A unified model of ketamine's dissociative and psychedelic properties.
Miriam Marguilho, Inês Figueiredo, Pedro Castro-Rodrigues
Journal of Psychopharmacology December 17, 2022 DOI: 10.1177/02698811221140011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Esketamine Ketamine |
| Keywords | Psychopharmacology Mental health Consciousness research Ketamine therapy |
| Citations | 57 |
| Key points | Proposes that ketamine's antidepressant effects are driven by acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. |
Abstract
Ketamine is an N-methyl-d-aspartate antagonist which is increasingly being researched and used as a treatment for depression. In low doses, it can cause a transitory modification in consciousness which was classically labelled as ‘dissociation’. However, ketamine is also commonly classified as an atypical psychedelic and it has been recently reported that ego dissolution experiences during ketamine administration are associated with greater antidepressant response. Neuroimaging studies have highlighted several similarities between the effects of ketamine and those of serotonergic psychedelics in the brain; however, no unified account has been proposed for ketamine’s multi-level effects – from molecular to network and psychological levels. Here, we propose that the fast, albeit transient, antidepressant effects observed after ketamine infusions are mainly driven by its acute modulation of reward circuits and sub-acute increase in neuroplasticity, while its dissociative and psychedelic properties are driven by dose- and context-dependent disruption of large-scale functional networks. Computationally, as nodes of the salience network (SN) represent high-level priors about the body (‘minimal’ self) and nodes of the default-mode network (DMN) represent the highest-level priors about narrative self-experience (‘biographical’ self), we propose that transitory SN desegregation and disintegration accounts for ketamine’s ‘ dissociative’ state, while transitory DMN desegregation and disintegration accounts for ketamine’s ‘ psychedelic’ state. In psychedelic-assisted psychotherapy, a relaxation of the highest-level beliefs with psychotherapeutic support may allow a revision of pathological self-representation models, for which neuroplasticity plays a permissive role. Our account provides a multi-level rationale for using the psychedelic properties of ketamine to increase its long-term benefits.
Comparable studies
Other theoretical and historical papers on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. | 2014 | Historical analysis | |
| A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics | 2020 | Theoretical or philosophical paper | |
| Neuroscience and the Near-Death Experience: Roles for the NMSA-PCP receptor, the sigma receptor and the endopsychosins | 1990 | Theoretical or philosophical paper | |
| An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression. | 2021 | Theoretical or philosophical paper | |
| Arketamine for cognitive impairment in psychiatric disorders | 2023 | Theoretical or philosophical paper |
Citations in the library
Cited by 54
- Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. Biomedicines October 9, 2024
- The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression Frontiers in Psychiatry September 19, 2023
- Novel rapid treatment options for adolescent depression. Pharmacological Research March 1, 2024
- Disembodiment and Affective Resonances in Esketamine Treatment of Depersonalized Depression Subtype: Two Case Studies. Psychopathology 2024
- The cognitive neuroscience of self‐awareness: Current framework, clinical implications, and future research directions Wiley Interdisciplinary Reviews: Cognitive Science December 3, 2023
and 49 more in the library
Cites 153
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- 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
- Interoceptive inference, emotion, and the embodied self Trends in Cognitive Sciences October 12, 2013
and 148 more in the library