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Psilocybin-containing mushrooms as a prospective therapeutic for Parkinson’s disease. Pre-clinical study
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Psilocybin-containing mushrooms as a prospective therapeutic for Parkinson’s disease. Pre-clinical study

Elisabete Godinho de Oliveira
Southern Cross University
Masters by Thesis, Southern Cross University
2025
DOI:
https://doi.org/10.25918/thesis.558
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Abstract

Psilocybin Parkinson's disease Neuroplasticity Alpha-synuclein
Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by motor and cognitive deterioration. Current therapies are predominantly symptomatic, alleviating clinical manifestations rather than curing the disease. The need for disease-modifying treatments has led to a resurgence of interest in psychedelic compounds as potential therapeutics, particularly the tryptamine alkaloids found in Psilocybe 'magic' mushrooms. Emerging evidence suggests that psilocybin can promote neuroplasticity, reduce inflammation, and improve cognitive function, presenting a novel therapeutic target for neurodegenerative conditions such as PD. Aim: To investigate the effects of Psilocybe cubensis extracts in an in vitro PD cell model, focusing on cellular phenotypes associated with PD, including neurite outgrowth and alpha-synuclein (α-syn) aggregation. Methodology: P. cubensis extracts were prepared using 70% ethanol, methanol or water, and subsequently characterised by Ultra High-Performance Liquid Chromatography (UHPLC) coupled with mass spectrometry (MS). SH-SY5Y cell lines stably expressing GFP-α-syn wild-type (WT), GFP-α-syn A53T (mutant), or GFP alone were treated with characterised extracts or purified compounds. Neurite outgrowth was assessed in differentiated cells, while α-syn aggregation was evaluated following rotenone exposure in both preventive and treatment models. Cellular phenotypes were imaged by confocal microscopy and quantified using ImageJ. Results: UHPLC-MS confirmed that 70% ethanol and methanol effectively extracted indole alkaloids, yielding measurable concentrations of psilocybin and psilocin (70% ethanol: 2.7 and 261 μg/mL; methanol: 43.3 and 93 μg/mL, respectively), while water preferentially extracted tryptamine. Both P. cubensis extracts and purified compounds promoted neurite outgrowth across all cell models. Purified psilocin significantly increased neurite projections in GFP control cells (p = 0.0463), while psilocybin produced the strongest effect in GFP-α-syn A53T mutant cells (p = 0.0544), with a 2.6-fold increase in neurite projections compared with controls. Interestingly, P. cubensis extracts promoted neurite outgrowth independently of exogenous BDNF, suggesting activation of endogenous neurotrophic pathways. In α-syn aggregation assays, extracts reduced rotenone-induced α-syn aggregation in GFP-α-syn WT cells, with the 70% ethanol extract demonstrating the strongest protective trend (p = 0.0756). In contrast, GFP-α-syn A53T cells showed no significant reduction in aggregation in either preventive or treatment assays (all p > 0.5). Conclusion: P. cubensis extracts and purified alkaloids enhanced neurite outgrowth across all cell models, with psilocybin showing particular efficacy in GFP-α-syn A53T cells and whole mushroom preparations exhibiting BDNF-independent neurotrophic activity. While extracts reduced α-syn aggregation in GFP-α-syn WT cells, this effect was absent in GFP-α-syn A53T cells, suggesting the pathogenic mutation may overwhelm the protective mechanisms of the extracts. Nevertheless, the ability of P. cubensis extracts to promote neurite outgrowth in mutant cells, despite lacking anti-aggregation effects in this model, suggests potential therapeutic value for supporting neuronal function in familial PD.

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