Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers.
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. In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 μg kg Sodium nitroprusside significantly reduced drug high AUC mean (standard deviation) placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P0.02, internal perception AUC placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01 and external perception AUC placebo 4110 (2840) vs nitroprusside 2890 (2120), P0.02 during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. 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. NTR 5359.