A unified model of ketamine’s dissociative and psychedelic properties

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.

Cannabis-assisted psychotherapy for complex dissociative posttraumatic stress disorder: A case report

“…Irrespective, these facets of mysticism have been reported with high dose cannabis and overlap with those produced by classic psychedelics, including lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and psilocybin ( 37 – 41 ). They also reflect properties of ketamine, a dissociative agent, known to reduce self-referential awareness and induce feelings of unity, spirituality, and insight ( 42 , 43 ). These parallels are intriguing, provided distinct mechanisms of action.…”

Depression with comorbid borderline personality disorder - could ketamine be a treatment catalyst?

“…Alexander speculates that ketamine acute effects on subgenual ACC reflect in shutting down emotional pain network and alleviating affective pain, whereas sustained effects on neuroplastic modulation in DMN contribute to resolving of ruminative thinking patterns ( 97 ). Similarly to serotoninergic psychedelics, ketamine has been shown to acutely disintegrate functional connectivity in DMN and decrease activity within this network ( 101 , 102 ).…”

“…Ketamine may also facilitate emotional learning and improvement of negative self-schema, which is one of the core cognitive aspects of both depression and BPD ( 125 , 129 ). Moreover, ketamine-induced alteration in DMN activity is thought to enable subsequent revision of mental representations of self ( 102 ).…”

The cognitive neuroscience of self‐awareness: Current framework, clinical implications, and future research directions

“…It is a feature essential for survival, by establishing boundaries between internal (self) and external environments. The notion that body ownership is not an a priori, but rather the result of a process, becomes particularly clear in cases of its disruption, for example in specific clinical conditions (e.g., alien hand syndrome; Hassan & Josephs, 2016) and with the action of certain substances (e.g., ketamine; Marguilho et al, 2022).…”