Summary: Apremilast, an FDA-approved drug for the treatment of skin conditions including psoriasis and psoriatic arthritis, triggers increased activity in the nucleus accumbens, a brain area associated with regulating alcohol intake. Apremilast reduced drinking behaviors in mouse models with a genetic risk of alcohol use disorder.
Source: Oregon Health and Science University
Researchers from Oregon Health & Science University and institutions across the country have identified a pill used to treat a common skin disease as an “incredibly promising” treatment for alcohol use disorder.
The study was recently published in the Journal of Clinical Investigation.
On average, the people who received the medication, called apremilast, reduced their alcohol intake by more than half — from five drinks per day to two.
“I’ve never seen anything like that before,” said co-senior author Angela Ozburn, Ph.D., associate professor of behavioral neuroscience in the OHSU School of Medicine and a research biologist with the Portland VA Health Care System.
The lead author is Kolter Grigsby, Ph.D., a postdoctoral fellow in the Ozburn laboratory at OHSU.
Beginning in 2015, Ozburn and collaborators searched a genetic database looking for compounds likely to counteract the expression of genes known to be linked to heavy alcohol use. Apremilast, an FDA-approved anti-inflammatory medication used to treat psoriasis and psoriatic arthritis, appeared to be a promising candidate.
They then tested it in two unique animal models that have a genetic of risk for excessive drinking, as well as in other strains of mice at laboratories across the country. In each case, apremilast reduced drinking among a variety of models predisposed to mild to heavy alcohol use. They found that apremilast triggered an increase in activity in the nucleus accumbens, the region of the brain involved in controlling alcohol intake.
Researchers at the Scripps Research Institute in La Jolla, California, then tested apremilast in people.
The Scripps team conducted a double-blind, placebo-controlled clinical proof-of-concept study involving 51 people who were assessed over 11 days of treatment.
“Apremilast’s large effect size on reducing drinking, combined with its good tolerability in our participants, suggests it is an excellent candidate for further evaluation as a novel treatment for people with alcohol use disorder,” said co-senior author Barbara Mason, Ph.D., Pearson Family professor in the Department of Molecular Medicine at Scripps.
The clinical study involved people with alcohol use disorder who weren’t seeking any form of treatment, and Mason predicts that apremilast may be even more effective among people who are motivated to reduce their alcohol consumption.
“It’s imperative for more clinical trials to be done on people seeking treatment,” Ozburn said. “In this study, we saw that apremilast worked in mice. It worked in different labs, and it worked in people. This is incredibly promising for treatment of addiction in general.”
An estimated 95,000 people in the United States die every year from alcohol-related deaths, according to the National Institute on Alcohol Abuse and Alcoholism. Image is in the public domain
An estimated 95,000 people in the United States die every year from alcohol-related deaths, according to the National Institute on Alcohol Abuse and Alcoholism.
Currently, there are three medications approved for alcohol use disorder in the United States: Antabuse, which produces an acute sensitivity akin to a hangover when alcohol is consumed; acamprosate, a medication thought to stabilize chemical signaling in the brain that is associated with relapse; and naltrexone, a medication that blocks the euphoric effects of both alcohol and opioids.
Funding: The research reported here was supported by the National Institutes of Health awards AA016651, AA013519, AA010760, AA07468, AA027692, U01 AA013498, DA013429, P60AA06420 and U01AA025476; the U.S. Department of Veterans Affairs awards BX000313, BX004699 and IK2 BX002488; and a gift from the John R. Andrews Family. The content is solely the responsibility of the researchers and does not necessarily represent the official views of the NIH or the U.S. Department of Veterans Affairs.
Pre-clinical and clinical evidence for suppression of alcohol intake by apremilast
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.