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

Glucocorticoid Antagonists in Heavy Drinkers: Effects on fMRI Connectivity, Withdrawal and Drinking

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.

Study Overview

• Status: Completed
• Conditions: Alcohol Use Disorder
• Intervention / Treatment: Drug: Mifepristone; Drug: Placebo - Cap

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 Type: Interventional
• Enrollment (Actual): 65
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Mary E McCaul, PhD; Phone Number: 410-955-9526; Email: mmccaul1@jhmi.edu
• Study Contact Backup: Name: Gary S Wand, MD; Phone Number: 410-955-3921; Email: gwand1@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Integrated Program for Substance Abuse Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Mifepristone; Participants receive 6 doses.; Other Names: Korlym
Placebo Comparator: Placebo - Cap; This is an inactive compound which appears physically identical to active medication.	Drug: Placebo - Cap; Participants receive 6 doses

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Mary E McCaul, PhD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): January 1, 2024
• Study Completion (Actual): January 1, 2024

Study Registration Dates

• First Submitted: December 5, 2016
• First Submitted That Met QC Criteria: December 7, 2016
• First Posted (Estimated): December 12, 2016

Study Record Updates

• Last Update Posted (Actual): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 22, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Alcoholic Intoxication; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Abortifacient Agents; Luteolytic Agents; Abortifacient Agents, Steroidal; Contraceptives, Postcoital, Synthetic; Contraceptives, Postcoital; Menstruation-Inducing Agents; Mifepristone
• Other Study ID Numbers: IRB00138426; U01AA020890 (U.S. NIH Grant/Contract); AA020890 (Other Identifier: Other)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO