New Study Identifies Novel Neural Pathway to Treat Alcohol Use Disorder

Researchers have identified a promising new strategy for treating alcohol use disorder (AUD). A novel study found that the dopamine-boosting drug tolcapone increases activity in the prefrontal cortex (PFC) during self-control tasks. Greater activation of the inferior frontal gyrus, part of the PFC, was associated with better behavioral control and reduced alcohol consumption. The findings from this new studyopens in new tab/window in Biological Psychiatry: Cognitive Neuroscience and Neuroimagingopens in new tab/window, published by Elsevier, indicate that medications with a similar mechanism could one day be used to treat AUD.

AUD is a devastating disorder characterized by loss of control over alcohol consumption, for which existing pharmacological treatments are modestly effective. Most approved and off-label pharmacological treatments for AUD target alcohol craving and/or alcohol withdrawal symptoms.

“We desperately need new pharmacological treatments for AUD. Our study shifts the focus to ‘rescuing’ impaired inhibitory control, which is the brain's ability to stop unwanted thoughts or actions, a function often compromised in AUD,“ says senior author Joseph P. Schacht, PhD, Department of Psychiatry, University of Colorado School of Medicine. “Our study suggests that medications that increase prefrontal dopamine are an important lead to pursue.”

The study involved 64 participants with AUD who were randomly assigned to receive either tolcapone, an FDA-approved medication that increases dopamine in the PFC by suppressing catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine, or a placebo for eight days. Participants completed a behavioral control task called a “stop signal” task while undergoing functional neuroimaging (fMRI), during which they had to try to stop themselves from pressing a button on certain trials. This task reliably elicits activation of regions of the PFC that underlie response inhibition. Analysis showed that tolcapone increased activation of cortical areas implicated in inhibitory control, as assessed by the fMRI blood oxygenation response.

Lead author Drew E. Winters, PhD, Department of Psychiatry, University of Colorado School of Medicine, notes, “Based on previous studies, we anticipated that greater inferior frontal gyrus activation would be associated with better behavioral control, but we were pleasantly surprised to find that it was also associated with reduced alcohol consumption. This association validates the importance of impaired control in the pathophysiology of AUD.“

Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine School of Medicine, concludes, “Dopamine is a crucial neurotransmitter involved in pleasure, motivation, reward, and control and decision-making. The findings of this study underscore the importance of targeting specific brain circuits that govern self-control to reduce problematic drinking. Future research should continue to investigate the neurobiological mechanisms of tolcapone and other cortical dopamine modulators to develop more effective treatments for AUD.”

Notes for editors

The article is "Effects of COMT Suppression in a Randomized Trial on the Neural Correlates of Inhibitory Processing Among People with Alcohol Use Disorder," by Drew E. Winters, PhD, and Joseph P. Schacht, PhD (https://doi.org/10.1016/j.bpsc.2025.06.003opens in new tab/window). It appears online in Biological Psychiatry: Cognitive Neuroscience and Neuroimagingopens in new tab/window, published by Elsevier.

The article is openly available for 60 days at https://www.biologicalpsychiatrycnni.org/article/S2451-9022(25)00196-X/fulltextopens in new tab/window.

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]opens in new tab/window. Journalists wishing to interview the study’s authors should contact Joseph P. Schacht, PhD, at [email protected]opens in new tab/window.

The authors’ affiliations and disclosures of financial and conflicts of interest are available in the article.

Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California Irvine School of Medicine. His disclosures of financial and conflicts of interest are available hereopens in new tab/window.

This study was funded by grants from the National Institute on Alcohol Abuse and Alcoholism P50 AA010761 and R01 AA026859. Dr. Winters’ time was supported by a philanthropic gift from an anonymous family in memory of their son and twin brother lost to alcohol.

About Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Biological Psychiatry: Cognitive Neuroscience and Neuroimagingopens in new tab/window is an official journal of the Society of Biological Psychiatryopens in new tab/window, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of non-invasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2024 Journal Impact Factor^TM score, from Clarivate, for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 4.8.www.sobp.org/bpcnniopens in new tab/window

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