Synergistic behavioral and neuroplastic effects of psilocybin-NMDAR modulator administration

Combining the psychedelic psilocybin with the NMDAR modulators D-serine or D-cycloserine reduced hallucinogenic-like effects and enhanced antipsychotic-like effects in male mice, while also promoting neuroplasticity-related synaptic protein expression. Psilocybin alone increased head twitch response, a surrogate for hallucinogenic effects, which was dose-dependently lowered by either modulator. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic action. The psilocybin-D-serine combination increased GAP43 expression across four brain regions and overall synaptic protein levels in the hippocampus; psilocybin-D-cycloserine elevated PSD95 across all regions. These results suggest that pairing serotonergic psychedelics with NMDAR modulators may improve therapeutic potential by reducing adverse effects and enhancing neuroplasticity.

Study at a glance

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.