Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers. Jonkman, K., van der Schrier, R., van Velzen, M., Aarts, L., Olofsen, E., Sarton, E., Niesters, M., & Dahan, A. British Journal of Anaesthesia, 120(5):1009-1018, Elsevier, 2, 2018. ![Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers [pdf]](https://bibbase.org/img/filetypes/pdf.svg "pdf")
Paper ![Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers [link]](https://bibbase.org/img/filetypes/link.svg "link")
Website abstract bibtex Abstract
Background
Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(–)-ketamine isomers, or esketamine, containing just the S(+)-isomer.
Methods
In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 μg kg−1 min−1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point.
Results
Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion.
Conclusions
These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(–)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms.
Clinical trial registration
NTR 5359.
@article{
title = {Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers},
type = {article},
year = {2018},
identifiers = {[object Object]},
pages = {1009-1018},
volume = {120},
websites = {http://linkinghub.elsevier.com/retrieve/pii/S000709121830059X},
month = {2},
publisher = {Elsevier},
id = {13113f54-cf43-3617-a02e-997de38e609c},
created = {2018-03-03T19:58:02.916Z},
accessed = {2018-03-03},
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last_modified = {2018-05-07T21:43:20.021Z},
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abstract = {<h2>Abstract</h2><h3>Background</h3><p>Animal studies suggest that <i>N</i>-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(–)-ketamine isomers, or esketamine, containing just the S(+)-isomer.</p><h3>Methods</h3><p>In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 μg kg<sup>−1</sup> min<sup>−1</sup> or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point.</p><h3>Results</h3><p>Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) <i>vs</i> sodium nitroprusside 7100 (3320), <i>P</i>=0.02], internal perception AUC [placebo 1310 (1250) <i>vs</i> nitroprusside 748 (786), <i>P</i><0.01] and external perception AUC [placebo 4110 (2840) <i>vs</i> nitroprusside 2890 (2120), <i>P</i>=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion.</p><h3>Conclusions</h3><p>These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(–)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms.</p><h3>Clinical trial registration</h3><p>NTR 5359.</p>},
bibtype = {article},
author = {Jonkman, K. and van der Schrier, R. and van Velzen, M. and Aarts, L. and Olofsen, E. and Sarton, E. and Niesters, M. and Dahan, A.},
journal = {British Journal of Anaesthesia},
number = {5}
}
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