By Olivia Trani

A research team from Virginia Commonwealth University has found that a drug currently in clinical trials for brain disorders such as Alzheimer’s disease might also have potential for treating alcohol misuse – one of America’s leading public health concerns.

The VCU team has been seeking more therapeutic solutions for unhealthy alcohol use, and in their most recent study, published in Addiction Biology, the researchers found that the drug tideglusib has shown promising preclinical results in curbing chronic alcohol consumption and binge drinking. While this research is preliminary, the findings suggest that the drug may be a good candidate for clinical trials and could ultimately be another tool to help patients overcome addiction.

About 1 in 10 Americans ages 12 or older meet the criteria for alcohol use disorder, and the consequent health implications are alarming. Excessive alcohol use is one of the leading causes of preventable death in the United States, and Americans are more than twice as likely to die from alcohol-related illnesses today than they were 20 years ago.

Medications can help people reduce their drinking and avoid relapse, and three – naltrexone, acamprosate and disulfiram – have been approved by the Food and Drug Administration to treat alcohol use disorder. However, these therapeutics are limited in who can receive treatment, especially for those who have kidney or liver problems or are taking opioid medicines.

“While these options can work for many people, they don’t work for everyone, and they are not as effective in the long term as we would like,” said Michael F. Miles, M.D., Ph.D., a professor in the VCU School of Medicine’s Departments of Pharmacology and Toxicology and Neurology and lead author of the new study. “We certainly need additional pharmaceutical options for treatment, but there hasn’t been a new medication for alcohol use disorder in more than 15 years. It’s a huge public health problem.”

Miles became interested in alcohol research as a neurology resident, where he saw how excessive alcohol use can take a toll on a person’s health, including high blood pressure, heart problems, stroke, neuropathy, severe liver disease and cancer.

“I was treating patients who were undergoing alcohol withdrawal and having other health complications from alcohol use,” he said. “I thought it was striking that the brain could become so addicted to this little two-carbon molecule.”

Today, Miles is the director of the VCU Alcohol Research Center and has dedicated his career trying to better understand the neuroscience of alcohol use disorder. By studying molecular changes that occur in the brain in response to alcohol use, his research lab discovered one protein closely linked to drinking behavior, called glycogen synthase kinase 3-beta (GSK3β).

Experts believe that GSK3β plays an important role in the brain’s ability to adapt to changes. When faced with new experiences, such as learning things while growing up or recovering from brain injuries, the neurons in our brain and nervous system respond by reorganizing their pathways and making new connections.

Over the years, experts have found that this protein’s dysfunction is linked to various neurological and psychiatric disorders, including Alzheimer’s disease, bipolar disorder, schizophrenia and depression. Researchers are also starting to realize its connection to substance use disorders, such as cocaine, morphine and now alcohol.

“In our previous studies, we discovered that increasing GSK3β activity in a mouse brain led to increased drinking behavior,” Miles said. “We hypothesized that if we used an inhibitor to reduce GSK3β activity, we could potentially decrease the level of alcohol consumed.”

In their search for a GSK3β inhibitor, Miles and his colleagues came across a drug candidate called tideglusib, which is being used in clinical trials for brain disorders like Alzheimer’s disease. The research team began to investigate whether tideglusib could also be considered for treating alcohol use disorder.

In their latest study, the researchers assessed its safety and effectiveness in reducing alcohol consumption in mouse models. They specifically looked into how tideglusib influenced chronic and binge drinking levels. Subjects were provided with either daily access to ethanol and water over an extended period of time or were given a higher level of ethanol over a short time span.

Their results showed that administering tideglusib significantly reduced the level of alcohol consumption in both cases, with a slightly higher impact in male mice compared with female. Behavioral and biochemical analysis also revealed that tideglusib did not cause any apparent toxicity or other significantly adverse side effects.

These findings suggest that tideglusib could potentially be utilized as a therapy for treating problematic alcohol use. Human clinical trials would be needed to fully understand the drug’s effect in patients with alcohol use disorder, though the researchers are encouraged by the fact that tideglusib is already being assessed for other conditions.

“It’s very fortunate that a GSK3β inhibitor already exists as a drug candidate and is being used in clinical trials for other diseases,” Miles said. “Rather than having to develop a new drug entirely, we already have a head start in potentially getting patients another therapeutic option for alcohol use disorder.”

Looking ahead, Miles is interested in learning more about how GSK3β inhibitors like tideglusib influence brain activity and how they drive changes in alcohol use. Understanding the molecular mechanisms behind tideglusib’s therapeutic impact could inform future drug development for treating alcohol use disorder.

“We want to know the exact region of the brain that is affected by tideglusib, the neurological pathways activated by this drug and how these processes translate into drinking behavior,” he said. “Once you understand the symphony of biological reactions connected to a condition, you can hopefully develop the best kinds of therapies for treating the disease.”

This research was supported by the National Institute on Alcohol Abuse and Alcoholism.