A Cognitive Behavioral Stress Intervention for Women Who Smoke

Objectives Aim 1: Examine the effect of using cognitive reappraisal and HRVb in a single
session on stress task performance. Investigators expect that participants assigned to
practice both cognitive reappraisal and HRVb will demonstrate greater cognitive performance
and persistence on stressful tasks during a laboratory visit in contrast to a control group
of female smokers.

Aim 2: Examine the effect of using cognitive reappraisal and HRVb on short-term HRV, craving,
and affect. Investigators expect that participants assigned to practice both cognitive
reappraisal and HRVb will exhibit the greatest HRV adaptations, and demonstrate less reactive
craving and affect by the end of the visit than participants randomized to a control group.

III. Background and Rationale Twenty percent of all deaths in the United States, or more than
480,000 deaths each year, are attributable to smoking (USDHHS, 2014). Cigarette smoking
remains the leading preventable cause of death, with 16.8% of adults currently smoking (CDC,
2015) and over 16 million Americans living with a smoking-related disease (USDHHS, 2014).
Smoking remains difficult to quit; even with the best available current treatments, quit
attempts are successful 35% of the time or less (Garrison & Dugan, 2009). Smoking cessation
and relapse to smoking is by far the most frequent path of cigarette use for smokers
(Garcia-Rodriguez et al., 2013; Piasecki, 2006; Rafful et al., 2013). Stress has been
implicated as a primary mechanism in smoking relapse (McKee et al., 2003; Baer et al., 1989;
Cohen & Lichtenstein, 1990), often triggering increases in negative affect (Shiffman, 2005;
Shiffman & Waters, 2004) and exposing difficulties in emotion regulation (Farris, Zvolensky,
& Schmidt, 2015). Evidence suggests that stress prospectively predicts smoking lapse
(Shiffman & Waters, 2004) and lapses triggered by stress progress more quickly to relapse
(Shiffman et al., 1996), suggesting deficits in the ability to cope with stress.

In particular, women's smoking habits show trends that are different from men's: reports have
shown that women consume more cigarettes than men (Hammond, 2009; Ng et al., 2014) and are
less likely to successfully quit smoking than men (Cepeda-Benito et al., 2004; Perkins, 2001;
Piper et al., 2010). While stress has been implicated in relapse for all smokers, recent
evidence indicates that stress is a principal factor in promoting relapse to smoking in
females, in part because women appear to be more strongly predisposed to stress responses
(Torres & O'Dell, 2016). It is therefore likely that women are at particular risk for relapse
due to stress.

Cognitive reappraisal has demonstrated positive effects on stress responding and
smoking-related outcomes. Cognitive reappraisal is the reframing of a situation in order to
influence one's emotional response to it (Gross, 1998). Compared with acceptance and
suppression, reappraisal as measured by the Emotion Regulation Questionnaire (ERQ; Gross &
John, 2003) is associated with overall lower craving and negative affect during craving
inductions and stress tasks, as well as improved performance on a cognitive stress task
(Szasz, Szentagotai, & Hofmann, 2012). Fucito, Juliano, and Toll (2010) found that frequent
reappraisal on the ERQ was cross-sectionally associated with smoking fewer cigarettes. Recent
evidence has indicated that reappraising stress-related arousal improves cognitive
performance and physiological reactivity (Jamieson et al., 2012; 2013). Evidence thus far
suggests that the use of cognitive reappraisal in particular as a self-regulation strategy
may have positive implications for smoking behavior, including cigarette craving.

HRVb has also shown promising evidence on stress outcomes. Utilizing behavioral
self-regulation strategies such as heart rate variability biofeedback (HRVb) to increase
heart rate variability (HRV) shows promise in coping with stress. HRV is a measure of
fluctuation from the mean heart rate, representing the interaction between sympathetic and
parasympathetic influences on the cardiac system (Siepmann et al., 2008), and serving as a
biomarker of autonomic nervous system functioning (Zucker et al., 2009). HRV biofeedback
training aims to improve adaptability to and recovery from fight or flight situations by
increasing HRV (Gevirtz, 2013). A single session of HRVb improves adaptability to stress as
measured with improved cognitive performance in a lab-induced stress task (Prinsloo et al.,
2010). Several weeks of HRVb practice have shown reductions in substance craving (Penzlin et
al., 2015; Eddie et al., 2014) and food craving (Meule et al., 2012), although no studies to
date have examined the effect of a single session of HRVb practice on cigarette craving.

