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Effects of mint, menthol, and tobacco-flavored e-cigarettes on appeal and sensory effects, tobacco withdrawal…

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Content Running Head: EFFECTS OF MINT, MENTHOL, & TOBACCO-FLAVORED
E-CIGARETTES IN MENTHOL SMOKERS
EFFECTS OF MINT, MENTHOL, AND TOBACCO-FLAVORED E-CIGARETTES ON
APPEAL AND SENSORY EFFECTS, TOBACCO WITHDRAWAL, AND THE RELATIVE
REINFORCING VALUE OF MENTHOL CIGARETTES IN MENTHOL SMOKERS:
A LABORATORY STUDY
by
Mariel S. Bello, M.A.
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
( PSYCHOLOGY)
December 2022
Copyright 2022 Mariel S. Bello

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ACKNOWLEDGEMENTS
Completing this dissertation and the additional training requirements towards my Ph.D.
would not have been possible without the unwavering love and support from my mentors, family,
friends, and communities along the way. I want to first extend my greatest appreciation and
gratitude to my graduate advisor and forever life-long research mentor/friend, Dr. Adam
Leventhal, who accepted me into his lab in 2013 and who had generously provided me with a great
deal of mentorship, insight, and guidance for my professional and personal development
throughout these nine past years. I will be forever grateful to him for being the very first faculty
member to believe in me and my abilities to pursue a career in research while others did not, and
I thank him tremendously for helping me become the clinical psychologist and addiction scientist
that I am today. I also extend my deepest gratitude and appreciation to all my exceptional mentors
and committee members at USC who cheered me on all these years—Drs. Gerald Davison, Raina
Pang, Jessica Barrington-Trimis, Mark Lai, and Lina D’Orazio—all your enthusiasm,
encouragements, guidance, and wisdom have made such a meaningful and positive impact in my
life and contributed to my broader research, clinical work, and professional aspirations.
Throughout my graduate career, I considered myself extremely fortunate to have
befriended so many wonderful colleagues who have made my experience in graduate school
worthwhile and quite possibly the best (and least painful) experience ever. First and foremost, I
need to thank my incredible cohort family who have been with me since day one of graduate
school—Drs. Crystal Wang, Annemarie Kelleghan, Shubir Dutt, and Nina Jhaveri—I couldn’t
have asked for a more perfect cohort and I consider myself blessed to have shared this journey
with them. A very special thank you to Drs. Crystal Wang, Annemarie Kelleghan, Miriam
Rubenson, Anna Blanken, Sofi Cardenas, Matt Multach, Cindy Chiang, Lynn Zhang, Sarah

iii
Stoycos, and Laura Garcia for supporting me through challenging times and helping me become
stronger by making me laugh when hanging out, working in coffee shops till the staff kicks us out,
exploring Los Angeles late at night, and walking around the wonderful rose garden at USC. Also,
a big thank you to Anthony Sierra for providing me with support and encouragement throughout
my journey pre- and post-graduate school and for creating the progressive ratio task in EPrime for
my dissertation. I also would like to extend my sincere appreciation to all the faculty, staff, and
students at USC-HEAL, which has been my academic family and home for the past nine years. I’ll
never forget the impact that you all have made in my life.
Lastly, I would not be here today without the love, support, and ongoing encouragement
from my partner, family, and friends who have all stood by my side and who have inspired me to
achieve greater heights beyond what I could have ever imagined for myself. Mom, Dad, Ryan, and
Lola Paz, thank you for always believing in me and my abilities and for supporting me in a myriad
of ways. Alex, my best friend and love of my life, thank you eternally for your unconditional love,
support, encouragement, cuddles, and exceptional coffee-making—I am so grateful for being with
you every day and you have filled my life with so much joy, happiness, color, adventure, and
wonder. I’m also grateful to my extended family in the Philippines, including the Estacios—thank
you for generously letting me stay at your home in January 2020 and helping me grow more
confident in myself. This dissertation was also supported by the USC Tobacco Center of
Regulatory Science (USC-TCORS) Pilot Project Grant (PI: Bello) and National Science
Foundation Graduate Research Fellowship (DGE-1418060; PI: Bello). I am immensely grateful
for being provided with grant funding that has allowed me to mainly focus on working towards
my professional aspirations to become a psychological scientist and strong scientific leader in the
field of health disparities and addiction.

TABLE OF CONTENTS
ACKNOWLEDGEMENTS ............................................................................................................ ii
LIST OF TABLES ......................................................................................................................... vi
LIST OF FIGURES ...................................................................................................................... vii
ABSTRACT ................................................................................................................................. viii
INTRODUCTION .......................................................................................................................... 1
Background and Significance ..................................................................................................... 1
Evaluating the Impact of E-Cigarette Product Characteristics for FDA Regulation .............. 1
The Reinforcing Sensory Effects of Menthol: Evidence that Mint- and Menthol-Flavored E-
Cigarettes Can Increase Appeal, Sensory Effects, and Reduce Tobacco Withdrawal in
Menthol Cigarette Smokers .................................................................................................... 4
The Importance of Distinguishing Between Mint- and Menthol-Flavored E-Cigarette
Solutions ................................................................................................................................. 6
The Current Study ....................................................................................................................... 7
METHODS ..................................................................................................................................... 9
Participants .................................................................................................................................. 9
Design ....................................................................................................................................... 10
Materials ................................................................................................................................... 11
Procedures ................................................................................................................................. 12
Measures ................................................................................................................................... 13
Data Analysis ............................................................................................................................ 20
RESULTS ..................................................................................................................................... 22
Preliminary Analyses ................................................................................................................ 22
Primary Analyses. ..................................................................................................................... 23
Secondary Analyses. ................................................................................................................. 24
DISCUSSION ............................................................................................................................... 25
Strengths of the Study ............................................................................................................... 32
Limitations of the Study ............................................................................................................ 33
Conclusions ............................................................................................................................... 34
TABLES ....................................................................................................................................... 35
FIGURES ...................................................................................................................................... 42

v
REFERENCES ............................................................................................................................. 50
APPENDICES .............................................................................................................................. 58
Appendix A: Example Slides from Animation Video of Standardized E-Cigarette
Administration Procedure ......................................................................................................... 58
Appendix B: Experimental Session Measures – Appeal and Sensory Effects ......................... 61
Appendix C: Experimental Session Measures – Tobacco Withdrawal .................................... 63
Appendix D: Example Slide and Script for Progressive Ratio Task ........................................ 67

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LIST OF TABLES
Table 1. Descriptive Statistics for the Overall Sample………………………………………………35

Table 2. Means (+SEs) for Flavored-Induced Satiation Effects by E-Cigarette Flavor Condition….36

Table 3. Multilevel Model Parameter Estimates for Main Effects of E-Cigarette Flavor
Conditions on Primary Study Outcomes….…………………………………………………….……38

Table 4. Multilevel Model Parameter Estimates for Main Effects of E-Cigarette Flavor
Conditions on Secondary Study Outcomes..………………………………………………….……...39

Supplemental Table 1. Additional Estimates for Main Effects of E-Cigarette Flavor
Conditions on Primary Study Outcomes.…………………………………………………….............40

Supplemental Table 2. Additional Estimates for Main Effects of E-Cigarette Flavor
Conditions on Secondary Study Outcomes.…………………………………………………….........41

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LIST OF FIGURES
Figure 1. Experimental Session Timeline……………………………………………………………42

Figure 2. Estimated Marginal Means (SEs) of Appeal Ratings and Sensory Effects
by E-Cigarette Flavor Condition…………………………………………………………………..…43

Figure 3. Estimated Marginal Means (SEs) of Additional Sensory Effects Measured via
the E-Cigarette Product Evaluation Scale by E-Cigarette Flavor Condition...……………..……..…44

Figure 4. Estimated Marginal Means (SEs) of Flavored-Induced Changes in Smoking
Urges/Cravings Over Time by E-Cigarette Flavor Condition……………………..……………...…45

Figure 5. Estimated Marginal Means (SEs) of Flavored-Induced Changes in Nicotine
Withdrawal Symptoms Over Time by E-Cigarette Flavor Condition……...…………..................…46

Figure 6. Estimated Marginal Means (SEs) of Flavored-Induced Changes in Negative
Affect States Over Time by E-Cigarette Flavor Condition……………………..………………...…47

Figure 7. Estimated Marginal Means (SEs) of Flavored-Induced Changes in Positive
Affect States Over Time by E-Cigarette Flavor Condition……………………..………………...…48

Figure 8. Estimated Marginal Means (SEs) of the Relative Reinforcing Value of
Menthol Cigarettes Measured via the Progressive Ratio Task by E-Cigarette Flavor Condition…...49

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ABSTRACT
Background: While cigarette smoking rates have substantially declined in the general U.S.
population over the past decade, the prevalence of menthol cigarette smoking has continued to
stagnate or increase in some vulnerable groups. Hence, understanding whether novel, emerging
alternative tobacco products, such as electronic cigarettes (e-cigarettes) alter patterns of menthol
cigarette use are critical to informing prevention, intervention, and policy efforts for reducing the
public health burden of menthol cigarette smoking in the U.S. This laboratory pilot study
evaluated whether the administration of mint-, menthol-, or tobacco-flavored e-cigarette
solutions would differentially impact e-cigarette product appeal, sensory effects, tobacco
withdrawal, and the relative reinforcing value of menthol cigarettes in e-cigarette-naïve adults
who smoked menthol cigarettes daily. Methods: Participants (N = 17; 35.3% Female; mean age
= 51.8) attended three laboratory sessions after 16-hours of nicotine/tobacco product deprivation.
Participants self-administered a study-provided JUUL e-cigarette (0.7 mL with 5% nicotine by
weight) in which only flavor was manipulated (mint vs. menthol vs. tobacco-flavored).
Participants then completed pre- and post-e-cigarette administration self-report assessments on
appeal, sensory effects, and tobacco withdrawal (i.e., smoking urges/cravings, nicotine
withdrawal, and affect states). The relative reinforcing value of menthol cigarettes was assessed
with a progressive ratio task in which participants earned choices to smoke menthol cigarettes
puffs vs. flavored e-cigarette puffs. Multilevel models tested differences between the three
flavored conditions on all study outcomes. Results: Primary analyses indicated that mint- and
menthol-flavored (vs. tobacco-flavored) e-cigarette conditions demonstrated significantly greater
flavored-induced reductions in overall smoking urges over time (mint effect estimate [mint –
tobacco difference] = -0.32, p = .001; menthol effect estimate [menthol – tobacco difference] = -

ix
0.35, p = .0002). Additional secondary analyses illustrated that mint and menthol-flavored (vs.
tobacco-flavored) e-cigarette conditions exhibited greater flavored-induced decreases in
appetitive urges to smoke across time (mint effect estimate [mint – tobacco difference] = -0.43, p
= .01; menthol effect estimate [menthol – tobacco difference] = -0.57, p = .001), with the effect
of menthol-flavored (vs. tobacco-flavored) e-cigarette condition on appetitive urges remaining
statistically significant after corrections for multiple testing. The menthol-flavored (vs. tobacco-
flavored) e-cigarette condition also demonstrated greater flavored-induced increases in
withdrawal-related anger (menthol effect estimate [menthol – tobacco difference] = 0.12, p =
.002). Appeal, sensory effects, nicotine withdrawal symptoms, positive affect states, and the
relative reinforcing value of menthol cigarettes did not significantly differ across e-cigarette
flavor conditions (ps = .11-.99). Conclusions: Mint- and menthol-flavored (vs. tobacco-
flavored) e-cigarettes may reduce some tobacco withdrawal symptoms in menthol smokers, yet
menthol-flavored e-cigarettes demonstrated more consistent associations with reductions in
smoking urges relative to mint-flavored e-cigarettes. Further work is warranted to guide future
regulatory decisions on the basis of whether menthol flavorings may alter patterns of menthol
cigarette smoking behavior via suppressing tobacco withdrawal.
Keywords: menthol, cigarette smoking, electronic cigarettes, mint e-cigarettes, tobacco, appeal,
tobacco withdrawal, reinforcing value of menthol cigarettes

