Psilocybin, a naturally occurring, tryptamine alkaloid prodrug, is currently being investigated for the treatment of a range of psychiatric disorders. Preclinical reports suggest that the biological effects of psilocybin-containing mushroom extract or “full spectrum” (psychedelic) mushroom extract (PME), may differ from those of chemically synthesized psilocybin (PSIL). We compared the effects of PME to those of PSIL on the head twitch response (HTR), neuroplasticity-related synaptic proteins and frontal cortex metabolomic profiles in male C57Bl/6j mice. HTR measurement showed similar effects of PSIL and PME over 20 min. Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed for the synaptic proteins, GAP43, PSD95, synaptophysin and SV2A, using western blots. These proteins may serve as indicators of synaptic plasticity. Three days after treatment, there was minimal increase in synaptic proteins. After 11 days, PSIL and PME significantly increased GAP43 in the frontal cortex (p = 0.019; p = 0.039 respectively) and hippocampus (p = 0.015; p = 0.027) and synaptophysin in the hippocampus (p = 0.041; p = 0.05) and amygdala (p = 0.035; p = 0.004). PSIL increased SV2A in the amygdala (p = 0.036) and PME did so in the hippocampus (p = 0.014). In the striatum, synaptophysin was increased by PME only (p = 0.023). There were no significant effects of PSIL or PME on PSD95 in any brain area when these were analyzed separately. Nested analysis of variance (ANOVA) showed a significant increase in each of the 4 proteins over all brain areas for PME versus vehicle control, while significant PSIL effects were observed only in the hippocampus and amygdala and were limited to PSD95 and SV2A. Metabolomic analyses of the pre-frontal cortex were performed by untargeted polar metabolomics utilizing capillary electrophoresis – Fourier transform mass spectrometry (CE-FTMS) and showed a differential metabolic separation between PME and vehicle groups. The purines guanosine, hypoxanthine and inosine, associated with oxidative stress and energy production pathways, showed a progressive decline from VEH to PSIL to PME. In conclusion, our synaptic protein findings suggest that PME has a more potent and prolonged effect on synaptic plasticity than PSIL. Our metabolomics data support a gradient of effects from inert vehicle via chemical psilocybin to PME further supporting differential effects. Further studies are needed to confirm and extend these findings and to identify the molecules that may be responsible for the enhanced effects of PME as compared to psilocybin alone.
