Wednesday, October 1, 2025 10/1/2025

High-throughput Identification of Non-hallucinogenic Psychoplastogens for Treating Addiction

Award Number: R01DA056365
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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High-throughput Identification of Non-hallucinogenic Psychoplastogens for Treating Addiction - PROJECT SUMMARY/ABSTRACT Pathological changes in neural circuitry underly a variety of neuropsychiatric diseases including addiction and depression. Accumulating evidence from human imaging, postmortem analysis, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC)—including the retraction of dendritic arbors, loss of dendritic spines, and reduction in synapse density—plays a key role in the pathophysiology of substance use disorders (SUDs). The PFC is well known to regulate limbic reward circuitry, modulate attention, and exert top- down control over drug-seeking behavior, and thus, the atrophy of neurons in the PFC is believed to worsen SUD by reducing executive control, exacerbating impulsivity, and leading to deficits in the extinction of drug-cue memories. Therapeutic strategies aimed at restoring PFC structure/function are hypothesized to have broad therapeutic potential for SUDs. Psychoplastogens—small molecules that activate TrkB signaling and serve as brain-derived neurotrophic factor (BDNF) mimetics—are able to rapidly restore functional connectivity in the PFC and produce long-lasting therapeutic effects after a single administration. However, the most prominent psychoplastogens—including serotonergic psychedelics—all produce hallucinations, which greatly limit their therapeutic potential. Recently, evidence has emerged suggesting that the hallucinogenic effects of these drugs may not be necessary for their therapeutic properties, and the first non-hallucinogenic psychoplastogens were introduced by our group this past year. One such molecule, known as tabernanthalog (TBG), produces both rapid and sustained anti-addictive effects in rodent models of heroin self-administration, much like the known anti-addictive psychedelic ibogaine. The advent of TBG represents an exciting new direction for the treatment of addiction, but there is an urgent need to develop new assays enabling the rapid identification of TBG-like molecules with optimized efficacy and safety profiles. Our overall objective is to develop high-throughput methods for identifying non-hallucinogenic psychoplastogens that, like TBG, can produce long-lasting therapeutic effects. To achieve this goal, we have developed psychLight—a genetically encoded, 5-HT2AR- based biosensor capable of predicting both the hallucinogenic and psychoplastogenic properties of small molecules. The proposed studies involve the use of this technology to rapidly identify new non-hallucinogenic psychoplastogens for treating addiction as well as probing potential 5-HT2AR interactions with dopamine, opioid, and cannabinoid receptors. We also propose studies to elucidate the molecular and circuit-level mechanisms of the anti-addictive, non-hallucinogenic psychoplastogen TBG. Ultimately, the work described here will fill the gap in our knowledge about how best to rapidly screen for non-hallucinogenic psychoplastogens, which will enable the rational design of safer, non-hallucinogenic alternatives to psychedelics for treating SUDs and related co- morbid diseases such as depression.


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 = $541,161 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Drug Use and Addiction Research Programs	001	4	4/10/2025	NON-COMPETING CONTINUATION	$54,117
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Drug Use and Addiction Research Programs	000	4	2/26/2025	NON-COMPETING CONTINUATION	$487,044
														Subtotal = $541,161

Issue Date FY: 2024 ( Subtotal = $540,503 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Drug Use and Addiction Research Programs	000	3	2/19/2024	NON-COMPETING CONTINUATION	$486,453
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Drug Use and Addiction Research Programs	001	3	4/25/2024	NON-COMPETING CONTINUATION	$54,050
														Subtotal = $540,503

Issue Date FY: 2023 ( Subtotal = $538,861 )
2023	2023	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Drug Use and Addiction Research Programs	000	2	1/25/2023	NON-COMPETING CONTINUATION	$538,861
														Subtotal = $538,861

Issue Date FY: 2022 ( Subtotal = $552,154 )
2022	2022	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Drug Use and Addiction Research Programs	000	1	5/4/2022	NEW	$552,154
														Subtotal = $552,154

Grand Total All Awards = $2,172,679

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High-throughput Identification of Non-hallucinogenic Psychoplastogens for Treating Addiction

Award Number: R01DA056365

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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