An inpatient human laboratory study assessing the safety and tolerability, pharmacokinetics, and biobehavioral effect of GET 73 when co-administered with alcohol in individuals with alcohol use disorder

Haass‐Koffler, Carolina L.; Perciballi, Roberta; Magill, Molly; Loche, Antonella; Cacciaglia, Roberto; Leggio, Lorenzo; Swift, Robert M.

doi:10.1007/s00213-021-06008-1

Cited by 9 publications

(9 citation statements)

References 54 publications

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“…One of the major strengths of this study is the within-subject, cross-over design which provided the same set of participants acting as their own controls, increasing power and reducing variability 23 . The cortisol level also provided robust results for medication compliance, as it increases with mifepristone administration 22 .…”

Section: Discussionmentioning

confidence: 99%

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Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial

Haass‐Koffler

Magill

Cannella

et al. 2023

Preprint

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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.

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Section: Discussionmentioning

confidence: 99%

“…Details of visit 1 ( screening ), visit 2 ( randomization ), visit 3 and 5 ( laboratory sessions ) and visit 4 and 6 ( follow up ) are published 23 and reported in Methods S1 . Mifepristone and matching placebo were provided by Corcept Therapeutics (Menlo Park, CA).…”

Section: Methodsmentioning

confidence: 99%

Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial

Haass‐Koffler

Magill

Cannella

et al. 2023

Preprint

Self Cite

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“…Co-administration also did not affect the pharmacokinetics of either GET73 or alcohol. However, GET73 also had no effect on alcohol cue-induced craving or self-administration, warranting additional research [ 251 ]. A clinical trial of the effects of GET73 on magnetic resonance spectroscopy (MRS) measures of glutamate and GABA levels in individuals with AUD was recently completed (NCT03418623); however, the results have not yet been posted, and another trial, which includes a free-drinking bar lab component, is ongoing (NCT04831684).…”

Section: Pharmacological Treatments For Audmentioning

confidence: 99%

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

Burnette

Nieto

Grodin

et al. 2022

Drugs

101

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Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.

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“…After the priming dose of alcohol, alcohol pharmacokinetics was measured by BrAC every 10 min, and stimulant/sedative effects of alcohol were assessed using the Biphasic Alcohol Effects Scale (BAES). [49][50][51] The 'open bar' phase provided a total of eight standard drink unit (SDU), and all could be consumed within 120 min, with two trays of four drinks (0.015 g/dl/each) every 60 min. 49,[52][53][54] As an alternative reinforcer for not drinking, we provided $3 per each drink not consumed.…”

Section: Visits 3 and 5 (Alcohol Laboratory Session)mentioning

confidence: 99%

“…[49][50][51] The 'open bar' phase provided a total of eight standard drink unit (SDU), and all could be consumed within 120 min, with two trays of four drinks (0.015 g/dl/each) every 60 min. 49,[52][53][54] As an alternative reinforcer for not drinking, we provided $3 per each drink not consumed. If the participant's BrAC reached 0.1 g/dl, the alcohol consumption ended.…”

Section: Visits 3 and 5 (Alcohol Laboratory Session)mentioning

confidence: 99%

Mifepristone as a pharmacological intervention for stress‐induced alcohol craving: A human laboratory study

et al. 2023

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Preclinical and clinical work suggests that mifepristone may be a viable treatment for alcohol use disorder (AUD). 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 assessed safety, alcohol craving and consumption, after 1-week mifepristone 600 mg/day administration, in a human laboratory study comprised of a single oral yohimbine administration (32.4 mg), a cue-reactivity procedure and alcohol self-administration. Safety was monitored by adverse events and hemodynamic parameters, alcohol craving by alcohol craving questionnaire and cue-induced saliva output. During the alcohol self-administration, we assessed alcohol pharmacokinetics, subjective effects and consumption. Outcomes were assessed using Generalized Estimating Equations and mediation analysis. Mild-moderate adverse events were reported in both conditions. There was no statistically significant difference between mifepristone and placebo in alcohol pharmacokinetics and subjective effects. Furthermore, blood pressure increased only in the placebo condition after the stress-induced laboratory procedures. Mifepristone, compared to placebo, significantly reduced Clinical trial registration: Clinicaltrials.gov; NCT02243709 IND/FDA: 121984, mifepristone and yohimbine (Holder: Haass-Koffler).

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An inpatient human laboratory study assessing the safety and tolerability, pharmacokinetics, and biobehavioral effect of GET 73 when co-administered with alcohol in individuals with alcohol use disorder

Cited by 9 publications

References 54 publications

Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial

Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

Mifepristone as a pharmacological intervention for stress‐induced alcohol craving: A human laboratory study

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