Nature Neuroscience
October 2, 2025
Ahmad Hammo, Stephen Wisser, Joseph Cichon
20 citations
A single dose of psilocybin rapidly and sustainably reversed both mechanical allodynia and anxiety-depression-like behaviors in adult male and female mice with chronic pain. The effect depended on psilocin, the active metabolite, engaging prefrontal cortical circuits. Two-photon calcium imaging showed that psilocin quickly normalized hyperactivity in anterior cingulate cortex layer 2/3 pyramidal neurons, a hallmark of chronic pain. Full agonists of 5-HT2A and 5-HT1A receptors replicated some but not all of psilocin's cellular and behavioral effects, indicating that partial agonism at these receptors within shared pain-and-mood circuits underlies the dual therapeutic action.
Molecular psychiatry
June 1, 2026
Charles F Zorumski, Joseph Cichon, Yukitoshi Izumi et al.
5 citations
Nitrous oxide (N2O), an inhalational anesthetic used for over 150 years, shows rapid and durable antidepressant effects in patients with major depressive disorder and treatment-resistant depression, according to recent clinical trials. Like ketamine, N2O inhibits N-methyl-D-aspartate receptors (NMDARs) but through distinct mechanisms. Cellular and neuronal circuit studies are early but suggest N2O shares some downstream mechanisms with ketamine while also having unique effects on neurophysiology and signaling. Human neuroimaging studies have begun identifying acute and persisting effects of N2O on brain circuits relevant to antidepressant responses. This review highlights current clinical and preclinical research, major unanswered questions, future directions, and potential barriers to clinical use.
The Neuroscientist
December 26, 2025
Kallol Bera, Loren L. Looger, Alex Proekt et al.
5 citations
Ketamine, an anesthetic that produces dissociative anesthesia—characterized by perceptual detachment, analgesia, and altered consciousness—also acts as a rapid antidepressant at low doses and serves as a tool to study consciousness and neuropsychiatric disorders. Its effects stem from actions on cortical circuits: blocking NMDA receptors and HCN1 channels, disinhibiting pyramidal neurons, and altering thalamocortical connectivity. The review synthesizes findings from pharmacology, cell-specific imaging, and systems neuroscience to explain how ketamine alters cortical dynamics to drive dissociation. It also explores the possibility that ketamine enters intracellular compartments, modulating neuronal excitability, signaling, and epigenetic state after a single dose. Understanding these processes may inform new treatments for treatment-resistant depression and the study of consciousness.
Translational Perioperative and Pain Medicine
June 29, 2022
Joseph Cichon, Renyu Liu, Hoang-Vinh Le
Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, is a potent and highly selective kappa opioid receptor (KOR) agonist with a unique chemical structure lacking nitrogen, unlike all classic opioid receptor ligands. Its fast metabolism via hydrolysis to inactive salvinorin B results in a short duration of action, but a single dose induces rapid and robust changes in neural activity and connectivity in disease-related circuits. These neurophysiological effects may explain its rapid and durable therapeutic effects in difficult-to-treat neuropsychiatric disorders. The compound also serves as a valuable backbone for developing novel KOR-targeting drugs.