Effects of Psilocybin on Mouse Brain Microstructure

BACKGROUND AND PURPOSE: There is surging interest in the therapeutic potential of psychedelic compounds like psilocybin in the treatment of psychiatric illnesses like major depressive disorder (MDD). Recent studies point to the rapid antidepressant effect of psilocybin; however, the biologic mechanisms underlying these differences remain unknown. This study determines the feasibility of using diffusion MRI to characterize and define the potential spatiotemporal microstructural differences in the brain following psilocybin treatment in C57BL/6J male mice.

MATERIALS AND METHODS: Eleven- to 15-week-old C57BL/6J male mice were randomly assigned to receive psilocybin, 6-fluoro-N, N-diethyltryptamine, or saline and ex vivo imaged 24 hours (n=18) and 72 hours (n=18) posttreatment. A 1-way ANOVA with multiple comparison testing (Bonferroni correction) assessed diffusion metric differences (tractography, DTI, neurite orientation dispersion and density imaging) between the 3 groups and was performed in the following regions of interest: amygdala, striatum, hippocampus, thalamus, primary visual cortex area, frontal association cortex, and medial prefrontal cortex at 24 hours and 72 hours postdrug administration.

RESULTS: Psilocybin-treated mice demonstrated structural connectivity differences at 72 hours in the frontal association cortex (compared with saline, mean tract length increases, P = .03). Psilocybin also induced microstructural differences at 24 hours postinjection in the primary visual cortex (compared with saline, mean diffusivity [MD] increases, P = .02) and 72 hours postinjection in the striatum (compared with saline; MD increases, P = .02, neurite density index [NDI] decreases, P = .02) and hippocampus (compared with saline; MD increases, P = .04, NDI decreases, P = .02).

CONCLUSIONS: Diffusion microstructure imaging and white matter tractography are sensitive methods to detect and characterize the neural substrates and microstructural differences accompanying psilocybin treatment. These findings suggest the potential role for diffusion microstructure imaging to quantify the bioeffects of psychedelics like psilocybin on the brain, monitor treatment response, and identify salient clinical end points in an emerging therapeutic option for patients with MDD.