Clinical trial NCT02989662: INIA Stress and Chronic Alcohol Interactions: Glucocorticoid Antagonists in Heavy Drinkers
Official title: Glucocorticoid Antagonists in Heavy Drinkers: Effects on fMRI Connectivity, Withdrawal and Drinking
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Alcohol Use Disorder
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2016-12-12
Enrollment: 65
Sex: ALL
Minimum age (years): 21
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli
timeFrame: Change from baseline (Day 1) to day 4 of MIFE dosing
Secondary outcomes:
measure: Mean of Alcohol Motivated Responses Made
timeFrame: single session on study day 5
measure: Alcohol Motivated Responding - Number of Drinks Earned
timeFrame: single session on study day 5
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Integrated Program for Substance Abuse Research
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Mary E McCaul, PhD
role: PRINCIPAL_INVESTIGATOR
References: