Ketamine’s acute effects on negative brain states are mediated through distinct altered states of consciousness in humans
Laura M Hack, Xue Zhang, B. Heifets, T. Suppes, P. V. van Roessel, Jerome A. Yesavage, Nancy J Gray, Rachel Hilton, Claire Bertrand, Carolyn I. Rodríguez, K. Deisseroth, B. Knutson, Leanne M. Williams
Nature Communications October 19, 2023 DOI: 10.1038/s41467-023-42141-5 via Semantic Scholar
Summary
Ketamine rapidly induces altered states of consciousness, but the neural mechanisms are unclear. In a randomized, placebo-controlled study with nonclinical adults, functional neuroimaging examined brain activity during emotional tasks under placebo, low-dose (0.05 mg/kg), and high-dose (0.5 mg/kg) ketamine. Different dissociative experiences had opposing effects on right anterior insula activity: depersonalization reduced task-evoked activity by 0.39 standard deviations, while dissociative amnesia increased it by 0.32 standard deviations. These findings suggest that specific dissociative states may influence how ketamine affects brain activity, potentially informing treatment responses in depression.
Study at a glance
| Characteristics | Randomized controlled trial Placebo-controlled Peer reviewed |
|---|---|
| Population | Nonclinical adult participants |
| Keywords | Medicine Psychology |
| Citations | 20 |
| Registration | NCT03475277 |
| Key finding | 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.