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Target Specificity of Tabernanthalog Treatment in Opioid Use Disorder

Award Number: R01DA056660
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Target Specificity of Tabernanthalog Treatment in Opioid Use Disorder - PROJECT SUMMARY Opioid use disorder (OUD) is characterized by persistent drug seeking often accompanied by a loss of interest in natural rewards. Current FDA-approved treatments for OUD target the endogenous opioid system directly, either as substitution therapies (e.g. buprenorphine, methadone) or antagonists that oppose opioid effects (e.g. naltrexone, naloxone). Although these therapies have helped reduce overall harm, they are rarely a cure for OUD. As the seat of executive function, the PFC plays an integral role in decision-making, impulse control, and the cognitive regulation of drug craving and relapse. Thus, novel compounds capable of promoting neural plasticity to augment or restore PFC function possess enormous therapeutic potential for treating substance use disorders (SUDs). Structural plasticity in the PFC could produce long-lasting protective effects against relapse, and would reduce the need for chronic medication. Plasticity-promoting, psychoplastogenic compounds may also have broad-spread restorative effects on downstream neural circuits, and may normalize aberrant plasticity and neural activity across addiction networks. Psychedelic compounds including 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) and ibogaine potently induce spine growth in the PFC in a serotonin 5-HT2A receptor-dependent manner. This class of drugs also elicits long-lasting anti-addictive properties across a wide variety of SUDs, but their side effects including hallucinations and cardiotoxicity limit their therapeutic potential. To overcome these barriers to therapeutic application, we engineered a safer psychoplastogenic 5-HT2A receptor ligand called tabernanthalog (TBG), which chemically resembles ibogaine and 5-MeO-DMT, yet lacks hallucinogenic effects and cardiotoxicity and does not bind to opioid receptors. We demonstrated that TBG decreases both alcohol and heroin consumption and reduces relapse rates long-term in a heroin self- administration model after a single treatment. However, the pharmacological and brain-specific mechanisms that mediate these anti-addictive effects are currently unknown. The overarching objectives of this project are to determine the in vivo receptor targets mediating the anti-addictive effects of TBG, and whether TBG’s psychoplastogenic effects within addiction neural circuitry is a mechanism of action for TBG therapy. Establishing the anti-addictive mechanism of TBG will aid continued drug discovery of more potent and selective compounds for treating addiction and may help identify patient populations that are likely to respond to treatment. In addition to identifying the role of serotonin receptors and structural plasticity in the effect of TBG, this proposal will also screen the therapeutic potential of TBG in a polydrug (opioid and alcohol) use model and determine the specificity of TBG therapy for opioids versus natural rewards. Information gained from this project will provide insight into TBG’s potential as an anti-OUD therapeutic and its mechanism of action, thus allowing us to further optimize TBG and related compounds for translation to the clinic.


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: 2025 ( Subtotal = $1,071,516 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	001	2	11/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$535,758
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	002	3	8/14/2025	EXTENSION WITH OR WITHOUT FUNDS	$535,758
2025	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	001	2	11/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$24,334
2025	2022	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	1	11/8/2024	NEW	-$24,334
														Subtotal = $1,071,516

Issue Date FY: 2023 ( Subtotal = -$115,866 )
2023	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	1	9/27/2023	NEW	-$1,532,404
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Drug Use and Addiction Research Programs	001	2	9/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,416,538
														Subtotal = -$115,866

Issue Date FY: 2022 ( Subtotal = $1,635,844 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Drug Use and Addiction Research Programs	000	1	6/23/2022	NEW	$1,635,844
														Subtotal = $1,635,844

Grand Total All Awards = $2,591,494

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Target Specificity of Tabernanthalog Treatment in Opioid Use Disorder

Award Number: R01DA056660

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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