Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers*

Abstract

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.

Does Ketamine-Mediated N-methyl-D-aspartate Receptor Antagonism Cause Schizophrenia-like Oculomotor Abnormalities?

“…The rating "Felt high" changed the most with ketamine infusion; in general, the size of the ketamine-induced changes was higher for dissociative symptoms, such as perceptual distortions, than it was for core psychotic symptoms. This pattern of results is consistent with multiple reports in the literature (Lear et al 1959;Luby et al 1959;Corssen and Domino 1966;Krystal et al 1994;Malhotra et al 1996;Hartvig et al 1995).…”

“…impairment in both delayed recall and recognition memory. As with Krystal et al (1994), but unlike Malhotra et al and Hartvig et al (1995), we did not observe any significant changes in measures of verbal attention during ketamine infusion. Because the instruments used and doses of ketamine seem comparable between studies, we conclude that the effects of ketamine on verbal attention, although present, are not very robust.…”

“…Krystal et al (1994) shows a tendency for ketamine effects to increase with time; however, the authors used a constant infusion for 40 min, and did not determine plasma concentrations so that accumulation of ketamine may have occurred. Two studies (Lahti et al 1995 andHartvig et al 1995) utilized different doses of ketamine on different days and found dose-dependent effects of ketamine similar in magnitude to the effects we found. Therefore, it is likely that the effects we found were attributable to increasing dose of ketamine, rather than total time exposed to ketamine.…”

“…In pursuit of this goal, Krystal et al (1994), Malhotra et al (1996) and Hartvig et al (1995) all found that intravenous administration of ketamine induces positive and negative symptoms of schizophrenia in a dose-dependent manner. These investigators also found that intravenous ketamine caused cognitive impairments similar to those noted among schizophrenia patients.…”

Magnesium deficiency increases ketamine sensitivity in rats

“…Further, in humans there is a difference in the relative anaesthetic potency of the stereoisomers of ketamine with the S(+) isomer being 3.4 times more potent than the K(-) isomer. 14,29,31 Inhibition of the NMDA receptor is also stereoselective and the potency ratio of the (S+) and (R-) isomers is 2:1. 32 The similarity of the potency ratios measured in vivo and in vitro suggests that inhibition of the NMDA receptor contributes to anaesthetic effects of ketamine.…”