1
INTRODUCTION
Background and Significance
While rates of combustible cigarette smoking have substantially decreased among the
general U.S. population over the past decade from 20.9% in 2005 to 12.5% in 2021 (CDC, 2022),
the prevalence of menthol cigarette smoking has continued to stagnate or increase in certain
vulnerable groups. From 2004 to 2014, the decline in cigarette smoking consumption rates were
higher for non-menthol cigarettes than menthol cigarettes (Villanti et al., 2016), with menthol
cigarette smoking prevalence now exceeding non-menthol cigarette smoking prevalence among
both youth and young adult smokers (Villanti, Collins, Niaura, Gagosian, & Abrams, 2017).
Menthol cigarette smoking is also disproportionately represented amongst populations subject to
health disparities, such as youth and young adults, females, sexual and racial/ethnic minorities,
and individuals with psychiatric disorders (Villanti et al., 2017). Given that there are well-
established associations between initiating smoking with menthol cigarettes and progression to
regular smoking, greater nicotine dependence, and a lower likelihood of smoking cessation
(Villanti et al., 2017), understanding whether novel, emerging alternative tobacco products, such
as electronic cigarettes (e-cigarettes), may alter patterns of menthol cigarette smoking are critical
to informing intervention efforts for reducing the public health burden triggered by menthol
cigarette use.
Evaluating the Impact of E-Cigarette Product Characteristics for FDA Regulation
E-cigarettes—a diverse group of devices that enables users to inhale an aerosol, which
typically contains nicotine, flavorings, and other additives—are becoming increasingly popular in
the United States and are available in numerous non-tobacco flavors (e.g., menthol, mint, fruit,
and other sweet flavors such as candy) and various nicotine concentration levels, including

2
nicotine-free solutions (Camenga et al., 2018; Zare, Nemati, & Zheng, 2018). E-cigarettes are
suggested to be considerably less harmful than tobacco cigarettes since they do not deliver
combustible tobacco smoke to users. Recent evidence indicates that menthol cigarette smokers
who are interested in quitting smoking report utilizing e-cigarettes for smoking reduction and
smoking cessation, and are more likely to report using mentholated e-cigarettes in the past 30 days
(Webb Hooper & Smiley, 2018).
In 2016, the FDA noted in their deeming regulations that the appeal of flavorings and use
of flavored products play an important role in the initiation and continued use of alternative
tobacco products (Food & Drug Administration, 2016). However, in 2019, results from the
National Youth Tobacco Survey (NYTS) showed a drastic increase in youth e-cigarette use that
reached epidemic proportions with more than 5 million U.S. middle and high school students
reporting current e-cigarette use within the last 30 days (Cullen et al., 2019). Additionally, a study
using data from another federal survey (i.e., Monitoring the Future [MTF] study) illustrated that a
majority of current youth e-cigarette users reported most often vaping fruit and mint-flavored e-
cigarettes relative to tobacco and menthol-flavored e-cigarettes (Leventhal et al., 2019). In
response to the surge in youth e-cigarette use, the FDA implemented an e-cigarette enforcement
policy in February 2020 that prohibited sales of fruit, dessert, and mint-flavored cartridge-based
e-cigarettes—a type of e-cigarette that involves a cartridge or pod that holds liquid that is
aerosolized when the product is used—to prevent youth access and appeal to these products while
also maintaining availability of tobacco- and menthol-flavored cartridge-based e-cigarettes for
adult menthol smokers seeking to transition away from cigarettes (Food & Drug Administration,
2020). Furthermore, the FDA required manufacturers of e-cigarettes, cigars, and other deemed
new tobacco products on the market as of August 8
th
, 2016 to submit premarket tobacco product

3
applications (PMTA) for FDA review. During this extensive review, the FDA proposed to assess
the scientific evidence and determine whether permitting the marketing of the tobacco product
would be “appropriate for the protection of the public health” by determining whether the product
increases or decreases the likelihood that existing users of tobacco products would stop using such
products, as well as whether the product increases or decreases the likelihood that non-users may
also start using such products.
Given that the FDA continues to review an increasingly large amount of PMTAs for e-
cigarette products, it is unknown whether currently available e-cigarette flavorings would satisfy
the FDA’s ‘population as a whole’ standard by aiding adult smokers, particularly menthol smokers,
in switching to e-cigarettes while also protecting vulnerable youth non-smokers who may find
available flavors differentially appealing. Recent data from the Truth Initiative suggests that partial
flavor restrictions may not be enough to reduce overall appeal and marketing of e-cigarettes to
youth, as manufacturers continue to adapt to new FDA regulations and have shifted sales and
marketing towards available flavored e-cigarettes in light of restricted flavored products (Do et al.,
2022). Most recently in 2022, the FDA proposed new tobacco product standards to prohibit
menthol as a characterizing flavor in cigarettes in order to reduce the appeal of cigarettes and
decrease the likelihood of youth initiation, experimentation, and progression to regular menthol
cigarette smoking (Food & Drug Administration, 2022). FDA suggested that this proposal would
ultimately “help prevent children from becoming the next generation of smokers and help adult
smokers quit,” yet this proposal did not include restrictions on flavors for other nicotine-containing
products, such as menthol-flavored e-cigarettes, which are also known to be highly appealing to
youth since 8 out of 10 youth e-cigarette users in the U.S. and Canada report vaping non-tobacco
flavors, including menthol (Gentzke et al., 2022). Furthermore, in light of the proposed menthol

4
cigarette ban, the scarcity of laboratory evidence exploring the effects of flavored e-cigarettes in
menthol smokers is concerning since it is unknown whether currently available e-cigarette flavors
may aid in switching from menthol cigarettes to e-cigarettes or contribute to greater motivation to
smoke tobacco-flavored cigarettes due to available e-cigarette flavors being unappealing. Hence,
evaluating the impact of e-cigarette flavors on important indices of menthol cigarette smoking
behavior (i.e., appeal, tobacco withdrawal, menthol cigarette reinforcement) will elucidate whether
specific flavors would differentially influence the adoption of e-cigarettes in adult menthol
smokers.
The Reinforcing Sensory Effects of Menthol: Evidence that Mint- and Menthol-Flavored
E-Cigarettes Can Increase Appeal, Sensory Effects, and Reduce Tobacco Withdrawal in
Menthol Cigarette Smokers

While nicotine is a primary psychoactive component and powerful reinforcer that leads to
continued tobacco use and addiction (Ahijevych & Garrett, 2010), there is evidence that non-
pharmacological product characteristics, such as flavors like menthol, may serve as a conditioned
stimulus that increase the strength or sensory impact of nicotine, thus increasing the rewarding and
reinforcing effects of nicotine in tobacco (Ahijevych & Garrett, 2010). A growing body of
evidence suggests that menthol—a chemical compound extracted from peppermint or corn mint
plant oils and an enduring additive in cigarettes since the 1920s—is not merely a “flavor” in
tobacco products, but a bioactive compound with a myriad of sensorimotor effects on the olfactory
(smell), gustatory (taste), and trigeminal (cooling and pain) systems (Alexander et al., 2016). Data
taken from tobacco industry documents suggests that higher levels of menthol can reduce negative
tobacco sensations (e.g., pain, stinging, bitter taste, and the harshness of cigarette smoke), trigger
activation of pain and thermal receptors, inhibit nicotine metabolism, reduce nausea and headaches
due to smoking, and decrease respiratory irritation due to its characteristic sensory and cooling

5
effects on the mouth, throat, and lungs (Alexander et al., 2016). Additionally, adults who smoke
menthol cigarettes daily report smoking menthol (vs. non-menthol) cigarettes due to their
characteristic “cool minty taste” (Richter, Beistle, Pederson, & O'Hegarty, 2008), and retrospective
reports indicated several positive sensory effects associated with menthol cigarette smoking, such
as higher levels of global pleasurable sensations, a pleasurable “rush or buzz,” more relaxation,
and lower rates of dizziness and less difficulty inhaling (Finkenauer, Pomerleau, Snedecor, &
Pomerleau, 2009). Moreover, prior work has shown the tobacco industry to aggressively target
menthol cigarette marketing to certain populations with specific chemosensory characteristics,
such as young people, women, sexual and racial/ethnic minority groups, particularly Black
individuals, due to being aware that these groups would be more sensitive to the bitter taste of
nicotine (Kreslake et al., 2008). As such, extensive studies have consistently shown the availability
of menthol cigarettes to substantially contribute to health disparities observed in the U.S., as youth,
women, and sexual and racial/ethnic minority populations continue to smoke menthol cigarettes
at disproportionately higher rates compared to other groups (Villanti et al., 2017).
Accumulating evidence suggests that e-cigarettes can also provide sensorimotor
stimulation that mirrors cigarette smoking (e.g., taste of aerosol, smell, airway sensation, hand-to-
mouth movements, and appearance of smoke-like aerosol; Guillot, Zvolensky, & Leventhal, 2015)
and that adult daily e-cigarette users report specific product characteristics, such as presence of
flavors and sensory satisfaction, as key reasons for the initiation and continued use of e-cigarettes
(Berg, 2015). A previous laboratory study showed that menthol inhaled from an e-cigarette
reduced perceived airway irritation and harshness produced by inhalation when nicotine
concentration was high, and also contributed to greater appeal of e-cigarettes when nicotine
concentrations were low (Rosbrook & Green, 2016). Furthermore, a 2019 study conducted by

