4-OH-DiPT, a fast-acting and shorter-lasting derivative of psilocybin, reduces learned fear responses in mice by enhancing inhibitory signaling in the brain. It activates 5-HT2A receptors on interneurons in the basolateral amygdala, increasing GABAergic inhibition of principal neurons. In female mice, 4-OH-DiPT before extinction training reduced freezing to conditioned cues and later decreased avoidance behaviors in several tests, while male mice showed no significant differences. The compound acts as a near full agonist at 5-HT2A receptors and has comparable activity at mouse and human 5-HT2A/2B/2C receptors. These findings suggest a potential mechanism for suppressing learned fear.
Post-traumatic stress disorder varies greatly in its clinical and biological features, making treatment difficult. The largest randomized trial of ketamine for PTSD found no overall benefit over placebo, highlighting the need to identify which patients might respond. Using pre-treatment blood DNA methylation profiles and clinical data from that trial, machine learning models predicted treatment response. A model based on 1,208 methylation sites outperformed models using only clinical variables, and combining both data types improved accuracy further. The methylation-derived score identified responders with 92.9% accuracy. Predictive methylation sites were near genes involved in glutamatergic signaling, immune regulation, and known PTSD risk loci, suggesting peripheral DNA methylation patterns can guide precision pharmacotherapy for PTSD.