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.
The International Journal of Neuropsychopharmacology
August 1, 2025
Bernard Lerer, T. Tal, Ilana Pogodin et al.
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.
bioRxiv (Cold Spring Harbor Laboratory)
November 28, 2024
T. Ben Tal, Ilana Pogodin, Alexaner Botvinnik et al.
preprint
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.
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.
Schizophrenia Bulletin
September 1, 2012
Daniel C Javitt, Stephen R Zukin, Uriel Heresco-Levy et al.
Over the past 20 years, glutamatergic models of schizophrenia have gained acceptance, based on phencyclidine (PCP) inducing psychosis by blocking NMDA-type glutamate receptors. This review examines two predictions: neurocognitive deficits in schizophrenia should mirror those from NMDAR dysfunction, and agents stimulating NMDAR function should be therapeutic. Studies show severe sensory dysfunction in schizophrenia, including impaired mismatch negativity and visual P1 potentials, similar to deficits from NMDAR antagonists like ketamine. Sensory dysfunction predicts impairments in higher-order cognition like emotion recognition. Treatment studies with glycine-site compounds (glycine, D-serine, D-cycloserine) and glycine transport inhibitors (RG1678) show significant beneficial effects on persistent symptoms, suggesting novel treatment and prevention approaches.