Long-Term Heavy Ketamine Use is Associated with Spatial Memory Impairment and Altered Hippocampal Activation

Abstract

Ketamine, a non-competitive N-methyl-d-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 poly-drug controls, matched for IQ, age, years in education. We used fMRI utilizing an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus, and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users.

Putative neuroprotective pharmacotherapies to target the staged progression of mental illness

“…High‐dose ketamine, such as is used for anaesthesia, is possibly neurotoxic to the developing brain (X. Zheng, Zhou, & Xia, ). Furthermore, chronic ketamine abuse is associated with an irreversible decline in brain function (Morgan et al, ). However, low‐dose acutely administered ketamine is an emerging therapy in treatment‐resistant depression and suicidality (C. Kraus et al, ).…”

Modulation of the activity of <em>N</em>-methyl-D-aspartate receptors as a novel treatment option for depression: current clinical evidence and therapeutic potential of rapastinel (GLYX-13)

“…Regrettably, these may not be the only deleterious effects precipitated by ketamine. Although serial infusions of ketamine in the short term (of 4 weeks) do not result in significant cognitive impairment,27 recent investigations underline serious cognitive deficits and altered hippocampal activation in heavy ketamine abusers 28. In addition, ketamine was shown to have several undesired actions in rodent models, inducing cortical neurotoxicity29 and the initiation of abnormal cortical oscillations 30.…”

La ketamina come antidepressivo ad azione rapida: controversia e implicazioni [translation of “Ketamine as a rapid antidepressant: the debate and implications” by Dr. Giacomo Galli and Dr. Serena Saraceni]

“…Altri meccanismi farmacodinamici includono la prevenzione del flusso di ioni calcio all'interno dei mitocondri, possibile causa di un effetto neurotossico a livello della corteccia frontale (Xu 2015), e l'alterazione del funzionamento del sistema limbico (Bergman 1999). La ketamina è anche associata ad alterazioni della memoria (Morgan 2014) e attraverso il blocco dei recettori NMDA è in grado di esacerbare i sintomi psicotici e cognitivi della schizofrenia (Malhotra 1997).…”