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Recent advances in the neuropsychopharmacology of metacognition indicate a constituent role of glutamate for the integrity of metamnestic processes. However, the extent to which previous results can be generalized across functional domains to characterize the relationship between glutamate and metacognition remains unclear. Here, in a randomized, double-blind, placebo-controlled, preregistered fMRI study, we tested the effects of a psychotomimetic dose (target plasma concentration 100 ng/mL) of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine on metacognition in a perceptual decision-making framework. We collected trial-by-trial metacognitive reports as participants performed a two-alternative forced-choice perceptual task during functional magnetic resonance imaging (fMRI). Results indicated ketamine-induced deterioration in metacognitive performance, whereas no significant effects were observed for perceptual performance, response times and - unexpectedly - metacognitive bias. Whilst there were no detectable ketamine effects on mean BOLD activation, exploratory psychophysiological interaction (PPI) analysis revealed alterations in functional connectivity during metacognitive confidence ratings under ketamine. Specifically, there was increased task-specific connectivity for ketamine compared to placebo between right anterior dorsolateral prefrontal cortex and left middle temporal, supramarginal and precentral gyrus, as well as between right insula/inferior frontal gyrus and left lingual gyrus, possibly indicating re-representations of object-level features supplied for metacognitive evaluations. Overall, these findings contribute towards the emerging picture of the substructures underlying metacognitive operations at the neurotransmitter level and may shed light on a neural pattern characteristic of pharmacologically challenged metacognition., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Only little research has been conducted on the pharmacological underpinnings of metacognition. Here, we tested the modulatory effects of a single intravenous dose (100 ng/ml) of the N -methyl-D-aspartate-glutamate-receptor antagonist ketamine, a compound known to induce altered states of consciousness, on metacognition and its neural correlates. Fifty-three young, healthy adults completed two study phases of an episodic memory task involving both encoding and retrieval in a double-blind, placebo-controlled fMRI study. Trial-by-trial confidence ratings were collected during retrieval. Effects on the subjective state of consciousness were assessed using the 5D-ASC questionnaire. Confirming that the drug elicited a psychedelic state, there were effects of ketamine on all 5D-ASC scales. Acute ketamine administration during retrieval had deleterious effects on metacognitive sensitivity (meta-d′) and led to larger metacognitive bias, with retrieval performance (d′) and reaction times remaining unaffected. However, there was no ketamine effect on metacognitive efficiency (meta-d′/d′). Measures of the BOLD signal revealed that ketamine compared to placebo elicited higher activation of posterior cortical brain areas, including superior and inferior parietal lobe, calcarine gyrus, and lingual gyrus, albeit not specific to metacognitive confidence ratings. Ketamine administered during encoding did not significantly affect performance or brain activation. Overall, our findings suggest that ketamine impacts metacognition, leading to significantly larger metacognitive bias and deterioration of metacognitive sensitivity as well as unspecific activation increases in posterior hot zone areas of the neural correlates of consciousness. [ABSTRACT FROM AUTHOR]