6
Leventhal and colleagues at USC found that menthol (vs. tobacco-flavored) e-cigarette solutions
enhanced the subjective appeal of e-cigarettes among current, former, and never smokers,
independent of nicotine (Leventhal, Goldenson, Barrington-Trimis, Pang, & Kirkpatrick, 2019).
Moreover, findings recently published in Tobacco Control from the same team of researchers at
USC demonstrated that appeal preferences for menthol (vs. tobacco-flavored) e-cigarette solutions
were mediated by menthol’s smoothness-enhancing and bitterness-reducing sensory effects
(Leventhal, Junhan Cho, et al., 2019). Thus, it is plausible that menthol or mint-flavored e-cigarette
solutions can increase appeal and sensory effects in menthol cigarette smokers, but no previous
laboratory studies have explored this hypothesis.
Preliminary evidence from laboratory and clinical studies suggests that use of e-cigarettes
without nicotine may also reduce tobacco withdrawal symptoms—a constellation of adverse
psychobiological symptoms that emerge upon acute smoking abstinence (e.g., heightened negative
affect; Przulj, McRobbie, & Hajek, 2016; Tseng et al., 2016). A recent laboratory demonstrated
that, independent of nicotine, menthol inhaled from an e-cigarette suppressed urges to smoke to
alleviate negative affect and severity of nicotine withdrawal symptoms in menthol (vs. non-
menthol) smokers (Valentine, DeVito, Jatlow, Gueorguieva, & Sofuoglu, 2018). This effect may
be due to the alleviating effects of sensorimotor features and other non-nicotine factors, which
underscores the importance of investigating product characteristics, such as appealing flavors, on
menthol cigarette smoking behavior and withdrawal (Przulj et al., 2016; Tseng et al., 2016).
The Importance of Distinguishing Between Mint- and Menthol-Flavored E-Cigarette
Solutions

It is unknown whether the addition of a mint flavoring for e-cigarettes is uniquely different
from menthol since laboratory research distinguishing between menthol and mint flavors is scarce
and/or typically combine these flavors into a single category. Existing qualitative data from social

7
networks (e.g., Reddit) and JUUL Labs, Inc. website described mint as “less traditional than
menthol and tobacco flavors” with a “lighter” and “sweeter” flavor than menthol cigarettes,
whereas menthol e-cigarette flavor being similar to menthol combustible cigarette flavor (JUUL
Labs; Reddit). Preliminary evidence comparing the effects of menthol and a combination of low
menthol concentration + mint-flavored e-cigarette on sensory effects in smokers found that
menthol and low menthol + mint flavors produced similarly intense coolness sensations and lower
irritation/harshness, with these sensations being stronger for the low menthol + mint flavor, further
underscoring the need to distinguish between menthol and mint flavors (Rosbrook & Green, 2016).
The Current Study
Currently, there is limited research investigating associations between mint, menthol, and
tobacco-flavored e-cigarette solutions and e-cigarette product appeal, sensory effects, and tobacco
withdrawal symptoms in menthol cigarette smokers. Furthermore, to our knowledge, no existing
study to date has explored associations of mint, menthol, or tobacco-flavored e-cigarette solutions
with the relative reinforcing value of menthol cigarettes utilizing a behavioral economics paradigm
that determines the motivation and willingness to work for puffs of a menthol cigarette when a
flavored e-cigarette is accessible. Utilizing a behavioral pharmacology paradigm, this
experimental human laboratory study will evaluate whether the administration of mint, menthol,
or tobacco-flavored e-cigarette solutions will differentially impact appeal and sensory effects,
tobacco withdrawal symptoms, and the relative reinforcing value of menthol cigarettes.
17 e-cigarette naïve adults aged > 21 years old who smoked menthol cigarettes daily and
who were interested in trying e-cigarettes attended 3 laboratory visits, each following 16 hours of
nicotine/tobacco product deprivation. At each visit, participants completed a standardized e-
cigarette administration procedure, as developed in our prior work, in which only flavor was

8
manipulated in a double-blind, cross-over, counterbalanced design (Aguirre, 2016; Goldenson,
2016). Following the e-cigarette administration procedure, participants completed: 1) subjective
ratings of e-cigarette product appeal and sensory effects; 2) subjective measures of tobacco
withdrawal symptomatology; and 3) a progressive ratio task that measured the relative reinforcing
effects of menthol cigarettes via the motivation and willingness to work increasingly harder for
puffs of a menthol cigarette relative to different e-cigarette solutions (i.e., mint, menthol, and
tobacco flavor).
The specific aims of this laboratory study were:
Aim 1. To evaluate differences in subjective ratings of appeal and sensory effects after
self-administration of mint, menthol, and tobacco-flavored e-cigarettes in e-cigarette naïve, adult
menthol cigarette smokers. Hypothesis: Menthol, mint, and tobacco-flavored e-cigarette solutions
will differentially increase appeal and sensory effects of e-cigarettes in menthol cigarette smokers.
Aim 2. To examine effects of mint, menthol, and tobacco-flavored e-cigarettes on
subjective measures of tobacco withdrawal in e-cigarette naïve, adult menthol cigarette smokers.
Hypothesis: Menthol, mint, and tobacco-flavored e-cigarette solutions will differentially reduce
tobacco withdrawal symptoms during acute nicotine/tobacco product deprivation in menthol
cigarette smokers.
Aim 3. To examine effects of mint, menthol, and tobacco-flavored e-cigarettes on the
relative reinforcing effects of menthol cigarettes. Hypothesis: Menthol, mint, and tobacco-flavored
e-cigarette solutions will differentially impact the motivation to work for puffs of a menthol
combustible cigarette when a flavored e-cigarette is accessible, as observed using a progressive
ratio task.
The current study can provide initial insight on the impact of e-cigarette flavorings (i.e.,

9
mint, menthol, and tobacco flavors) on utilization of e-cigarettes in adults who smoke menthol
cigarettes. If we find that the effects of mint and menthol (vs. tobacco-flavored) e-cigarettes
enhance e-cigarette product appeal and sensory effects, reduce tobacco withdrawal, and the
reinforcing effects of menthol cigarettes, our data can suggest that non-tobacco flavors may be
beneficial for adult smokers who may use e-cigarettes to try to quit smoking. Similarly, if we find
that the effects of mint-flavored e-cigarettes are superior to menthol (or vice versa), our data will
illuminate which flavors menthol cigarette smokers prefer, which will inform regulatory policies
on which flavors to keep available for menthol smokers seeking to quit smoking and which flavors
to propose stricter sales restrictions to protect youth. Alternatively, if we find that mint and menthol
flavors are no different than tobacco e-cigarettes, we can determine that our study provides no
evidence to suggest that placing stricter sales restrictions on menthol flavors similar to mint-
flavored e-cigarettes would adversely harm menthol smokers since these flavors may not assist
menthol smokers in transitioning away from cigarettes and may result in a net population deficit
in health, given the high popularity of these flavors in youth. Thus, this study will provide
preliminary data that can inform future regulatory decisions on the basis of whether mint, menthol,
or tobacco flavors: 1) promote initiation and transitions to use of e-cigarettes in menthol cigarette
smokers; and 2) alter patterns of menthol combustible cigarette smoking by suppressing tobacco
withdrawal and the reinforcing value of menthol cigarettes.
METHODS
Participants
Participants were 17 e-cigarette-naïve adults who smoked menthol cigarettes daily (see
descriptive statistics in Table 1) recruited from the Los Angeles, CA metropolitan area via online
advertisements (e.g., Craigslist, Clinical Connection) and an existing database from previous

10
laboratory smoking studies. Inclusion criteria for the study were: 1) age > 21 years old; 2) daily
cigarette smoking (i.e., > 8 cigarettes/day) for at least the past 2 years; 3) interest in trying e-
cigarettes and self-reported no previous significant experience with e-cigarettes to be considered
an e-cigarette-naïve vaper (Farsalinos et al., 2015); see exclusion criteria); and 4) report smoking
mentholated cigarettes. Exclusion criteria were: 1) self-reported previous significant experience
with e-cigarettes (i.e., self-report > 10 puffs lifetime, use on more than two occasions, purchased
own device); 2) current use of non-mentholated cigarettes; 3) daily use of other tobacco products
(e.g., cigars, cigarillos, chewing tobacco) to control for variable patterns of nicotine intake
caused by poly-tobacco use; 4) had a desire to substantially cut down or quit smoking in the next
30 days; 5) breath carbon monoxide (CO) < 10 at intake to exclude those who may be
overreporting their smoking; 6) current Diagnostic and Statistical Manual (DSM) 5 dependence
for substances other than nicotine (to minimize the likelihood of alcohol and/or other drug
withdrawal symptoms during the study sessions); 7) current use of medications that impact
withdrawal or smoking (e.g., bupropion, varenicline, nicotine replacement, anti-depressants,
anxiolytics); and 8) current pregnancy, breastfeeding, and/or intent to get pregnant. All
participants provided written informed consent and were compensated approximately $260 for
their participation ($25 for completing an in-person baseline session, $50 each for the first and
second experimental sessions, and $75 for completing the third and final experimental session;
we also included a $60 bonus after completing the entire study protocol to minimize attrition).
The University of Southern California Institutional Review Board approved all study procedures.
Design
Participants attended a total of four laboratory sessions: an initial baseline session followed
by three experimental sessions that each occurred after 16 hours of nicotine/tobacco product

11
deprivation; each experimental session were scheduled within 2-14 days apart. In the three
experimental sessions, e-cigarette flavor was experimentally manipulated (mint vs. menthol vs.
tobacco) according to a within-subject, double-blind, counterbalanced experimental design.
Participants completed a battery of subjective assessments on e-cigarette product appeal, sensory
effects, and tobacco withdrawal symptomatology, before and after the controlled e-cigarette
administration, and then completed a progressive ratio task that measured the relative reinforcing
value of menthol cigarettes (Figure 1).
Materials
To enhance the generalizability of our findings to use of e-cigarette products that have
become increasingly popular in the general population (Barrington-Trimis & Leventhal, 2018;
Gentzke et al., 2022), all participants were provided with a commercially available and popular
JUUL e-cigarette device and solutions. For this study, we utilized three 5% e-cigarette solutions
(JUULpods; Mint, Menthol, and Tobacco flavors), which were purchased from domestic
providers. A tobacco-flavored solution (vs. flavorless) was selected as the control condition for
this study as unflavored e-cigarette solutions have been shown to lack appeal among smokers
(Audrain-McGovern, Strasser, & Wileyto, 2016). As specified on the JUUL Labs, Inc. website
(JUUL Labs), each 5% JUULpod is designed to contain “approximately 0.7 mL with 5% nicotine
by weight (approximately 40 mg per pod based upon 59 mg/mL) at time of manufacture”, and
recent work from the Truth Initiative indicated that 1 JUULpod is equivalent to 1 pack of 20
cigarettes (Truth Initiative, 2018a). Heart rate and blood pressure were assessed with a digital
Sphygmomanometer monitor and breath CO levels were assayed with a Bedfont Scientific
Smokelyzer® breath CO monitor.

