Role of endogenous serotonin in psychedelic-like effects of psilocybin in mice
The International Journal of Neuropsychopharmacology – May 25, 2025
Source: OpenAlex
Summary
Prior antidepressant use may diminish the acute effects of the hallucinogen psilocybin. Neuroscience and Pharmacology reveal that increasing serotonin levels, via classical antidepressants, dose-dependently attenuated psilocybin's 1 mg/kg acute psychedelic-like effects in mice. Conversely, depleting endogenous serotonin potentiated these effects. Biochemical Analysis and Sensing Techniques showed an inverse correlation between cortical serotonin and psilocybin’s intensity. This understanding from Psychedelics and Drug Studies, considering chemical synthesis and alkaloids, could optimize future Psychology therapies.
Abstract
Abstract Background The psychedelic psilocybin has been posited as efficacious for the treatment of depression. However, the potential link between the intensity of acute psychedelic effects and long-term therapeutic outcomes remains undiscovered. Moreover, the impact of classical antidepressant drugs that modulate serotonergic activity on psilocybin’s effects is a clinically relevant concern. The aim of the present study was to assess serotonergic mechanisms implicated in the regulation of the intensity of the psilocybin-induced acute effects. Methods The head-twitch response (HTR), the most translational behavioral assay to characterize the psychedelic-like effect in rodents was performed. Moreover, the role of endogenous serotonin (5-HT) on psilocybin-induced HTR was studied by in vivo brain microdialysis technique. Results Maximally effective psilocybin dose (1 mg/kg) induced progressively lower HTR in heterozygous and homozygous knockout mice for serotonin 2A receptor (5HT2AR), compared to wild type. Synaptic increase of 5-HT by citalopram dose-dependently attenuated psilocybin-induced HTR after both acute and chronic dosing regimens. Conversely, depletion of 5-HT by p-chlorophenylalanine potentiated psilocybin-evoked HTR. Serotonin 1A receptor (5HT1AR) agonist 8-OH-DPAT dose-dependently decreased psilocybin-induced HTR, demonstrating functional interaction between 5HT2AR and 5HT1AR for psychedelic effects. Conclusions The present findings reveal an inverse correlation between cortical 5-HT levels and the acute psychedelic-like effects of psilocybin. Consequently, the enhancement of serotonergic activity induced by prior antidepressant treatment may underlie interindividual variability in the acute response to psychedelics. Investigating these mechanisms in relation to the sustained therapeutic outcomes of psilocybin could contribute to optimizing the efficacy of psychedelic-based therapies.