Glutamate and the Neural Basis of the Subjective Effects of Ketamine: A Pharmaco–Magnetic Resonance Imaging Study

This double-blind, placebo-controlled, randomized, crossover, counterbalanced study (n=33) investigated whether ketamine-induced (20.5mg/70kg) dissociative mental state is blocked via pretreatment with the glutamate release inhibitor lamotrigine (300mg/70kg). Ketamine produced dissociative effects which corresponded to decreased activity in the ventromedial frontal cortex, including the orbitofrontal cortex and subgenual cingulate, and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions. Most of these effects were mitigated by lamotrigine, thereby indicating that the dissociative effects of ketamine are mediated by glutamate release.


Context: Ketamine evokes psychosis like symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release.

Objectives: To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine.

Design: Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level– dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release.

Setting: Wellcome Trust Clinical Research Facility, Manchester, England.

Participants: Thirty-three healthy, right-handed men were recruited by advertisements.

Interventions: In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1. Main

Outcome Measures: Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores.

Results: Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r=0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms.

Conclusions: These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.”

Authors: J. F. William Deakin, Jane Lees, Shane McKie, Jaime E. C. Hallak, Steve R. Williams & Serdar M. Dursun


This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health

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Study details

Topics studied

Study characteristics
Placebo-Controlled Double-Blind Within-Subject Randomized Bio/Neuro


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