Dopamine-boosting drug enhances self-control and reduces drinking in people with alcohol use disorder

A new clinical trial has found evidence that the dopamine-enhancing drug tolcapone can help improve self-control and reduce alcohol consumption in people with alcohol use disorder. The study, published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, found that tolcapone increased activity in brain regions involved in inhibitory control, particularly the inferior frontal gyrus and dorsolateral prefrontal cortex. These changes were associated with improved performance on a self-control task and fewer drinks consumed during the trial.

Alcohol use disorder involves both strong motivation to consume alcohol and a reduced ability to inhibit that motivation. Brain circuits that support self-control are thought to be impaired in people with this condition. Specifically, lower dopamine signaling in the prefrontal cortex has been observed in individuals with alcohol use disorder, and this may contribute to the loss of behavioral control.

Previous attempts to treat alcohol use disorder with dopamine-related medications have had mixed results, possibly because these drugs influence dopamine levels across broad brain regions. In contrast, tolcapone offers a more targeted approach. It inhibits an enzyme called catechol-O-methyltransferase, which breaks down dopamine primarily in the prefrontal cortex. By increasing dopamine availability specifically in this region, tolcapone may help restore some of the self-regulatory functions that are disrupted in alcohol use disorder.

“Alcohol use disorder is a prevalent and devastating disease for which only three medications are currently approved by the U.S. Food and Drug Administration (FDA),” said study author Joseph P. Schacht, an associate professor of psychiatry at the University of Colorado School of Medicine.

“These existing medications are believed to work by reducing craving for alcohol and/or changing its acute effects (increasing negative effects or reducing euphoric effects). A core symptom of alcohol use disorder is loss of control over drinking, and we wanted to explore whether a different kind of medication, which might increase behavioral control, might be effective for people with alcohol use disorder.

“We conducted a randomized, placebo-controlled trial of tolcapone, an FDA-approved medication for Parkinson’s disease. Tolcapone inhibits the enzyme catechol-O-methyltransferase (COMT), which degrades catecholamine neurotransmitters in the brain. This means that it can transiently increase concentrations of the neurotransmitter dopamine. We often think of dopamine as being related to reward and euphoria, but in the prefrontal cortex, dopamine is critical for many cognitive processes that involve behavioral control. We thought that, by increasing prefrontal dopamine, tolcapone might increase behavioral control among people with alcohol use disorder.”

The trial was conducted at the Medical University of South Carolina. Participants were adults aged 21 to 40 who met diagnostic criteria for moderate or severe alcohol use disorder. They were required to drink at least 20 standard drinks per week and were not seeking treatment for their alcohol use. A total of 64 individuals with usable brain imaging data were included in the final analysis.

Participants were randomly assigned to receive either tolcapone or a placebo for eight days. Tolcapone dosage was gradually increased to a maximum of 200 mg three times per day. Brain activity was measured using functional magnetic resonance imaging (fMRI) before and after the medication period. The primary task used to measure self-control was the stop-signal task, which requires individuals to inhibit a dominant motor response when signaled.

The researchers also tracked participants’ alcohol consumption using a daily self-report tool. To ensure the accuracy of the brain imaging results, several quality control measures were implemented, including controlling for motion during scanning and using different MRI scanner settings as covariates in the analysis.

The researchers found that participants who received tolcapone showed improvements in inhibitory control. This was measured by shorter stop-signal reaction times, indicating that they were better able to withhold a response when prompted. They also showed more behavioral adjustment after making errors, another indicator of improved self-regulation. These improvements were not seen in the placebo group.

In addition to changes in behavior, tolcapone also increased activity in brain areas involved in self-control, particularly the inferior frontal gyrus and dorsolateral prefrontal cortex. These increases were only observed in the tolcapone group. Notably, individuals who showed greater increases in activation in these areas also tended to report less alcohol consumption during the trial.

