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

Phase 1

Completed

• Conditions: Alcohol Use Disorder
• Interventions: Drug: Placebo - Cap; Drug: Mifepristone

• Registration Number: NCT02989662
• Lead Sponsor: Johns Hopkins University

Brief Summary

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.

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.

Study Timeline

• Study First Submitted: 2016-12-05
• Study First Submitted QC: 2016-12-07
• Study First Posted: 2016-12-12
• Study Start: 2017-09-26
• Primary Completion: 2024-01-31
• Study Completion: 2024-01-31
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-23
• Last Update Posted: 2024-05-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 65

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo - Cap	Placebo - Cap	This is an inactive compound which appears physically identical to active medication.
Mifepristone	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.

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Integrated Program for Substance Abuse Research; 🇺🇸 Baltimore, Maryland, United States