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. 2025 Jun 13;15(1):200.
doi: 10.1038/s41398-025-03428-x.

Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration

Tom Ben-Tal #  1 , Ilana Pogodin #  1 , Alexander Botvinnik  1 , Tzuri Lifschytz  1 , Uriel Heresco-Levy  2 , Bernard Lerer  3
Affiliations

Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration

Tom Ben-Tal et al. Transl Psychiatry. .

Abstract

The full therapeutic potential of serotonergic psychedelics (SP) in treating neuropsychiatric disorders, such as depression and schizophrenia, is limited by possible adverse effects, including perceptual disturbances and psychosis, which require administration in controlled clinical environments. This study investigates the synergistic benefits of combining psilocybin (PSIL) with N-methyl-D-aspartate receptor (NMDAR) modulators D-serine (DSER) and D-cycloserine (DCS) to enhance both efficacy and safety. Using ICR male mice, we examined head twitch response (HTR), MK-801-induced hyperlocomotion, and neuroplasticity related synaptic protein levels in the frontal cortex, hippocampus, amygdala, and striatum. Our results indicate that PSIL significantly increased HTR-a surrogate measure for hallucinogenic effects-which was reduced by the co-administration of DSER or DCS in a dose-dependent manner. Similarly, combining PSIL with DSER or DCS significantly decreased MK-801-induced hyperactivity, modeling antipsychotic effects. Neuroplasticity-related synaptic protein assays demonstrated that the PSIL-DSER combination enhanced GAP43 expression over all 4 brain examined and overall expression of the 4 assayed synaptic proteins in the hippocampus, while PSIL-DCS elevated PSD95 levels across all 4 brain regions, suggesting a synaptogenic synergy. These findings support the hypothesis that combinations of SP with NMDAR modulators could optimize the therapeutic potential of SP by mitigating adverse effects and enhancing neuroplasticity. Future studies should focus on refining administration protocols and evaluating translational applicability for broader clinical use.

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Conflict of interest statement

Competing interests: PCT WO 2024/052895 A1 (Inventors: BL, UHL), submitted by Hadasit Medical Research and Development Ltd and Ezrath Nashim - the Rabanit Herzog Memorial Hospital discloses SP-NMDAR modulator combination therapy for psychiatric and other disorders. Ethics approval: Experiments were approved by the Authority for Biological and Biomedical Models, Hebrew University of Jerusalem, Israel (Animal Care and Use Committee Approval Numbers: MD-22-17000-4 and MD-24-17494-4). All methods were performed in accordance with the relevant guidelines and regulations and all efforts were made to minimize animal suffering and the number of animals used.

Figures

Fig. 1
Fig. 1. PSIL, DSER and HTR.
A. Effect of VEH, PSIL 4.4 mg/kg, DSER 3000 mg/kg, PSIL 4.4 mg/kg + DSER 3000 mg/kg on HTR over 30 min (F = 15.33, df 3, 34, p < 0.0001). B. Effect of VEH, PSIL 1.5 mg/kg, DSER 1500 mg/kg, PSIL 1.5 mg/kg + DSER 1500 mg/kg on HTR over 30 min (F = 32.17, df 3, 20, p < 0.0001). ****p < 0.0001.
Fig. 2
Fig. 2. Psilocybin, D-cycloserine and Head Twitch Response.
A Effect of VEH, PSIL 4.4 mg/kg, DCS 320 mg/kg, PSIL 4.4 mg/kg + DCS 320 mg/kg on HTR over 20 min (F = 39.10, df3, 36, p 0.0001) B. Effect of VEH, PSIL 4.4 mg/kg, DCS 22.2 mg/kg, PSIL 4.4 mg/kg + DCS 22.2 mg/kg; DCS 176.19 mg/kg, PSIL 4.4 mg/kg + DCS 176.19 mg/kg; DCS 176.19 mg/kg, PSIL 4.4 mg/kg + DCS 176.19 mg/kg; on HTR over 20 min (F = 35.04, df 7, 38, p < 0.0001). **p < 0.01; ***p < 0.001; ****p < 0.0001.
Fig. 3
Fig. 3. MK-801-Induced Hypeerlocomotion: PSIL, DSER and DCS.
A. Effect of VEH, PSIL 4.4 mg/kg, DSER 3000 mg/kg, PSIL 4.4 mg/kg + DSER 3000 mg/kg on hyperlocomotion induced by MK-801 0.5 mg/kg (F = 4.069, df 3, 35, p = 0.0140). B. Effect of VEH, PSIL 4.4 mg/kg, DCS 320 mg/kg, PSIL 4.4 mg/kg + DCS 320 mg/kg on hyperlocomotion induced by MK-801 0.5 mg/kg (F = 4.15, df 3, 28, p = 0.02). *P < 0.05.
Fig. 4
Fig. 4. GAP43 Levels: Effect of PSIL and DSER.
Effect of VEH, PSIL 4.4 mg/kg, DSER 3000 mg/kg, PSIL 4.4 mg/kg + DSER 3000 mg/kg on GAP43 levels in: A. Frontal Cortex (F = 5.181, df 3, 27, p = 0.0059), B. Hippocampus (F = 5.775, df 3, 27, p = 0.0035), C. Amygdala (F = 5.795, df 3, 26, p = 0.0036), D. Striatum (Not significant). *p < 0.05; **p < 0.01.
Fig. 5
Fig. 5. PSIL and DSER: Nested ANOVA.
A. Nested ANOVA across 4 brain regions (frontal cortex, hippocampus, amygdala, striatum) showing effect of VEH, PSIL 4.4 mg/kg, DSER 3000 mg/kg, PSIL 4.4 mg/kg + DSER 3000 mg/kg. (F = 6.126, df 3, 117, p = 0.0007) on GAP43 levels. B. Nested ANOVA showing effect of VEH, PSIL 4.4 mg/kg, DSER 3000 mg/kg, PSIL 4.4 mg/kg + DSER 3000 mg/kg. on all 4 synaptic proteins (GAP43, PSD95, synaptophysin, SV2A) within the hippocampus (F = 2.747, df 3, 123, p = 0.0458). *p < 0.05; **p < 0.01, ***p < 0.001.
Fig. 6
Fig. 6. PSD95: Effect of PSIL and DCS.
A. PSD95 levels in the frontal cortex 11 days after treatment with VEH, PSIL 4.4 mg/kg. DCS 320 mg/kg, PSIL 4.4 mg/kg + DCS 320 mg/kg (F = 2.30, df 3, 95, p = 0.04). B. Nested ANOVA of PSD95 levels across 4 brain regions (Frontal cortex, hippocampus, amygdala, striatum) (F = 3.02, df 3, 95, p = 0.03). *p < 0.05.
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