. Differences in nicotine boost between OB menthol cigarettes (Fri, week 1; study day 
5) and IQOS (Fri, week 2; study day 12) were assessed within each group using Wilcoxon 

Signed Rank tests. Pre- and post-puff plasma nicotine concentrations at each session were 
compared within-group using Wilcoxon Signed Rank tests to determine if pre- and post-puff 
plasma nicotine concentrations differed.  
 
Puff Topography  
 
The main puff topography outcome was the average puff duration during the 10-puff 
directed use bout at the final clinical laboratory session (Fri, week 2; session 4, study day 12). 
Mann-Whitney U tests compared the mean puff duration during the 10-puff directed use bout 
across the IQOS-M and IQOS-T groups (Stata 17).  
To assess whether puff topography patterns changed during the 5-day naturalistic 
exposure to IQOS, topography outcomes at session 3 (Mon, week 2; study day 8) and session 4 
(Fri, week 2; study day 12) were compared within-group using Wilcoxon Signed Rank tests. 
Difference in topography outcomes between OB menthol cigarettes (Fri, week 1; study day 5) 
and IQOS (Fri, week 2; study day 12) were assessed within-group using Wilcoxon Signed Rank 
tests.   
 
Self-Reported Effects 
 
The main self-reported effects outcome was the change in self-reported “craving a 
cigarette/nicotine” on the MNWS from before the 10-puff directed use bout to after at the final 
clinical laboratory session (Fri, week 2; session 4, study day 12). The change in “craving a 
cigarette/nicotine” was calculated for each participant by subtracting the pre-puff measurement 
from the post-puff measurement (i.e., cigarette craving suppression). Mann-Whitney U tests 
compared differences in cigarette craving suppression across the IQOS-M and IQOS-T groups 
(Stata 17).  
Differences across experimental groups in pre- to post-puff changes in QSU-B Factor 1, 
pre- to post-puff changes in QSU-B Factor 2, pre- to post-puff changes in all MNWS items, PEQ 
subscales, and the study specific questions were explored at session 2 (OB; Fri, week 1), session 
3 (IQOS; Mon, week 2), and session 4 (IQOS; Fri, week 2) using Mann-Whitney U tests. 
Exploratory analyses compared within-group differences in all self-reported effects outcomes at 
session 3 (IQOS; Mon, week 2; study day 8) to session 4 (IQOS; Fri, week 2; study day 12) 
using Wilcoxon Signed Rank tests. Wilcoxon Signed Rank tests compared self-reported effects 
outcomes associated with use of OB menthol cigarettes (Fri, week 1; study day 5) to IQOS 
(Friday, week 2; study day 12) within each experimental group. Differences in the pre-puff and 
post-puff values for items on the QSU-B and MNWS were explored within-group using 
Wilcoxon Signed Rank tests.  
 
Experimental Tobacco Marketplace  
The main ETM outcome was IQOS’ CPE with respect to OB menthol cigarettes. Demand 
for all products in the ETM was converted to milligrams (mg) of nicotine to allow for cross-
product comparisons (Bickel et al., 2018; Appendix 4) then log transformed (zero consumption 
values were converted to a nonzero integer by adding 0.1). CPE estimates for each alternative 
product in the ETM were estimated using an approach based on linear regression (Heckman, 
Cummings et al., 2017; Quisenberry, Koffarnus et al., 2017; Quisenberry, Koffarnus et al., 2016). 
CPE estimates were generated for each fixed-price alternative, for each individual, by creating a 

linear regression of log-transformed fixed-price alternative demand as a function of log-
transformed OB menthol cigarette prices,   
 
log(𝐷𝑒𝑚𝑎𝑛𝑑) = 𝛽0 + 𝛽1 log(𝑂𝐵 𝑀𝑒𝑛𝑡ℎ𝑜𝑙 𝐶𝑖𝑔𝑎𝑟𝑒𝑡𝑡𝑒 𝑃𝑟𝑖𝑐𝑒) + 𝑒, 
 
where 𝛽0 represented the cross-price intensity of demand, 𝛽1 represented the CPE of the fixed-
price alternative as a function of OB menthol cigarette price (main outcome), and e was the error 
term. Mann-Whitney U tests compared the individual-level CPE estimates for IQOS across 
participants with access to both flavors of HeatSticks (IQOS-M group) to participants with 
access to only Regular/Tobacco HeatSticks (IQOS-T group) at the final clinical laboratory 
session (IQOS; Fri, week 2; session 4, study day 12). As an alternative strategy for calculating 
CPE estimates, demand for each fixed-price alternative was averaged within-group at each price 
trial in the ETM then a single regression for each group was fit to Equation 1. The resulting 𝛽1 
coefficient estimates were compared across experimental groups using a linear combination of 
parameters approach. 
To ensure data quality and that participants were responding to the price cues within the 
task, demand for OB menthol cigarettes in the ETM was modeled using an exponentiated 
demand equation (GraphPad Prism 9; Hursh & Silberberg, 2008),  
 
𝑄= 𝑄0 + 10 ∗𝑘(𝑒(−𝛼(𝐶∗𝑄0))) −1), 
 
where C represented the cost of the OB menthol cigarettes, Q represented cigarette consumption 
at price C, Q0 represented OB menthol cigarette demand intensity (i.e., cigarette consumption at 
the lowest price trial), k represented the range of cigarette demand across price trials in log units, 
and α was the free parameter that represented the rate of change in demand elasticity. k was set 
equal to 4.89 for all participants (Hursh & Roma, 2013; Hursh & Silberberg, 2008; Quisenberry, 
Koffarnus et al., 2016). Group-level averages for α and R2 were the outcomes of interest; α was 
expressed in terms of log(α) because α values tend to be very small. OB menthol cigarette 
demand was also assessed for each participant using criteria (i.e., trend, bounce, reversal from 
zero) for identifying nonsystematic demand in purchase tasks (Stein, Koffarnus et al., 2015). 
Exploratory analyses compared the observed cross-price intensity of IQOS (i.e., demand 
for IQOS at the lowest price of OB menthol cigarettes [$0.12/cigarette]) across the IQOS-M and 
IQOS-T groups using Mann-Whitney U tests. CPE estimates for all other alternative products 
were compared across experimental groups using Mann-Whitney U tests (individual-level 
analyses) and a linear combination of parameters (group-level analyses). Wilcoxon Signed Rank 
tests compared ETM outcomes (within-group) across sessions 2 (OB, Fri) and 4 (IQOS, Fri) as 
well as across sessions 3 (IQOS, Mon) and 4 (IQOS, Fri) to gauge if exposure to IQOS in the 
clinical laboratory or at home influenced purchasing decisions in the ETM.  
 

