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.
Classical psychedelics are being studied as potential treatments for PTSD. Research in rodents shows these substances affect fear learning, recall, and extinction. The amygdala, a brain region central to fear processing, is key to these effects. Psychedelics interact with different cell types in the amygdala, and specific neural circuits may underlie their fear-suppressing effects. Because rodent and human amygdalas are functionally similar, findings from animal studies can guide clinical trials for psychedelic-assisted PTSD therapy. The authors emphasize that each psychedelic's unique pharmacology and duration of action are important factors for future research.