Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Preclinical and clinical evidence for suppression of alcohol intake by apremilast
Kolter B. Grigsby, … , Barbara J. Mason, Angela R. Ozburn
Kolter B. Grigsby, … , Barbara J. Mason, Angela R. Ozburn
Published January 19, 2023
Citation Information: J Clin Invest. 2023;133(6):e159103. https://doi.org/10.1172/JCI159103.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 453

Preclinical and clinical evidence for suppression of alcohol intake by apremilast

  • Text
  • PDF
Abstract

Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non–treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.

Authors

Kolter B. Grigsby, Regina A. Mangieri, Amanda J. Roberts, Marcelo F. Lopez, Evan J. Firsick, Kayla G. Townsley, Alan Beneze, Jessica Bess, Toby K. Eisenstein, Joseph J. Meissler, John M. Light, Jenny Miller, Susan Quello, Farhad Shadan, Michael Skinner, Heather C. Aziz, Pamela Metten, Richard A. Morrisett, John C. Crabbe, Marisa Roberto, Howard C. Becker, Barbara J. Mason, Angela R. Ozburn

×

Figure 3

Apremilast reduces dependence-induced escalations in ethanol drinking in C57BL/6J mice.

Options: View larger image (or click on image) Download as PowerPoint
Apremilast reduces dependence-induced escalations in ethanol drinking in...
(A) Ethanol intake (g/kg/2 hours) for male C57BL/6J mice (n = 9–10/vapor group/stress group/apremilast treatment) during baseline and tests 1 and 2; main effect of group [F(3, 114) = 15.22; P < 0.001], phase [F(2, 114) = 60.80; P < 0.001], and a group × phase interaction [F(6, 228) = 13.25; P < 0.001]; CIE and CIE + FSS had higher intake compared with baseline and control (CTL) values (*P < 0.05) and their own baseline (^P < 0.05); CIE + FSS had higher intake in test 2 than all other groups and their own baseline (#P < 0.05). (B) Ethanol intake (g/kg/2 hours) during test 3; main effect of group [F(3, 106) = 16.28; P < 0.001], apremilast [F(2, 106) = 21.83; P < 0.001], and a group × treatment interaction [F(6, 106) = 3.25; P < 0.01]; for mice that received vehicle, ethanol intake was higher for CIE mice compared with CTL mice (*P < 0.05) and higher for CIE + FSS compared with the 3 groups that also received vehicle (#P < 0.05). CIE + FSS mice that received 20 mg/kg apremilast continued to drink more ethanol than CTL mice (*P < 0.05). However, this dose reduced ethanol intake compared with its vehicle condition group (^P < 0.05). The 40 mg/kg apremilast dose resulted in a significant decrease in ethanol intake in CIE and CIE + FSS mice compared with their vehicle equivalent (^P < 0.05). (C) Ethanol (EtOH) intake (g/kg/2 hours) for female and male C57BL/6J mice (n = 10/vapor group/apremilast treatment) following 3 weeks of CIE, main effect of vapor exposure, whereby ethanol vapor increased intake (*P < 0.05 by 1-way ANOVA). (D) Ethanol intake (g/kg/2 hours) during test week, main effect of treatment, 40 mg/kg (p.o.) reduced intake in ethanol vapor and air exposed mice. *P < 0.05, ***P < 0.001, ****P < 0.0001 by 2-way (A and B) or 1-way (C and D) ANOVA followed by Newman-Keuls post hoc test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 57 news outlets
Blogged by 5
Posted by 24 X users
Referenced in 1 Wikipedia pages
Reddited by 2
On 1 videos
45 readers on Mendeley
See more details