Aim 2 Analyses.  
Naturalistic Use  
The main naturalistic use outcome was the percentage reduction in the mean number of 
cigarettes smoked per day from the baseline week (Tues-Thurs, week 1) to the intervention week 
(Tues-Thurs, week 2) based on responses to EMA prompts. The percentage reduction in mean 
number of cigarettes smoked per day was calculated for each individual as (Stone, DeAtley et al., 
2022): 
% 𝑟𝑒𝑑𝑢𝑐𝑡𝑖𝑜𝑛 𝑖𝑛 𝑐𝑖𝑔𝑎𝑟𝑒𝑡𝑡𝑒𝑠 𝑐𝑜𝑛𝑠𝑢𝑚𝑒𝑑 𝑝𝑒𝑟 𝑑𝑎𝑦=  100 ×
(
𝐴𝑣𝑔 # 𝑚𝑒𝑛𝑡ℎ𝑜𝑙 𝑐𝑖𝑔𝑎𝑟𝑒𝑡𝑡𝑒𝑠 𝑝𝑒𝑟 𝑑𝑎𝑦𝑊𝑒𝑒𝑘 1,   𝑇𝑢𝑒𝑠−𝑇ℎ𝑢𝑟𝑠  − 𝐴𝑣𝑔 # 𝑚𝑒𝑛𝑡ℎ𝑜𝑙 𝑐𝑖𝑔𝑎𝑟𝑒𝑡𝑡𝑒𝑠 𝑝𝑒𝑟 𝑑𝑎𝑦𝑊𝑒𝑒𝑘 2,   𝑇𝑢𝑒𝑠−𝑇ℎ𝑢𝑟𝑠 
𝐴𝑣𝑔 # 𝑚𝑒𝑛𝑡ℎ𝑜𝑙 𝑐𝑖𝑔𝑎𝑟𝑒𝑡𝑡𝑒𝑠 𝑝𝑒𝑟 𝑑𝑎𝑦𝑊𝑒𝑒𝑘 1,   𝑇𝑢𝑒𝑠−𝑇ℎ𝑢𝑟𝑠
)
. 
 
Percentage reductions in OB menthol cigarette consumption from the baseline week to the 
intervention week were compared across the IQOS-M and IQOS-T groups using Mann-Whitney 
U tests. As sensitivity analyses, statistical comparisons were repeated using responses to the 
three-day TLFBs conducted at sessions 2 (OB, Fri) and 4 (IQOS, Fri) and by imputing missing 
EMA values with multiple imputation by chained equations (i.e., predictive mean matching 
based on five nearest neighbors across 10 imputed datasets). Exploratory analyses compared 
mean daily use of IQOS HeatSticks (Tues-Thurs) during the intervention week across the IQOS-
M and IQOS-T groups using Mann-Whitney U tests. Within-group differences in total tobacco 
consumption (i.e., sum of IQOS and OB consumption), OB cigarette consumption, and IQOS 
consumption during week 1 compared to week 2 were evaluated using Wilcoxon Signed Rank 
tests.  
 
 
10. Withdrawing Participants 
Participation in this study may be stopped at any time by the investigator without 
participant consent. The reasons might include: 
● the investigator thinks it necessary for the participant’s health or safety 
● the participant is found to not be eligible for the study 
● the sponsor has stopped the study  
● the participant has not followed study instructions 
● administrative reasons require the participant’s withdrawal 
 
References 
Adriaens, K., Gucht, D. V., & Baeyens, F. (2018). IQOS vs. e-Cigarette vs. Tobacco Cigarette: A 
direct comparison of short-term effects after overnight-abstinence. International Journal 
of Environmental Research and Public Health, 15(12), 2902. 
doi:10.3390/ijerph15122902. PMID: 30567400.  
 
Ahijevych, K., & Garrett, B. E. (2010). The role of menthol in cigarettes as a reinforcer of 
smoking behavior. Nicotine & Tobacco Research, 12(suppl 2), S110-S116. 
doi:10.1093/ntr/ntq203. PMID: 21177367.  
 

Allen, B., Jr., Cruz, T. B., Leonard, E., & Unger, J. B. (2010). Development and validation of a 
scale to assess attitudes and beliefs about menthol cigarettes among African American 
smokers. Evaluation & the Health Professions, 33(4), 414-436. 
doi:10.1177/0163278710383276. PMID: 21149394.  
 
Ashley, D. L., & Backinger, C. L. (2012). The Food and Drug Administration's regulation of 
tobacco: the Center for Tobacco Products' Office of Science. American Journal of 
Preventative Medicine, 43(5 Suppl 3), S255-S263. doi:10.1016/j.amepre.2012.08.004. 
PMID: 23079225.  
 
Ashley, D. L., Backinger, C. L., van Bemmel, D. M., & Neveleff, D. J. (2014). Tobacco regulatory 
science: research to inform regulatory action at the Food and Drug Administration's 
Center for Tobacco Products. Nicotine & Tobacco Research, 16(8), 1045-1049. 
doi:10.1093/ntr/ntu038. PMID: 24638850.  
 
Audrain-McGovern, J., Strasser, A. A., & Wileyto, E. P. (2016). The impact of flavoring on the 
rewarding and reinforcing value of e-cigarettes with nicotine among young adult 
smokers. Drug and Alcohol Dependence, 166, 263-267. 
doi:10.1016/j.drugalcdep.2016.06.030. PMID: 27426010.  
 
Auer, R., Concha-Lozano, N., Jacot-Sadowski, I., Cornuz, J., & Berthet, A. (2017). Heat-Not-
Burn tobacco cigarettes: smoke by any other name. JAMA Internal Medicine, 177(7), 
1050-1052. doi:10.1001/jamainternmed.2017.1419. PMID: 28531246.  
 
Backinger, C. L., Meissner, H. I., & Ashley, D. L. (2016). The FDA "Deeming Rule" and tobacco 
regulatory research. Tobacco Regulatory Science, 2(3), 290-293. 
doi:10.18001/TRS.2.3.8. PMID: 29423429.  
 
Barnes, A. J., Bono, R. S., Lester, R. C., Eissenberg, T. E., & Cobb, C. O. (2017). Effect of 
flavors and modified risk messages on e-cigarette abuse liability. Tobacco Regulatory 
Science, 3(4), 347-387. PMID: 29204463.  
 
Barnes, A. J., Bono, R. S., Rudy, A. K., Hoetger, C., Nicksic, N. E., & Cobb, C. O. (2020). Effect 
of e-cigarette advertisement themes on hypothetical e-cigarette purchasing in price-
responsive adolescents. Addiction, 115(12), 2357-2368. doi:10.1111/add.15084. PMID: 
32285978.  
 
Beckham, J. C., Wiley, M. T., Miller, S. C., Dennis, M. F., Wilson, S. M., McClernon, F. J., & 
Calhoun, P. S. (2008). Ad lib smoking in post-traumatic stress disorder: An electronic 
diary study. Nicotine & Tobacco Research, 10(7), 1149-1157. 
doi:10.1080/14622200802123302. PMID: 18629724.  
 
Benowitz, N. L., Herrera, B., & Jacob, P. (2004). Mentholated cigarette smoking inhibits nicotine 
metabolism. Journal of Pharmacology and Experimental Therapeutics, 310(3), 1208-
1215. doi:10.1124/jpet.104.066902. PMID: 15084646.  
 
Berman, M. L., Connolly, G., Cummings, K. M., Djordjevic, M. V., Myers, M., O'Connor, R. J., 
Parascandola, M., Rees, V., Rice, J. M., Shields, P. G. (2015). Providing a science base 
for the evaluation of tobacco products. Tobacco Regulatory Science, 1(1), 76-93. 
doi:10.18001/TRS.1.1.8. PMID: 26665160.  
 
Bickel, W. K., Johnson, M. W., Koffarnus, M. N., MacKillop, J., & Murphy, J. G. (2014). The 
behavioral economics of substance use disorders: reinforcement pathologies and their 
repair. Annual Review of Clinical Psychology, 10, 641-677. doi:10.1146/annurev-clinpsy-
032813-153724. PMCID: PMC4501268.  
 

Bickel, W. K., Snider, L. N., Mellis, S. E., Stein, J. S., & Quisenberry, A.J. (2017). The 
behavioral economics of tobacco products. In Hanoch, Y. B., Barnes, A.J., & Rice, T. 
(Ed.), Behavioral Economics and Healthy Behaviors: Key Concepts and Current 
Research. New York, NY: Routledge. 
 
Bickel, W. K., Pope, D. A., Kaplan, B. A., DeHart, W. B., Koffarnus, M. N., & Stein, J. S. (2018). 
Electronic cigarette substitution in the experimental tobacco marketplace: A review. 
Preventative Medicine, 117, 98-106. doi:10.1016/j.ypmed.2018.04.026. PMCID: 
PMC6685072.  
 
Blank, M. D., Disharoon, S., & Eissenberg, T. (2009). Comparison of methods for measurement 
of smoking behavior: mouthpiece-based computerized devices versus direct 
observation. Nicotine & Tobacco Reserach, 11(7), 896-903. doi:10.1093/ntr/ntp083. 
PMCID: PMC2699933.  
 
Blank, M. D., Breland, A. B., Enlow, P. T., Duncan, C., Metzger, A., & Cobb, C. O. (2016). 
Measurement of smoking behavior: Comparison of self-reports, returned cigarette butts, 
and toxicant levels. Experimental and Clinical Psychopharmacology, 24(5), 348-355. 
doi:10.1037/pha0000083. PMCID: PMC5048488.  
 
Bono, R. S., Cobb, C. O., Wall, C. S., Lester, R. C., Hoetger, C., Lipato, T., Guy, M. C., 
Eissenberg, T., Bickel, W.K., & Barnes, A. J. (2020). Behavioral economic assessment 
of abuse liability for Black & Mild cigar flavors among young adults. Experimental and 
Clinical Psychopharmacology, Advance online publication. doi:10.1037/pha0000400. 
PMCID: PMC8513892.  
 
Bono, R., Cobb, C. O., Hoetger, C., White, A. M., & Barnes, A. J. (2021a). Beyond cross-price 
elasticity: What else can we learn from the cross-price purchase task [poster]? NIH 
Tobacco Regulatory Science Meeting, Virtual.  
 
Bono, R., Cobb, C. O., Hoetger, C., White, A. M., & Barnes, A. J. (2021b). Beyond cross-price 
elasticity: What else can we learn from the cross-price purchase task? Manuscript in 
progress.   
 
Bover, M. T., Foulds, J., Steinberg, M. B., Richardson, D., & Marcella, S. W. (2008). Waking at 
night to smoke as a marker for tobacco dependence: patient characteristics and 
relationship to treatment outcome. International Journal of Clinical Practice, 62(2), 182-
190. doi:10.1111/j.1742-1241.2007.01653.x. PMID: 18199277.  
 
Breland, A. B., Buchhalter, A. R., Evans, S. E., & Eissenberg, T. (2002). Evaluating acute 
effects of potential reduced-exposure products for smokers: clinical laboratory 
methodology. Nicotine & Tobacco Research, 4(Suppl 2), S131-S140. 
doi:10.1080/1462220021000032780. PMID: 12573174.  
 
Breland, A. B., Kleykamp, B. A., & Eissenberg, T. (2006). Clinical laboratory evaluation of 
potential reduced exposure products for smokers. Nicotine & Tobacco Research, 8(6), 
727-738. PMID: 17132520.  
 
Buchhalter, A. R., & Eissenberg, T. (2000). Preliminary evaluation of a novel smoking system: 
effects on subjective and physiological measures and on smoking behavior. Nicotine & 
Tobacco Research, 2(1), 39-43. doi:10.1080/14622200050011286. PMID: 11072439.  
 
Bullen, C., McRobbie, H., Thornley, S., Glover, M., Lin, R., & Laugesen, M. (2010). Effect of an 
electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user 
preferences and nicotine delivery: randomised cross-over trial. Tobacco Control, 19(2), 
98. doi:10.1136/tc.2009.031567. PMID: 20378585.  

 
Butschky, M. F., Bailey, D., Henningfield, J. E., & Pickworth, W. B. (1995). Smoking without 
nicotine delivery decreases withdrawal in 12-hour abstinent smokers. Pharmacology, 
Biochemistry and Behavior, 50(1), 91-96. doi:10.1016/0091-3057(94)00269-O. PMID: 
7700960.  
 
Caponnetto, P., Campagna, D., Cibella, F., Morjaria, J. B., Caruso, M., Russo, C., & Polosa, R. 
(2013). EffiCiency and Safety of an eLectronic cigAreTte (ECLAT) as tobacco cigarettes 
substitute: A prospective 12-Month randomized control design study. PLoS One, 8(6), 
e66317. doi:10.1371/journal.pone.0066317. PMID: 23826093.  
 
Carter, L. P., & Griffiths, R. R. (2009a). Principles of laboratory assessment of drug abuse 
liability and implications for clinical development. Drug and Alcohol Dependence, 105 
(Suppl 1), S14-S25. doi:10.1016/j.drugalcdep.2009.04.003. PMCID: PMC2763984.  
 
Carter, L. P., Stitzer, M. L., Henningfield, J. E., O'Connor, R. J., Cummings, K. M., & Hatsukami, 
D. K. (2009b). Abuse liability assessment of tobacco products including potential 
reduced exposure products. Cancer Epidemiology, Biomarkers & Prevention, 18(12), 
3241-3262. doi:10.1158/1055-9965.EPI-09-0948. PMCID: PMC2798587.  
 
Cobb, C. O., Weaver, M. F., & Eissenberg, T. (2010). Evaluating the acute effects of oral, non-
combustible potential reduced exposure products marketed to smokers. Tobacco 
Control, 19(5), 367. doi:10.1136/tc.2008.028993. PMCID: PMC3207996.  
 
Cobb, C. O., Lester, R. C., Rudy, A. K., Hoetger, C., Scott, M., Austin, M., Montpetit, A., Lipato, 
T., Graham, A. L., Barnes, A. J., & Eissenberg, T. (2020). Tobacco-use behavior and 
toxicant exposure among current dual users of electronic cigarettes and tobacco 
cigarettes. Experimental and Clinical Psychopharmacology, Advance online publication. 
doi:10.1037/pha0000417. PMID: 32658532.  
 
Cobb, C. O., Foulds, J., Yen, M.S., Veldheer, S., Lopez, A. A., Yingst, J. M., Bullen, C., Kang, 
L., & Eissenberg, T. (2021). Effect of an electronic nicotine delivery system with 0, 8, or 
36 mg/mL liquid nicotine versus a cigarette substitute on tobacco-related toxicant 
exposure: a four-arm, parallel-group, randomised, controlled trial. The Lancet 
Respiratory Medicine, 9(8), 840-850. doi:10.1016/S2213-2600(21)00022-9. PMCID: 
PMC8349799.  
 
Cox, L. S., Tiffany, S. T., & Christen, A. G. (2001). Evaluation of the brief questionnaire of 
smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine & Tobacco 
Research, 3(1), 7-16. doi:10.1080/14622200020032051. PMID: 11260806.  
 
Curtin, G. M., Sulsky, S. I., Landingham, C. V., Marano, K. M., Graves, M. J., Ogden, M. W., & 
Swauger, J. E. (2014). Primary measures of dependence among menthol compared to 
non-menthol cigarette smokers in the United States. Regulatory Toxicology and 
Pharmacology, 69(3), 451-466. doi:10.1016/j.yrtph.2014.05.011. PMID: 24852490.  
 
D'Silva, J., Amato, M. S., & Boyle, R. G. (2015). Quitting and switching: menthol smokers' 
responses to a menthol ban. Tobacco Regulatory Science, 1(1), 54-60. 
doi:10.18001/trs.1.1.6 
 
Davis, B., To, V., & Talbot, P. (2019). Comparison of cytotoxicity of IQOS aerosols to smoke from 
Marlboro Red and 3R4F reference cigarettes. Toxicology In Vitro, 61, 104652. 
https://dx.doi.org/10.1016/j.tiv.2019.104652. PMID: 31526836.  
 

Dawkins, L., Turner, J., Roberts, A., & Soar, K. (2013). 'Vaping' profiles and preferences: an 
online survey of electronic cigarette users. Addiction, 108(6), 1115-1125. 
doi:10.1111/add.12150. PMID: 23551515.  
 
deBethizy, J. D., Robinson, J. H., Davis, R. A., Doolittle, D. J., Burger, G. T., Reynolds, J. H., 
Fletcher, R. G., Hayes, A. W. (1988). Absorption of nicotine from a cigarette that does 
not burn tobacco. Pharmacology, 37(5), 328-332. doi:10.1159/000138484. PMID: 
3237761.  
 
Denlinger-Apte, R. L., Cassidy, R. N., Carey, K. B., Kahler, C. W., Bickel, W. K., O'Connor, R., 
Thussu, S., Tidey, J. W. (2021). The impact of menthol flavoring in combusted tobacco 
on alternative product purchasing: A pilot study using the Experimental Tobacco 
Marketplace. Drug and Alcohol Dependence, 218, 108390. 
doi:10.1016/j.drugalcdep.2020.108390. PMCID: PMC7750267.  
 
Donny, E. C., Denlinger, R. L., Tidey, J. W., Koopmeiners, J. S., Benowitz, N. L., Vandrey, R. 
G., al’Absi, M., Carmella, S. G., Cinciripini, P. M., Dermody, S. S., Drobes, D. J., Hecht, 
S. S., Jensen, J., Lane, T., Le, C. T., McClernon, J. M., Montoya, I. D., Murphy, S. E., 
Robinson, J. D., Stitzer, M. L., Strasser, A. A., Tindle, H., & Hatsukami, D. K. (2015). 
Randomized trial of reduced-nicotine standards for cigarettes. New England Journal of 
Medicine, 373(14), 1340-1349. doi:10.1056/NEJMsa1502403. PMCID: PMC4642683.  
 
Eissenberg, T., & Shihadeh, A. (2009). Waterpipe tobacco and cigarette smoking: Direct 
comparison of toxicant exposure. American Journal of Preventive Medicine, 37(6), 518-
523. doi:https://doi.org/10.1016/j.amepre.2009.07.014. PMCID: PMC2805076.  
 
European Network for Smoking and Tobacco Prevention (ENSP). (2020). Ban on menthol 
cigarettes: European Union member states shall prohibit the placing on the market of 
tobacco products with a characterising flavour. Tobacco Prevention and Cessation, 6, 
40. doi:10.18332/tpc/124164. PMCID: PMC7549510.  
 
Evangelista-Falcon, W., Ellingson, S. R., Smith, J. C., & Baudry, J. (2019). Ensemble docking in 
drug discovery: How many protein configurations from molecular dynamics simulations 
are needed to reproduce known ligand binding? The Journal of Physical Chemistry B, 
123(25), 5189-5195. doi:10.1021/acs.jpcb.8b11491. PMID: 30695645.  
 
Fagan, P., Pohkrel, P., Herzog, T., Pagano, I., Vallone, D., Trinidad, D. R., Sakuma, K, Sterling, 
K., Fryer, C. S., & Moolchan, E. (2015). Comparisons of three nicotine dependence 
scales in a multiethnic sample of young adult menthol and non-menthol smokers. Drug 
and Alcohol Dependence, 149, 203-211. doi:10.1016/j.drugalcdep.2015.02.005. PMCID: 
PMC4865397.  
 
Fallin, A., Goodin, A. J., & King, B. A. (2015). Menthol cigarette smoking among lesbian, gay, 
bisexual, and transgender adults. American Journal of Preventative Medicine, 48(1), 93-
97. doi:10.1016/j.amepre.2014.07.044. PMCID: PMC4454462.  
 
Farsalinos, K. E., Spyrou, A., Stefopoulos, C., Tsimopoulou, K., Kourkoveli, P., Tsiapras, D., 
Kyrzopoulos, S., Poulas, K., & Voudris, V. (2015). Nicotine absorption from electronic 
cigarette use: comparison between experienced consumers (vapers) and naive users 
(smokers). Scientific Reports, 5, 11269. doi:10.1038/srep11269. PMCID: PMC3935206.  
 
Felicione, N. J., Karaoghlanian, N., Shihadeh, A., Eissenberg, T., & Blank, M. D. (2020). 
Comparison of measurement methods for electronic cigarette puff topography. Tobacco 
Regulatory Science, 6(5), 318-330. doi:10.18001/TRS.6.5.2. PMCID:PMC8096180.  
 