12
Procedures
After a preliminary phone screening, participants attended a baseline session in which they
completed informed consent and provided an end-tidal breath sample for carbon monoxide (CO)
measurement to confirm daily smoking and study eligibility (i.e., CO > 10). Eligible participants
completed self-report questionnaires on demographics and smoking history characteristics and
then viewed a video tutorial from the JUUL Labs, Inc. website explaining how to utilize the
experimenter-provided JUUL e-cigarette device that they would use in subsequent experimental
sessions. Participants then attended three randomized, counterbalanced experimental laboratory
sessions beginning at 12:00pm and after completing 16-hours of nicotine/tobacco product
deprivation. Participants were instructed to avoid using any alcohol and/or psychoactive
substances 24 hours prior to the three experimental sessions to prevent masking of tobacco
withdrawal, and were also required to abstain from all nicotine/tobacco products 16-hours prior to
each appointment.
Experimental procedures across all three sessions were identical, with the exception of the
randomly assigned e-cigarette flavor condition (i.e., mint vs. menthol vs. tobacco) varying at each
session. Compliance with instructions was biologically verified via assessing breath alcohol
(BrAC = 0.000 required for all sessions) and CO (reduction in breath CO level < 4 ppm required
to determine sufficient nicotine/tobacco product deprivation; Cropsey et al., 2014; Perkins,
Karelitz, & Jao, 2013) at the beginning of each session. After breath alcohol and CO assessments,
participants completed 15-minute pre-e-cigarette administration assessments that included self-
report measures to evaluate subjective tobacco withdrawal symptoms (i.e., smoking
urges/cravings, nicotine withdrawal, and negative and positive affect states) as well as
physiological measures (i.e., heart rate and blood pressure).

13
After the pre-e-cigarette administration assessments were completed, the standardized e-
cigarette administration procedure occurred, and was immediately followed by a 20-minute post-
e-cigarette administration assessment of e-cigarette subjective effects and measures of tobacco
withdrawal described below. Based on prior experimental and naturalistic data on topography of
e-cigarette use, the duration of the standardized e-cigarette administration procedure was 10
minutes long and consisted of an animated video of a digital slideshow that cued participants to
inhale and exhale (10 total puffs) from the e-cigarette device in accordance with procedure
parameters shown to be approximately equivalent to average vaping patterns for regular vapers
(i.e., a 3-second preparation interval, a 4-second inhalation interval, a 1-second hold interval, a
3.5-second exhale period, repeated 10 times with 30-second interpuff intervals; (Farsalinos,
Romagna, Tsiapras, Kyrzopoulos, & Voudris, 2013; Goniewicz, Lingas, & Hajek, 2013) and
shown to significantly suppress withdrawal symptoms (Aguirre, 2016). After the completion of
post-e-cigarette administration assessments, participants then completed two additional
assessments of self-reported tobacco withdrawal symptoms separated by 30 minutes to assess the
dissipation time course of effects. Approximately at 2:00 pm, participants began the progressive
ratio task followed by an hour-long rest period and dismissal from the study at 4:30 pm (Figure 1).
At the end of the third and final experimental session, participants were debriefed, informed about
the purpose of the study, and provided with referral services for smoking cessation, community
health, and mental health treatment.
Measures
All questionnaire-based measures were administered to participants using a desktop
computer in the laboratory observation suite via REDCap (Research Electronic Data Capture;
Harris et al., 2009).

14
Baseline Session Measures
We administered the following questionnaires to describe the sample and include as
potential covariates that may confound associations between flavor effects and study outcomes.
Demographics and medical history were evaluated by an investigator-developed questionnaire and
smoking history characteristics were captured by the Tobacco Product Use History Questionnaire,
which assessed for history of smoking and other tobacco product use, including age of onset,
heaviness/frequency of smoking, and prior quit attempts (Brown, Lejuez, Kahler, & Strong, 2002).
The Fagerström Test of Cigarette Dependence (FTCD; Heatherton, Kozlowski, Frecker, &
Fagerstrom, 1991) is a 6-item self-report measure of cigarette dependence severity (range 0-10).
The Barriers to Cessation Scale (BCS; Macnee & Talsma, 1995) evaluated factors that prevent
smoking cessation success and the Wisconsin Inventory of Smoking Dependence Motives-Brief
Form (WISDM; Megan E Piper et al., 2004) is a 37-item measure used to assess 11
multidimensional motives underlying smoking behavior (e.g., cognitive enhancement, negative
reinforcement, craving, weight control). Participants also completed the Inventory of Depression
and Anxiety Symptoms (IDAS; Watson et al., 2008), which evaluated the experience of depressive
and anxiety symptoms within the past two weeks, and the 10-item Drug Abuse Screening Test
(DAST; Skinner, 1982), 10-item Alcohol Use Disorder Identification Test (AUDIT; Bohn, Babor,
& Kranzler, 1995), and 6-item Cannabis Abuse Screening Test (CAST; Legleye, Karila, Beck, &
Reynaud, 2007) to assess alcohol, cannabis, and non-nicotine drug use and dependence.
Experimental Session Measures
Self-Report Appeal Ratings and Sensory Effects.
Immediately after the standardized 10-puff e-cigarette administration procedure,
participants responded to a series of questions that assessed for the appeal and sensory effects of

15
each e-cigarette condition. Participants were instructed to rate the appeal of each e-cigarette flavor
with three questions: 1) “How much did you like the e-cigarette?”; 2) “How much did you dislike
the e-cigarette?”; and 3) “Would you use this e-cigarette again?”. Participants also rated the
attractive sensory effects with three questions: 1) “How sweet was the e-cigarette?”; 2) “How
smooth was the e-cigarette?”; and 3) “How much did you like the throat hit?” and the aversive
sensory effects with two questions: 1) “How harsh was the e-cigarette?”; and 2) “How bitter was
the e-cigarette?” as in previous laboratory work (Goldenson et al., 2016). Appeal and sensory
effect outcomes were summed and averaged to form three composite measures based on prior
work (Song, Lin, Ward, & Fine, 2013), with only “Dislike” being reverse-scored. All questions
were answered on 100-point visual analog scales (VAS) with anchors of “Not at All” to
“Extremely,” with the exception of willingness-to-use-again, which used anchors of “Not at all”
to “Definitely.” Cronbach’s alphas for appeal (range of Cronbach’s α across all 3 conditions =
0.77-0.96), attractive sensory effects (range of Cronbach’s α across all 3 conditions = 0.38-0.85),
and aversive sensory effects (range of Cronbach’s α across all 3 conditions = 0.79-0.91) indicated
acceptable to excellent reliability for appeal and aversive sensory effect outcomes, whereas the
attractive sensory effect outcome demonstrated unacceptable to good reliability.
E-Cigarette Product Evaluation Scale.
To capture additional subjective sensory effects and psychological reward of each e-
cigarette condition, we utilized the previously-validated E-Cigarette Product Evaluation Scale
(Cappelleri et al., 2007; Westman, Levin, & Rose, 1992), which is an adapted version of the
Cigarette Rating Scale (CRS; Waters et al., 2003) to assess for acute subjective vaping effects.
Items were rated on 100-point VAS with anchors of “Not at All” to “Extremely” and we computed
five subscales based on mean rating per item: Vaping Satisfaction (“How satisfying were the puffs

16
you just took?” and “How good did it taste?”; range of Cronbach’s α across all 3 conditions = 0.35-
0.82), Psychological Reward (“Did it calm you down?”, “Did it make you feel more awake?”,
“Did it make you feel less irritable?”, “Did it help you concentrate?”, and “Did it reduce your
hunger for food?”; range of Cronbach’s α across all 3 conditions = 0.86-0.87), Aversion (“Did it
make you dizzy?” and “Did it make you nauseated?”; range of Cronbach’s α across all 3 conditions
= 0.64-0.93), Enjoyment of Respiratory Tract Sensations (“Did you enjoy the sensations of the
vapor in your throat and chest?”), and Cigarette Craving Reduction (“Did it immediately reduce
your craving for cigarettes?”). Higher scores reflected higher intensity of sensory effects.
Tobacco Withdrawal.
Participants completed the following measures at both the pre- and post-e-cigarette
administration assessments as well as two additional post-e-cigarette administration assessments
separated by 30 minutes to assess the dissipation time course of effects. Each measure described
below has demonstrated sufficient psychometric properties and sensitivity to overnight
nicotine/tobacco product deprivation challenges (Cox, Tiffany, & Christen, 2001; Hughes,
2007).
Smoking Urges/Cravings.
The Brief Questionnaire of Smoking Urges (QSU; Cox et al., 2001) is a 10-item measure
that included statements assessing desire and intention to smoke cigarettes for pleasure (Factor 1;
e.g., “A cigarette would taste good.”; five items) and desire to smoke to alleviate negative affect
(Factor 2; e.g., “Smoking would make me less depressed.”; five items; Cox et al., 2001).
Participants were instructed to rate the extent of agreement based on how they felt “right now”
on 6-point Likert scales (0 = Strongly disagree to 5 = Strongly agree). We calculated a total
composite index for smoking urges/cravings based on mean responses across items, and

17
calculated separate subscales for Factor 1 and Factor 2 based on mean rating per item within
each respective subscale. Factors 1 and 2 reflected appetitive and aversive urges, respectively.
Cronbach’s alphas for the total composite index (range of Cronbach’s α across all e-cigarette
administration assessments = 0.93-0.98), Factor 1 (range of Cronbach’s α across all e-cigarette
administration assessments = 0.93-0.99), and Factor 2 (range of Cronbach’s α across all e-
cigarette administration assessments = 0.91-0.98) indicated excellent reliability for these
outcomes.
Nicotine Withdrawal Symptoms.
The Minnesota Nicotine Withdrawal Scale (MNWS; Hughes & Hatsukami, 1986) is a well-
validated 8-item measure that assessed overall nicotine withdrawal severity by asking participants
to rate tobacco withdrawal symptoms (i.e., angry/irritable/frustrated, anxious/nervous,
sad/depressed mood, difficulty concentrating, increased appetite/hunger/weight gain,
insomnia/sleep problems/awakening at night, restlessness, and desire or craving to smoke)
experienced “right now” on 5-point Likert scales (0 = None to 4 = Severe). We calculated a
composite index based on mean responses across all items (range of Cronbach’s α across all e-
cigarette administration assessments = 0.81-0.92).
Negative and Positive Affect States.
The Profile of Mood States (POMS; McNair, Lorr, & Droppleman, 1971) instructed
participants to rate 72 adjectives of various affect states (e.g., tense, unhappy, hopeless, cheerful,
lonely, anxious, agreeable, relaxed) based on how they were feeling “right now” on 5-point
Likert scales (0 = Not at all to 4 = Extremely). Based on prior laboratory work (Bello et al.,
2021; Bello, Pang, Chasson, Ray, & Leventhal, 2017; Bello et al., 2016), we calculated subscales
for negative affect (Anger [12 items; range of Cronbach’s α across all e-cigarette administration

