Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers

Eur Neuropsychopharmacol. 2021 Mar;44:92-104. doi: 10.1016/j.euroneuro.2021.01.005. Epub 2021 Jan 21.


Ketamine and its (S)-enantiomer show distinct psychological effects that are investigated in psychiatric research. Its antidepressant activity may depend on the extent and quality of these psychological effects which may greatly differ between the enantiomers. Previous data indicate that the (S)-ketamine isomer is a more potent anesthetic than (R)-ketamine. In contrast, in subanesthetic doses (R)-ketamine seems to elicit fewer dissociative and psychotomimetic effects compared to (S)-ketamine. In this randomized double-blind placebo-controlled trial the effects of (R/S)-ketamine and (S)-ketamine on standardized neuropsychological and psychopathological measures were compared. After an initial bolus equipotent subanesthetic doses of (R/S)- and (S)-ketamine or placebo were given by continuous intravenous infusion to three groups of 10 healthy male volunteers each (n = 30). (R/S)-Ketamine and (S)-ketamine produced significant psychopathology and neurocognitive impairment compared to placebo. No significant differences were found between (R/S)-ketamine and (S)-ketamine. (S)-Ketamine administration did not result in reduced psychopathological symptomatology compared to (R/S)-ketamine as suggested by previous studies. However, this study revealed a somewhat more "negatively experienced" psychopathology with (S)-ketamine, which opens questions about potential "protective effects" associated with the (R)-enantiomer against some psychotomimetic effects induced by the (S)-enantiomer. As the antidepressant effect of ketamine might depend on a pleasant experience of altered consciousness and perceptions and avoidance of anxiety, the ideal ketamine composition to treat depression should include (R)-ketamine. Moreover, since preclinical data indicate that (R)-ketamine is a more potent and longer acting antidepressant compared to (S)-ketamine and (R/S)-ketamine, randomized controlled trials on (R)-ketamine and comparative studies with (S)-ketamine and (R/S)-ketamine are eagerly awaited.

Keywords: (S)-ketamine; Altered states of consciousness; Anesthesia; Ketamine; Neurocognition; Psychopathology.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Analgesics / pharmacology*
  • Antidepressive Agents / pharmacology
  • Consciousness
  • Healthy Volunteers
  • Humans
  • Ketamine* / pharmacology
  • Male
  • Mental Disorders


  • Analgesics
  • Antidepressive Agents
  • Ketamine