Ferguson, S. G., & Shiffman, S. (2011). Using the methods of ecological momentary 
assessment in substance dependence research—smoking cessation as a case study. 
Substance Use & Misuse, 46(1), 87-95. doi:10.3109/10826084.2011.521399. PMID: 
21190409.  
 
Food and Drug Administration (FDA). (2018). Regulation of flavors in tobacco products. 21 CFR 
Parts 1100, 1140, and 1143, Docket No. FDA-2017-N-6565, RIN 0910-AH60. Federal 
Register, 83(55), 12294-12301.  
 
Food and Drug Administration (FDA). (2020, July). FDA Authorizes Marketing of IQOS Tobacco 
Heating System with ‘Reduced Exposure’ Information. U.S. Food & Drug. 
https://www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-iqos-
tobacco-heating-system-reduced-exposure-information 
 
Foulds, J., Ramstrom, L., Burke, M., & Fagerström, K. (2003). Effect of smokeless tobacco 
(snus) on smoking and public health in Sweden. Tobacco Control, 12(4), 349-359. 
doi:10.1136/tc.12.4.349. PMCID: PMC1747791.  
 
Foulds, J., Hooper, M. W., Pletcher, M. J., & Okuyemi, K. S. (2010). Do smokers of menthol 
cigarettes find it harder to quit smoking? Nicotine & Tobacco Reserach, 12 (Suppl 2), 
S102-109. doi:10.1093/ntr/ntq166. PMCID: PMC3145377.  
 
Frati, G., Carnevale, R., Nocella, C., Peruzzi, M., Marullo, A. G., De Falco, E., Chimenti, I., 
Cammisotto, V., Valenti, V., Cavarretta, E., Carrizzo, A., Versaci, F., Vitali, M., Protano, 
C., Roever, L., Giordano, A., Sciarretta, S., & Biondi-Zoccai, G. (2020). Profiling the 
acute effects of modified risk products: Evidence from the Sur-Vapes cluster study. 
Current Atherosclerosis Reports, 22(2), 8. doi: 10.1007/s11883-020-0824-4. PMID: 
32034541.  
 
Gades, M. S., Petersen, A., Meier, E., Lindgren, B. R., O’Connor, R. J., Shields, P. G., & 
Hatsukami, D. (2020). The role of subjective responses in electronic cigarette uptake 
and substitution in adult smokers. Drug and Alcohol Dependence, 212, 107999. 
doi:https://doi.org/10.1016/j.drugalcdep.2020.107999. PMCID: PMC7315796.  
 
Giovino, G. A., Villanti, A. C., Mowery, P. D., Sevilimedu, V., Niaura, R. S., Vallone, D. M., & 
Abrams, D. B. (2015). Differential trends in cigarette smoking in the USA: is menthol 
slowing progress? Tobacco Control, 24(1), 28-37. doi:10.1136/tobaccocontrol-2013-
051159. PMID: 23997070.  
 
Gray, J. N., Breland, A. B., Weaver, M., & Eissenberg, T. (2008). Potential reduced exposure 
products (PREPs) for smokeless tobacco users: Clinical evaluation methodology. 
Nicotine & Tobacco Research, 10(9), 1441-1448. 
https://dx.doi.org/10.1080/14622200802323258. PMCID: PMC3212707.  
 
Gritz, E. R., Baer-Weiss, V., Benowitz, N. L., Van Vunakis, H., & Jarvik, M. E. (1981). Plasma 
nicotine and cotinine concentrations in habitual smokeless tobacco users. Clinical 
Pharmacology & Therapeutics, 30(2), 201-209. doi:https://doi.org/10.1038/clpt.1981.149. 
PMID: 7195786.  
 
Hammond, D., Fong, G. T., Cummings, K. M., & Hyland, A. (2005). Smoking topography, brand 
switching, and nicotine delivery: Results from an in vivo study. Cancer Epidemiology, 
Biomarkers, & Prevention, 14(6), 1370-1375. doi:10.1158/1055-9965.EPI-04-0498. 
PMID: 15941943.  
 
Harris, P. A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., & Conde, J. G. (2009). Research 
electronic data capture (REDCap)- a metadata-driven methodology and workflow 

process for providing translational research informatics support. Journal of Biomedical 
Informatics, 42(2), 377-381. https://doi.org/10.1016/j.jbi.2008.08.010. PMCID: 
PMC2700030.  
 
Harris, P. A., Taylor, R., Minor, B. L. Elliott, V. Fernandez, M., O’Neal, L., McLeod, L., Delacqua, 
G., Delacqua, F., Kirby, J., & Duda, S. N. (2019). The REDCap consortium: Building an 
international community of software platform partners. Journal of Biomedical Informatics, 
95, 103208. https://doi.org/10/1016/j.jbi.2019.103208. PMCID: PMC7254481.  
 
Haziza, C., de La Bourdonnaye, G., Merlet, S., Benzimra, M., Ancerewicz, J., Donelli, A., Baker, 
G., Picavet, P., & Lüdicke, F. (2016). Assessment of the reduction in levels of exposure 
to harmful and potentially harmful constituents in Japanese subjects using a novel 
tobacco heating system compared with conventional cigarettes and smoking abstinence: 
A randomized controlled study in confinement. Regulatory Toxicology and 
Pharmacology, 81, 489-499. doi:https://doi.org/10.1016/j.yrtph.2016.09.014. PMID: 
27693654.  
 
Haziza, C., de La Bourdonnaye, G., Donelli, A., Poux, V., Skiada, D., Weitkunat, R., Baker, G., 
Picavet, P. & Ludicke, F. (2020). Reduction in exposure to selected harmful and 
potentially harmful constituents approaching those observed upon smoking abstinence 
in smokers switching to the menthol tobacco heating system 2.2 for 3 months (Part 1). 
Nicotine & Tobacco Research, 22(4), 539-548. doi:10.1093/ntr/ntz013. PMCID: 
PMC716481.  
 
Henderson, B. J., Wall, T. R., Henley, B. M., Kim, C. H., McKinney, S., & Lester, H. A. (2017). 
Menthol enhances nicotine reward-related behavior by potentiating nicotine-induced 
changes in nAChR function, nAChR upregulation, and DA neuron excitability. 
Neuropsychopharmacology, 42(12), 2285-2291. doi:10.1038/npp.2017.72. PMCID: 
PMC5645749.  
 
Henningfield, J. E., & Keenan, R. M. (1993). Nicotine delivery kinetics and abuse liability. 
Journal of Consulting and Clinical Psychology, 61(5), 743-750. doi:10.1037/0022-
006X.61.5.743. PMID: 8245272.  
 
 
 
Hiler, M., Breland, A., Spindle, T., Maloney, S., Lipato, T., Karaoghlanian, N., Shihadeh, A., 
Lopez, A., Romoa, C., & Eissenberg, T. (2017). Electronic cigarette user plasma nicotine 
concentration, puff topography, heart rate, and subjective effects: Influence of liquid 
nicotine concentration and user experience. Experimental and Clinical 
Psychopharmacology, 25(5), 380-392. doi:10.1037/pha0000140. PMCID: PMC5657238.  
 
