Combining psilocybin with NMDAR modulators D-serine or D-cycloserine may enhance therapeutic benefits while reducing adverse effects. In mice, psilocybin alone increased head twitch response, a proxy for hallucinogenic effects, but co-administration of D-serine or D-cycloserine reduced this response dose-dependently. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic effects, whereas psilocybin alone did not. Additionally, psilocybin with D-serine boosted GAP43 protein expression across four brain regions and overall synaptic protein levels in the hippocampus, while psilocybin with D-cycloserine elevated PSD95 levels across all regions. These results suggest that such combinations could optimize psilocybin's therapeutic potential by mitigating side effects and enhancing neuroplasticity.
Combining psilocybin with NMDAR modulators D-serine or D-cycloserine reduces hallucinogenic-like effects and enhances neuroplasticity in mice. Psilocybin alone increased head twitch response, a surrogate for hallucinogenic effects, which was dose-dependently reduced by either modulator. The combinations also decreased MK-801-induced hyperactivity, modeling antipsychotic effects. The psilocybin-D-serine combination increased GAP43 expression across all four brain regions examined and overall synaptic protein expression in the hippocampus, while psilocybin-D-cycloserine elevated PSD95 levels in all four regions, indicating synaptogenic synergy. These results suggest that pairing serotonergic psychedelics with NMDAR modulators may improve therapeutic efficacy and safety.