Nicotine Withdrawal Symptoms and Smoking Relapse

Objective

The primary objective of the current protocol is to gain a greater understanding of the
neurobiological mechanisms underlying acute nicotine withdrawal and contributing to the
maintenance of, or return to smoking behavior among nicotine-dependent individuals, in the
service of developing future smoking cessation treatments. The Nicotine Withdrawal Syndrome
is a major cause of failed quit attempts in smokers, and targeting this time period for
intervention may help improve smoking cessation outcomes.

Study Population

We will recruit treatment seeking and non-treatment seeking smokers, as well as matched
non-smoker control participants.

Design

There are 3 arms included in this protocol, each of which aims to understand the neurobiology
of the Nicotine Withdrawal Syndrome during the initial quit period, with the broader goal of
increasing quit success rate in the future.

Main Study: To understand (1) the acute neurobiological effects of nicotine withdrawal on
treatment-seeking and non-treatment seeking smokers, (2) the long term neurobiological
outcomes of varenicline treatment and smoking cessation counseling at 1, 6, and 12 months. We
will recruit 85 treatment seeking and 35 non-treatment seeking smokers for a within (nicotine
deprivation), between (treatment-seeking status) subjects randomized, double blind, placebo
controlled study.

Motivational Interviewing Arm: (1) To increase motivation and preparation for smoking
cessation treatment among individuals who express an interest in quitting smoking but are not
currently ready to enter treatment, in the service of increasing quit success rate and (2) to
understand the neurobiological basis of motivation to quit smoking, and the interaction
between motivation to quit and mechanisms that underlie acute nicotine withdrawal. We will
recruit 300 current smokers interested in quitting smoking, but not yet ready to set a quit
date.

Transcranial Direct Current Stimulation (tDCS) Arm: To understand the acute effect of tDCS on
3 large-scale brain networks dysregulated in nicotine addiction and withdrawal, the Default
Mode Network, the Executive Control Network, and the Salience Network. We will enroll 60
non-treatment seeking smokers, with the expectation of 35 completers; and enroll 55
non-smoking controls, with the expectation of 45 completers, for a double blind, sham
controlled, randomized crossover study. Smokers will be studied in nicotine abstinence and
nicotine sated conditions, as in the Main Study design.

Outcome measures

Primary outcome measures:

1. Change in BOLD signal and FC related to task parameters, between drug (or tDCS)
condition.

2. Behavioral performance on each of the tasks assessing inhibitory control processes,
reward responsiveness, amygdala, striatal, BNST reactivity, impulsive decision making,
cue reactivity and working memory (e.g., reaction time, error rate, hit rate, reward
bias).

3. Self-reported craving, withdrawal symptoms and mood/affect

4. Smoking abstinence as determined by self-reported tobacco use, urine cotinine, and
breath CO.

Secondary outcome measures:

1. MRS for glutamate concentration.

2. Plasma ACTH and cortisol.

3. Resting state CBF from ASL.

4. ERP and EEG measures.

5. Ratings and scores on self-report characterization measures.

6. Structural MRI and DTI data.

7. Resting state FC at 1, 6 and 12 months post-treatment.

- INCLUSION CRITERIA:

All Participants must:

- Be between the ages of 18-55. Be right-handed. Assessment tool(s): Edinburgh
Handedness Inventory.

- Be in good health. Justification: Many illnesses may alter fMRI signals as well as
cognitive processes and neural functioning. Assessment tool(s): Participants will
provide a brief health history during phone screening, and undergo a medical history
and physical examination with a qualified IRP clinician.

- Be free of active DSM-IV dependence, or dependence in partial remission, on alcohol or
any drug except nicotine. Past active dependence is acceptable provided it is at least
five years in the past and total time of active dependence did not exceed 4 years.
Those with past dependence on any substance other than alcohol or marijuana may not
have any current use (past 6 months) of the substance on which they were dependent.
For individuals with past alcohol or marijuana dependence, current use of the
previously dependent substance will be allowed providing they do not meet any current
DSM-IV criteria for substance dependence, with the exception of tolerance.
Justification: Dependence on other substances (drugs or alcohol) may result in unique
CNS deficits that could confound results and introduce excessive variance. Assessment
tool(s): The computerized SCID and clinical substance abuse/dependence assessment.
While recreational/intermittent use of alcohol and/or marijuana will be tolerated in
all participant groups, individuals will be excluded if they meet current or recent
(within 5 years) DSM-IV diagnostic criteria for dependence on any substances. A
positive drug test for marijuana will not be exclusionary as long as participants have
not used in the 24hrs preceding the imaging visits. In the event of a positive drug
test for marijuana, self-reports of current marijuana use will be used to
differentiate intermittent/infrequent from chronic/frequent users. Given a possible
link between marijuana use and psychosis (Ben Amar and Potvin, 2007) frequent users,
defined as those using twice or more per week within the last month, will be excluded
from participation.

