Temporal effects of a single oral dose of psilocybin on plasma circulating miRNAs in healthy young adults.

Background: Psilocybin, a classic psychedelic, produces acute alterations in brain function, and has shown sustained therapeutic effects in psychiatric disorders. However, most studies focus on acute brain imaging readouts (e.g., fMRI) and rarely assess longer-term molecular changes. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, are enriched in the brain, and can be released into blood, potentially indexing brain-relevant molecular processes. We hypothesised that a single psilocybin dose would show acute changes in miRNAs with predicted relevance to neuroplasticity related signalling and immune/inflammatory regulation in healthy adults. Methods: In a randomised, double-blind, placebo-controlled study (N=62; 31 psilocybin, 31 placebo), volunteers received psilocybin (0.17 mg/kg) or placebo. Blood was collected at baseline, 360 minutes, and 7 days after dosing. Plasma miRNAs were quantified by small RNA sequencing. Elastic net regression was used for feature selection, followed by differential expression analysis and validation with linear mixed models. Pathway enrichment used Reactome and Gene Ontology. Results: Two circulating miRNAs (let-7g-5p and miR-150-5p) met criteria for differentially expressed at 360 minutes following psilocybin administration, with no significant differences detected at 7 days or in the placebo condition under the statistical thresholds used. Over representation analysis suggested enrichment of molecular processes involved in neuroplasticity (e.g., TrkA, MAPK), inflammation (e.g., IL-6, TGF-{beta}), and transcriptional regulation (e.g., RNA polymerase II, SMAD2/3/4). Conclusions: A single oral dose of psilocybin was associated with transient alterations in circulating miRNA expression, consistent with an acute shift in circulating gene-regulatory miRNA signals, without sustained miRNA changes at 7 days. These findings provide initial evidence that circulating miRNA changes after psilocybin may reflect acute molecular process responses and support further investigation of circulating miRNAs as potential biomarkers of psychedelic-induced molecular responses.