Hoetger, C., Bono, R. S., White, A. M., Barnes, A. J., & Cobb, C. O. (2021). The interaction of 
nicotine concentration and device power on electronic nicotine delivery system (ENDS) 
abuse liability among exclusive ENDS users and dual users of ENDS and combustible 
cigarettes. Experimental and Clinical Psychopharmacology, Advance online publication. 
doi:10.1037/pha0000523. PMID: 34547773.  
 
Hoffman, A. C. (2011). The health effects of menthol cigarettes as compared to non-menthol 
cigarettes. Tobacco Induced Diseases, 9(Suppl 1), S7. doi:10.1186/1617-9625-9-s1-s7. 
PMCID: PMC3102906.  
 
Hursh, S. R., & Roma, P. G. (2013). Behavioral economics and empirical public policy. Journal 
of the Experimental Analysis of Behavior, 99(1), 98-124. doi:10.1002/jeab.7. PMID: 
23344991.  
 

Hursh, S. R., & Roma, P. G. (2016). Behavioral economics and the analysis of consumption and 
choice. Managerial and Decision Economics, 37(4), 224-238. doi:10.1002/mde.2724 
 
Institute of Medicine (IOM). (2012). Scientific Standards for Studies on Modified Risk Tobacco 
Products. Washington, DC. http://www.nap.edu/catalog/13294/scientific-standards-for-
studies-on-modified-risk-tobacco-products 
 
Kostygina, G., Glantz, S. A., & Ling, P. M. (2016). Tobacco industry use of flavours to recruit 
new users of little cigars and cigarillos. Tobacco Control, 25(1), 66-74. 
doi:10.1136/tobaccocontrol-2014-051830. PMCID: PMC4414663.  
 
Laverty, A. A., Vardavas, C. I., & Filippidis, F. T. (2021). Prevalence and reasons for use of 
Heated Tobacco Products (HTP) in Europe: an analysis of Eurobarometer data in 28 
countries. The Lancet Regional Health - Europe, 8, 100159. 
doi:10.1016/j.lanepe.2021.100159. PMCID: PMC8454644.  
 
Lee, E. M., Malson, J. L., Moolchan, E. T., & Pickworth, W. B. (2004). Quantitative comparisons 
between a nicotine delivery device (Eclipse) and conventional cigarette smoking. 
Nicotine & Tobacco Research, 6(1), 95-102. doi:10.1080/14622200310001656911. 
PMID: 14982693.  
 
Leigh, N. J., Tran, P. L., O’Connor, R. J., & Goniewicz, M. L. (2018). Cytotoxic effects of Heated 
Tobacco Products (HTPs) on human bronchial epithelial cells. Tobacco Control, 27(Suppl 1), 
S26-S29. https://dx.doi.org/10.1136/tobaccocontrol-2018-054317. PMCID: PMC6252481.  
 
Levy, D. T., Meza, R., Yuan, Z., Li, Y., Cadham, C., Sanchez-Romero, L. M., Nargiz, T., Knoll, 
M., Liber, A. C., Mistry, R., Hirschtick, J. L., Fleischer, N. L., Skolnick, S., Brouwer, A. F., 
Douglas, C., Jeon, J., Cook, S., Warner, K. E. (2021). Public health impact of a US ban 
on menthol in cigarettes and cigars: a simulation study. Tobacco Control, Published 
online ahead of print. doi:10.1136/tobaccocontrol-2021-056604. PMID: 34475258.  
 
Lunell, E., Fagerström, K., Hughes, J., & Pendrill, R. (2020). Pharmacokinetic comparison of a 
novel non-tobacco-based nicotine pouch (ZYN) with conventional, tobacco-based 
swedish snus and american moist snuff. Nicotine & Tobacco Research, 22(10), 1757-
1763. doi:10.1093/ntr/ntaa068. PMID: 32319528.  
 
MacKillop, J., Murphy, J. G., Ray, L. A., Eisenberg, D. T., Lisman, S. A., Lum, J. K., & Wilson, 
D. S. (2008). Further validation of a cigarette purchase task for assessing the relative 
reinforcing efficacy of nicotine in college smokers. Experimental and Clinical 
Psychopharmacology, 16(1), 57-65. doi:10.1037/1064-1297.16.1.57. PMID: 18266552.  
 
MacKillop, J., Murphy, C. M., Martin, R. A., Stojek, M., Tidey, J. W., Colby, S. M., & Rohsenow, 
D. J. (2016). Predictive validity of a cigarette purchase task in a randomized controlled 
trial of contingent vouchers for smoking in individuals with substance use disorders. 
Nicotine & Tobacco Research, 18(5), 531-537. doi:10.1093/ntr/ntv233. PMCID: 
PMC5896828.  
 
Maloney, S., Eversole, A., Crabtree, M., Soule, E., Eissenberg, T., & Breland, A. B. (2020). 
Acute effects of JUUL and IQOS in cigarette smokers. Tobacco Control, Published 
online ahead of print. doi:10.1136/tobaccocontrol-2019-055475. PMCID: PMC7864587.  
 
Mead, E. L., Chen, J. C., Kirchner, T. R., Butler, J., & Feldman, R. H. (2018). An ecological 
momentary assessment of cigarette and cigar dual use among african american young 
adults. Nicotine & Tobacco Research, 20(Suppl 1), S12-S21. doi:10.1093/ntr/nty061. 
PMCID: PMC6093372.  
 

Moazed, F., Chun, L., Matthay, M. A., Calfee, C. S., & Gotts, J. (2018). Assessment of industry 
data on pulmonary and immunosuppressive effects of IQOS. Tobacco Control, 27(Suppl 
1), S20-S25. https://dx.doi.org/10.1136/tobaccocontrol-2018-054296. PMCID: 
PMC6252496.  
 
O'Connor, R. J., Bansal-Travers, M., Carter, L. P., & Cummings, K. M. (2012). What would 
menthol smokers do if menthol in cigarettes were banned? Behavioral intentions and 
simulated demand. Addiction, 107(7), 1330-1338. doi:10.1111/j.1360-
0443.2012.03822.x. PMCID: PMC3370153.  
 
Ossip-Klein, D. J., Martin, J. E., Danley Lomax, B., Prue, D. M., & Jo Davis, C. (1983). 
Assessment of smoking topography generalization across laboratory, clinical, and 
naturalistic settings. Addictive Behaviors, 8(1), 11-17. doi:10.1016/0306-4603(83)90049-
7. PMID: 6880921.  
 
Ozga, J. E., Bays, C., Haliwa, I., Felicione, N. J., Ferguson, S. G., Dino, G., & Blank, M. D. 
(2021). Measurement of cigarette smoking: Comparisons of global self-report, returned 
cigarette filters, and ecological momentary assessment. Experimental and Clinical 
Psychopharmacology, Advance online publication. doi:10.1037/pha0000449. PMCID: 
PMC8384977.  
 
