Alcohol Use Disorder
Conditions
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.
Interventions
DRUGMifepristone
Participants receive 6 doses.
DRUGPlacebo - Cap
Participants receive 6 doses
Sponsors
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Change from baseline (Day 1) to day 4 of MIFE dosing | Participants observed alcohol and neutral cues during functional MRI (fMRI) scans. Larger numbers indicate greater activation to alcohol versus non alcohol stimuli. Mean response Pre and Post medication (mifepristone (MIFE), placebo), is measured. The greater the number the greater the reactivity to alcohol-related cues. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean of Alcohol Motivated Responses Made | single session on study day 5 | Participants made alcohol motivated responses with a computer mouse to earn either alcohol drinks or money. Each mouse click equaled one response. Mean of all responses made are reported. |
| Alcohol Motivated Responding - Number of Drinks Earned | single session on study day 5 | Participants can earn up to 10 drinks during a 1-hr session. Each drink was the equivalent of 0.5 standard drink. |
Countries
United States
Participant flow
Pre-assignment details
Of the 65 participants who were consented for the study, 33 were determined to be ineligible during the assessment procedures. Among the 32 persons who were eligible, 16 were not randomized to study medication (8 participants were lost to follow-up and 8 participants withdrew from the study).
Participants by arm
| Arm | Count |
|---|---|
| Alcohol Use Disorder - Mifepristone 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. | 4 |
| Alcohol Use Disorder - Placebo Participants diagnosed with alcohol use disorder who were randomized to receive placebo. This is an inactive compound which appears physically identical to active medication. | 3 |
| Healthy Control - Mifepristone 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. | 6 |
| Healthy Control - Placebo Healthy control participants who were randomized to receive placebo. This is an inactive compound which appears physically identical to active medication. | 3 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 2 |
| Overall Study | Physician Decision | 3 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Alcohol Use Disorder - Mifepristone | Total | Healthy Control - Placebo | Healthy Control - Mifepristone | Alcohol Use Disorder - Placebo |
|---|---|---|---|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 11.8 | 39.1 years STANDARD_DEVIATION 11.5 | 33.7 years STANDARD_DEVIATION 8.6 | 38.3 years STANDARD_DEVIATION 13.8 | 41.3 years STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 8 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 6 Participants | 1 Participants | 3 Participants | 1 Participants |
| Region of Enrollment United States | 4 Participants | 16 Participants | 3 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 3 Participants | 12 Participants | 3 Participants | 5 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 3 | 0 / 6 | 0 / 3 |
| other Total, other adverse events | 0 / 4 | 0 / 3 | 2 / 6 | 0 / 3 |
| serious Total, serious adverse events | 0 / 4 | 0 / 3 | 0 / 6 | 0 / 3 |
Outcome results
Primary
Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli
Participants observed alcohol and neutral cues during functional MRI (fMRI) scans. Larger numbers indicate greater activation to alcohol versus non alcohol stimuli. Mean response Pre and Post medication (mifepristone (MIFE), placebo), is measured. The greater the number the greater the reactivity to alcohol-related cues.
