Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration
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 environ...
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Nature Publishing Group
2025-06-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03428-x |
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| author | Tom Ben-Tal Ilana Pogodin Alexander Botvinnik Tzuri Lifschytz Uriel Heresco-Levy Bernard Lerer |
| author_facet | Tom Ben-Tal Ilana Pogodin Alexander Botvinnik Tzuri Lifschytz Uriel Heresco-Levy Bernard Lerer |
| author_sort | Tom Ben-Tal |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b469260dc5444388b5e43e5e33cdb7a2 |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-b469260dc5444388b5e43e5e33cdb7a22025-08-20T03:45:32ZengNature Publishing GroupTranslational Psychiatry2158-31882025-06-0115111110.1038/s41398-025-03428-xSynergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administrationTom Ben-Tal0Ilana Pogodin1Alexander Botvinnik2Tzuri Lifschytz3Uriel Heresco-Levy4Bernard Lerer5Hadassah BrainLabs Center for Psychedelic Research, Hadassah Medical Center, Hebrew UniversityHadassah BrainLabs Center for Psychedelic Research, Hadassah Medical Center, Hebrew UniversityHadassah BrainLabs Center for Psychedelic Research, Hadassah Medical Center, Hebrew UniversityHadassah BrainLabs Center for Psychedelic Research, Hadassah Medical Center, Hebrew UniversityHerzog Medical Center, Hebrew UniversityHadassah BrainLabs Center for Psychedelic Research, Hadassah Medical Center, Hebrew UniversityAbstract 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.https://doi.org/10.1038/s41398-025-03428-x |
| spellingShingle | Tom Ben-Tal Ilana Pogodin Alexander Botvinnik Tzuri Lifschytz Uriel Heresco-Levy Bernard Lerer Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration Translational Psychiatry |
| title | Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration |
| title_full | Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration |
| title_fullStr | Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration |
| title_full_unstemmed | Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration |
| title_short | Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration |
| title_sort | synergistic behavioral and neuroplastic effects of psilocybin nmdar modulator administration |
| url | https://doi.org/10.1038/s41398-025-03428-x |
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