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Evaluation of the Combination Muscarinic Cholinergic Receptor Drug Product Cobenfy as a Medication for Cocaine Use Disorder Using Translational Human and Rat Cocaine Choice Procedures

Award Number: R01DA064646
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Evaluation of the Combination Muscarinic Cholinergic Receptor Drug Product Cobenfy as a Medication for Cocaine Use Disorder Using Translational Human and Rat Cocaine Choice Procedures - ABSTRACT Cocaine use disorder (CUD) is a persistent public health problem and existing treatments are insufficient. The primary goal of this translational cross-species project is to address this need by determining the ability of Cobenfy, a newly FDA-approved schizophrenia medication that acts on muscarinic acetylcholine receptors, to reduce cocaine self-administration using choice procedures that are predictive of clinical efficacy. Accumulating evidence indicates that selective modulation of muscarinic receptors has exciting potential for treating CUD. However, clinical evaluation of muscarinic receptor drugs for CUD has been hampered by a lack of available medications. Cobenfy is combination of the M1/M4-preferring agonist xanomeline, which is responsible for its psychiatric efficacy, and the peripheral non-selective muscarinic antagonist trospium, which reduces xanomeline’s peripheral side effects of while sparing its CNS activity. MPI Thomsen’s group showed that xanomeline monotherapy attenuated the effects of cocaine in non-human animals across multiple measures relevant to CUD. Therefore, the present project seeks to translate promising preclinical findings with Cobenfy to the human laboratory. Two groups who meet criteria for CUD will participate as inpatients and be maintained on Cobenfy 100/20 until steady state is attained or placebo, prior to completion of money-vs-IV cocaine choice sessions. MPI Thomsen’s prior work also demonstrated that the effects of M1 agonists on cocaine choice persisted beyond the end of treatment. Therefore, this project also proposes to determine the dose-dependence and time course of Cobenfy’s on- and post-treatment effects on cocaine choice in rats. Due to the extended number of sessions needed to accomplish this aim, it could not practicably be accomplished in an inpatient human laboratory experiment; therefore, the rat research provides a valuable complement that will inform future clinical research with Cobenfy. Moreover, exploratory research will determine the impact of Cobenfy on cocaine-cued decision-making bias in humans and cocaine-induced neurotoxicity in rats. These innovative, cross-species translational experiments will move Cobenfy, a promising treatment for CUD, further through the drug development pipeline. In addition, the human laboratory experiment will contribute to our understanding of the clinical neurobiology of cocaine addiction by focusing on M1 and M4, which appear critical to CUD, but are understudied in humans. Further, the rat studies will serve as a valuable complement to the human experiment by providing important new information about other potential benefits of Cobenfy treatment (i.e., persistent treatment effects, reduced cocaine neurotoxicity).


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 = $663,978 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Drug Use and Addiction Research Programs	000	1	5/1/2026	NEW	$663,978
														Subtotal = $663,978

Grand Total All Awards = $663,978

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Evaluation of the Combination Muscarinic Cholinergic Receptor Drug Product Cobenfy as a Medication for Cocaine Use Disorder Using Translational Human and Rat Cocaine Choice Procedures

Award Number: R01DA064646

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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