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.
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Research Article Neuroscience

Preclinical and clinical evidence for suppression of alcohol intake by apremilast

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

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Figure 4

Apremilast reduces alcohol intake in non–treatment-seeking individuals with an AUD.

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Apremilast reduces alcohol intake in non–treatment-seeking individuals w...
(A) Apremilast (90 mg/d) significantly (z = 2.24; P < 0.025) reduces the number of drinks per day relative to placebo in 51 non–treatment-seeking individuals with alcohol use disorder of moderate severity or greater. A negative binomial latent growth curve model was used to calculate an effect size for apremilast versus placebo in the decrease in drinks per day from baseline through 11 days of ad libitum drinking. This procedure generated 11-day change values totaling 2.74 drinks per day for apremilast and 0.48 for placebo, and yields a Cohen’s d value of 0.77, which can be interpreted as a “large” effect of apremilast on decreasing drinking. (B) Proportion of heavy drinking days (4+ for women, 5+ for men) is significantly (z = 2.17, P = 0.030) reduced for apremilast versus placebo. A latent logistic regression model (retransformed to units of proportion) was used to calculate differences in daily risk of heavy drinking through 11 days of treatment. Risk reduction between day 1 and day 11 was 0.39 for apremilast versus 0.05 for placebo; Cohen’s d for this difference was 0.26, a “small-medium” value.