This study assesses whether combining a cognitive and behavioral approach to improve stress
responding in smokers may be especially efficacious. No other study to date has examined
examined potential additive benefits of combining both strategies. Combining both cognitive
and behavioral self-regulation skills for stress adaptation is consistent with
cognitive-behavioral theory upon which evidence-based treatments for Axis I pathology were
developed, as behavioral (e.g., HRVb) and cognitive (e.g., reappraisal) approaches to
self-management allow the individual to target both internal and external stimuli when coping
with stress (Rokke & Rehm, 2001). Beyond psychological effects of stress, the combination of
such approaches has implications for informing smoking cessation treatments, as it has been
previously noted that current treatments for substance addiction "are failing to address
important factors that are active in sustaining [such] pathology, because phenomena that lead
to relapse... are mediated by physiological as well as cognitive processes" (Eddie,
Vaschillo, Vaschillo, & Lehrer, 2015, p. 266). In order to further improve cessation rates,
cognitive reappraisal instruction and HRVb can be incorporated at low cost into standard
smoking cessation treatment, which currently consists of pharmacotherapy and smoking
cessation counseling according to the Clinical Practice Guideline (Fiore et al., 2008). HRVb
technology ranges from free smartphone applications (e.g., Elite HRV) to sophisticated
devices available for purchase online (e.g. EmWave), making it an affordable and feasible
addition to enhance current smoking cessation treatment.

As no studies to date have explored the effects of HRVb in a single session on smoking
craving, this study will be the first to address the potential use of a relatively new
technology for its short-term effects on variables that increase lapse risk, such as affect,
craving, and stress responding. This pilot study will assess the efficacy of practicing HRVb
using a device that is available to the general public that has not been previously tested
for its short-term effects on craving. Combining HRVb training prior to a stressful task,
followed by cognitive reappraisal during a task, has also never been explored for its
additive effects above the use of either strategy alone. Both strategies would allow for a
more comprehensive approach to managing stress responding, both cognitively and
physiologically. Moreover, promising research on self-regulatory strategies like cognitive
reappraisal has not compared it with HRVb to assess relative efficacy in improving stress
responding, or in assessing its relative efficacy in improving smoking-related outcomes.

IV. Procedures

1. Research Design This study is a single-session experimental trial using two
interventions (heart rate variability biofeedback and cognitive reappraisal of stress)
as independent variables and examining smoking craving, affect, and heart rate
variability as dependent variables. The laboratory visit includes a baseline
questionnaire, pre-test and post-test measures of smoking craving, affect, and heart
rate variability. Participants will be randomized to practice both interventions, or to
a control group that undergoes all procedures excluding the two interventions
(independent variables).

2. Sample Participants will consist of 60 English-speaking females ages 18-65. As this is
an experimental study with both between-subjects and within-subjects measurements, 60
participants will be sufficient for a power level of .8.

3. Measurement/Instrumentation Objective Measures

Heart rate variability will be measured as one of the primary outcome measures of this study.
As heart rate variability is susceptible to several other environmental and mental factors
that affect the sympathetic nervous system, additional measures need to be taken to ensure
the validity of the heart rate variability data. As secondary measures, blood pressure and
breath carbon monoxide will be recorded. Specifically, the following measures will be used
for data collection, all of which are non-invasive:

- Heart Rate Variability (HRV). HRV will be examined using electrocardiogram (ECG)
measurement with Biopac Acqknowledge software. Electrodes will be placed on the torso of
each participant by a trained, same-sex research staff member in order to detect heart
rate, cardiac impedance, and respiration rate. HRV data cleaning will follow standard
guidelines (Bernston et al., 1990).

- Blood Pressure (BP). An inflating arm cuff will be used to detect blood pressure.

- Respiration. To control for compensatory breathing that may lead to hyperventilation
when reducing breathing rate during biofeedback practice, respiration belts will be
attached around participants' ribcage to monitor breathing rate and tidal volume. 800mL
spirobag calibration will follow standard guidelines, asking participants to inflate and
deflate the bag five times in order to obtain an accurate estimate of tidal volume.

- Carbon monoxide (CO). A standard carbon monoxide monitor will be used to detect carbon
monoxide levels in participants' breath, as an objective measure of cigarette smoking.
This will be used for eligibility purposes (establishing that participants are not light
smokers) and to ensure that participants have been abstinent from smoking for at least
12 hours prior to the start of the study visit.

