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Mechanistic Evaluation of Psilocybin in Opioid Use Disorder: A Randomized, Double-Blind, Active-Placebo-Controlled Crossover Trial with Pharmacokinetic/Pharmacodynamic Modeling

Award Number: R01DA066503
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Mechanistic Evaluation of Psilocybin in Opioid Use Disorder: A Randomized, Double-Blind, Active-Placebo-Controlled Crossover Trial with Pharmacokinetic/Pharmacodynamic Modeling - Project Summary/Abstract Opioid use disorder (OUD) remains a leading cause of preventable death. FDA-approved medications reduce overdose risk, yet relapse is common, driven by early withdrawal, cue-evoked craving, and persistently high opioid valuation. Serotonergic (5-HT2A) agonism may dampen opioid motivation, but human data in OUD separating pharmacology from psychotherapy are lacking. This randomized, double-blind, two-period, two-sequence crossover trial (N=40 completers) tests whether psilocybin engages relapse-relevant mechanisms in non–treatment-seeking adults with OUD. Each participant completes two oral psilocybin sessions (30 mg vs 5 mg; counterbalanced) separated by a 14–21-day washout. Last opioid use is time-aligned so early spontaneous withdrawal can emerge during observation. Pharmacokinetics (psilocin) are sampled pre-dose and through 8 hours and linked to continuous autonomic monitoring (heart rate/HRV, electrodermal activity, distal skin temperature). Primary dosing-day outcomes are cumulative withdrawal burden (COWS/SOWS area-under-effect) and behavioral-economic valuation assessed outside the psychedelic peak, using purchase tasks or brief valuation measures as appropriate. Post-dose mechanistic outcomes (24–72 h) include cue-evoked craving and autonomic reactivity during a standardized neutral→drug cue paradigm. To contextualize benefit with risk, we will also generate an FDA-aligned human abuse-liability (HAL) profile. Analyses use likelihood-based mixed- effects models that leverage within-participant contrasts and evaluate exposure–response links between psilocin levels (e.g., C_max, T_max, AUC_0–8 h) and mechanistic change. Innovation lies in a psychotherapy-independent design, time-locked assessment to withdrawal onset, integrated PK/PD with objective physiology, and inclusion of regulator-interpretable HAL methods. Expected outcomes include effect sizes for withdrawal, valuation, and cue-reactivity; psilocybin/psilocin PK in OUD; and exposure–response functions to guide dose selection and session timing. Impact: These data will de-risk and rationally design later-phase, treatment-seeking trials aimed at durable relapse prevention in OUD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $683,851 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Drug Use and Addiction Research Programs	000	1	9/18/2026	NEW	$683,851
														Subtotal = $683,851

Grand Total All Awards = $683,851

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Mechanistic Evaluation of Psilocybin in Opioid Use Disorder: A Randomized, Double-Blind, Active-Placebo-Controlled Crossover Trial with Pharmacokinetic/Pharmacodynamic Modeling

Award Number: R01DA066503

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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