# Psilocybin: Capturing brain mechanisms of motivation and neurocognition in individuals with opioid use disorder

> **NIH NIH R61** · UNIVERSITY OF PENNSYLVANIA · 2024 · $495,024

## Abstract

Abstract
The urgency of the opioid crisis (over 80,000 deaths in the past year) has encouraged research
on understudied agents, such as the 5HT2A agonist psilocybin (PSI), for potential clinical benefit.
Recently, PSI has been designated as a "breakthrough therapy" for depression and has
demonstrated its potential benefits in substance-use disorders, including alcohol and nicotine
addiction. Observational data suggest a link between PSI use and reduced odds of developing
opioid use disorder (OUD). Emerging preclinical data suggest PSI may have neuroplasticity and
greater neurocognitive flexibility as potential mechanisms of action in clinical disorders, but clinical
trials have generally proceeded without mechanistic information in either the neurocognitive
flexibility (FLEX), or the “classic” motivational (“GO”!) and regulatory (STOP!) domains. The
proposed R61/R33 will address this need, examining PSI's impact on these 3 brain-behavioral
domains in OUD patients. 72 individuals (R61 = 24; R33 = 48) will be prospectively assigned to
receive either 25mg) or 1mg (control) of PSI, with selected pre- and post-PSI assessments that
probe brain, cognition, and behavior. Aim 1 ("GO!" motivational domain), will examine brain and
behavioral responses to cues and to drug-related videos. The hypothesis is PSI will reduce the
brain (motivational circuitry) and behavioral (reduced positive affective bias) response to drug
cues. Aim 2 ("STOP!" inhibitory domain) will assess brain responses during a valenced Go-NoGo
task and during attempted inhibition of craving to drug videos and during behavioral performance
of a standard (motor pre-protency) Go-NoGo task. The hypothesis is PSI will increase recruitment
of STOP circuitry in the brain tasks and will reduce errors of commission in the behavioral probe.
Aim 3 will investigate the "FLEX" (neurocognitive flexibility) domain using the Wisconsin Card Sort
Task (brain) and Penn Conditional Exclusion Task (behavior). The hypothesis is PSI will enhance
recruitment in FLEX substrates and reduce perseverative errors. Exploratory measures will
include craving, withdrawal, psychedelic effects, depression, and prior adversity. Brain-behavioral
probes showing large effect sizes will proceed to the R33 phase, and examinations will expand
to include network-level changes in the brain. This proposal is of high importance for
understanding PSI's effects on brain, cognition, and behavior in those with OUD – critical for the
rational advance of PSI for OUD – and for the many other disorders with unmet need.

## Key facts

- **NIH application ID:** 10978862
- **Project number:** 1R61DA061206-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Anna Rose Childress
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $495,024
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978862

## Citation

> US National Institutes of Health, RePORTER application 10978862, Psilocybin: Capturing brain mechanisms of motivation and neurocognition in individuals with opioid use disorder (1R61DA061206-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10978862. Licensed CC0.

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