Varenicline to Reduce Alcohol Consumption in Heavy Drinkers

Objective:

Considerable clinical and experimental evidence in humans and animal models links nicotine
use with heavy alcohol consumption. Varenicline, an alpha4beta2 (nicotinic) acetylcholine
receptor (nAchR) partial agonist, is an oral medication approved by the FDA (2006) for
smoking cessation. Recently, it has been shown to reduce alcohol consumption in a rodent
model of alcohol dependence. In the present short-term experimental study, it will be
assessed primarily for its ability to reduce alcohol self-administration in heavy drinkers.
Secondarily, its effects on alcohol urges (cravings), as well as smoking parameters will be
measured. In addition, effects of varenicline on incentive motivation for alcohol and the
underlying brain reward system activation, as well as on activation of brain reward systems
in response to intravenously administered alcohol will be measured.

Study Population:

Fifty healthy, adults (smokers and non-smokers), age 21 to 60 years, will be studied.
Individuals must drink alcohol regularly at a heavy level, on average greater than 20 drinks
per week for men, and greater than 15 drinks per week for women, and not be seeking help for
alcohol-related problems.

Design:

Following protocol screening and medical evaluation, qualified subjects will undergo an
initial ( pre-study drug ) intravenous alcohol self-administration session (hereafter,
called computer-assisted self-infusion of ethanol, or CASE). Following this, subjects will
be randomized to varenicline or placebo. Subjects will be clinically evaluated on three
occasions while on study drug: once after one week of study medication; again, prior to the
fMRI; and again, at the end of treatment, when they undergo the second ( on-study drug )
CASE session. Between days 13 and 21, all subjects will be scheduled to undergo functional
magnetic resonance imaging (fMRI) of the brain while performing a task designed to evaluate
the incentive salience for alcohol cues as well as the pharmacological effects of alcohol.
Thereafter, all subjects will receive two courses of counseling for heavy drinking, using
motivational enhancement techniques, aimed at enhancing their readiness for behavioral
change and seeking treatment, if needed.

Outcome Measures:

The primary outcome will be the peak breath alcohol exposure achieved during the on-study
drug CASE session. Secondary outcomes during the study drug phase will include measures of
alcohol consumption, and urges to drink, as well as alcohol cravings and effects during the
on-study drug CASE session. Additionally, fMRI BOLD responses in the ventral striatum, an
area involved in brain reward circuitry and shown to be activated by acute IV alcohol
administration as well as anticipation of working for reward will be measured. In smokers,
cigarette use and quite rates as well as urges to smoke and nicotine withdrawal will also be
measured. Safety and tolerability will be followed during the course of taking study drug
with symptom checklists, profiles of mood and anxiety and by clinical interview. Serum
varenicline concentrations will also be measured to assess compliance and control for
potential pharmacokinetic variation.

- INCLUSION CRITERIA:

- Age 21 to 60 years of age.

- In good health.

- Drink a weekly average of 15 and 20 standard alcoholic drinks (12 gm
ethanol/beverage), respectively, for women and men.

- Have a working phone number.

EXCLUSION CRITERIA:

- Currently seeking help for an alcohol problem.

- Subjects with clinically significant alcohol withdrawal.

- More than thirty days of abstinence from alcohol in the ninety days prior to
enrollment.

- A positive breath alcohol concentration (BrAC) at the first visit

- A history of major alcohol-related complications at any time, such as pancreatitis.

- Any serious cardiovascular condition or high risk factors, evidenced by any of the
following:

- Current or past diagnosis of coronary artery disease (such as ischemia, angina,
congestive heart failure, myocardial infarction) or peripheral arterial disease;

- Current or past diagnosis of diabetes, or casual glucose level > 200 mg/dl;

- Elevated blood pressure (above 160/100) at screening,

- Elevated lipid levels: LDL > 160 mg/dL, HDL < 40 mg/dL for males or < 45
mg/dL for females;

- Clinically significant ECG abnormalities or unstable arrhythmias.

- Contraindication(s) to take the study medication as listed in the package
insert.

- Contraindication(s) to take the study medication as listed in the package insert.

- Psychiatric problems requiring clinical attention: a current or past diagnosis of
major depression, panic disorder, eating disorders, post traumatic stress disorder,
schizophrenia, bipolar disorder, or obsessive compulsive disorder. Individuals who
report lifetime (past or current) history of suicidal ideation, suicide attempts or
self injury.

- Recent (within the last two months) or regular use of illicit or non-prescribed
psycho-active substances such as opiates, benzodiazepines, cocaine, PCP,
methamphetamines/other psychostimulants or marijuana.

- Psycho-social instability (e.g. no fixed address, no reliable secondary person to
contact in case of an emergency).

- Women who are lactating, are trying to become pregnant or who are not willing to
practice safe and effective birth control.

- Moderate-to-severe renal impairment defined as estimated or measured creatinine
clearance less than 30 mL/min.

- Use of bupropion or nicotine replacement therapy within 90 days of the protocol,
inhibitors/substrates for renal cationic transporters, or medications contraindicated
with ethanol.

- Exclusion criteria for MRI scanning, including metal in body (such as implants,
pacemaker, prostheses, shrapnel, irremovable piercing), left-handedness, and
claustrophobia.

- A history of violence or aggression, assessed as part of the clinical interview at
screening visit.