Preclinical and clinical work suggests that mifepristone (glucocorticoid receptor antagonist), may be a viable treatment for alcohol use disorder (AUD). The aim of this work was to translate our preclinical mifepristone study using yohimbine (alpha2 receptor antagonist) stress-induced reinstatement of alcohol-seeking to a clinical setting. This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N=32). We investigated the safety, alcohol craving and consumption after oral administration of mifepristone (600mg daily for a week) in a human laboratory study comprised of administration of yohimbine in a cue-reactivity procedure and alcohol self-administration. Outcomes were assessed using Generalized Estimating Equations and mediation and moderation analyses assessed mechanisms of action and precision medicine targets. We did not observe serious adverse events related to the study drugs or study procedure and mild to moderate non-serious adverse events were reported by both study conditions. Also, there was no statistically-significant difference between the mifepristone and placebo in the hemodynamic response, alcohol subjective effects and pharmacokinetics parameters. Mifepristone significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Moderation analysis with family history density of AUD (FHDA) and mifepristone, suggested that reduced craving was present in individuals with low, but not high FHDA. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a preclinical paradigm to a human laboratory study confirming safety, tolerability and efficacy of mifepristone in an alcohol paradigm. Mediation analysis showed that the effect of mifepristone on craving was not related to mifepristone-induced increases in cortisol and moderation of FHDA suggested the importance of evaluating AUD endophenotypes for pharmacotherapies.

The medication (mifepristone and matching placebo) was kindly provided by Corcept Therapeutics. Corcept Therapeutics did not have any role in the study design, execution or interpretation of the results, and this publication does not necessarily represent the official views of Corcept Therapeutics. CLH-K traveled to CA to attend and present the data to the Corcept Therapeutic Conference (September 2022). The views expressed herein are those of the authors and do not reflect the official policy or position of the funding agencies. The other authors declare no competing interests.

NCT02243709; IND121984

This study was fully funded by the National Institute on Alcohol Abuse and Alcoholism (K01 AA023867 to CLH-K) and the Research Excellence Award from the Center of Alcohol and Addiction Studies, Brown University (CLH-K). Dr. Haass-Koffler is also supported by the National Institute on Alcohol Abuse and Alcoholism (K01 AA023867; R01 AA026589; R01 AA027760; R21 AA027614) and by the National Institute of General Medical Sciences (NIGMS), Center of Biomedical Research Excellence (COBRE, P20 GM130414). Drs. Magill and Cioe are supported by the National Institute on Alcohol Abuse and Alcoholism (R01 AA027760; R21 AA027614). Dr. Leggio is supported by the National Institute on Drug Abuse Intramural Research Program and the National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research (ZIA DA000635 and ZIA AA000218).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was conducted at the Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA from 2014-2021. The trial was approved by the Brown University Institutional Review Board, conducted under an FDA Investigational New Drug application (IND121984) and registered at clinicaltrials.gov (NCT02243709).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors