Ghrelin for Alcohol Use in Non-Treatment-Seeking Heavy Drinkers
Condition: fMRI; Alcohol Drinking; Alcoholism
MeSH terms: Alcoholism; Alcoholic Intoxication; Alcohol Drinking
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

      - Ghrelin is a hormone in the human body that is mostly produced by the stomach. It makes
      people feel hungry, and also is connected with the desire to drink alcohol. Researchers want
      to test ghrelin to see if it can be used to control alcohol cravings and use. They will
      compare doses of ghrelin with a placebo in people who drink heavily.

      Objectives:

      - To study the effects of ghrelin on alcohol craving and use.

      Eligibility:

        -  Individuals between 21 and 60 years of age who are heavy drinkers but are not seeking
           treatment for alcohol use.

        -  Participants must on average have more than 20 drinks per week for men, and more than 15
           drinks per week for women.

      Design:

        -  Participants will have a screening visit, four 2-night study visits, and a follow-up
           visit.

        -  Participants will be screened with a physical exam and medical history. They will
           provide urine and breath samples for drug testing. They will also answer questions about
           mood and physical symptoms, and about alcohol and other cravings.

        -  At the study visits, participants will stay overnight at the National Institutes of
           Health clinical center. They will spend the night at the center, have tests on the next
           day, and go home on the following morning. At each visit, participants will receive a
           ghrelin or placebo infusion, and will complete a series of tasks.

        -  For the first and second study visits, participants will have tests of alcohol craving
           and use. They will be able to receive alcohol infusions through a computer program that
           tests response time and craving reactions. At the same time, they will have a ghrelin or
           a placebo infusion. Blood alcohol levels, reaction time, and craving will be studied.

        -  For the third and fourth study visits, participants will have a magnetic resonance
           imaging (MRI) study. They will have an initial MRI to provide a picture of the brain.
           They will then have a functional MRI during which they will respond to a computer test.
           The test will allow them to win points for snack food or alcohol. This test will look at
           the brain s response time and craving reactions.

        -  There will be a follow-up visit 1 week after the fourth study visit. Some of the tests
           from the screening visit will be repeated.
    

Detailed description: 
      Objective:

      Ghrelin is a 28-amino acid peptide acting as the endogenous ligand for the growth hormone
      secretagogue receptor (GHS-R). Ghrelin stimulates appetite by acting on the hypothalamic
      arcuate nucleus (ARC), a region that controls the intake of food and other substances,
      including alcohol. In addition to the ARC, GHS receptors (GHS-Rs) are also highly expressed
      in the caudal brain stem, the ventral tegmental area (VTA), hippocampus, substantia nigra,
      and dorsal and medial raphe nuclei. The expression of the GHS-R in the mesolimbic dopamine
      (DA) pathway suggests that ghrelin could play a role in reward processing. The role of
      ghrelin in the DA reward processing and the role of the DA reward system in alcoholism
      suggest a role of ghrelin in alcoholism. Consistent with this hypothesis, preclinical studies
      demonstrate that both ghrelin and ethanol activate the cholinergic-dopaminergic reward link,
      implying neurochemical analogies between ghrelin and ethanol. This supports the hypothesis
      that ghrelin is involved in mediating the rewarding properties of ethanol. Additional animal
      experiments demonstrate that the central ghrelin action not only stimulates the reward
      processing but is also required for stimulation of that system by alcohol. Human studies show
      reduced ghrelin levels in actively drinking alcoholics; increased ghrelin levels during
      alcohol abstinence; and a positive correlation between ghrelin level and alcohol craving
      scores. More recently, a study conducted at Brown University by the PI demonstrated the
      safety of the administration IV of human ghrelin to non-treatment seeking alcohol-dependent
      heavy drinking individuals. Furthermore, a preliminary interim analysis shows that IV ghrelin
      administration may lead to a temporary significant increase in alcohol craving. The primary
      objective of this protocol is to investigate whether IV ghrelin, as compared to placebo, will
      increase motivation for alcohol reward, as measured by a progressive ratio (PR) schedule
      paradigm with IV alcohol self-infusion (primary aim). We will also assess a number of
      secondary aims. Specifically, we will also assess whether IV ghrelin, as compared to placebo,
      will also alter urges to drink and the subjective response to IV alcohol. Adverse events will
      also be assessed to ensure the safety of the IV coadministration of ghrelin and alcohol.
      During an fMRI/alcohol clamp session, fMRI will be used to see whether ghrelin affects the
      activation of the ventral striatum induced by acute IV alcohol administration and the
      incentive salience of cues associated with alcohol administration.

      Study Population:

      Male and female participants will be non-treatment seeking heavy drinking volunteers.

      Design:

      The study is designed as a within-subject, double-blind, placebo-controlled study of ghrelin.
      The first visit will be the initial screening visit. The second and third visits will be PR
      sessions with IV ethanol, during which each participant will also receive IV ghrelin (or
      matched placebo). The fourth and fifth visits will combine an fMRI session with an alcohol
      clamp session (i.e. a fixed dose of alcohol will be administered) and subjects will
      participate in a modified version of the monetary incentive delay (MID) task in which they
      will respond to cues that indicate the opportunity to press a button to gain a reward. On
      some trials the reward will be points that can be exchanged for snack foods while on other
      trials the reward will be points that will determine how much intravenous alcohol a subject
      will be given during the alcohol clamp procedure which will immediately follow the modified
      MID task. After the modified MID task is complete subjects will have a short break and then
      begin the alcohol IV infusion.

      Outcome measures:

      The primary measure of this study will be the breakpoint, which is the schedule (number of
      button presses) at which the individual stops to work for more alcohol. Also, the BrAC
      exposure measures will be determined. Alcohol craving in response to ghrelin will be measured
      using the Alcohol Visual Analogue Scale (A-VAS) and the Alcohol Urge Questionnaire (AUQ)
      during the PR sessions. Sensitivity to alcohol will be measured using the Drug Effects
      Questionnaire (DEQ), Biphasic Alcohol Effects Scale (BAES), and the Profile of Mood States
      (POMS), repeatedly during the PR sessions and the CASE Experience Questionnaire (CEQ) at the
      end of all sessions. fMRI BOLD signal in brain areas associated with incentive salience and
      areas associated with reward circuitry (including the ventral striatum) will be measured
      during the fMRI/alcohol clamp session. This study may facilitate the identification of a
      novel neuropharmacological target, thus facilitating the development of novel pharmacological
      treatments for alcoholism.
    

Intervention name(s): Ghrelin; Placebo; fMRI; Alcohol
Intervention type(s): Drug; Drug; Procedure; Drug
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Addiction; Alcohol; Alcohol Clamp