Molecular psychiatry
January 1, 2024
Uriel Heresco-Levy, Bernard Lerer
17 citations
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.
Translational Psychiatry
June 13, 2025
Tom Ben-Tal, Ilana Pogodin, Alexander Botvinnik et al.
2 citations
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.
Molecular psychiatry
January 1, 2023
Gilly Wolf, Sandeep Singh, Karin Blakolmer et al.
Negative symptoms of schizophrenia, which cause long-term disability and respond poorly to antipsychotic drugs, are linked to cortical atrophy and cell loss. Psychedelic drugs, which show promise for other psychiatric conditions and enhance neuroplasticity in preclinical studies, might help treat these pathological changes. The main risk is inducing or worsening psychosis. Strategies to mitigate this risk include using non-hallucinogenic derivatives, sub-psychedelic or microdosing, harnessing entourage effects in psychedelic mushroom extracts, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies with appropriate animal models are needed before careful clinical trials can proceed.