Varenicline to Reduce Alcohol Consumption in Heavy Drinkers
Condition: Alcohol Drinking
MeSH terms: Alcoholic Intoxication; Alcohol Drinking
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This study will determine whether varenicline, a drug that acts on the brain's nicotine
      receptors and is used to help smokers stop smoking, will have an impact on alcohol
      self-administration.

      People between 24 and 60 years of age who regularly consume alcoholic drinks (more than 15
      drinks per week for women, and more than 20 drinks per week for men) may be eligible for this
      study. The study requires five outpatient visits and one overnight hospital admission at the
      NIH Clinical Center.

      Participants undergo the following procedures:

      Visit 1 (outpatient: 4-5 hours)

        -  Standard assessments, including vital signs measurements, breathalyzer test, blood and
           urine tests (including pregnancy test for females), questionnaires about mood, symptoms,
           alcohol use and smoking, if applicable

        -  Questionnaires about medical and psychological status

        -  Health assessment and assessment of alcohol drinking behavior

      Visit 2 (outpatient: 8 hours)

        -  Standard assessments (see above)

        -  Computer-Assisted Self-infusion of Ethanol (CASE) session: Subjects will receive a
           priming intravenous infusion of alcohol. After 25 min, they will be allowed to give
           themselves additional exposures of alcohol over a period of 2 hours by pressing a button
           on a computer that controls the infusion pump.

      Visit 3 (outpatient: 2 hours)

      -Standard assessments

      Visit 4 (outpatient: 8 hours)

        -  Standard assessments

        -  Brain functional magnetic resonance imaging scan (MRI). This test uses a magnetic field
           and radio waves to produce images of the brain. The patient lies on a table that can
           slide in and out of the scanner, wearing earplugs to muffle loud sounds that occur
           during the scanning process. Initial pictures are taken of the brain's structure and
           additional scans measure brain activity while the subject performs simple tasks.

        -  Alcohol Infusion. Subjects receive an intravenous infusion of alcohol while in the MRI
           scanner to measure the brain s response to alcohol.

      Visit 5 (overnight)

        -  Standard assessments

        -  Repeat CASE session

        -  Interview about the subject's experiences participating in the protocol, including any
           symptoms and urges to drink

      Visit 6 (outpatient)

        -  Standard assessments (without blood tests)

        -  Interview about participation in the study

      Telephone follow-up

      After 3 weeks, subjects are called to check on their symptoms and gather information on their
      drinking and, if applicable, smoking.
    

Detailed description: 
      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.
    

Intervention name(s): Varenicline; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Varenicline tablets, 2 mg per day for 3 weeks; Placebo tablets, 0 mg per day for 3 weeks
Intervention MeSH terms: Varenicline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Varenicline; Alcohol; Alcohol Use