A single dose of the psychedelic DOI produces rapid and sustained antidepressant-like effects by altering chromatin organization at enhancer regions of genes involved in synaptic assembly in the frontal cortex, an effect mediated by the 5-HT2A receptor. These epigenetic changes drive lasting synaptic plasticity and accelerate fear extinction. The findings suggest that epigenetic-driven synaptic plasticity underlies psychedelics' long-lasting antidepressant action, but also indicate potential risks for individuals with underlying vulnerability to psychosis, as the altered neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression, and attention deficit hyperactivity disorder.
A single dose of the psychedelic psilocybin reduces conditioned behavior and withdrawal caused by the opioid oxycodone in male mice but not in females. This sex-specific effect is mediated by the 5-HT2A receptor in frontal cortex pyramidal neurons that project to the nucleus accumbens. Psilocybin also alters epigenomic regulation after repeated oxycodone exposure and induces sex-specific structural plasticity in the nucleus accumbens independently of the 5-HT2A receptor. Female frontal cortex and nucleus accumbens show fewer changes at gene enhancer regions in response to psilocybin, repeated oxycodone, or their combination compared to males, with the frontal cortex displaying more pronounced sex differences at the epigenomic level.