Psilocybin is rapidly converted to psilocin in the body, which causes psychedelic effects by binding to the 5-HT2A receptor. Psilocin is mainly broken down by glucuronidation or conversion to 4-hydroxyindole-3-acetic acid (4-HIAA). In laboratory experiments with human liver microsomes, about 29% of psilocin was metabolized, while specific enzymes CYP2D6 and CYP3A4 metabolized nearly 100% and 40%, respectively. Monoamine oxidase A produced small amounts of 4-HIAA and 4-hydroxytryptophol (4-HTP), but 4-HTP appeared only in lab tests and neither metabolite showed activity at serotonin receptors. Two new potential metabolites were found: norpsilocin in mice and an oxidized form in humans, though CYP2D6 genotype did not affect psilocin levels in people. These findings help understand drug interactions and psilocybin's therapeutic use.
Psilocybin, a serotonin 2A receptor agonist, alters functional connectivity in the brain's default-mode network, which is involved in self-reference and disrupted in depression. In lightly-anesthetized mice, resting-state fMRI showed psilocybin reduced connectivity within the ventral striatum. Using gene expression maps and viral tracer projections, two distinct effects emerged: psilocybin increased connectivity between serotonin-associated networks and parts of the mouse default-mode network, thalamus, and midbrain, while decreasing connectivity within dopamine-associated striatal networks. These findings suggest that interactions between serotonin- and dopamine-regulated neural networks contribute to psilocybin's neural and psychological effects, and show how molecular and structural connectivity data can clarify pharmaco-fMRI results.
Psilocybin, a serotonin 2A receptor agonist, alters functional connectivity across the mouse brain in two distinct ways: it increases connectivity between serotonin-associated networks and cortical areas including the default-mode network, thalamus, and midbrain, while decreasing connectivity within dopamine-associated striatal networks. These opposing effects, observed in lightly-anesthetized mice using resting-state fMRI, suggest that interactions between serotonin- and dopamine-regulated neural networks contribute to psilocybin's neural and psychological effects. The findings also demonstrate how gene expression maps and viral tracer projection fields can help interpret pharmaco-fMRI results.