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.