Distinctive Molecular and Metabolic Profiles of Chemically Synthesized Psilocybin and Psychedelic Mushroom Extract

Author:

Shahar Orr1,Botvinnik Alexander1,Shwartz Amit1,Lerer Elad1,Buko Alex2,Hamid Ethan1,Kahn Dani1,Guralnick Miles1,Blakolmer Karin3,Wolf Gilly4,Lerer Leonard5ORCID,Lerer Bernard1ORCID,Lifschytz Tzuri1

Affiliation:

1. Biological Psychiatry Laboratory and Hadassah BrainLabs Center for Psychedelic Research, Hadassah Medical Center, Hebrew University, Jerusalem, Israel

2. Human Metabolome Technologies, Boston, MA, USA

3. Parow Entheobiosciences (ParowBio), Chicago, IL, USA

4. Biological Psychiatry Laboratory and Hadassah BrainLabs Center for Psychedelic Research, Hadassah Medical Center, Hebrew University, Jerusalem, Israel; Achva Academic College, Beer Tuvia, Israel

5. Parow Entheobiosciences (ParowBio), Chicago, IL, USA; Back of the Yards Algae Sciences (BYAS), Chicago, IL, USA

Abstract

Abstract 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 minutes. Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed for the synaptic proteins, GAP43, PSD95, synaptophysin and SV2A, using western blots. These proteins are indicators of synaptic plasticity. Three days after treatment, there was minimal increase in synaptic proteins. After 11 days, nested analysis of variance (ANOVA) showed a significant increase in each of the 4 proteins over all brain areas studied 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.

Publisher

Research Square Platform LLC

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