18
assessments = 0.25-0.95], Anxiety [8 items; range of Cronbach’s α across all e-cigarette
administration assessments = 0.70-0.93], and Depression [15 items; range of Cronbach’s α across
all e-cigarette administration assessments = 0.69-0.96]) and positive affect (Elation [6 items;
range of Cronbach’s α across all e-cigarette administration assessments = 0.77-0.90],
Friendliness [8 items; range of Cronbach’s α across all e-cigarette administration assessments =
0.82-0.95], and Vigor [8 items; range of Cronbach’s α across all e-cigarette administration
assessments = 0.86-0.95]) based on mean rating per item within respective subscale items, and
overall scores for negative affect valence (Negative Affect Composite; mean of three negative
affect subscales; range of Cronbach’s α across all e-cigarette administration assessments = 0.84-
0.98) and positive affect valence (Positive Affect Composite; mean of three positive affect
subscales; range of Cronbach’s α across all e-cigarette administration assessments = 0.93-0.98).
Behavioral Task Assessing the Relative Reinforcing Value of Menthol Cigarettes (Behavioral
Choice of Menthol Cigarette Smoking vs. E-Cigarette Vaping).
Following the completion of all post-e-cigarette administration assessments, participants
engaged in a well-validated behavioral economics paradigm that has been shown to be sensitive
to the rewarding and reinforcing effects of both combustible cigarettes (Shahan, Bickel, Badger,
& Giordano, 2001; Shahan, Bickel, Madden, & Badger, 1999; Tidey, Higgins, Bickel, &
Steingard, 1999) and e-cigarettes (Audrain-McGovern, Strasser, Ashare, & Wileyto, 2015;
Audrain-McGovern et al., 2016). Participants completed a 50-minute computerized progressive
ratio task in which they were given 10 opportunities to earn either two standardized e-cigarette
puffs of the flavored e-cigarette solution that they received in the standardized e-cigarette
administration procedure during that session or two standardized puffs of their preferred menthol
cigarette (see Appendix D for example slide and script of procedure). Given recent surveys from

19
Truth Initiative suggesting that 1 JUULpod is equivalent to 200 cigarette puffs (Truth Initiative,
2018a), we proposed that two controlled e-cigarette puffs would be of equivalent value to two
controlled puffs of their preferred menthol cigarette. At the outset of this procedure, participants
were told that they would not have an opportunity to smoke until at least 90 minutes after the
progressive ratio task to prevent suppression of menthol cigarette choices due to knowledge of the
impending opportunity to smoke. Participants were instructed that they could choose not to
respond, but the duration would be 60 minutes regardless of whether they completed none or all
of the 10 trials for cigarette smoking or vaping opportunities. During this task, participants first
indicated their choice on the computer keyboard (by pressing “A” for smoking cigarette or “L” for
vaping e-cigarette) followed by finger presses on the space bar repeatedly in order to trigger an
animated video of a digital slideshow (similar to the standardized e-cigarette administration
procedure) that administered 2 standardized puffs of their choice. Based on prior work (Audrain-
McGovern et al., 2015; Audrain-McGovern et al., 2016), the reinforcement schedule for the e-
cigarette choices remained constant at a fixed ratio FR-25 (25 responses to earn e-cigarette puffs)
while the reinforcement schedule for the menthol cigarette choice increased with each trial and
required more effort with a progressive ratio schedule of PR-25´ over 10 trials: 25, 50, 75, 100,
125, 150, 175, 200, 225, and 250 responses. As such, this task determined how reinforcing menthol
cigarette puffs were relative to flavored e-cigarette puffs by capturing the motivation and
willingness of the participant to work increasingly harder for puffs of their preferred menthol
cigarette when a flavored e-cigarette is accessible. The relative reinforcing value of menthol
cigarettes was defined by the breakpoint or the highest trial (out of 10 trials) that was completed
for menthol cigarette puffs.

20
Data Analysis
Preliminary Analyses.
Preliminary analyses involved calculating descriptive statistics for all sociodemographic
variables and menthol cigarette smoking characteristics. A multilevel dataset was then created in
which participant outcomes during each experimental session (i.e., appeal ratings and sensory
effects, tobacco withdrawal, and the relative reinforcing value of menthol cigarettes) were
stratified by the within-subject e-cigarette flavor condition (i.e., mint vs. menthol vs. tobacco).
Participants’ baseline CO levels were also compared to the CO readings from the three
experimental sessions to confirm a significant reduction in cigarette smoking from baseline
(aggregated across the three experimental sessions) with multilevel linear models.
Primary Analyses.
Primary analyses utilized multilevel linear models or generalized linear mixed models with
an independent, fixed effect of flavor (i.e., mint vs. menthol vs. tobacco) as the sole regressor to
assess the effect of e-cigarette flavor condition on appeal ratings and sensory effects, tobacco
withdrawal, and the relative reinforcing value of menthol cigarettes. Appeal ratings, attractive and
aversive sensory effects, e-cigarette product evaluation subscales (i.e., vaping satisfaction,
psychological reward, aversion, enjoyment of respiratory tract sensations, and cigarette craving
reduction), and the progressive ratio task outcome (i.e., breakpoint), which were assessed at only
a single time point at each session, were analyzed as continuous variables and tested in separate
multilevel linear models. Tobacco withdrawal outcomes (i.e., smoking urges/cravings [QSU],
nicotine withdrawal [MNWS], and negative and positive affect states [POMS]) were assessed over
time (i.e., every 30 minutes with the first measurement occurring immediately after post-e-
cigarette administration) and were modeled as a change from baseline (i.e., [post-e-cigarette

21
administration assessment score] – [pre-e-cigarette administration assessment score]). Utilizing
generalized linear mixed models described above, we tested the effect of e-cigarette flavor
conditions on change from baseline scores of tobacco withdrawal (i.e., QSU-Total, MNWS-Total,
POMS-Negative Affect Composite, POMS-Positive Affect Composite) across time and expanded
these models to include the additional within-participant centered predictor of time corresponding
to all three post-e-cigarette administration assessments.
Secondary Analyses.
To determine the effects of e-cigarette flavor conditions on distinct factors of smoking
urges/cravings and specific negative and positive affect states, we utilized generalized linear mixed
models described above to evaluate the effect of e-cigarette flavor conditions on change from
baseline subscale scores of smoking urges/cravings (QSU-Factor 1 [Appetitive Urge], QSU-Factor
2 [Aversive Urge]), negative affect states (POMS-Anger, POMS-Anxiety, POMS-Depression),
and positive affect states (POMS-Elation, POMS-Friendliness, and POMS-Vigor) across time and
expanded these models to include the additional within-participant centered predictor of time
corresponding to all three post-e-cigarette administration assessments.
All models adjusted for the following covariates: age, gender, race/ethnicity, education,
cigs/day, and cigarette dependence. In all models, the main effect of randomization order (i.e.,
whether participants were randomized to the mint-, menthol-, or tobacco-flavored e-cigarette
condition first) was also tested to determine whether the results were dependent on a certain session
completion order. Furthermore, to determine whether results were affected by participants
experiencing any fatigue, boredom, practice, or other effects while completing the pre- and post-
e-cigarette administration assessments over time, we also tested the main effects of time and the
e-cigarette flavor condition × time interaction on tobacco withdrawal outcomes. Data were

22
analyzed using IBM SPSS Statistics Version 28 (Corp., 2021) with alpha level set to 0.05. A
Benjamini-Hochberg multiple test correction was used to maintain a 0.05 study-wise false
discovery rate (Benjamini & Hochberg, 1995). We also report effect sizes to illustrate the
magnitude of effects using Cohen’s d statistics (Hedges, 2007) and provide additional multilevel
model parameter estimates and 95% confidence intervals for main effects of e-cigarette flavor
conditions on primary and secondary outcomes (see Supplemental Tables 1 and 2).
RESULTS
Preliminary Analyses
Descriptive statistics for sociodemographic variables and menthol cigarette smoking
characteristics are reported in Table 1. Our sample was composed primarily of older adult (M
[SD] age = 51.76 [12.07]), Non-Hispanic Black or African American (82.4%), male (64.7%)
participants who smoked approximately 11.12 (SD = 4.1) menthol cigarettes per day. Half of our
sample (52.9%) reported currently being unemployed, retired, or on disability services, 47.1%
completed a high school diploma, GED, or less education, and 41.2% reported earning an annual
income of $15,000 or less. The average age that participants began smoking everyday was 19.41
(SD = 10.96) and participants reported, on average, low-to-moderate cigarette dependence on the
FTCD (M [SD] = 4.29 [1.69]) and engaging in 1.76 (SD = 1.20) serious quit attempts in their
lifetime. Additionally, we found significant reductions in breath CO levels from baseline to all
three of the experimental sessions (ps < .0001). There were no significant main and interactive
effects of randomization order and time for any of the study outcomes (ps > 0.05), indicating that
results were not influenced by randomization order or fatigue effects. Means (+SEs) for flavored-
induced satiation effects across study outcomes by e-cigarette flavor condition are illustrated in
Table 2.

23
Primary Analyses.
Effects of Mint, Menthol, and Tobacco-Flavored E-Cigarette Conditions on Appeal
and Sensory Effects. Table 3 depicts results of the multilevel linear models testing the main
effects of e-cigarette flavor condition on appeal ratings, attractive and aversive sensory effects,
and e-cigarette product evaluation subscales (i.e., vaping satisfaction, psychological reward,
aversion, enjoyment of respiratory tract sensations, and cigarette craving reduction). We found
no significant main effects of the e-cigarette flavor condition (mint vs. menthol vs. tobacco) on
appeal and sensory effects of vaping (ps = .11-.99; see Table 3, Figures 2 and 3) with the
exception of the psychological reward outcome on the E-Cigarette Product Evaluation Scale,
which indicated significantly lower ratings of the psychological reward of vaping in the mint-
flavored (M [SE] = 34.36 [9.87]) vs. tobacco-flavored (M [SE] = 41.83 [9.87]) e-cigarette
conditions (mint effect estimate [mint – tobacco difference] = -7.47, p = .04; Table 3, Figure 3);
this result did not remain statistically significant after the Benjamini-Hochberg correction.
Effects of Mint, Menthol, and Tobacco-Flavored E-Cigarette Conditions on Tobacco
Withdrawal. Adjusted models demonstrated significant main effects of e-cigarette flavor
condition on change from baseline scores in smoking urges/cravings for combustible menthol
cigarettes (i.e., QSU-Total) and negative affect states across time (i.e., POMS-Negative Affect
Composite; see Table 3). Specifically, mint- and menthol-flavored (vs. tobacco-flavored) e-
cigarette conditions demonstrated significantly greater flavored-induced reductions in overall
smoking urges/cravings for combustible menthol cigarettes over time (mint effect estimate [mint
– tobacco difference] = -0.32, p = .001; menthol effect estimate [menthol – tobacco difference] =
-0.35, p = .0002; Table 3, Figure 4), with effect sizes being medium in magnitude as evidenced
by Cohen’s d statistics (ds = -0.53 to -0.48; see Table 3). For negative affect states, mint- and