Pacek, L. R., Wiley, J. L., & McClernon, F. J. (2019). A conceptual framework for understanding 
multiple tobacco product use and the impact of regulatory action. Nicotine & Tobacco 
Research, 21(3), 268-277. doi:10.1093/ntr/nty129. PMCID: PMC6379035.  
 
Phillips, E., Wang, T. W., Husten, C. G., Corey, C. G., Apelberg, B. J., Jamal, A., Homa, D. N., 
King, B. A. (2017). Tobacco product use among adults - United States, 2015. Morbidity 
and Mortality Weekly Report, 66(44), 1209-1215. doi:10.15585/mmwr.mm6644a2. 
PMCID: PMC5679591.  
 
Pomerleau, O. F., Pomerleau, C. S., & Rose, J. E. (1989). Controlled dosing of nicotine: a 
review of problems and progress. Annals of Behavioral Medicine, 11(4), 158-163. 
doi:10.1207/s15324796abm1104_6 
 
Pope, D. A., Poe, L., Stein, J. S., Kaplan, B. A., DeHart, W. B., Mellis, A. M., Heckman, B. W., 
Epstein, L. H., Chaloupka, F. J., Bickel, W. K. (2020). The experimental tobacco 
marketplace: demand and substitutability as a function of cigarette taxes and e-liquid 
subsidies. Nicotine & Tobacco Research, 22(5), 782-790. doi:10.1093/ntr/ntz116. 
PMCID: PMC7171289.  
 
Quisenberry, A. J., Koffarnus, M. N., Hatz, L. E., Epstein, L. H., & Bickel, W. K. (2016). The 
experimental tobacco marketplace I: substitutability as a function of the price of 
conventional cigarettes. Nicotine & Tobacco Research, 18(7), 1642-1648. 
doi:10.1093/ntr/ntv230. PMCID: PMC4902880.  
 
Reilly, S. M., Goel, R., Bitzer, Z., Elias, R. J., Foulds, J., Muscat, J., & Richie, J. P. (2017). 
Effects of topography-related puff parameters on carbonyl delivery in mainstream 
cigarette smoke. Chemical Research in Toxicology, 30(7), 1463-1469. 
doi:10.1021/acs.chemrestox.7b00104. PMCID: PMC5556925.  
 
Rezk-Hanna, M., Doering, L., Robbins, W., Sarna, L., Elashoff, R. M., & Victor, R. G. (2018). 
Acute effect of hookah smoking on arterial stiffness and wave reflections in adults aged 
18 to 34 years of age. American Journal of Cardiology, 122(5), 905-909. 
doi:10.1016/j.amjcard.2018.05.033. PMID: 30057235.  
 

Roulet, S., Chrea, C., Kanitscheider, C., Kallischnigg, G., Magnani, P., & Weitkunat, R. (2019). 
Potential predictors of adoption of the Tobacco Heating System by U.S. adult smokers: 
An actual use study. F1000Research, 8, 214. doi:10.12688/f1000research.17606.1. 
PMCID: PMC6743249.  
 
Russell, M. A., Feyerabend, C., & Cole, P. V. (1976). Plasma nicotine levels after cigarette 
smoking and chewing nicotine gum. British Medical Journal, 1(6017), 1043-1046. 
doi:10.1136/bmj.1.6017.1043. PMCID: PMC1639908.  
 
Serre, F., Fatseas, M., Debrabant, R., Alexandre, J.-M., Auriacombe, M., & Swendsen, J. 
(2012). Ecological momentary assessment in alcohol, tobacco, cannabis and opiate 
dependence: A comparison of feasibility and validity. Drug and Alcohol Dependence, 
126(1), 118-123. doi:https://doi.org/10.1016/j.drugalcdep.2012.04.025. PMID: 22647899.  
 
Shadel, W.G., Edelen, M.O., Tucker, J.S., Stucky, B.D., Hansen, M., and Cai, L. (2014). 
Development of the PROMIS Nicotine Dependence Item Banks. Nicotine & Tobacco 
Research, 16 (Supp 3); S190-S201. 
 
Shein, M., & Jeschke, G. (2019). Comparison of free radical levels in the aerosol from 
conventional cigarettes, electronic cigarettes, and heat-not-burn tobacco products. 
Chemical Research in Toxicology, 32(6), 129-98. 
https://dx.doi.org/10.1021/acs.chemrestox.9b00085. PMCID: PMC6584902.  
 
Shiffman, S., Stone, A. A., & Hufford, M. R. (2008). Ecological momentary assessment. Annual 
Review of Clinical Psychology, 4(1), 1-32. 
doi:10.1146/annurev.clinpsy.3.022806.091415. PMID: 18509902.  
 
Shiffman, S. (2009a). Ecological momentary assessment (EMA) in studies of substance use. 
Psychological Assessment, 21(4), 486-497. doi:10.1037/a0017074. PMCID: 
PMC2846437.  
 
Shiffman, S. (2009b). How many cigarettes did you smoke? Assessing cigarette consumption 
by global report, time-line follow-back, and ecological momentary assessment. Health 
Psychology, 28(5), 519-526. doi:10.1037/a0015197. PMCID: PMC2762359.  
 
Simonavicius, E., McNeill, A., Shahab, L., & Brose, L. S. (2019). Heat-not-burn tobacco 
products: a systematic literature review. Tobacco Control, 28(5), 582-594. 
doi:10.1136/tobaccocontrol-2018-054419. PMCID: PMC6824610.  
 
Soussy, S., El-Hellani, A., Baalbaki, R., Salman, R., Shihadeh, A., & Saliba, N. A. (2016). 
Detection of 5-hydroxymethylfurfural and furfural in the aerosol of electronic cigarettes. 
Tobacco Control, 25(Suppl 2), 88-93. doi:10.1136/tobaccocontrol-2016-053220. PMID: 
27798321.  
 
Spindle, T. R., Breland, A. B., Karaoghlanian, N. V., Shihadeh, A. L., & Eissenberg, T. (2015). 
Preliminary results of an examination of electronic cigarette user puff topography: the 
effect of a mouthpiece-based topography measurement device on plasma nicotine and 
subjective effects. Nicotine & Tobacco Research, 17(2), 142-149. 
doi:10.1093/ntr/ntu186. PMCID: PMC4838000.  
 
Spindle, T. R., Talih, S., Hiler, M. M., Karaoghlanian, N., Halquist, M. S., Breland, A. B., Shihadeh, A., & 
Eissenberg, T. (2018). Effects of electronic cigarette solvents propylene glycol and vegetable 
glycerin on user nicotine delivery, heart rate, subjective effects, and puff topography. Drug and 
Alcohol Dependence, 188, 193-199. https://dx.doi.org/10.1016/j.drugalcdep.2018.03.042. 
PMCID: PMC7193252.  
 