- Be able to abstain from alcohol 24hrs before each of the imaging sessions and able to
moderate their caffeine intake 12hrs before each session. Justification: Alcohol and
caffeine modulate neural functioning in a way that would complicate data
interpretation. Assessment tool(s): Self-report and breathalyzer.

- Must have a urine cotinine (NicAlert) level of 4 or higher and have been smoking
consistently for at least one year. For lighter smokers (less than 10 cpd), this is
defined as smoking at their current level or more for at least the past year
(excluding any quit attempts in the last year). For heavier smokers (more than 10
cpd), they must have been smoking at least an average of 10 cpd for at least the past
year (excluding quit attempts).

- Be able to abstain from smoking for 36hrs on two occasions during the study.
Justification: The present protocol will investigate the effect of acute nicotine
withdrawal on affective, inhibitory control and decision making processes and their
neurobiological correlates. Previous research suggests that a 36hrs deprivation period
is appropriate to produce robust effects across these domains (Kozink et al., 2010a;
McClernon et al., 2009b; VanderVeen, Cohen, Cukrowicz, & Trotter, 2008). To isolate
effects to nicotine-withdrawal (as opposed to tobacco withdrawal), participants will
be required to abstain from smoking prior to both scanning session. They will be
delivered nicotine during one abstinence period (non-deprived) via a dose-matched
transdermal patch, and will wear a placebo patch during the other abstinence period
(nicotine-deprived). Assessment tool(s): video recorded measurement of expired CO
levels plasma nicotine levels.

- Agree to also participate in NIDA-IRP protocol 10-DA-N457.

Treatment-seeking smokers will also have to meet the following inclusion criteria:

-Be actively seeking treatment for smoking cessation and willing to engage in 12-weeks of
treatment involving daily administration of Varenicline and weekly counseling sessions, as
well as follow-up assessments at 1, 6 and 12 months following treatment onset.

EXCLUSION CRITERIA:

All participants will be excluded if they:

- are not suitable to undergo an fMRI experiment due to certain implanted devices
(cardiac pacemaker or neurostimulator, some artificial joints, metal pins, surgical
clips or other implanted metal parts), body morphology, or claustrophobia.
Justification: MR scanning is one of the primary measurement tools used in the
protocol. Assessment tool(s): Prospective participants will fill out an MRI screening
questionnaire and undergo an interview with an MR technologist. Questions concerning
suitability for scanning will be referred to the MR Medical Safety Officer.
Prospective participants will be questioned about symptoms of claustrophobia and
placed in the mock scanner during their first visit to assess for possible difficulty
tolerating the confinement of the scanner and for ability to fit into the scanner.

- have coagulopathies, history of, current superficial, or deep vein thrombosis,
musculoskeletal abnormalities restricting an individual s ability to lie flat for
extended periods of time. Justification: MR scanning sessions require participants to
lie flat on their backs and remain perfectly still for approximately two hours.
Therefore, conditions that would make that difficult (e.g. chronic back pain,
significant scoliosis) or dangerous (e.g. familial hypercoagulability syndrome,
history of thrombosis) will be exclusionary. Assessment tool(s): History and physical
examination by a qualified IRP clinician, supplemented with a trial of lying in the
mock scanner to assess comfort issues.

- have HIV or Syphilis. Justification: HIV and Syphilis both can have central nervous
system (CNS) sequelae, thus introducing unnecessary variability into the data.
Assessment tool(s): Oral HIV followed by blood test if oral test is + and STS+ without
adequate prior treatment

- regularly use any prescription (e.g., antidepressants, benzodiazepines,
antipsychotics, anticonvulsants, barbiturates), over-the-counter (e.g., cold medicine)
or herbal medication (e.g., Kava, Gingko biloba, St. John s wort) that may alter CNS
function, cardiovascular function, or neuronal-vascular coupling. Justification: The
use of these substances may alter the fMRI signal and/or neural functions of interest
in the current study. Assessment tool(s): History and comprehensive urine drug
screening to detect antidepressants, benzodiazepines, antipsychotics, anticonvulsants,
and barbiturates.

