Effects of Varenicline in Heavy Drinking Smokers

There is a strong positive association between cigarette smoking and alcohol use both at the
epidemiologic and behavioral levels. This co-use can create substantial impediments in
smoking cessation. Approximately 25% of current smokers are heavy drinkers. Alcohol use is a
risk factor for relapse during smoking cessation and is associated with lower odds of
quitting smoking. Smokers are five times as likely to experience a smoking lapse during
drinking episodes than at other times. Further, heavy drinking smokers experience more health
consequences than individuals who are either only smokers or heavy drinkers, such as
impairments in brain morphology and function and greater risk for various cancers. Given the
high co-occurrence of smoking and drinking and the health risks associated with the co-use of
these substances, it has been convincingly argued that heavy drinking smokers constitute a
distinct sub-population of smokers with a unique clinical profile and treatment needs. Yet,
there are no available pharmacological treatments or guidelines tailored to heavy drinking
smokers, despite the evidence that this is a treatment-resistant sub-group. Thus, treatment
development for heavy drinking smokers represents a highly significant and understudied
research area. Varenicline is a first-line treatment for nicotine dependence that may also be
effective in reducing alcohol use. Recent studies have indicated that varenicline reduces the
pleasurable effects of alcohol and its self-administration in the laboratory, as well as
alcohol craving and consumption in clinical trials. These findings suggest that varenicline
is a promising medication for smoking cessation in heavy drinking smokers, as reducing
alcohol craving and consumption may be a key component to effectively reducing smoking and
preventing relapse in this sub-group.

In early abstinence, one of the most reliable predictors of relapse is the occurrence of a
single smoking lapse, which is generally defined as smoking at least a puff of a cigarette.
As much as 95% of smokers who experience a lapse will progress to relapse, which has led to
the first lapse being theorized to represent the transition from abstinence to regular
smoking. Alcohol consumption is one of the most consistently identified risk factors for a
smoking lapse and, therefore, may contribute to the maintenance of nicotine dependence in
heavy drinking smokers. Recent clinical trial and laboratory evidence suggests that
varenicline is effective in reducing general smoking lapse behavior, although it is unknown
whether this effect translates to alcohol-mediated smoking lapse behavior.

To address this important gap in the literature, this human laboratory study will use two
laboratory paradigms, namely alcohol administration and a smoking lapse task, to examine
clinically-relevant effects of varenicline among heavy-drinking smokers (i.e., individuals
who smoke ≥ 10 cigarettes/day and who meet National Institute on Alcohol Abuse and Alcoholism
(NIAAA) guidelines for heavy drinking). The investigators will enroll 22 non-treatment
seeking heavy drinking smokers in a randomized, double-blind, placebo-controlled, crossover
laboratory study, testing the efficacy of varenicline in reducing smoking behavior after
controlled alcohol administration among heavy drinking smokers. All participants will be
daily smokers (≥ 10 cig/day) who are also heavy drinkers according to NIAAA guidelines.
Interested individuals will come in to the laboratory for an in-person screening visit and
physical exam. Eligible participants will then be randomized to a medication sequence,
varenicline (1 mg twice daily) or placebo. Medication will be titrated over a 12-day period
and within each medication condition participants will complete two laboratory sessions on
days 9 and 12. The laboratory sessions will consist of placebo-controlled alcohol
administration followed by the McKee smoking lapse task. After completing both laboratory
sessions for the first medication condition, and after a seven-day wash-out period,
participants will be begin the second medication condition and again complete laboratory
sessions on days 9 and 12 of the titration period (i.e., each participant will complete four
laboratory sessions and experience all four combinations of varenicline/placebo pill and
alcohol/placebo beverage). In each laboratory session, participants will receive a dose of
alcohol [target breath alcohol concentration (BrAC) = 0.08 g/dl] or placebo beverage, in a
randomized and double-blind fashion, and will then complete a smoking lapse task. In this
paradigm, participants are presented with their preferred brand of cigarettes, a lighter, and
an ashtray. Participants are then informed that they can begin a cigarette
self-administration session or delay smoking in exchange for a fixed amount of monetary
reinforcement. If the participant decides to smoke, they then begin the self-administration
session in which they are again given the choice to smoke their preferred brand of cigarettes
or receive a fixed monetary reinforcement for each cigarette that is not smoked. In addition
to these smoking outcomes, measures of craving, mood, and subjective effects will be
administered at baseline, after alcohol administration, and during the lapse paradigm. The
study design allows for a within-subjects comparison of the effects of varenicline (versus
placebo), alcohol (versus placebo), and their interaction on smoking behavior in the
laboratory.

The Specific Aims of this project proposal are: Aim 1: To test whether varenicline is
effective at reducing alcohol and cigarette craving, as well as reducing the acute subjective
effects of alcohol and cigarettes; Aim 2: To test whether varenicline is effective at
mitigating alcohol's effects on smoking lapse behavior; Aim 3: To test whether acute
subjective response to alcohol is predictive of subsequent smoking lapse behavior and to
examine if varenicline reduces this effect. The investigators hypothesize that varenicline,
compared to placebo, will reduce cigarette and alcohol craving, attenuate subjective response
to alcohol and cigarette smoking, and improve performance on the smoking lapse task by
increasing the participant's ability to resist smoking. Furthermore, the investigators
hypothesize that varenicline's ability to reduce alcohol craving and subjective response to
an acute dose of alcohol will be directly predictive of performance on the smoking lapse
task. Since heavy drinking smokers have been shown to be relatively treatment-resistant, the
results of the current study could have sizable implications for supporting varenicline as a
potential tailored treatment for this sizable and at-risk sub-group.

Inclusion Criteria:

1. Be between the ages of 21 and 55 and provide informed consent;

2. Smoke > 10 cigarettes per day for > 2 years and have a carbon monoxide (CO) > 10 ppm;

3. Report an interest in quitting smoking in the near future, but currently not in the
process of quitting;

4. Report current heavy drinking according to NIAAA guidelines (62): for men, > 14 drinks
per week or ≥ 5 drinks per occasion at least once per month over the past 12 months;
for women, > 7 drinks per week or ≥ 4 drinks per occasion at least once per month over
the past 12 months;

5. Not seeking or receiving treatment for alcohol use;

6. No current (last 12 months) diagnosis of substance use disorder for any psychoactive
substances other than alcohol and nicotine on the Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-V);

7. Negative urine toxicology screen for narcotics, amphetamines, and sedative hypnotics
at screening;

8. No lifetime history of psychotic disorders, bipolar disorders, or major depression
with suicidal ideation;

9. No current symptoms of moderate depression or higher, indexed by a score ≥ 20 on the
Beck Depression Inventory-II (BDI);

10. No serious alcohol withdrawal symptoms as indicated by a score < 10 on the Clinical
Institute Withdrawal Assessment for Alcohol-Revised;

11. Not pregnant, nursing, or planning on becoming pregnant in the next month (if female);

12. Have no medical condition that may interfere with safe study participation (e.g.,
unstable cardiac, renal, or liver disease, uncontrolled hypertension or diabetes);

13. Within normal limit aspartate transaminase (AST), alanine transaminase (ALT), or
gamma-glutamyl transferase (GGT) levels;

14. Not currently on prescription medication that contraindicates use of VAR.