“We suspected that greater tolcapone-induced prefrontal cortex activation might be related to better performance on the task, but were pleasantly surprised to find that it was also related to less alcohol consumption,” Schacht told PsyPost. “This suggests that tolcapone’s effect on behavioral control in the brain scanner translated to changes in real-world behavior.”

The researchers also found changes in how brain regions communicated with each other. Tolcapone increased connectivity between the inferior frontal gyrus and two other brain regions—the anterior insula and anterior cingulate cortex—that are also involved in emotion regulation and cognitive control. These enhanced connections were linked to better task performance and fewer drinks consumed, but again, only in participants who received tolcapone.

The results provide evidence that boosting dopamine levels specifically in the prefrontal cortex may help restore self-control in people with alcohol use disorder. This has been a longstanding goal in addiction research, but previous approaches have struggled to achieve this without unintended effects in other parts of the brain.

By showing that tolcapone can influence both brain activity and real-world drinking behavior, the findings suggest that targeted dopamine modulation could be a promising therapeutic approach. The inferior frontal gyrus, in particular, emerged as a central hub in the network supporting self-regulation, with its activity and connectivity predicting both task performance and drinking outcomes.

“We used brain imaging (functional magnetic resonance imaging) to measure activity in the prefrontal cortex while people engaged in a simple behavioral control task,” Schacht summarized. “We found that tolcapone, relative to placebo, increased activation of a brain region called the dorsolateral prefrontal cortex, and that increased activation of this region was associated with better behavioral control (better performance on the task) and less alcohol consumption during the time people were taking the medication. This suggests that medications like tolcapone that affect prefrontal dopamine might be a novel strategy for treating alcohol use disorder.”

While the mechanism appears to be related to dopamine, the researchers caution that other neurotransmitter systems—such as norepinephrine and glutamate—could also be involved. Additional studies will be needed to disentangle these contributions and to examine whether the effects of tolcapone extend beyond self-control to other aspects of alcohol use disorder, such as craving or mood regulation.

Although the findings are promising, some limitations should be noted. The sample size, while sufficient for the planned analyses, was relatively small. Larger trials will be needed to confirm these results and assess how long the benefits of tolcapone might last. The study also excluded people with psychiatric comorbidities or other substance use disorders, so the generalizability of the findings to more diverse clinical populations remains uncertain.

In addition, the researchers were not able to test genetic differences in how participants responded to the drug. The study was designed to examine whether genetic variation in a dopamine-related gene (COMT rs4680) affected the drug’s impact, but the number of participants in each genetic subgroup was too small to draw firm conclusions. Prior studies suggest that people with certain genetic variants may respond more strongly to tolcapone, and this will be an important area for future research.

“Although it is approved for Parkinson’s disease, tolcapone has the potential for liver toxicity, which can be dangerous among people who may have alcohol-associated liver disease,” Schacht noted. “In this study, we used tolcapone under very controlled conditions (people had to have normal liver function to participate, and they took the medication for only 8 days). There are several approved COMT inhibitors that are not toxic to the liver, but they do not cross the blood-brain barrier like tolcapone does. We hope that COMT inhibitors that are brain-penetrant but not hepatotoxic will be developed in the near future.”

There is also a need to better understand whether the effects of tolcapone are specific to improving inhibition of alcohol-related impulses or whether they reflect a broader enhancement of executive function. Future studies could compare how the drug affects brain responses to alcohol cues versus non-alcohol-related tasks, or examine whether it changes patterns of decision-making or emotional regulation in everyday life.

“We are currently completing a large study in which we are testing tolcapone among people with alcohol use disorder and attention-deficit/hyperactivity disorder,” Schacht said. “This is a population for which improvements in behavioral control might be especially impactful. We hope to publish our findings within the next year.”

“More efficacious medications for alcohol use disorder are badly needed. This study was one small step towards a larger goal within the alcohol research community of identifying novel medications to help improve the treatment of this disease.”

The study, “Effects of COMT suppression in a randomized trial on the neural correlates of inhibitory processing among people with Alcohol Use Disorder,” was authored by Drew E. Winters and Joseph P. Schacht.