Serotonergic psychedelics like psilocybin show promise for treating depression and other neuropsychiatric disorders, but their psychotomimetic effects may limit use. They enhance neuroplasticity through serotonin 2A receptor activation and interactions with glutamate receptors, TrkB, and mTOR. Drugs like ketamine, D-serine, and D-cycloserine share some of these mechanisms and have neuroplastic and antidepressant effects, with D-serine and D-cycloserine also showing procognitive effects. The authors hypothesize that combining a psychedelic with an NMDAR modulator could increase therapeutic impact, allow dose adjustments, and improve safety. They propose initial research on acute concurrent administration of psilocybin with D-serine or D-cycloserine for depression.
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.