Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration
Tom Ben-Tal, Ilana Pogodin, Alexander Botvinnik, Tzuri Lifschytz, Uriel Heresco-Levy, Bernard Lerer
Translational Psychiatry June 13, 2025 DOI: 10.1038/s41398-025-03428-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Peer reviewed |
|---|---|
| Population | ICR male mice |
| Interventions | Psilocybin D-serine D-cycloserine |
| Topics | Psychedelic-assisted therapy Psilocybin |
| Keywords | Mental health treatment Neuroscience research Psilocybin studies Brain chemistry |
| Citations | 2 |
| Key findings | Combining psilocybin with D-serine or D-cycloserine reduced hallucinogenic-like effects and enhanced antipsychotic-like effects while promoting neuroplasticity-related synaptic protein expression in male mice. |
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.
Comparable studies
Other preclinical and animal studies on psilocybin and psychedelic-assisted therapy, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin prevents reinstatement of alcohol seeking by disrupting the reconsolidation of alcohol-related memories. Male and female Marchigian Sardinian alcohol-preferring (msP) rats | 2023 | Preclinical experimental study | |
| A Proposal to Study the Safety and Efficacy of Psilocybe cubensis in Preclinical and Clinical Studies as a Therapeutic Alternative for Major Depressive Disorder Healthy adults and patients with major depressive disorder | 2023 | Research project design with preclinical and clinical experimental components | |
| Efficient Acyloxymethylation of Psilocin and Other Tryptamines Yielding ACOM Prodrugs for Psychedelic-Assisted Therapy. | 2025 | In vitro study |
Citations in the library
Cited by 3
- Psychedelics in Multiple Sclerosis: Mechanisms, Challenges, and Prospects for Neuroimmune Modulation and Repair. Cells November 26, 2025
- PSYCHEDELICS IN PSYCHIATRY - OVERVIEW OF PSILOCYBIN RESEARCH International Journal of Innovative Technologies in Social Science September 1, 2025
- From network destabilisation to adaptive reconfiguration: A hippocampal longitudinal axis model of psychedelic therapy. Progress in Neuro-Psychopharmacology and Biological Psychiatry August 20, 2026
Cites 34
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 29 more in the library