Cortical Mechanisms Contributing to Ketamine-Induced Dissociation
Kallol Bera, Loren L. Looger, Alex Proekt, Joseph Cichon
The Neuroscientist December 26, 2025 DOI: 10.1177/10738584251403946 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Ketamine Esketamine |
| Keywords | Disinhibition Dissociative Nmda receptor Intracellular Dissociation chemistry Human brain Ampa receptor Biological neural network Glutamate receptor Antidepressant Mechanism biology Consciousness |
| Citations | 5 |
| Key findings | Ketamine's dissociative and antidepressant effects arise from NMDA receptor and HCN1 channel antagonism, pyramidal neuron disinhibition, altered thalamocortical connectivity, and potential intracellular actions modulating excitability and epigenetic state. |
Abstract
Ketamine is a unique anesthetic agent that induces dissociative anesthesia, characterized by perceptual detachment, analgesia, and altered states of consciousness. Beyond its widespread use in anesthesia, subhypnotic ketamine dosing has emerged as a rapid-acting antidepressant and a valuable model for probing the neural mechanisms underlying consciousness and neuropsychiatric disorders. At the core of its effects are actions on cortical circuits, primarily through NMDA receptor and HCN1 channel antagonism, disinhibition of pyramidal neurons, and altered thalamocortical connectivity. This review brings together emerging findings from ketamine pharmacology, cell type-resolved and region-specific in vivo imaging, and systems neuroscience to define how ketamine alters cortical circuit dynamics to drive dissociation. We further explore the intriguing possibility that ketamine freely diffuses into and concentrates within intracellular compartments and, in doing so, modulates neuronal excitability, intracellular signaling, and an epigenetic state, even following a single dose. A deeper mechanistic understanding of these cortical and cellular processes will not only advance our knowledge of ketamine's complex pharmacology but may also inform new therapeutic strategies for treatment-resistant depression and facilitate the study of diverse states of consciousness.
Comparable studies
Other narrative reviews on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms | 2018 | Review | |
| Mechanisms of Ketamine Action as an Antidepressant | 2018 | Review | |
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) | 2013 | Review | |
| A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders | 2017 | Review and consensus statement |
Citations in the library
Cited by 2
- The Dark Side of Ketamine: Brain, Bladder, and Beyond: a Focused Clinical Review for Emergency Medicine Clinicians Anatolian Journal of Emergency Medicine June 28, 2026
- Ketamine Across the Dose-State Continuum: EEG Signatures, Network Dynamics, and Implications for Brain-State Monitoring in Anesthesia and Critical Care. Brain Sciences August 9, 2026
Cites 68
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
and 63 more in the library