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, Peter J. Roessel, Jerome A. Yesavage, Nancy J. Gray, Rachel Hilton, Claire Bertrand, Carolyn I. Rodriguez, Karl Deisseroth, Brian Knutson and Leanne M. Williams ()
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Laura M. Hack: Stanford University School of Medicine
Xue Zhang: Stanford University School of Medicine
Boris D. Heifets: Stanford University School of Medicine
Trisha Suppes: Stanford University School of Medicine
Peter J. Roessel: Stanford University School of Medicine
Jerome A. Yesavage: Stanford University School of Medicine
Nancy J. Gray: Stanford University School of Medicine
Rachel Hilton: Stanford University School of Medicine
Claire Bertrand: Stanford University School of Medicine
Carolyn I. Rodriguez: Stanford University School of Medicine
Karl Deisseroth: Stanford University School of Medicine
Leanne M. Williams: Stanford University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42141-5

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