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Targeting Reward Circuits: Psilocybin as a Novel Therapy for Residual Anhedonia

Award Number: R01MH142698
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 11/30/2030

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Targeting Reward Circuits: Psilocybin as a Novel Therapy for Residual Anhedonia - Project Abstract In recent years, the prevalence of depression has risen, and with it, the prescribing of serotonergic antidepressants. Approximately 13.2% of adults aged 18 and over report using antidepressant in the past 30 days. Anhedonia (loss of interest or pleasure in previously rewarding activities) is a common symptom of depression. First-line antidepressants, selective serotonin reuptake inhibitors (SSRIs), can effectively lift low mood, but often come at the cost of further blunting emotion and reward-processing. In contrast, psilocybin (a 5HT-2A psychedelic) has shown promise in alleviating anhedonia and improving emotional range, even outperforming SSRIs in head-to-head trials. Emerging clinical research supports the safety and efficacy psilocybin in individuals currently taking an SSRI, offering a promising new adjunctive treatment option for those experiencing residual anhedonia. Despite this potential, the neural mechanisms underlying psilocybin's therapeutic effects on anhedonia remain poorly understood. Parallel fronto-limbic circuits—connections between the medial prefrontal cortex (mPFC) and limbic system—regulate motivation and emotional response. One crucial circuit, connecting the pregenual anterior cingulate cortex (pgACC) and the nucleus accumbens (NAcc), forms the core of the brain’s reward system and is implicated in anhedonia. In anhedonia, activity and connectivity in this pgACC-NAcc circuit is suppressed. SSRIs may further suppress this circuit, leading to residual deficits in motivation and pleasure. This study will use a clinical trial to assess the effects of a single dose of psilocybin (25 mg single dose) or control (psilocybin 1mg) in individuals experiencing SSRI-induced anhedonia. We will utilize Precision Functional Mapping (PFM), a novel fMRI technique enabling individual-specific brain mapping, to investigate how psilocybin modulates fronto-limbic circuitry in individuals with SSRI-induced anhedonia. In addition to PFM, we will use well-validated task-fMRI (emotional processing, monetary incentive delay) to probe key fronto-limbic circuits. Then we will test the ability of psilocybin to engage reward circuitry relevant to anhedonia. This work will advance our mechanistic understanding of anhedonia, identify biomarkers for targeted treatment, and potentially lead to more effective therapies.


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 = $871,225 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Mental Health Research Grants	000	1	2/19/2026	NEW	$871,225
														Subtotal = $871,225

Grand Total All Awards = $871,225

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Targeting Reward Circuits: Psilocybin as a Novel Therapy for Residual Anhedonia

Award Number: R01MH142698

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 11/30/2030

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