Instrumentation One of the interventions examined in this study is heart rate variability
biofeedback, which involves breathing at a slow and steady rate and receiving feedback from a
device about one's heart rate. The EmWave2® HRVb device (HeartMath®, Boulder Creek, Colorado)
will be used for HRVb practice and will serve as an additional measure of HRV for the HRVb
group. The EmWave2® device trains the user in HRVb and provides readings of HRV, time
elapsed, and varying levels of physiological coherence (Edwards, 2014). Repeated use of the
device has demonstrated clinically significant improvement in performance on tests of
executive functioning associated with emotional dysregulation (O'neill & Findlay, 2014) and
statistically significant increases on measures of general health and mindfulness (Edwards,
2014).

Baseline Self-Report Measures After consenting procedures are complete, participants will be
directed to a website (Qualtrics) where they will complete a battery of baseline self-report
questionnaires. Qualtrics is an online-based, private research company that specializes in
data collection. All data entered through Qualtrics will be connected only to participants'
unique identifying numbers that will not be associated with any identifying information
(e.g., name or contact information). Participants will fill out self-report questionnaires
that assess demographic information, smoking history and behavior, clinical symptoms, emotion
regulation, and other mental health-related indices. (See Attachment 7 for the study
measures.)

Specifically, the following measures will be administered:

- Demographics. General demographic information will be collected, including sex/gender,
age, height, weight, hormonal contraceptive use, menstruation pattern, sexual
orientation, race/ethnicity, education/career history, and mental health history.
Additionally, several items assessing DSM-IV criteria for bulimia nervosa will be
included.

- The Timeline Followback (TLFB). The TLFB will be used to quantify daily smoking behavior
over the past 30 days, as a measure of smoking heaviness. It has demonstrated high
test-retest reliability for 30-day intervals in cigarette smokers (Robinson et al.,
2014).

- The Fagerstrom Test for Nicotine Dependence (FTND). The FTND is among the most widely
used measures of nicotine dependence, with confirmed reliability in different settings
and populations that smoke cigarettes (Agrawal et al., 2011; Fagerstrom, 2012).

- The Reasons for Smoking Questionnaire (RFS). The RFS has been used for over 30 years to
assess smokers' motives for smoking, and has demonstrated good convergent validity and
internal consistency (Currie, 2004) and adequate test-retest reliability (Tate, Schmitz,
& Stanton, 1991).

- The Beck Depression Inventory-II (BDI-II). The BDI-II is a 21-item measure of depression
that has demonstrated reliability and stability (Beck, Steer, et al., 1988; Beck, Steer,
& Brown, 1996).

- The Emotion Regulation Questionnaire (ERQ). The ERQ is a validated measure of emotion
regulation strategies with good test-retest reliability (Gross & John, 2003).

- The Perceived Stress Scale (PSS). The PSS is the most widely used measure of the
perception of stress, and was designed for use in community samples (Cohen, Kamarck &
Mermelstein, 1983). Higher PSS scores are associated with failure to quit smoking,
greater vulnerability to depression, and more colds (Cohen et al. 1988).

- The Generalized Anxiety Disorder-7 (GAD-7). The GAD-7 is a brief, validated measure of
generalized anxiety with demonstrated reliability that has been recommended for clinical
practice and research (Spitzer et al., 2006).

- The Social Desirability Scale (SDS). The SDS-16 measures social desirability, which is
helpful in studies with objective and subjective outcomes with potential inconsistency.

- The Difficulties with Emotion Regulation Scale (DERS). The DERS will be used to measure
problems with emotion regulation within six domains: nonacceptance of emotional
responses, difficulties engaging in goal-directed behavior, impulse control
difficulties, lack of emotion awareness, limited access to emotion regulation
strategies, and lack of emotion clarity. It has been shown to have good internal
consistency, validity, and test-retest reliability (Gratz & Roemer, 2004).

- The Ruminative Responses Scale (RRS). The RRS will be used to measure the degree to
which individuals respond in ruminative ways during depressed moods. It has been
demonstrated to have strong inter-item consistency (Treynor, Gonzalez, & Nolen-Hoeksema,
2003).

- The Emotional Cascade Assessment Measure (ECAM). The ECAM will be used to measure how
individuals respond to upsetting situations, and the degree to which they engage in
emotional cascades (Selby & Joiner, 2009). This measure is currently being validated in
our lab.

- The Three-Factor Eating Questionnaire (EQ). The EQ will be used to assess
overconsumption of food as a response to emotional, cognitive, and social cues, as food
cravings and weight gain are common concerns for smokers who want to quit. Several
subscales have been shown to have adequate test-retest reliability, and the
disinhibition subscale predicts weight gain (Cuntz et al., 2001; Foster et al., 1998).
The cognitive restraint subscale has demonstrated construct validity (Karlsson et al.,
2000).

The BDI-II includes an item that measures an individual's suicidality. If at any point a
participant indicates they are feeling significantly suicidal, a message will pop-up at the
end of the survey, informing the study staff of the individual's risk for high suicidality.
Study staff will then perform a brief assessment and intervention to determine if further
professional attention is required to keep the participant safe. (See "Protection Against
Potential Risks" and Appendix 2 for more detailed information.)

Additional Self-Report Measures At multiple points throughout the study, additional
self-report measures will be used to assess smoking craving and affect, which are the
subjective outcomes of the study.

- The Positive and Negative Affect Schedule (PANAS) is a 20-item measure of affect that
has demonstrated test-retest reliability, as well as good convergent and divergent
validity (Watson, 2000).

- The Questionnaire on Smoking Urges-Brief (QSU-B; Cox, Tiffany, & Christen, 2001) is a
10-item measure of smoking urges and cravings, where a higher score indicates a stronger
craving.

Finally, several subscales of the Stress Appraisal Measure (SAM; Peacock & Wong, 1989) will
be used as a manipulation check for the cognitive restructuring intervention. The SAM has
demonstrated reliability and good internal consistency of its subscales (Carpenter, 2016).

Computer Stress Tasks Participants will first have ten minutes to complete a Mirror Tracing
Task (MTT; Quinn, Brandon, & Copeland, 1996) that measures persistence on a stressful task,
which is associated with nicotine dependence treatment outcome (Brandon et al., 2003) and can
distinguish cigarette smokers from non-smokers (Quinn et al., 1996). The MTT involves tracing
three shapes displayed on a computer screen, using the mouse of the computer screen. A
buzzing sound indicates whether the shape is being traced incorrectly. As the primary purpose
of this task in the study is to induce stress, participants will be instructed to complete
the task without the option of termination for ten minutes.

Second, participants will complete the validated Montreal Imaging Stress Task (MIST; Dedovic
et al., 2005) which involves mental arithmetic with negative feedback from the investigator,
who will be a female member of study staff. The MIST was specifically designed for eliciting
psychosocial stress when participant movement is restricted and has demonstrated effects on
biological indices of stress, including cortisol (Dedovic et al., 2005) and brain areas
associated with the limbic system (Dedovic et al., 2009) and HPA axis (Zschucke et al.,
2015).

Third, a computerized Stroop task (Stroop, 1935) will be implemented to induce mental stress.
The Stoop task is a well-known and validated measure of mental stress and cognitive
performance that involves reading words and identifying colors on a computer screen.

e. Detailed study procedures Interested participants will complete a phone interview for
eligibility. Participants referred from the Tobacco Dependence Program will have provided a
breath carbon monoxide sample meeting eligibility criteria, which is at least 15ppm.
Participants recruited from other sources will be asked to provide a breath sample during a
5-minute visit to the laboratory in order to confirm smoking status at least one day prior to
the scheduled study visit.

Eligible participants will be scheduled for a 2.5-hour visit and asked to refrain from
alcohol, tobacco, or e-cigarette use for 12 hours prior to their appointment time. The study
visit will consist of a breath CO test to confirm tobacco abstinence in the past 12 hours
(indicated by a breath CO level of less than 10ppm. Evidence shows that daily smokers who
have not yet smoked the first cigarette of the day exhibit expired CO levels between 9 and
11ppm (Adan, Prat, & Sanchez-Turet, 2004). Interested participants who are not CO-eligible
will be rescheduled for another study visit day. CO confirmation of study eligibility will be
followed by the informed consent process, and finally the completion of a baseline
questionnaire packet (detailed below). They will also be instrumented with the BioPac
psychophysiology stations by a trained female study staff member. They will then be asked to
conduct a baseline psychophysiological assessment for 10 minutes, which is done in order to
provide a comparison for the effects of the interventions and stress tasks.

