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Psilocybin-Assisted ACT for Co-Occurring Cocaine Use Disorder and Major Depressive Disorder

Award Number: R01DA067060
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Psilocybin-Assisted ACT for Co-Occurring Cocaine Use Disorder and Major Depressive Disorder - PROJECT SUMMARY Cocaine use disorder (CUD) is notoriously difficult to treat and is frequently complicated by major depressive disorder (MDD), a clinically significant comorbidity affecting as many as 40% of individuals with CUD. This co-occurrence is associated with greater illness severity, impaired psychosocial functioning, and poorer treatment outcomes. Despite its high prevalence and clinical significance, CUD-MDD has received far less research attention than either condition alone, and traditional pharmacological approaches have shown limited efficacy. Although there is broad consensus on the need for interventions that target shared mechanisms underlying both CUD and MDD, no integrated interventions have yet been developed or empirically validated. The long-term goal of this initial research is to address this critical gap by evaluating an integrated treatment for individuals with co-occurring CUD-MDD. We present a strong scientific premise for developing and preliminarily testing psilocybin-assisted Acceptance and Commitment Therapy (ACT) for CUD-MDD. Psilocybin has shown robust, consistent efficacy for MDD, earning “Breakthrough Therapy” designation from the US FDA, with emerging evidence supporting its potential utility in treating substance use disorders. Contextual behavioral therapies such as ACT have shown efficacy in treating CUD in our prior work and have also been found to enhance outcomes in psilocybin- assisted therapy for MDD. At the process level, both psilocybin and ACT promote psychological flexibility (PF) by disrupting maladaptive repetitive or ruminative thought patterns and allowing for increased focus on values-based action. Neuroimaging studies further indicate that both interventions reduce activity within the Default Mode Network (DMN) – a brain network associated with self-referential processing and rumination, which are centrally implicated in PF. These shared psychological and neural processes represent key transdiagnostic mechanisms that can be effectively targeted through psilocybin-assisted ACT. We will conduct a randomized controlled trial to evaluate psilocybin-assisted ACT for individuals with CUD-MDD. In a 6-week primary treatment phase (Phase 1), participants (N=50) will be randomized to a single, blinded dose of psilocybin (25 mg) or an active placebo (diphenhydramine, 50 mg), both delivered within a manualized ACT platform. Aim 1 will assess effects on cocaine abstinence and depressive symptoms; Aim 2 will examine mechanistic outcomes, including PF and DMN changes using novel multimodal imaging. In a subsequent 6-week blinded extension phase (Phase 2), all participants will receive 25 mg psilocybin to examine within- and between-group effects of one versus two doses (Exploratory Aim 3), while mitigating potential unblinding and nocebo effects. Bayesian posterior probabilities indicating strong evidence for psilocybin-assisted ACT will inform progression to a larger efficacy-effectiveness trial, laying the foundation for an integrated, behavioral-pharmacological intervention for this underserved population.


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 = $699,431 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	000	1	9/1/2026	NEW	$699,431
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Drug Use and Addiction Research Programs	001	1	9/18/2026	NEW	$0
														Subtotal = $699,431

Grand Total All Awards = $699,431

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Psilocybin-Assisted ACT for Co-Occurring Cocaine Use Disorder and Major Depressive Disorder

Award Number: R01DA067060

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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