Preclinical and clinical research provides strong evidence that psilocybin and other 5-HT2A agonist/partial agonist psychedelics have antiaddictive effects. In a double-blind randomized controlled trial of psilocybin- assisted treatment for alcohol use disorder (AUD), administration of psilocybin resulted in robust decreases in drinking which were sustained for 28 weeks following drug administration. Self-report measures showed that psilocybin treatment was associated with decreased alcohol craving and decreased negative emotionality (NE). Data from an fMRI pilot study in a sub-sample of trial participants (n = 11) showed normalization of response to alcohol cues and negative emotional stimuli following psilocybin (relative to active placebo). A substantial body of research investigating on the antidepressant effects of psilocybin have confirmed the positive effects of psilocybin on NE in several animal models of depression and chronic stress, and four recent randomized controlled trials (RCTs) of psilocybin in the treatment of major depression have demonstrated consistently large effects of psilocybin on mood, persisting for weeks or months after a single administration of the drug. Building on the work described above, we now propose a mechanistic trial specifically designed to elucidate the effects of psilocybin on neural activity in AUD, and the relationship of these effects to treatment outcomes. We will focus primarily on the effects of psilocybin on the processing of alcohol cues and NE stimuli. Participants (n = 90) with moderate to severe AUD who are currently engaged in residential treatment and have achieved initial sobriety will be randomly assigned to receive a single administration of high-dose psilocybin (n = 60) vs. low-dose psilocybin control (n = 30), using a low-intensity supportive therapy model designed to minimize and account for the effect of patient and therapist expectancies. While in residential treatment, participants will complete fMRI sessions 3 days before and 2 days after psilocybin administration. fMRI measures include a well- validated task to evaluate neural and subjective response to negative affective visual stimuli and alcohol cues, as well as resting state functional connectivity. Alcohol use data (self-report and serum biomarkers) and self- report measures tapping NE, craving, and aspects of executive function will be collected prior to psilocybin administration and during the 24 weeks following discharge from residential treatment. Aims are 1) to evaluate the effects of high- vs. low-dose psilocybin on AUD patients’ neural response to visual negative affective stimuli and alcohol cues, drinking outcomes and self-report measures related to NE, craving, and EF; 2) to identify neural metrics (activation and functional connectivity) that best predict drinking outcomes (TLFB) and self-report measures of craving and negative affect; and 3) to identify likely responders to high-dose psilocybin treatment by using machine learning and other advanced statistical methods. Understanding psilocybin’s mechanisms of action may lead to new therapeutic targets in AUD and new medications that engage them, including both psychedelic and non-psychedelic 5-HT2A agonists.

Project Narrative There an urgent need for new effective treatments to decrease the toll that alcohol use disorder takes on individuals and society. The experimental medication psilocybin has produced positive results in early-stage clinical trials using it to treat alcohol use disorder, and depression, but very little is known about how it might work to help people stop or decrease their drinking. In this study we will determine the effects of psilocybin on brain activity related to alcohol craving and negative emotion, and test whether these effects contribute to the therapeutic benefits of psilocybin.