INIA Stress and Chronic Alcohol Interactions: Glucocorticoid Antagonists in Heavy Drinkers

Overview

In alcohol use disorder (AUD) and matched healthy control (HC) men and women, the proposed research examines the effects of MIFE, with demonstrated preclinical effects on drinking-related behaviors, compared with placebo on a breadth of alcohol-related measures. All subjects will be randomized to daily MIFE or placebo. Before and during medication, AUD and HC subjects undergo fMRI scanning measuring resting-state functional connectivity and alcohol cue-induced brain activation focused on brain reward and stress pathways. All subjects are admitted to the Clinical Research Unit; AUD subjects undergo supervised alcohol withdrawal with daily measurements of alcohol craving and symptom severity. Using validated human laboratory procedures in AUD subjects, this study will examine the effects of stress on motivation to drink and alcohol sensitivity/reward as a function of GR antagonism.

Full Title of Study: “Glucocorticoid Antagonists in Heavy Drinkers: Effects on fMRI Connectivity, Withdrawal and Drinking”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Basic Science
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: January 2024

Detailed Description

Cortisol (CORT) is a glucocorticoid hormone, often associated with response to stress and playing a key role in alcohol use and problems. First, acute alcohol administration increases CORT, which in turn amplifies the mesolimbic dopamine reward signal. Second, alcohol withdrawal elevates CORT levels in AUD compared with healthy control subjects, and CORT levels in early abstinence predict subsequent relapse to drinking. Finally, the magnitude of CORT response to external stressors predicts motivation to work for and consumption of alcohol in the human laboratory and in the natural environment. Importantly, recent studies in rodents and humans have demonstrated that blocking CORT activity using a glucocorticoid receptor (GR) antagonist reduces these effects of CORT on alcohol behaviors, indicating a causal role for glucocorticoids in these relationships. In alcohol use disorder (AUD) and matched healthy control (HC) men and women, the proposed research examines the effects of MIFE, with demonstrated preclinical effects on drinking-related behaviors, compared to placebo on a breadth of alcohol-related measures. All subjects will be randomized to daily MIFE or placebo. Before and during medication, AUD and HC subjects undergo fMRI scanning measuring resting-state functional connectivity and alcohol cue-induced brain activation focused on brain reward and stress pathways. All subjects are admitted to the Clinical Research Unit; AUD subjects undergo supervised alcohol withdrawal with daily measurements of alcohol craving and symptom severity. Using validated human laboratory procedures in AUD subjects, this study will examine the effects of stress on motivation to drink and alcohol sensitivity/reward as a function of GR antagonism. This work will help pave the way for improved pharmacotherapies that target stress and reward pathways in the brain involved in initiating and maintaining drinking.

Interventions

  • Drug: Mifepristone
    • Participants receive 6 doses.
  • Drug: Placebo – Cap
    • Participants receive 6 doses

Arms, Groups and Cohorts

  • Active Comparator: Mifepristone
    • Mifepristone is a high affinity antagonist of the glucocorticoid receptor (GR). It is FDA approved to treatment hyperglycemia caused by high cortisol levels in adults with endogenous Cushing’s syndrome.
  • Placebo Comparator: Placebo – Cap
    • This is an inactive compound which appears physically identical to active medication.

Clinical Trial Outcome Measures

Primary Measures

  • fMRI function connectivity
    • Time Frame: Change from baseline to day 4 of MIFE dosing
    • fMRI data including resting state and alcohol cue induced measures

Secondary Measures

  • Alcohol motivated responding
    • Time Frame: single session on study day 5
    • Participants can earn up to 5 standard drinks during a 1-hr session.
  • Alcohol sensitivity
    • Time Frame: single session on study day 6
    • Subjective and physiological effects of alcohol are measured repeatedly during a 4-hr session

Participating in This Clinical Trial

Inclusion Criteria

  • Nontreatment seeking AUD volunteers – English speaking – healthy – Not pregnant or nursing Exclusion Criteria:

  • Women on hormonal birth control, pregnant or nursing – Current health or psychiatric problems – Potassium level below normal – Any medication or health condition that is known to interact with MIFE or CORT metabolism – History of metal implantation that would preclude MRI scan.

Gender Eligibility: All

Minimum Age: 21 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Johns Hopkins University
  • Collaborator
    • National Institute on Alcohol Abuse and Alcoholism (NIAAA)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Mary E McCaul, PhD, Principal Investigator, Johns Hopkins University

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