PROJECT SUMMARY Background: There is an urgent need for new medications for OUD that can improve treatment outcomes when used alone or in combination with existing treatments. Early stage trials of psilocybin for the treatment of substance use disorders have consistently shown robust effects on target drug use and underlying neuropsychopathology. Despite these promising findings, there are no published data on the clinical effects of psilocybin in OUD, either alone or in combination with empirically supported treatment. Objective: We propose to use the UG3/UH3 mechanism to jump-start research on psilocybin to treat OUD. The study will use an innovative “seamless” adaptive design and an equally innovative treatment model to test the efficacy of psilocybin in OUD patients who continue to use non-prescribed opioids despite adherence to methadone treatment. Method: We will recruit 240 participants (90 in the UG3 phase, 150 in the UH3 phase) from four opioid treatment programs (OTPs) serving predominantly minoritized and marginalized communities in New York and New Mexico. Psilocybin treatment—implemented as an adjunct to ongoing OTP treatment—will be provided by a clinician from an academic research center who has training in psychedelic treatment, working with an OTP staff member who has a clinical relationship with the patient. Participants will continue methadone treatment and will receive a single dose of investigational product (IP) during an all-day IP administration session. Weekly urine drug screens and continuous self-report of opioid and other drug use will be collected for 24 weeks after IP administration, along with measures probing OUD-related neuropsychopathology and functional outcomes. In the UG3 phase, participants will be randomly assigned to one of three groups: high dose psilocybin, medium dose psilocybin, and low-dose psilocybin control. In order for the study to continue to the UH3 phase, the UG3 phase must demonstrate successful completion operational milestones, and an interim analysis must demonstrate that pre-specified “Go” criteria for safety and efficacy have been met. Using a priori decision rules, the interim analysis will also determine which of the active treatment groups (high-dose, medium-dose, or both) will be retained of the UH3 phase of the trial. Significance: This rigorous, well-powered efficacy trial will rapidly and efficiently advance understanding of the potential value of psilocybin in the treatment of OUD. If the trial finds a robust efficacy signal, the data will provide strong evidence and a practical treatment model for a full-scale drug development program to achieve an FDA indication for psilocybin as a treatment for OUD.

PROJECT NARRATIVE There an urgent need for new effective treatments to decrease the toll that opioid 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 it has not yet been tested in opioid use disorder. This study investigates whether psilocybin can help patients in opioid use disorder treatment stop using illicit opioids.