A single dose of psilocybin (2.5 mg/kg) given to mice before extinction training reduced freezing time—a measure of fear—24 hours, 6 days, and 7 days later, indicating rapid and sustained facilitation of fear extinction. Psilocybin also reversed fear-conditioning-induced decreases in hippocampal dendritic complexity, spine density, levels of BDNF and mTOR proteins, and numbers of DCX- and BrdU-positive cells (markers of neurogenesis). These findings suggest psilocybin promotes hippocampal neuroplasticity, which may partially underlie its ability to enhance fear extinction. The authors propose psilocybin could be a useful adjunct to exposure-based therapies for PTSD and other disorders involving impaired fear extinction.
Several anesthetic agents—ketamine, propofol, nitrous oxide, sevoflurane, and isoflurane—show promise as rapid antidepressants, especially for treatment-resistant depression. Their effects appear to involve modulation of glutamate and GABA signaling, interactions with serotonin, dopamine, and norepinephrine, activation of BDNF and VGF pathways, regulation of the HPA axis, and suppression of inflammation. These mechanisms overlap with core depression-related changes. While traditional antidepressants have limited efficacy and delayed onset, anesthetics offer faster alternatives. However, their precise mechanisms, long-term safety, and optimal clinical use remain unclear. This review summarizes recent experimental and clinical research on these agents, highlighting molecular mechanisms, therapeutic potential, and current limitations.