O'Shea, A. | bioRxiv Science

bioRxiv2026

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

BackgroundPsilocybin, 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. MethodsIn 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. ResultsTwo 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). ConclusionsA 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.

neuroscience↗

bioRxiv2026

Circulating MicroRNAs and Their Associations with Neurotrophic, Inflammatory and Glutamate Markers in Healthy Volunteers

Psilocybin acutely alters neurotrophic, neurochemical, and immune markers, but the relationships between these responses and circulating microRNAs (miRNAs), i.e. non-coding RNAs that regulate post-transcriptional gene expression, remain unclear. In a randomized, double-blind, placebo-controlled study of 62 healthy adults who received psilocybin (0.17 mg/kg) or placebo, we previously demonstrated that let-7g-5p and miR-150-5p were transiently differentially expressed 360 minutes after psilocybin administration. Here, we examined whether changes in these miRNAs were associated with concurrent neurotrophic, inflammatory, pharmacokinetic, and glutamatergic measures. Expression changes from baseline to 360 min and 7 days were analysed using linear regression against changes in BDNF, TNF-, IL-6, C-reactive protein, cortisol, medial prefrontal cortex glutamate/total creatine, and psilocin concentrations. Psilocybin increased let-7g-5p and decreased miR-150-5p expression. Changes in let-7g-5p were positively associated with psilocin concentrations, suggesting sensitivity to inter-individual pharmacokinetic variability, whereas miR-150-5p showed no concentration-dependent association. In both groups, miRNA changes were negatively related to baseline expression: lower baseline let-7g-5p predicted larger increases, whereas higher baseline miR-150-5p predicted larger decreases. BDNF changes were associated with both miRNAs under placebo but not psilocybin, consistent with reduced between-subject variability and a flattened BDNF-miRNA relationship following treatment. Medial prefrontal glutamate was negatively associated with miR-150-5p change under psilocybin. No associations were found with immune biomarkers. Together, these findings support the predicted involvement of let-7g-5p and miR-150-5p in neuroplasticity and their potential as accessible blood-based biomarkers of individual neurobiological responsiveness to psilocybin and other psychedelics.

neuroscience↗