Preclinical and clinical evidence for suppression of alcohol intake by apremilast

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Abstract
Treatment options for Alcohol Use Disorders (AUD) 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 novel 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 for 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.
Funding Information
  • National Institute on Alcohol Abuse and Alcoholism (AA016651, AA013519, AA010760, AA07468, AA027692, U01 AA013498, P60AA06420)
  • National Institute on Drug Abuse (DA013429)
  • US Department of Veterans Affairs Grants (BX000313, BX004699, IK2 BX002488)
  • National Institute on Alcohol Abuse and Alcoholism (U01AA025476)

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