24
tobacco-flavored (vs. menthol-flavored) e-cigarette conditions exhibited significantly greater
flavored-induced reductions in overall negative affect states over time (POMS-Negative Affect
Composite: mint effect estimate [mint – menthol difference]: -0.09; p = .008; tobacco effect
estimate [tobacco – menthol difference]: -0.07; p = .04; Table 3, Figure 6); however, these
results did not survive the Benjamini-Hochberg corrections. Nicotine withdrawal symptom
severity (MNWS-Total) and positive affect states (POMS-Positive Affect Composite)
experienced across time did not significantly differ across e-cigarette flavor conditions (ps = .26-
.97; Table 3, Figures 5 and 7).
Effects of Mint, Menthol, and Tobacco-Flavored E-Cigarette Conditions on the
Relative Reinforcing Value of Menthol Cigarettes. Adjusted models found no significant main
effects of the e-cigarette flavor condition (mint vs. menthol vs. tobacco) on the breakpoint
outcome for the progressive ratio task (ps = .18-.65; see Table 3; Figure 8), suggesting that e-
cigarette flavor manipulation did not significantly impact participants’ motivation and
willingness to work increasingly harder for puffs of their preferred menthol cigarette relative to
flavored e-cigarette puffs during the progressive ratio task across e-cigarette conditions.
Secondary Analyses.
Table 4 illustrates findings of the generalized linear mixed models testing the main
effects of e-cigarette flavor condition on change from baseline subscale scores of smoking
urges/cravings and negative and positive affect states. For QSU-Factors 1 and 2, which assessed
the rewarding effects and relief of negative affect respectively, we found that mint and menthol-
flavored (vs. tobacco-flavored) e-cigarette conditions exhibited greater flavored-induced
reductions in appetitive urges/cravings across time (mint effect estimate [mint – tobacco
difference] = -0.43, p = .01; menthol effect estimate [menthol – tobacco difference] = -0.57, p =

25
.001; Table 4, Figure 4). The effect of menthol-flavored (vs. tobacco-flavored) e-cigarette
condition on appetitive urges remaining statistically significant after Benjamini-Hochberg
correction for multiple testing and the magnitude of the effect was medium (d = -0.50).
Regarding specific negative affect states, mint-flavored (vs. tobacco-flavored) e-cigarette
condition showed significantly greater flavored-induced reductions in POMS-Depression over
time (mint effect estimate [mint – tobacco difference] = -0.11, p = .004), whereas the menthol-
flavored (vs. tobacco-flavored) e-cigarette condition demonstrated greater flavored-induced
increases in POMS-Anger (menthol effect estimate [menthol – tobacco difference] = 0.12, p =
.002) and POMS-Anxiety across time (menthol effect estimate [menthol – tobacco difference] =
0.10, p = .04; Table 4, Figure 6). Results were non-significant after Benjamini-Hochberg
corrections with the exception of the POMS-Anger finding, which had an effect size that was
small in magnitude (d = 0.28). Additionally, we found significant differences between mint- vs.
menthol-flavored e-cigarette conditions for POMS-Anxiety and POMS-Depression change from
baseline scores, with mint-flavored (vs. menthol-flavored) e-cigarette conditions demonstrating
significantly greater flavored-induced decreases in POMS-Anxiety and POMS-Depression over
time relative to menthol-flavored conditions (POMS-Anxiety: mint effect estimate = -0.11, p =
.02; POMS-Depression: mint effect estimate = -0.10, p = .01); results did not survive the
Benjamini-Hochberg correction.
DISCUSSION
The current laboratory study investigated whether the self-administration of mint- or
menthol-flavored (vs. tobacco-flavored) e-cigarette solutions among nicotine/tobacco-deprived
adult menthol cigarette smokers would differentially impact appeal and sensory effects, tobacco
withdrawal symptoms, and the relative reinforcing value of menthol cigarettes. These findings

26
provide the first experimental evidence to demonstrate differential effects of mint-, menthol-, and
tobacco-flavored e-cigarettes on tobacco withdrawal, such that participants reported greater
flavored-induced reductions in overall smoking urges/cravings for combustible menthol cigarettes
over time after self-administering the mint- and menthol-flavored (vs. tobacco-flavored) e-
cigarettes. Additionally, we found some preliminary evidence of potential differences between the
effects of mint- vs. menthol-flavored e-cigarette conditions on self-report measures of negative
affect. Although, some of these findings did not remain statistically significant after corrections
for multiple testing except for the result showing that tobacco-flavored e-cigarettes may be
associated with greater flavored-induced reductions in withdrawal-related anger over time
compared to menthol-flavored e-cigarettes. In contrast, there were no significant differences
between the three flavor conditions in self-report measures of appeal and sensory effects, nicotine
withdrawal symptoms, positive affect states, and the relative reinforcing value of menthol
cigarettes.
Consistent with recent laboratory evidence showing the efficacy of menthol inhaled from
an e-cigarette in suppressing urges/cravings to smoke to alleviate negative affect and nicotine
withdrawal severity, independent of nicotine effects (Valentine et al., 2018), our results extend
prior work by demonstrating that, in combination with nicotine: 1) mint and menthol-flavored
(vs. tobacco-flavored) e-cigarettes may attenuate overall smoking urges/cravings for combustible
menthol cigarettes over time; and 2) mint and menthol-flavored (vs. tobacco-flavored) e-
cigarettes may differentially reduce distinct facets of smoking urges/cravings across time.
Specifically, mint and menthol (vs. tobacco) flavored e-cigarettes exhibited greater flavored-
induced attenuation of urges/cravings to smoke for pleasure over time (QSU-Factor 1 [Appetitive
Urges]). However, after correcting for multiple testing, the effect of menthol-flavored (vs.

27
tobacco-flavored) e-cigarette condition on appetitive-related smoking urges/cravings remained
significant whereas the effect of mint-flavored e-cigarette condition reduced in significance.
Reasons for why mint- and menthol-flavored e-cigarettes may exhibit differential effects
on specific indices of smoking urges/cravings may be due to differences in sensorimotor features
and/or other non-pharmacological factors across mint and menthol-flavored e-cigarette
conditions. For instance, extensive research suggests that menthol is not merely a “flavor” in
cigarettes, but a bioactive compound that produces a myriad of sensorimotor effects on the
olfactory (smell), gustatory (taste), and trigeminal (cooling and pain) systems (Alexander et al.,
2016). In preclinical laboratory work, a conditioned menthol stimulus has been shown to
reinstate extinguished nicotine-seeking behavior, which suggests that menthol may also serve as
a conditioned cue that may trigger nicotine craving and relapse (Harrison et al., 2017). Since our
study sample consisted exclusively of menthol cigarette smokers who experience habitual
menthol inhalation, it is plausible that the menthol-flavored e-cigarette used in this study might
have served as a conditioned sensory (Rose & Behm, 2004) and interoceptive cue (Harrison et
al., 2017) that, when co-administered with nicotine, may have predicted nicotine delivery. Thus,
the self-administration of a menthol-flavored e-cigarette in our study may have provided some
negative reinforcement through acute reductions in smoking urges/cravings for pleasure that
developed during nicotine/tobacco product deprivation, which is concordant with some findings
described in previous work (Ahijevych & Garrett, 2004; Valentine et al., 2018; Van Heel, Van
Gucht, Vanbrabant, & Baeyens, 2017; Wang, Wang, & Chen, 2014). However, further
replications of our findings are warranted, given that our study also indicated that menthol-
flavored e-cigarettes exhibited less flavored-induced reductions in withdrawal-related anger over
time relative to tobacco-flavored e-cigarettes, which was unexpected and surprising. Currently, it

28
is unclear why menthol-flavored (vs. tobacco-flavored) e-cigarettes were associated with greater
flavor-induced increases in anger over time. It may be possible that, while menthol inhaled from
our experimenter-provided JUUL device may have served as a conditioned sensory stimulus that
suppressed appetitive smoking urges/cravings, menthol-flavored e-cigarettes may still differ in
various sensorimotor and non-pharmacological properties from combustible menthol cigarettes.
As a result, menthol-flavored e-cigarettes may not be able to sufficiently suppress other indices
of tobacco withdrawal, such as negative affect states, compared to menthol cigarettes in menthol
smokers.
In contrast to menthol, mint—an oil extracted from the same peppermint or corn mint
plants used to create menthol synthetically—is a flavorant that is used widely in food and other
consumer products, and that has been previously suggested to produce similar stimulation of cold
receptors and cooling sensations in the respiratory tract after e-cigarette self-administration in
initial studies (Rosbrook & Green, 2016). However, current reports from the Truth Initiative
indicate that, while JUUL claims the mint flavor to be similar to menthol cigarettes, mint-
flavored e-cigarettes may not, in fact, mirror combustible menthol cigarettes as users describe
mint as a “lighter” and “sweeter flavor” that is less similar to menthol cigarettes, compared to
menthol-flavored e-cigarettes (Truth Initiative, 2018b). Recent data investigating the chemical
composition of menthol and mint-flavored JUUL e-cigarette products have shown that mint and
menthol-flavored e-liquids may contain some menthol at similar (but not equivalent) levels and
may produce distinct and non-identical “minty flavors” for users (Omaiye, Luo, McWhirter,
Pankow, & Talbot, 2022). Hence, differences in mint’s sensorimotor and non-pharmacological
features may be evident in this experiment, as we observed that mint (vs. tobacco) flavored e-
cigarettes suppressed smoking urges/cravings for pleasure similar to menthol-flavored e-

29
cigarettes while also simultaneously suppressing several negative affect states over time, which
were no longer significant after corrections for multiple testing. Given that the mint-flavored e-
cigarette was a relatively new flavor to our sample of menthol cigarette smokers who had never
used e-cigarettes, it is possible that mint may not have served as a conditioned stimulus for
nicotine delivery and as a result, did not provide equivalent negative reinforcement effects like
menthol, but rather produced alternative sensorimotor and non-pharmacological properties that
may have differentially affected tobacco withdrawal symptoms in our sample of menthol
smokers.
Our findings provide some important insights and implications for smoking cessation
treatment, tobacco regulatory science, and advancing health equity by illuminating possible
mechanisms through which mint, menthol, and tobacco e-cigarette flavors may: 1) promote
initiation of and transition to use of e-cigarettes in menthol cigarette smokers; and 2) alter
patterns of menthol combustible cigarette smoking by suppressing tobacco withdrawal. In
February 2020, the FDA enforced sales restrictions on fruit, dessert, and mint-flavored e-
cigarettes to prevent youth access and appeal to these flavored products while also maintaining
availability of tobacco- and menthol-flavored e-cigarettes for adult menthol smokers seeking to
transition away from cigarettes. Given that menthol smokers have been shown to prefer using
menthol-flavored e-cigarettes (Denlinger-Apte et al., 2021; Shang et al., 2020; Stein, Koffarnus,
Stepanov, Hatsukami, & Bickel, 2018) and considering that menthol-flavored e-cigarettes
demonstrated robust, suppressive effects on change from baseline scores of smoking
urges/cravings (which remained significant after corrections) relative to the effects of mint-
flavored e-cigarettes, results of this study may suggest that maintaining access to menthol-
flavored e-cigarettes may benefit adult menthol smokers who may use e-cigarettes for quitting

30
smoking. In our sample, menthol-flavored e-cigarettes suppressed smoking urges/cravings for
pleasure, which has been shown to be a strong predictor of successful smoking cessation (Fidler
& West, 2011). This is particularly important, as our sample were predominantly Black menthol
smokers, which is a population that has been shown to be at increased risk of smoking relapse
following a quit attempt (Babb et al., 2017), despite reporting higher levels of motivation to quit
smoking relative to other racial/ethnic groups (Alexander et al., 2016). Given that Black smokers
continue to experience persistently higher rates of tobacco-related health disparities as a
consequence of aggressive menthol cigarette marketing tactics by the tobacco industry (Cruz et
al., 2019; Kreslake et al., 2008; Villanti et al., 2017), providing greater access to alternative
tobacco products, such as menthol-flavored e-cigarettes, may ultimately aid in the overall effort
towards reducing the public health burden of menthol cigarette smoking in this population.
Contrary to menthol, our findings also suggest that continuing to maintain FDA’s sales
restrictions on mint-flavored e-cigarettes may protect the public health of Americans since this
flavor did not effectively suppress withdrawal in our sample and may pose additional public
health concerns due to the high popularity of this flavor among young and young adults in the
U.S. (Gentzke et al., 2022; Truth Initiative, 2022; Leventhal et al., 2019). Specifically, the
inconsistent findings in suppressive effects on overall smoking urges experienced across time vs.
non-significant effects on urges to smoke for pleasure and negative affect suggests that the FDA
allowing access to and marketing of mint-flavored e-cigarettes may not contribute towards
successful menthol smoking cessation efforts and instead, may contribute to a net population
deficit in health (Truth Initiative, 2018b; Truth Initiative, 2022). Moreover, there are rising
concerns about the toxicity of mint-flavored tobacco products. A growing body of research has
illuminated alarming levels of pulegone—a carcinogenic mint flavorant banned by FDA in

31
food—found in both menthol and mint-flavored JUUL e-cigarette products (Omaiye et al.,
2022), with higher concentrations levels of pulegone and increased cancer risk observed for mint
vs. menthol-flavored JUUL e-cigarette products. Since mint-flavored products are typically
flavored with mint oil (which usually contains pulegone) while menthol-flavored products are
more likely to be made with crystalline menthol (which contains lower concentrations of
pulegone due to higher purity), researchers had advised that using pure menthol rather than mint
oil in e-cigarette fluids may reduce the risk of developing cancer and could also provide a basis
for the regulation of additives in mint- and menthol-flavored tobacco products (Omaiye et al.,
2022). Thus, future mechanistic work and replications of our findings are warranted to further
explore the effects of menthol flavorings in alternative tobacco products in order to determine
whether maintaining the availability of this e-cigarette flavor would satisfy the FDA’s
‘population as a whole’ standard by aiding adult smokers, particularly menthol smokers, in
switching to e-cigarettes while also protecting vulnerable youth non-smokers who may find this
flavor appealing.
There are some possible explanations for why we did not find any significant effects of e-
cigarette flavor on subjective reports of e-cigarette product appeal, sensory effects, specific
indices of tobacco withdrawal (i.e., nicotine withdrawal and positive affect states), and the
relative reinforcing value of menthol cigarettes. First, this study was significantly impacted by
the COVID-19 pandemic as the initial planned sample size was N = 30. However, participant
recruitment was prematurely halted in March 2020 due to COVID-19 restrictions and safety
concerns. Thus, it is plausible that our limited sample size of N = 17 menthol cigarette smokers
may have reduced power to detect differences between flavor conditions and appeal, sensory
effects, other indices of withdrawal, and the relative reinforcing value of menthol cigarettes;

32
however, we found some evidence of flavor-related differences in sensory effects (mint [vs.
tobacco] flavored e-cigarettes had lower ratings of the psychological reward of vaping) and
differences between mint and menthol-flavored conditions (mint [vs. menthol] flavored e-
cigarettes exhibiting greater declines in negative affect states), which did not remain significant
after corrections for multiple testing. Although previous studies have shown menthol and mint
(vs. tobacco) flavored e-cigarettes to differ in self-report measures of e-cigarette product appeal
and sensory effects (Leventhal, Junhan Cho, et al., 2019; Li et al., 2022; Rosbrook & Green,
2016), these studies did not conduct direct comparisons between menthol and mint flavor effects
on study outcomes and instead, combined menthol and mint into a single category
(menthol/mint) to compare with tobacco-flavored effects. Hence, it is also possible that the self-
report and behavioral measures used within this study and in prior work may not be sensitive to
detecting differences in menthol and mint flavor effects and use of alternate methods to assess
these variables (e.g., other behavioral tasks assessing cigarette reinforcement and motivation to
reinstate smoking, biomarkers of flavor exposures, puffing topography, measuring plasma
nicotine concentration levels) may be more effective in capturing differential effects between
mint vs. menthol-flavored e-cigarettes.
Strengths of the Study
Strengths of the current study include the utilization of a double-blind, cross-over,
counterbalanced experimental design in which we manipulated flavor (mint vs. menthol vs.
tobacco) in our sample, as well as the experimental induction of tobacco withdrawal via 16 hours
of nicotine/tobacco product deprivation in order to explore the effects of e-cigarette flavor
conditions on specific, clinically-relevant indices of tobacco withdrawal well-known to be
implicated in the progression and maintenance of tobacco addiction (Aguirre, Madrid, &

33
Leventhal, 2015; M. E. Piper et al., 2011) and predict higher risk of smoking relapse in chronic
smokers (Aguirre et al., 2015; Herd, Borland, & Hyland, 2009; Hyland et al., 2004). Also, our
sample consisted of chronic, low-to-moderately dependent combustible menthol cigarette
smokers who reported no significant prior experience with e-cigarettes in their lifetime, which
may generalize to treatment-seeking chronic menthol smoker populations who may be interested
in quitting smoking and trying e-cigarettes. Moreover, we also used a recent-generation and
commercially available JUUL e-cigarette device and highly appealing e-cigarette flavors (i.e.,
JUULpods: Mint and Menthol), which may have enhanced generalizability of our findings, given
that these e-cigarette products and flavorings have continued to become increasingly popular in
the general population (Barrington-Trimis & Leventhal, 2018; Gentzke et al., 2022). Finally, our
experimental design allowed for a within-subjects comparison of the effects of e-cigarette
flavors, and the multilevel dataset provided sufficient power to detect some main effects of
flavor manipulation on study outcomes. Future work with larger samples of smokers can test
interactive effects and between-subjects moderators (e.g., gender, race/ethnicity, socioeconomic
status [SES]) of main effects between e-cigarette flavors, tobacco withdrawal, and the
reinforcing value of menthol cigarettes.
Limitations of the Study
Limitations of this study include the investigation of only mint, menthol, and tobacco
flavorings and the exclusion of other flavors, such as fruit and confectionary/sweets/candy
flavors, which are also widely available on the market (Zhu et al., 2014). Further work may
benefit from evaluating differences in appeal and sensory properties across fruit,
confectionary/sweets/candy, mint, menthol, and tobacco e-cigarette flavors in menthol smokers
as well as understanding the effectiveness of these flavored tobacco products at reducing tobacco

34
withdrawal and the reinforcing effects of menthol cigarettes. In addition, the exclusion of all
participants who smoked non-mentholated combustible cigarettes may limit the generalizability
of our results, as smokers of mentholated cigarettes may differ from smokers of non-mentholated
cigarettes in flavor preferences. Also, our experimental study utilized a standardized e-cigarette
administration procedure within a laboratory setting. Thus, we are unable to determine whether
our findings would generalize to the natural ecology and more frequent patterns of menthol
cigarette and e-cigarette use. Lastly, we did not collect blood samples in our laboratory study and
thus were unable to evaluate the levels of nicotine delivered to the blood by our experimenter-
provided JUUL relative to other previous-generation and current-generation e-cigarettes.
Conclusions
This study provides preliminary results suggesting that some flavorings may be an
important e-cigarette product characteristic to further consider among adults who smoke menthol
cigarettes daily and who are seeking to transition away from combustible cigarettes to less
harmful alternative tobacco products. Findings of this study illustrated that mint- and menthol-
flavored (vs. tobacco-flavored) e-cigarettes may reduce some tobacco withdrawal symptoms in
menthol smokers, yet menthol-flavored e-cigarettes may demonstrate more consistent
associations with reductions in smoking urges/cravings relative to mint-flavored e-cigarettes.
Further work is warranted to guide future regulatory decisions on the basis of whether menthol
flavorings may alter patterns of menthol cigarette smoking behavior via suppressing tobacco
withdrawal. Furthermore, innovative prevention strategies and policy efforts that protect youth
and young adults while also simultaneously promoting smoking cessation among adult smokers
are needed in order to address ongoing regulatory challenges of flavored e-cigarettes.

35
TABLES
Table 1. Descriptive Statistics for the Overall Sample
Key Variables M (SD) or n (%)
Demographics
Age 51.76 (12.07)
Female Gender 6 (35.3%)
Race/Ethnicity

Non-Hispanic Black or African American 14 (82.4%)
Non-Hispanic White 1 (5.9%)
Other 2 (11.8%)
Low Education (High school diploma, GED, or lower) 8 (47.1%)
Low Annual Income (Less than $15,000) 7 (41.2%)
Unemployed or Retired/Disability 9 (52.9%)
Menthol Cigarette Smoking Characteristics
Age of onset first started smoking 1 cigarette/day (years) 17.41 (9.99)
Age of onset daily smoking (years) 19.41 (10.96)
Number of cigarettes currently smoked per day 11.12 (4.08)
Cigarettes/day when smoking heaviest 16.82 (4.56)
Cigarette Dependence (FTCD) 4.29 (1.69)
Lifetime number of serious quit attempts 1.76 (1.20)
Baseline CO levels (ppm) 15.82 (5.04)
Experimental CO levels (ppm) 3.45 (0.70)
Note: N = 17. FTCD = Fagerström Test for Cigarette Dependence (range 0-10);
CO = Carbon Monoxide (ppm = parts per million); Education (High school
degree, GED, or lower vs. Some college or higher); Annual Income (Less than
$15,000 vs. $15,000 or more); Employment (Unemployment or Retired/Disability
vs. Employed).

