Psilocybin therapy alters prefrontal and limbic brain circuitry in alcohol use disorder

A recent study published in Scientific Reports reveals new insights into how psilocybin-assisted therapy modifies brain function in people with alcohol use disorder (AUD). These changes suggest a potential mechanism behind the therapy’s success and could point toward new avenues for treatment.

Psilocybin is the psychoactive compound found in certain species of mushrooms, often referred to as “magic mushrooms,” known for its ability to produce profound changes in consciousness, perception, and mood. Psilocybin-assisted therapy combines the administration of psilocybin with psychological support and therapeutic practices, aiming to leverage the compound’s unique effects to facilitate deep psychological insights and emotional processing.

“A recent Phase II clinical trial in patients with alcohol use disorder (AUD) found that psilocybin-assisted therapy significantly improved drinking outcomes for up to 8 months relative to an active placebo. The positive effects of this treatment were observed rapidly (as early as the day after treatment), large in magnitude, and sustained after only one to two applications,” said study author Broc Pagni, a cognitive neuroscientist and postdoctoral fellow in the Center for Psychedelic Medicine at NYU Grossman School of Medicine.

“These are especially promising findings, as currently available treatments for AUD, and psychiatric disorders more generally, do not have these combined properties. However, it is unclear how psilocybin therapy works on the brains of patients with AUD. Thus, this was a perfect opportunity to begin studying what brain mechanisms are responsible for these encouraging clinical outcomes.”

The current study was conducted within the framework of the larger Phase II clinical trial, which was randomized, double-blind, and placebo-controlled. The research included 11 adults, chosen based on specific inclusion criteria such as age range (25 to 65 years), a confirmed diagnosis of AUD, and a history of heavy drinking days within the past month.

Exclusion criteria were designed to rule out individuals with other major psychiatric or substance use disorders, previous hallucinogen use, or any medical condition or medication that could interfere with the study’s safety or outcomes.

Upon entering the study, participants were randomly assigned to receive either psilocybin or an active placebo (diphenhydramine) in combination with psychotherapy sessions. This therapeutic approach aimed to enhance the psychological insights and emotional processing facilitated by psilocybin.

Before the medication session, participants underwent preparatory therapy sessions incorporating motivational interviewing and cognitive behavioral strategies. This preparatory phase was crucial for setting expectations, establishing trust, and providing participants with coping strategies for navigating the psilocybin experience.

The core of the methodology involved functional magnetic resonance imaging (fMRI) scans conducted three days before and two days after the treatment. These scans allowed researchers to observe changes in brain activity as participants were exposed to images of alcoholic beverages and pictures designed to evoke positive, negative, and neutral emotional responses.

The researchers observed notable changes in brain activity patterns in response to alcohol-related and emotionally charged cues. These changes were indicative of altered neural processing in areas of the brain associated with craving, emotional regulation, and decision-making.

Specifically, psilocybin treatment led to increased activity in the medial and lateral prefrontal cortex (PFC) and left caudate — regions implicated in higher-order cognitive functions such as goal-directed behavior, decision-making, and emotional regulation.

Additionally, a decrease in activity was noted in the insula, motor, temporal, parietal, and occipital cortices, as well as the cerebellum. These areas are often associated with craving, automatic behavior patterns, and sensory processing, indicating that psilocybin may diminish the salience of alcohol cues.

The study also revealed unique responses to different types of emotional cues. For negative cues, psilocybin increased activity in the supramarginal gyrus, a region involved in empathy and emotional processing. For positive cues, there was an increase in right hippocampus activity and a decrease in left hippocampus activity, which may reflect changes in how positive emotional experiences are processed and integrated.

“Patients treated with psilocybin showed similar brain responses to pictures of alcohol and positive and negative emotional scenes,” Pagni told PsyPost. “This suggests psilocybin may have a general mood stabilizing effect, rather than altering processes specific to alcohol or negative emotions. The pattern of neural response was characterized by increased activity in the lateral and medial prefrontal cortex, brain regions associated with regulating emotions and behavior, and decreased activity in the insula, a brain region associated with craving for alcohol.”

“We also identified functional connectivity changes in key cognitive and motor areas of the brain that were specific to processing alcohol stimuli, suggesting psilocybin may strengthen specific circuits. However, the number of participants in this pilot study was very small and the findings should be interpreted with caution.”

Contrary to their expectations, the researchers did not observe changes in several regions involved in the brain’s reward system.

“We anticipated to see changes in the reward circuitry of the brain, which is excessively active in AUD patients, when viewing images of alcohol,” Pagni explained. “Surprisingly, we did not see changes in the nucleus accumbens, a core reward region of the brain, and we saw increased activity in other parts of the reward pathway, including the caudate and medial prefrontal cortex.

“These increases in activation were in the opposite direction that we would have hypothesized. If these findings are replicated in larger studies, it could be that psilocybin is recruiting compensatory brain mechanisms, rather than normalizing brain responses to resemble those without AUD.”

While the study’s findings are promising, they come with several limitations, primarily due to the small sample size and the homogeneous nature of the participant group. These factors limit the generalizability of the results and highlight the need for further research with larger, more diverse populations.

“Until larger studies have replicated some of these findings, we should not make too much of these results,” Pagni said. “The standard statistical corrections used in the field were not performed due to the sample being so small, and the results are strictly descriptive and serve to guide hypotheses for future research.”

“It is also unclear how these changes in the brain relate to the clinical outcomes that have been observed in AUD. Although inferences are commonly made in neuroimaging studies about the types of cognitive and psychological processes that underlie functional changes in specific brain regions, these processes must be verified by using specific tasks that tap into these constructs.”

“For this reason, we cannot say that changes in activity mean anything,” Pagni explained. “We can only say that the involvement of these brain regions might mean that the cognitive and psychological functions associated with them are involved. To this end, future research may base decisions to include relevant tasks to test these ideas directly.”

By shedding light on the neural changes that accompany psilocybin treatment, the research opens up new pathways for developing more effective, targeted interventions for AUD and possibly other psychiatric disorders.

“Our long-term goals for this research are to identify shared and unique psychological and neurobiological mechanisms of psychedelic-based treatments that both cut across psychiatric disorders, and are specific to particular clinical populations,” Pagni told PsyPost. “By leveraging different neuroimaging methods (e.g., fMRI, EEG, PET), machine learning techniques, and clever experimental designs, we hope to better understand what optimal brain functioning entails, what treatments will work best at the patient level, and how to maximize the duration of clinical improvement.”

“We are gearing up to conduct a large neuroimaging study of 120 patients with AUD to examine the effects of psilocybin-assisted psychotherapy on alcohol cue reactivity, emotional processing, and self-referential cognition. The goals of this research will be to characterize how psilocybin-assisted therapy intervenes on AUD-specific neurobiology, and more general neurobiological processes related to mood and self-awareness.”

The study, “Psilocybin-induced changes in neural reactivity to alcohol and emotional cues in patients with alcohol use disorder: an fMRI pilot study,” was authored by B. A. Pagni, P. D. Petridis, S. K. Podrebarac, J. Grinband, E. D. Claus, and M. P. Bogenschutz.