- have any current neurological illnesses including, but not limited to, seizure
disorders, frequent migraines or on prophylaxis, multiple sclerosis, movement
disorders, history of significant head trauma, or CNS tumor. Justification:
Neurological diseases alter CNS function and, possibly, the neuronal-vascular coupling
that forms the basis of the fMRI signal. Assessment tool(s): History and physical
examination by a qualified IRP clinician, urine drug screening for anticonvulsants not
disclosed by history. History of head trauma with loss of consciousness of more than
30 minutes or with post-concussive sequelae lasting more than two days, regardless of
loss of consciousness, will be exclusionary.

The MAI who will also retain discretion to exclude based on a history of neurological
illness that may compromise data integrity.

- have any current major psychiatric disorders to include, but not limited to, mood,
anxiety, psychotic disorders, or substance-induced psychiatric disorders, or any
current suicidal ideations or history of suicide attempts or currently under
antidepressant or antipsychotic medication treatment. The MAI will reserve the right
to exclude on the basis of psychiatric history not explicitly described in this
criterion Justification: Psychiatric disorders involve the central neural system (CNS)
and, therefore, can be expected to alter the fMRI measures being used in this study. A
recent FDA communication (2/1/2008) indicates that there may be an association between
varenicline and the worsening of current psychiatric illness even if the illness is
currently under control. Assessment tool(s): Computerized SCID, Beck Depression
Inventory, Beck Anxiety Inventory, Adult ADHD Self-Report Scales and clinical
interview confirmation by clinician.

- are cognitively impaired or learning disabled. Justification: Cognitive impairment and
learning disabilities may be associated with altered brain functioning in regions
recruited during laboratory task performance. Cognitive impairment may affect one s
ability to give informed consent. Assessment tool(s): History of placement in
special-education classes as a consequence of serious learning problems and not solely
as a consequence of behavioral problems, assessed during the History and Physical
screening assessment.

- have significant cardiovascular or cerebrovascular conditions. Justification: Such
conditions may alter blood flow, the fMRI signal and other autonomic signals, and
increase risks associated with nicotine patch use. Assessment tool(s): History and
physical exam, including 12-lead EKG.

- have any other major medical condition that in the view of the investigators would
compromise the safety of an individual during participation. Justification: Many
illness not explicitly covered here may increase risk or alter important outcome
measures. Assessment tool(s): History and physical examination by a qualified IRP
clinician and CBC, urinalysis, NIDA chemistry panel (liver function tests,
electrolytes, kidney function). The following lab values will result in exclusion from
the study:

- Hemoglobin < 10 g/dl

- White Blood Cell Count < 2400/(micro)l

- Liver Function Tests > 3X normal

- Serum glucose > 200 mg/dl

- Urine protein > 2+

- Serum creatinine > 2 mg/dl

- Estimated glomerular filtration rate <60ml/min

- The MAI will retain discretion to exclude based on less extreme lab results.
After the screening process has been completed, the MAI will take into
account all data collected in order to decide if there is an existing
medical illness that would compromise participation in this research.

- pregnant, planning to become pregnant, or breastfeeding. Females are instructed in the
consent to use effective forms of birth control during the study period.
Justification: study procedures and drugs used in the current protocol may complicate
pregnancy or be transferred to nursing children. Assessment tool(s): Urine and/or
serum pregnancy tests, and clinical interview. Urine pregnancy tests will be conducted
at the beginning of each imaging visit.

Treatment-seeking smokers will also be excluded if they:

- have moderate to severe renal impairment. Justification. Given that renal secretion is
varenicline s major route of clearance, kidney impairment may result in higher
systemic levels of the drug than intended. Per Pfizer s chantix insert, varenicline
pharmacokinetics were unchanged in subjects with mild renal impairment in comparison
to those with normal renal function, whereas individuals with moderate and severe
impairment presented with varenicline levels 1.5 and 2.1-fold higher, respectively.
Assessment tool(s): Estimated glomerular filtration rate. Renal insufficiency with
estimated creatinine clearance < 60 ml/min calculated by the Cockcroft-Gault equation
will be excluded.

- are diabetic. Justification. A recent case report describes multiple episodes of
severe hypoglycemia experienced by a 51 year old Type-I diabetic after beginning
varenicline treatment (Kristensen et al., 2008). The discontinuation of varenicline
resolved any further hypoglycemic episodes. The safety of varenicline has not been
investigated in patients with diabetes. Assessment tool(s): Casual plasma glucose
testing. Individuals with glucose levels above 200 mg/dl may be further evaluated for
diabetes using a fasting glucose test or be excluded.