Time frame: Change from baseline (Day 1) to day 4 of MIFE dosing
Population: No data were collected for the AUD Mifepristone participants. AUD Mifepristone participants either dropped out or were withdrawn from the study prior to fMRI procedures. In addition, fMRI data were lost on one AUD-Placebo participant and one Healthy Control - Placebo participant due to head movement artifact.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, centromedian - day 1 | 0.267390 BOLD response | Standard Error 0.128827 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, centromedian - day 4 | -0.069048 BOLD response | Standard Error 0.142952 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, lateral - day 1 | 0.091174 BOLD response | Standard Error 0.190861 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, lateral - day 4 | 0.294417 BOLD response | Standard Error 0.115607 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | medial prefrontal cortex - day 1 | 0.044635 BOLD response | Standard Error 0.287281 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | medial prefrontal cortex - day 4 | 0.439822 BOLD response | Standard Error 0.226576 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | nucleus accumbens - day 1 | 0.138441 BOLD response | Standard Error 0.147427 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | nucleus accumbens - day 4 | 0.285409 BOLD response | Standard Error 0.106153 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, superficial - day 1 | 0.583073 BOLD response | Standard Error 0.269851 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, superficial - day 4 | 0.149175 BOLD response | Standard Error 0.347008 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | ventral tegmental area - day 1 | 0.405165 BOLD response | Standard Error 0.227379 |
| Alcohol Use Disorder - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | ventral tegmental area - day 4 | 0.430387 BOLD response | Standard Error 0.176868 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | ventral tegmental area - day 4 | -0.150802 BOLD response | Standard Error 0.102115 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, centromedian - day 1 | 0.040281 BOLD response | Standard Error 0.074378 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | nucleus accumbens - day 1 | 0.131360 BOLD response | Standard Error 0.085117 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, superficial - day 1 | 0.252555 BOLD response | Standard Error 0.155799 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, centromedian - day 4 | 0.037178 BOLD response | Standard Error 0.082533 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | medial prefrontal cortex - day 4 | 0.257514 BOLD response | Standard Error 0.130814 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | ventral tegmental area - day 1 | 0.566876 BOLD response | Standard Error 0.131277 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, lateral - day 1 | 0.151864 BOLD response | Standard Error 0.110194 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | nucleus accumbens - day 4 | 0.138914 BOLD response | Standard Error 0.061287 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | medial prefrontal cortex - day 1 | -0.323039 BOLD response | Standard Error 0.165862 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, lateral - day 4 | -0.021411 BOLD response | Standard Error 0.066746 |
| Healthy Control - Mifepristone | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, superficial - day 4 | 0.172212 BOLD response | Standard Error 0.200345 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, lateral - day 4 | 0.126445 BOLD response | Standard Error 0.115607 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | medial prefrontal cortex - day 1 | 0.031454 BOLD response | Standard Error 0.287281 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, superficial - day 4 | 0.118748 BOLD response | Standard Error 0.347008 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | medial prefrontal cortex - day 4 | -0.514729 BOLD response | Standard Error 0.226576 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | nucleus accumbens - day 1 | 0.262425 BOLD response | Standard Error 0.147427 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | nucleus accumbens - day 4 | -0.003538 BOLD response | Standard Error 0.106153 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | ventral tegmental area - day 1 | -0.019192 BOLD response | Standard Error 0.227379 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, centromedian - day 1 | 0.058670 BOLD response | Standard Error 0.128827 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, centromedian - day 4 | 0.052388 BOLD response | Standard Error 0.142952 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, superficial - day 1 | -0.111622 BOLD response | Standard Error 0.269851 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | Amygdala, lateral - day 1 | 0.099169 BOLD response | Standard Error 0.190861 |
| Healthy Control - Placebo | Change in Blood Oxygen Level Dependent (BOLD) fMRI Signal for Alcohol Versus Non-alcohol Stimuli | ventral tegmental area - day 4 | 0.104408 BOLD response | Standard Error 0.176868 |
Secondary
Alcohol Motivated Responding - Number of Drinks Earned
Participants can earn up to 10 drinks during a 1-hr session. Each drink was the equivalent of 0.5 standard drink.
Time frame: single session on study day 5
Population: This measure was designed to only be collected among the participants with alcohol use disorder (AUD). None of the AUD participants randomized to mifepristone completed the study. No data were collected for participants in the AUD-Mifepristone group. Participants either dropped out or were withdrawn from the study before completing this procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alcohol Use Disorder - Placebo | Alcohol Motivated Responding - Number of Drinks Earned | 7 drinks earned | Standard Deviation 3 |
Secondary
Mean of Alcohol Motivated Responses Made
Participants made alcohol motivated responses with a computer mouse to earn either alcohol drinks or money. Each mouse click equaled one response. Mean of all responses made are reported.
Time frame: single session on study day 5
Population: This measure was designed to only be collected among the participants with alcohol use disorder (AUD). None of the AUD participants randomized to mifepristone completed the study. No data were collected for AUD-Mifepristone participants as they either dropped out or were withdrawn from the study prior to completing this procedure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alcohol Use Disorder - Placebo | Mean of Alcohol Motivated Responses Made | 9517 responses made | Standard Deviation 1497.6 |