Psilocybin acutely alters circulating micro-RNA expression, and predicts condition-specific biomarker dissociation in healthy volunteers

Psilocybin is metabolised to psilocin, a non-selective partial 5-HT2A receptor agonist that alters mood, cognition and perception. Single doses of psilocybin have been found to alter glutamate concentration in the medial prefrontal cortex (mPFC) and decrease immune markers including TNF-α and IL-6 in healthy volunteers, with preclinical studies suggesting increased BDNF. Circulating micro-RNAs (cimiRNAs) are small non-coding RNAs (18–25 nucleotides) that regulate post-transcriptional gene expression and are stable, blood-based candidate biomarkers. Previous work by our group demonstrated that, besides changes in glutamate and immune markers, psilocybin acutely influences cimiRNA expression related to neuroplasticity and inflammation. Whether these acute miRNA changes are associated with downstream immune and neurotrophic responses remains unknown, despite over-representation analysis (ORA) implicating precisely these pathways. This study characterise baseline-to-360 min changes in let-7g-5p and miR-150-5p, and determine whether acute cimiRNA delta scores predict neuroplasticity, inflammatory, pharmacokinetic and neurochemical outcomes in the same randomised placebo-controlled cohort. Blood plasma samples were collected from healthy young adult volunteers who received a single oral dose of psilocybin (0.17 mg/kg) or placebo, as part of a randomised, double-blind, placebo-controlled, parallel-group study (N=62; 31 per group). Plasma cimiRNA expression was profiled by next-generation sequencing (NGS) at baseline, 360 min, and 7 days post-administration. The candidate miRNAs, let-7g-5p and miR-150-5p, were selected from prior NGS-based differential-expression analyses showing acute psilocybin-specific changes, with pathway enrichment via Reactome using experimentally validated miRTarBase targets. The present analysis examined previously reported psilocybin-associated biomarkers from the same participants. BDNF was newly included as a neurotrophic outcome. BDNF, TNF-α, IL-6, CRP, and psilocin were analysed as baseline-to-360 min change scores; cortisol as baseline-to-80 min; and mPFC glutamate as an absolute MRS measure at +65 min. Associations with miRNA delta scores were tested using simple linear regression, pooled (primary) and group-separated (secondary). Nominal significance was p < 0.05, uncorrected for multiple comparisons. Two cimiRNAs were significantly differentially expressed at 360 min post-psilocybin (FDR < 0.05), with no significant changes at 7 days or in placebo. ORA revealed enrichment of targets in neuroplasticity pathways (TrkA, MAPK, mTOR) and inflammatory pathways (IL-6, TGF-β, SMAD2/3/4). Both miRNAs significantly predicted BDNF change scores in the pooled analysis (let-7g-5p: p=0.028, R²=0.10; miR-150-5p: p=0.031, R²=0.09) and in the placebo group (let-7g-5p: p=0.006, R²=0.26; miR-150-5p: p=0.031, R²=0.17). In the psilocybin group, let-7g-5p predicted psilocin concentration at 360 min (p=0.008, R²=0.30), and miR-150-5p predicted mPFC glutamate concentration (p=0.030, R²=0.28). No significant associations were found between either miRNA and TNF-α, IL-6, CRP, or cortisol in primary or secondary analyses. Notably, pooled miRNA-BDNF associations were driven by placebo participants, whereas psilocin and mPFC glutamate were predicted only in psilocybin participants. This may reflect stronger baseline-dependent miRNA normalisation under psilocybin, attenuating inter-individual variability relevant to miRNA-BDNF coupling. Psilocybin acutely and transiently alters cimiRNA expression, with ORA implicating neuroplasticity and inflammatory regulatory pathways. The condition-specific dissociation between placebo-linked BDNF prediction and psilocybin-linked psilocin/mPFC glutamate prediction suggests that psilocybin may acutely alter miRNA-biomarker coupling. These exploratory findings support cimiRNAs as accessible blood-based candidate biomarkers of individual neurobiological sensitivity to psilocybin.

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