Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
April 1, 2024
Thomas J Kelly, Emma M Bonniwell, Lianwei Mu et al.
26 citations
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.
Nature Communications
April 8, 2026
Thomas J. Kelly, Xiaojie Liu, Yao Huang et al.
High doses of cannabinoids like THC produce anxiety, but the underlying brain mechanisms were unclear. This study in mice identifies a specific neural circuit—projections from the anterior cingulate cortex to the dorsomedial striatum—where cannabinoid signaling promotes anxiety and aversion. Activating this circuit reduces anxiety, whereas cannabinoids suppress its activity via CB1 receptors. Deleting CB1 receptors specifically in this circuit reduced both innate anxiety and conditioned place aversion to THC. These findings reveal a circuit-level mechanism for cannabinoid-induced anxiety.
Psychedelics
August 9, 2024
Thomas J. Kelly, Qing-Song Liu
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.