Ketamine-induced changes in accumbal glutamate and their association with altered states of consciousness

Ketamine has been shown to modulate glutamate signaling in animals and may therefore have the potential to restore glutamate imbalances in the brain. Impaired glutamate homeostasis has been implicated in mental health disorders such as substance use disorders (SUDs). Thus, we investigated ketamine's potential to increase glutamate levels in the nucleus accumbens (NAc), a key region for the development and maintenance of SUD. We further examined whether glutamate changes are associated with ketamine's potential to induce altered states of consciousness. A single intravenous dose of R,S-ketamine (0.71 mg/kg bodyweight) was administered to 10 healthy volunteers over 40 min. Glutamate levels were measured by using a tailored proton magnetic resonance spectroscopy (¹H-MRS) sequence in the left NAc on a 3 T scanner, before and during the infusion. Subjective effects were measured by using the Five-Dimensional Altered States of Consciousness (5D-ASC) questionnaire. Glutamate levels were considered from the overall spectrum average (22 min) as well as three shorter, overlapping sub-blocks (each 10 min), to capture the progression of glutamate over time. Mean glutamate levels in the NAc were not significantly altered between baseline and ketamine ¹H-MRS measurement. However, glutamate changes were positively associated with anxious ego dissolution and reductions in vigilance. In conclusion, ketamine did not significantly increase glutamate levels across our sample of 10 healthy volunteers, but individual glutamate changes induced by ketamine correlate with anxious ego dissolution and reductions in vigilance, indicating that ketamine-induced glutamate alterations in the NAc underly specific alterations in perception and consciousness.