Ketamine’s acute effects on negative brain states are mediated through distinct altered states of consciousness in humans
Laura M Hack, Xue Zhang, Boris D. Heifets, Trisha Suppes, P. V. van Roessel, Jerome A. Yesavage, Nancy J Gray, Rachel Hilton, Claire Bertrand, Carolyn I. Rodríguez, Karl Deisseroth, Brian Knutson, Leanne M Williams
Nature Communications October 19, 2023 DOI: 10.1038/s41467-023-42141-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Placebo-controlled Peer reviewed |
|---|---|
| Population | Nonclinical adult participants |
| Intervention | Ketamine |
| Dose | 0.05 mg/kg, 0.5 mg/kg |
| Topics | Altered states of consciousness Esketamine Ketamine |
| Citations | 20 |
| Registration | NCT03475277 |
| Key findings | Ketamine-induced depersonalization reduced right anterior insula activity, while dissociative amnesia increased it. |
Abstract
Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain’s affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.
Comparable studies
Other randomized controlled trials on altered states of consciousness, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor Healthy human participants | 2018 | Double-blind, randomized, counterbalanced, cross-over study | n = 24 |
| Effective connectivity changes in LSD-induced altered states of consciousness in humans. Healthy participants | 2019 | Double-blind, randomized, placebo-controlled, cross-over study | n = 25 |
| Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects. Healthy hallucinogen-using adults | 2013 | Double-blind, placebo-controlled study | n = 8 |
| High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens. Healthy volunteers with histories of hallucinogen use | 2012 | Randomized controlled trial | n = 12 |
| A placebo-controlled investigation of synaesthesia-like experiences under LSD. | 2016 | Within-groups placebo-controlled pilot study |
Citations in the library
Cited by 10
- (R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders. International Journal of Molecular Sciences June 20, 2024
- Psychedelics for the Treatment of Psychiatric Disorders: Interpreting and Translating Available Evidence and Guidance for Future Research. American Journal of Psychiatry 2025
- Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care. Anesthesiology August 1, 2024
- Listening to music during intranasal (es)ketamine therapy in patients with treatment-resistant depression correlates with better tolerability and reduced anxiety Frontiers in Psychiatry January 23, 2024
- Towards an expanded neurocognitive account of ketamine's rapid antidepressant effects. The International Journal of Neuropsychopharmacology February 4, 2025
and 5 more in the library
Cites 32
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Measurement of dissociative states with the Clinician‐Administered Dissociative States Scale (CADSS) Journal of Traumatic Stress 1998
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Psychometric Evaluation of the Altered States of Consciousness Rating Scale (OAV) PLoS One August 31, 2010
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
and 27 more in the library