36
Table 2. Means (+SEs) for Flavored-Induced Satiation Effects by E-Cigarette Flavor Condition
Study Outcomes
Mint Flavor
Mean (SE)
Menthol Flavor
Mean (SE)
Tobacco Flavor
Mean (SE)
Appeal Ratings 55.58 (6.76) 52.17 (6.76) 49.62 (6.76)
Sensory Effects
Attractive Sensory Effects 51.36 (5.05) 52.26 (5.05) 47.65 (5.05)
Aversive Sensory Effects 35.33 (8.04) 43.98 (8.04) 44.36 (8.04)
E-Cigarette Product Evaluation
Scale

Vaping Satisfaction 56.12 (6.43) 55.33 (6.43) 55.24 (6.43)
Psychological Reward 34.36 (3.55) 39.02 (3.55) 41.83 (3.55)
Aversion 20.63 (7.60) 28.39 (7.60) 29.81 (7.60)
Enjoyment of Respiratory Tract
Sensations 32.53 (7.79) 39.24 (7.79) 39.41 (7.79)
Cigarette Craving Reduction 42.58 (6.88) 53.81 (6.88) 47.70 (6.88)
Tobacco Withdrawal (CFB Scores)
a

Smoking Urges/Cravings
QSU-Total -0.44 (0.09) -0.47 (0.09) -0.12 (0.09)
QSU-Factor 1 (Appetitive Urge) -0.80 (0.17) -0.94 (0.17) -0.37 (0.17)
QSU-Factor 2 (Aversive Urge) -0.08 (0.11) 0.002 (0.11) 0.14 (0.11)
Nicotine Withdrawal Symptoms
MNWS-Total -0.37 (0.08) -0.41 (0.08) -0.47 (0.08)
Negative Affect States
POMS-Negative Affect Composite -0.08 (0.03) 0.01 (0.03) -0.06 (0.03)
POMS-Anger -0.07 (0.04) -0.01 (0.04) -0.13 (0.04)
POMS-Anxiety -0.09 (0.05) 0.02 (0.05) -0.08 (0.05)
POMS-Depression -0.07 (0.04) 0.03 (0.04) 0.04 (0.04)
Positive Affect States
POMS-Positive Affect Composite 0.10 (0.08) 0.12 (0.08) 0.12 (0.08)
POMS-Elation 0.17 (0.10) 0.18 (0.10) 0.18 (0.10)
POMS-Friendliness 0.16 (0.09) 0.31 (0.09) 0.16 (0.09)
POMS-Vigor -0.04 (0.09) -0.12 (0.09) 0.02 (0.09)
Relative Reinforcing Value of
Menthol Cigarettes

Progressive Ratio Task
Breakpoint
b
3.90 (0.51) 3.66 (0.51) 4.37 (0.51)
Note: N = 17. Appeal Ratings = average of “liking,” “willingness-to-use-again,” and “disliking”
(reverse-scored; range 0-100). Attractive Sensory Effects = Mean of “Sweet,” “Smooth,” and
“Throat Hit (Like)” (range 0-100). Aversive Sensory Effects = Mean of “Bitter” and “Harsh” (range
0-100). Vaping Satisfaction = Mean of “How satisfying were the puffs you just took?” and “How
good did it taste?” (range 0-100). Psychological Reward = Mean of “Did it calm you down?”, “Did
it make you feel more awake?”, “Did it make you feel less irritable?”, “Did it help you
concentrate?”, and “Did it reduce your hunger for food?” (range 0-100). Aversion = Mean of “Did
it make you dizzy?” and “Did it make you nauseated?” (range 0-100). Enjoyment of Respiratory
Tract Sensations = “Did you enjoy the sensations of the vapor in your throat and chest?” (range 0-
100). Cigarette Craving Reduction = “Did it immediately reduce your craving for cigarettes?”

37
(range 0-100). CFB = Change from Baseline (i.e., [post-e-cigarette administration assessment
score] – [pre-e-cigarette administration assessment score]). QSU = Questionnaire of Smoking
Urges; MNWS = Minnesota Nicotine Withdrawal Scale; POMS = Profile of Mood States.
a
Means
(SEs) of CFB scores for tobacco withdrawal outcomes were averaged across all post-e-cigarette
administration assessments.
b
Breakpoint was defined as the highest number of trials (out of 10
trials) that was completed for menthol cigarette puffs (vs. mint-, menthol-, and tobacco-flavored e-
cigarette puffs).

38

39

40

41

42
FIGURES

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44

45

46

47

48

49

50
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58
APPENDICES

Appendix A: Example Slides from Animation Video of Standardized E-Cigarette
Administration Procedure

59

60

61
Appendix B: Experimental Session Measures – Appeal and Sensory Effects

E-Cigarette Product Appeal

Sensory Effects

62
E-Cigarette Product Evaluation Scale

63
Appendix C: Experimental Session Measures – Tobacco Withdrawal

Smoking Urges/Cravings (QSU)

10-item Brief Questionnaire of Smoking Urges (QSU)

Instructions: Indicate how much you agree or disagree with each of the following statements by
circling the number between strongly disagree and strongly agree. The closer you choose a
number to one end or the other indicates the strength of your disagreement or agreement. Please
complete every item. We are interested in how you are thinking or feeling right now as you are
filling out the questionnaire.

Strongly
Disagree

Strongly
Agree

1. I have a desire for a cigarette.
0 1 2 3 4 5

2. Nothing would be better than
smoking a cigarette.
0 1 2 3 4 5

3. If it were possible, I probably would
smoke a cigarette.
0 1 2 3 4 5

4. I would control things better if I could
smoke.
0 1 2 3 4 5

5. All I want is a cigarette.
0 1 2 3 4 5

6. I have an urge for a cigarette.
0 1 2 3 4 5

7. A cigarette would taste good.
0 1 2 3 4 5

8. I would do almost anything for a
cigarette.
0 1 2 3 4 5

9. Smoking would make me less
depressed.
0 1 2 3 4 5

10. I am going to smoke as soon as
possible.
0 1 2 3 4 5

64
Nicotine Withdrawal Symptoms (MNWS)

65
Negative and Positive Affect States (Profile of Mood States)

66

67
Appendix D: Example Slide and Script for Progressive Ratio Task

68
Progressive Ratio Task (PRT) Script

1) Place E-Cigarette Device and 10 Cigarettes in white box. Place ashtray, lighter, and white
box in front of participant and the computer screen.

2) Click on “PRT2019avi.ebs2” file in “PRT” folder on Desktop. Enter SID and Session #.

3) Read script below.

We’re now going to start a computer task where you will have the opportunity to make 10
choices between smoking your own cigarettes or vaping the e-cigarette device provided to you
during this experimental session. During this task, you will have the opportunity to earn points
towards choosing between either vaping 2 puffs of an e-cigarette or smoking 2 puffs of your
preferred menthol cigarette. On the screen, the computer task will instruct you to press “A” for
smoking a cigarette (point to “A” on the keyboard) or press “L” for vaping an e-cigarette
(point to “L” on the keyboard). Once you select your choice, press the space bar repeatedly
on the keyboard till the screen tells you that you’ve earned your choice and starts showing
you the instructional video.

Once you’ve earned your choice, you can open the white box and take out whichever product
you earned. A video will then pop up to instruct you on when to smoke your cigarette or vape the
e-cigarette device (similar to the video you saw earlier during the e-cigarette administration).
When the video ends, please place the e-cigarette back in the box or extinguish your cigarette
and place it back in the box.
This computer task is not optional; however, you may choose not to smoke or vape as part of this
procedure after you select your choices. Regardless of whether or not you choose to smoke or
vape, you will be required to complete all 10 choices, so this task will last about 1-2 hours.
During this task, we ask that you not eat, sleep, drink, or use any personal belongings. After
this task, there will be a rest period of 90 minutes where you can relax and use personal
belongings, but will not be allowed to smoke till the end of the session.
Do you have any questions? Go ahead and read these instructions and begin the task.

4) Begin recording responses on MINT PRT Worksheet.

5) Hit “Q” to exit E-Prime program.

6) Make sure to back up E-Prime file (“.edat”).

Abstract (if available)

Abstract Full title: Effects of mint, menthol, and tobacco-flavored e-cigarettes on appeal and sensory effects, tobacco withdrawal, and the relative reinforcing value of menthol cigarettes in menthol smokers: a laboratory study. Background: While cigarette smoking rates have substantially declined in the general U.S. population over the past decade, the prevalence of menthol cigarette smoking has continued to stagnate or increase in some vulnerable groups. Hence, understanding whether novel, emerging alternative tobacco products, such as electronic cigarettes (e-cigarettes) alter patterns of menthol cigarette use are critical to informing prevention, intervention, and policy efforts for reducing the public health burden of menthol cigarette smoking in the U.S. This laboratory pilot study evaluated whether the administration of mint-, menthol-, or tobacco-flavored e-cigarette solutions would differentially impact e-cigarette product appeal, sensory effects, tobacco withdrawal, and the relative reinforcing value of menthol cigarettes in e-cigarette-naÃ¯ve adults who smoked menthol cigarettes daily. Methods: Participants (N = 17; 35.3% Female; mean age = 51.8) attended three laboratory sessions after 16-hours of nicotine/tobacco product deprivation. Participants self-administered a study-provided JUUL e-cigarette (0.7 mL with 5% nicotine by weight) in which only flavor was manipulated (mint vs. menthol vs. tobacco-flavored). Participants then completed pre- and post-e-cigarette administration self-report assessments on appeal, sensory effects, and tobacco withdrawal (i.e., smoking urges/cravings, nicotine withdrawal, and affect states). The relative reinforcing value of menthol cigarettes was assessed with a progressive ratio task in which participants earned choices to smoke menthol cigarettes puffs vs. flavored e-cigarette puffs. Multilevel models tested differences between the three flavored conditions on all study outcomes. Results: Primary analyses indicated that mint- and menthol-flavored (vs. tobacco-flavored) e-cigarette conditions demonstrated significantly greater flavored-induced reductions in overall smoking urges over time (mint effect estimate [mint â€“ tobacco difference] = -0.32, p = .001; menthol effect estimate [menthol â€“ tobacco difference] = -0.35, p = .0002). Additional secondary analyses illustrated that mint and menthol-flavored (vs. tobacco-flavored) e-cigarette conditions exhibited greater flavored-induced decreases in appetitive urges to smoke across time (mint effect estimate [mint â€“ tobacco difference] = -0.43, p = .01; menthol effect estimate [menthol â€“ tobacco difference] = -0.57, p = .001), with the effect of menthol-flavored (vs. tobacco-flavored) e-cigarette condition on appetitive urges remaining statistically significant after corrections for multiple testing. The menthol-flavored (vs. tobacco-flavored) e-cigarette condition also demonstrated greater flavored-induced increases in withdrawal-related anger (menthol effect estimate [menthol â€“ tobacco difference] = 0.12, p = .002). Appeal, sensory effects, nicotine withdrawal symptoms, positive affect states, and the relative reinforcing value of menthol cigarettes did not significantly differ across e-cigarette flavor conditions (ps = .11-.99). Conclusions: Mint- and menthol-flavored (vs. tobacco-flavored) e-cigarettes may reduce some tobacco withdrawal symptoms in menthol smokers, yet menthol-flavored e-cigarettes demonstrated more consistent associations with reductions in smoking urges relative to mint-flavored e-cigarettes. Further work is warranted to guide future regulatory decisions on the basis of whether menthol flavorings may alter patterns of menthol cigarette smoking behavior via suppressing tobacco withdrawal.

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Core Title Effects of mint, menthol, and tobacco-flavored e-cigarettes on appeal and sensory effects, tobacco withdrawal…

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Degree Conferral Date 2022-12

Publication Date 09/25/2022

Defense Date 08/18/2022

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