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

Johns Hopkins University

Status and phase: Completed; Phase 2; Phase 1

Conditions: Alcohol Use Disorder

Treatments: Drug: Placebo - Cap; Drug: Mifepristone

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02989662

IRB00138426

U01AA020890 (U.S. NIH Grant/Contract)

AA020890 (Other Identifier)

Details and patient eligibility

About

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 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.

Enrollment: 65 patients

Sex: All

Ages: 21 to 55 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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65 participants in 4 patient groups, including a placebo group

Alcohol Use Disorder - Mifepristone

Active Comparator group

Description:

Participants diagnosed with alcohol use disorder who were randomized to receive 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.

Treatment:

Drug: Mifepristone

Alcohol Use Disorder - Placebo

Placebo Comparator group

Description:

Participants diagnosed with alcohol use disorder who were randomized to receive placebo. This is an inactive compound which appears physically identical to active medication.

Treatment:

Drug: Placebo - Cap

Healthy Control - Mifepristone

Active Comparator group

Description:

Healthy control participants who were randomized to receive 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.

Treatment:

Drug: Mifepristone

Healthy Control - Placebo

Placebo Comparator group

Description:

Healthy control participants who were randomized to receive placebo. This is an inactive compound which appears physically identical to active medication.

Treatment:

Drug: Placebo - Cap