Participants will be randomized to one of two conditions, blocked by age and level of
motivation to quit smoking in the next 30 days. Participants ages 18-39 will be randomized
separately from participants ages 40-65. Blocking randomization by age group will reduce age
confounds within the sample of adult women, as age is correlated with smoking behavior and
heart rate variability (Zhang, 2007). Motivation to quit smoking in the next 30 days, on a
scale of 1-10, will be assessed in the initial phone interview to block randomization by
level of motivation to quit (1-5 versus 6-10). Participants will be randomly assigned to one
of two study conditions reflecting the presence or absence of the interventions: 1) HRVb and
cognitive reappraisal instructions, or 2) Sitting quietly while engaging in a neutral control
task and no reappraisal instructions. HRVb will involve paced breathing as guided by a moving
light on a portable biofeedback device (described below). The neutral control tasks will
involve pressing a computer key whenever a shape appears on the computer screen, which will
occur approximately every minute. To maintain a neutral control condition for 30 minutes, a
neutral nature video will supplement the task to prevent significant participant boredom or
frustration.

Cognitive reappraisal instructions will explain the function of the stress response as an
adaptation to effectively overcome challenges, following an example by Jamieson, Nock, and
Mendes (2012). Remaining study visit procedures are detailed in Figure 1.

Debriefing Following the completion of computer tasks, 15 minute recovery period, and removal
of psychophysiological recording equipment, participants will be debriefed about the study
and its purposes. They also will be provided with a Debriefing/Resources Sheet with
information and contact information about mental health. Participants will then be
compensated for their participation.

The study staff member will review the Resources Sheet with the individual and provide the
participant with a physical copy to take home with them. The Resource Sheet (attachment 9)
will include information on resources specific to Rutgers and central New Jersey.

Protections Against Potential Risks Every effort will be made to minimize any risks
associated with participation. Our procedures are generally non-invasive and pose little to
no physical risk to the participants. As such, the risks involved with participation in this
study are minor, though there are a few concerns.

1. Questionnaires. Some of the content of the questionnaires for this proposed project may
be distressing for participants to answer (e.g. questions about substance use,
self-injury, etc.), although risks from their use is likely to be uncommon as these
measures have commonly been used in previous studies without incident. Though distress
while answering questions from self-report measures is not extremely likely,
participants will be informed that they are not required to answer any questions that
they do not wish to answer, and that they may end their participation in the study at
any time.

2. Suicide Risk. Although the risk of suicidal participants in this study is relatively
low, it is imperative that any participant identified at high suicide risk, when
answering the BDI-II during the study visit, be approached with appropriate evaluation
and intervention procedures. Participants whose risk is determined to be serious
(defined as endorsement of suicide plans or preparation, or imminent suicidal intent)
will be referred to appropriate mental health providers for suicidal crisis
intervention. If a participant endorses imminent suicide risk during an assessment, he
or she will be voluntarily escorted to Rutgers University Counseling Center for further
assessment. If necessary, Rutgers Campus Police will be contacted for transport of the
participant for further mental health assessment, particularly in cases where imminent
suicide risk is indicated and the participant refuses to undergo additional screening.
The suicide risk assessment procedures, as well as the appropriate actions to be taken
according to suicide risk are described in the Appendix 2. These potential actions will
also be described in the informed consent form so that participants are aware prior to
the clinical interviews. In the case that a participant exhibits suicidal ideation, the
assessor will contact Dr. Selby to ensure that appropriate safety measures are taken
prior to the participant leaving the lab. Importantly, research has found that
conducting a suicide risk assessment on people who are not suicidal will not cause them
to experience suicidality, and furthermore those who are experiencing suicidal ideation
frequently report feeling better following a suicide risk assessment. This assessment
approach has been used successfully in previous research to protect human subjects who
were potentially experiencing suicidal ideation.

3. Confidentiality. Procedures will be completed once for each participant throughout the
project period. There is a minimal risk that confidential information could be breached.
The identifying information of all participants will not be included in the same survey
as the self-report questionnaires or in the same file as their consent forms (for
in-person participants). Confidentiality will be maintained in the reporting of all
results. The information gathered will be used only for scientific purposes and will be
reported only in aggregate form of group totals or averages. All physical data forms
(from in-person participants) will be kept in a locked file cabinet in the primary
investigator's lab. All personnel will be carefully trained by the investigators
regarding the collection and storage of sensitive information. Data entered into
statistical databases will be kept in investigators' lab space, and will be kept in
locked space to which only investigators and authorized personnel will have access. All
electronic data downloaded from participant surveys will be stored on a secure server in
the investigator's lab (further details described below).

4. Data Security. Participants will provide electronic data via online surveys as part of
their participation in the laboratory. There is small risk that data could be
compromised. Each questionnaire survey and electronic data set will be numbered, and the
in-person informed consent form will have an attached sheet containing that number,
which will be removed once data collection is complete.

f. Consent Procedures Participants will be provided with the consent form and given time
to read it, then the study will be explained by a trained, CITI-certified study staff
member who will also answer participants' questions. Participants will initial all pages
of the consent form before signing and dating the consent form with a study staff member
witness. A dated and signed copy will be given to the participant.

g. Internal Validity Threats to internal validity in the study have been considered and
addressed through the inclusionary and exclusionary criteria for the study. Furthermore,
all participants are adult women to reduce age and gender confounds in HRV data, and
randomization to study condition will be blocked by age to further reduce confounds for
HRV measurement. Additionally, blood pressure will be recorded to assess potential HRV
confounds. During the intervention, the biofeedback device will serve as a secondary
measure of HRV and a manipulation check. Cognitive reappraisal instructions will include
practice exercises and questions to ensure understanding of the intervention, and
subscales from the Stress Appraisal Measure will be utilized as manipulation checks.
Self-report measures have been selected for their validity and appropriateness for the
study sample. Furthermore, the stress tasks were specifically selected for their effects
on different facets of stress, including social stress, in order to capture the
potential stressors faced by real-life smokers that lead to relapse.

h. Data Analysis In order to examine the effect of practicing cognitive reappraisal and
HRVb in a single laboratory session on stress task performance, investigators will
examine persistence on the MTT and performance on the Stroop task separately.
Persistence on the MTT will be measured via time to completion or termination of the
task as an outcome measure. Reaction time and response accuracy (as averages for each
individual) will be examined as outcome measures on the Stroop task. Generalized
estimated equations analyses will examine the effects of the two experimental
manipulations (HRVb and cognitive reappraisal) and covariates including age, average
daily cigarettes smoked, Body Mass Index (as calculated from demographics information in
the baseline questionnaire), and demographic variables on the three outcome measures for
the MTT and Stroop task.

In order to examine the effect of practicing cognitive reappraisal and HRVb on
short-term HRV, craving, and affect, investigators will first clean all HRV data
following standard guidelines (Bernston et al., 1990). Within-subject changes in HRV
will be assessed via changes from baseline HRV measurement averages. Change scores for
HRV, craving, and affect will be explored as between-group differences using 2x2
analyses of variance. Multiple regression analyses will then examine the effect of
cognitive reappraisal and HRVb on changes in HRV, craving, and affect, with age, average
daily cigarettes smoked, Body Mass Index, and demographic variables entered as
covariates.

Second, investigators will explore changes over time for the multiple assessments of
HRV, craving, and affect by examining within-subject changes over time. Within-subject
data analysis will be conducted in Hierarchical Linear Modeling (HLM) Version 7 software
(Raudenbush et al., 2011) to account for the nesting structure of the data as well as
missingness of data, and allow for analysis with random intercepts. Multilevel models
will include the covariates mentioned above in addition to the experimental
manipulations of cognitive reappraisal and HRVb.

Inclusion Criteria:

- To be included in the study, participants must report smoking at least 10 cigarettes
per day, and agree to complete study procedures, which requires a willingness to
practice quitting smoking.

- They must also provide a breath carbon monoxide sample of at least 15ppm to verify
their smoking status.

Exclusion Criteria:

- Exclusionary criteria include being pregnant or trying to become pregnant

- Color-blindness

- Current psychosis, current substance dependence, current body mass index (BMI) of over
40

- Current diagnosis of a cardiac rhythm abnormality (mitrovalve prolapse, frequent
premature ventricular contractions

- Atrial fibrillation, bundle branch block) or a major neurological problem, history of
a myocardial infarction, or past-week use of illicit drugs

- Nicotine replacement therapy, bupropion, varenicline, anti-cholinergic medications,
beta blockers, Ritalin

- Benzodiazepines

- Tricyclic antidepressants

- Antipsychotic medication.