St Helen, G., Jacob, P., Nardone, N., & Benowitz, N. L. (2018). IQOS: examination of Philip 
Morris International's claim of reduced exposure. Tobacco Control, 27(Suppl 1), S30-
S36. doi:10.1136/tobaccocontrol-2018-054321. PMCID: PMC6252487.  
 
Stoklosa, M., Cahn, Z., Liber, A., Nargis, N., & Drope, J. (2019). Effect of IQOS introduction on 
cigarette sales: evidence of decline and replacement. Tobacco Control, 29, 381-387. 
doi:10.1136/tobaccocontrol-2019-054998 
 
Sutanto, E., Miller, C., Smith, D. M., O'Connor, R. J., Quah, A. C. K., Cummings, K. M., Xu, S., 
Fong, G. T., Hyland, A., Ouimet, J., Yoshimi, I., Mochizuki, Y., Tabuchi, T., & Goniewicz, 
M. L. (2019). Prevalence, use behaviors, and preferences among users of heated 
tobacco products: findings from the 2018 ITC Japan survey. International Journal of 
Environmental Research and Public Health, 16(23), 4630. doi:10.3390/ijerph16234630. 
PMCID: PMC6926809.  
 
Vansickel, A. R., Cobb, C. O., Weaver, M. F., & Eissenberg, T. (2010). A Clinical laboratory 
model for evaluating the acute effects of electronic cigarettes: Nicotine delivery profile 
and cardiovascular and subjective effects. Cancer Epidemiology, Biomarkers, & 
Prevention, 19(8), 1945-1953. doi:10.1158/1055-9965.EPI-10-0288. PMCID: 
PMC2919621.  
 
Voos, N., Smith, D., Kaiser, L., Mahoney, M. C., Bradizza, C. M., Kozlowski, L. T., Benowitz, N. 
L., O’Connor, R. J., & Goniewicz, M. L. (2020). Effect of e-cigarette flavors on nicotine 
delivery and puffing topography: results from a randomized clinical trial of daily smokers. 
Psychopharmacology, 237(2), 491-502. doi:10.1007/s00213-019-05386-x. PMCID: 
PMC7691130.  
 
Vorster, P., Mori, M., Mills, C., Erskine, A., Baig, F., Eggleton, M. (2020). Next generation 
products: Big in Japan. Global Equity Research Tobacco. https://plus.credit-
suisse.com/rpc4/ravDocView?docid=_XCsR2AL-YxKG. 
 
Wackowski, O., & Delnevo, C. D. (2007). Menthol cigarettes and indicators of tobacco 
dependence among adolescents. Addictive Behaviors, 32(9), 1964-1969. 
doi:10.1016/j.addbeh.2006.12.023. PMID: 17229528.  
 
Wackowski, O., Delnevo, C. D., & Pearson, J. L. (2015). Switching to e-cigarettes in the event of 
a menthol cigarette ban. Nicotine & Tobacco Research, 17(10), 1286-1287. 
doi:10.1093/ntr/ntv021. PMCID: PMC4592340.  
 
Wall, C. S., Bono, R. S., Lester, R. C., Hoetger, C., Lipato, T., Guy, M. C., Eissenberg, T., 
Bickel, W. K., Barnes, A. J., & Cobb, C. O. (2018). Triangulating abuse liability 
assessment for flavoured cigar products using physiological, behavioural economic and 
subjective assessments: a within-subjects clinical laboratory protocol. British Medical 
Journal Open, 8(10), e023850. doi:10.1136/bmjopen-2018-023850. PMCID: 
PMC6252773.  
 
Wang, T. W., Marynak, K. L., Gentzke, A. S., & King, B. A. (2019, February). Awareness and 
ever use of heated tobacco products among US adults, 2018 [poster]. Society for 
Research on Nicotine and Tobacco Annual Meeting, San Francisco, CA.  
 
White, A. M., Bono, R., Lester, R., Barnes, A. J., & Cobb, C. O. (2019). Effects of e-cigarette 
power and nicotine content on indices of abuse liability among dual users and exclusive 
e-cigarette users [poster]. NIH Tobacco Regulatory Science Meeting, Bethesda, MD. 
 
White, A. M., Li, D., Snell, L. M., O'Connor, R., Hoetger, C., Croft, D., Lester, R. C., McIntosh, 
S., Underwood, M., Schneller, L., Breland, A., Barnes, A. J., Cobb, C. O., & Ossip, D. J. 

(2021a). Perceptions of tobacco product-specific COVID-19 risk and changes in tobacco 
use behaviors among smokers, e-cigarette users, and dual users. Nicotine & Tobacco 
Research, 23(9), 1617-1622. doi:10.1093/ntr/ntab053. PMCID: PMC8083727.  
 
White, A. M., Ossip, D. J., Snell, L. M., Li, D., Hoetger, C., O'Connor, R., Lester, R. C., Croft, D., 
Underwood, M., McIntosh, S., Breland, A., Schneller, L., Cobb, C. O., & Barnes, A. J. 
(2021b). Tobacco product access scenarios influence hypothetical use behaviors. 
Tobacco Regulatory Science, 7(3), 184-202. doi:10.18001/trs.7.3.4 
 
White, A. M., Barnes, A. J., & Garner, W. (2021c). The association of menthol cigarette 
use with any mental illness (AMI) and serious mental illness (SMI) among US 
smokers. Manuscript under review.  
 
White, A. M. (2021d). The Medicaid expansion: Modeling of important factors in state 
decision making. Haslam Scholars Project. 
https://trace.tennessee.edu/utl_haslamschol/21  
 
Wickham, R. J. (2020). The biological impact of menthol on tobacco dependence. Nicotine & 
Tobacco Research, 22(10), 1676-1684. doi:10.1093/ntr/ntz239. PMID: 31867627.  
 
Wilson, A. G., Franck, C. T., Koffarnus, M. N., & Bickel, W. K. (2016). Behavioral economics of 
cigarette purchase tasks: Within-subject comparison of real, potentially real, and 
hypothetical cigarettes. Nicotine & Tobacco Research, 18(5), 524-530. 
doi:10.1093/ntr/ntv154. PMCID: PMC5896813.  
 
Wipfli, H. L., Berman, M., Hanson, K., Kelder, S., Solis, A., Villanti, A. C., Ribeiro, C. M., 
Meissner, H. I., & Anderson, R. (2017). Defining tobacco regulatory science 
competencies. Nicotine & Tobacco Research, 19(2), 222-230. doi:10.1093/ntr/ntw178. 
PMCID: PMC5234367.  
 
Young-Wolff, K. C., Hickman, N. J., Kim, R., Gali, K., & Prochaska, J. J. (2015). Correlates and 
prevalence of menthol cigarette use among adults with serious mental illness. Nicotine & 
Tobacco Research, 17(3), 285-291. doi:10.1093/ntr/ntu141. PMCID: PMC4342677.