Network pharmacology and molecular simulation reveal the entourage effect mechanisms of psilocybin-producing mushrooms on the brain
Scientific Reports – February 14, 2026
Source: OpenAlex
Summary
Whole mushroom extracts containing psilocybin may offer enhanced therapeutic potential for psychiatric disorders, outperforming isolated psilocybin. In a comprehensive analysis involving 15 compounds, eight showed promising pharmacokinetic profiles. Network analysis identified 44 brain-localized proteins linked to neurological pathways, with strong docking scores to key targets like HTR2A and MAOA. Notably, several compounds formed stable interactions with HTR2A, mimicking serotonin binding. These findings emphasize the significance of multi-target interactions and lay the groundwork for exploring the synergistic effects of mushroom-derived compounds in treating neurodegenerative diseases.
Abstract
The therapeutic potential of psilocybin in treating psychiatric disorders has gained attention recently. While most research has focused on isolated psilocybin, evidence suggests that whole mushroom extracts exhibit greater efficacy, implicating a possible entourage effect of additional bioactive compounds. This study aimed to elucidate the holistic neuropharmacological effects of psilocybin-producing mushroom compounds through a computational framework incorporating network pharmacology, molecular docking, and molecular dynamics. Fifteen mushroom-derived compounds were identified from literature, of which eight exhibited favorable pharmacokinetic profiles. Target prediction and network analysis identified 44 brain-localized proteins with partial biological connectivity. Functional enrichment and pathway analyses implicate key neurological pathways. The compounds exhibited strong docking scores to neurologically relevant targets. Several compounds formed stable salt bridges with the Asp155 residue of HTR2A, mirroring serotonin’s binding behavior. Molecular dynamics simulations further confirmed high residence stability of the compounds within the binding pockets of HTR2A and MAOA. These findings support a mechanistic rationale for the enhanced efficacy of whole mushroom extracts over isolated psilocybin and underscore the therapeutic potential of other constituent compounds. The study highlights the importance of multi-target interactions in mediating neuropsychiatric effects and provides a foundation for further investigations into the synergistic roles of these compounds in CNS modulation.