Preclinical and clinical evidence for suppression of alcohol intake by apremilast

• Published in: The Journal of clinical investigation Vol. 133; no. 6; pp. 1 - 9
• Main Authors: Grigsby, Kolter B, Mangieri, Regina A, Roberts, Amanda J, Lopez, Marcelo F, Firsick, Evan J, Townsley, Kayla G, Beneze, Alan, Bess, Jessica, Eisenstein, Toby K, Meissler, Joseph J, Light, John M, Miller, Jenny, Quello, Susan, Shadan, Farhad, Skinner, Michael, Aziz, Heather C, Metten, Pamela, Morrisett, Richard A, Crabbe, John C, Roberto, Marisa, Becker, Howard C, Mason, Barbara J, Ozburn, Angela R
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.03.2023
• Subjects: Acamprosate; Alcohol Drinking - genetics; Alcohol use; Alcoholism; Animal models; Animals; Behavior; Bioinformatics; Biomedical research; Brain; Care and treatment; Casualties; Clinical trials; Drinking behavior; Drinking of alcoholic beverages; Drug dependence; Drug dosages; Drug therapy; Electrophysiology; Ethanol; Health risk assessment; Humans; Intoxication; Mice; Neuroscience; Nucleus accumbens; Phosphodiesterase; Phosphodiesterase 4 Inhibitors - pharmacology; Phosphodiesterase 4 Inhibitors - therapeutic use; Physiology; Psoriasis; Psoriasis - drug therapy; Substance abuse; Thalidomide - pharmacology; United States; United States > US; Neuroscience; Addiction; Drug therapy; Clinical Trials
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI159103

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.