Evaluation of psilocybin as an adjunctive treatment for opioid use disorder in methadone-maintained patients who continue to use illicit opioids

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.

Grant Number: 5UG3DA062088-02
NIH Institute/Center: NIH
Principal Investigator: Michael Bogenschutz