A single psychedelic dose of psilocybin increases synaptic density and temporarily reduces serotonin 2A receptor density in the pig brain. One day after injection, hippocampal synaptic vesicle protein 2A (SV2A) density was 4.42% higher, while hippocampal and prefrontal cortex 5-HT2AR density dropped by 15.21% to 50.19%. Seven days later, SV2A density remained significantly higher in the hippocampus (+9.24%) and prefrontal cortex (+6.10%), but 5-HT2AR density had returned to baseline. These persistent synaptic changes and acute receptor down-regulation may underlie psilocybin’s antidepressant effects.
A single dose of psilocybin alters the expression of specific microRNAs (miRNAs) in the prefrontal cortex and hippocampus of pigs, brain regions central to depression. One day after administration, 12 miRNAs were dysregulated in the prefrontal cortex and 2 in the hippocampus; after one week, only 4 dysregulated miRNAs remained in the hippocampus. Nine of the 18 identified miRNAs have been previously linked to depression. Two miRNAs, miR-212-3p and miR-107, showed robust acute regulation in the prefrontal cortex and are known to exert anti-inflammatory effects, mirroring previously reported effects of psilocybin. These results suggest psilocybin may exert its molecular effects through miRNA regulation.