Ketamine produces both pain relief (analgesia) and psychedelic effects, and these two effects are linked, possibly because dissociation generates analgesia. In healthy male volunteers receiving escalating doses of S-ketamine and racemic ketamine, the concentration-effect relationship and the speed of onset and offset were the same for both antinociception and altered external perception. S-ketamine had a potency (C50) of 0.51 nmol/ml and a blood-effect site equilibration half-life of 8.3 minutes. R-ketamine did not contribute to either effect, while S-norketamine had a small antagonistic effect. The authors suggest further studies are needed to explore brain connectivity underlying these effects.
Intravenous esketamine up to a total dose of 1 mg per kg does not impair the ventilatory response to hypoxia in healthy adults. In an open-label study of 18 subjects, esketamine increased resting ventilation by about 3.1 L per minute and raised mean arterial pressure by 10 mm Hg and heart rate by 10 beats per minute, but it did not alter the increase in breathing triggered by acute or sustained low oxygen. The drug also increased anxiety and alertness and altered external perception, which may contribute to the sustained hypoxic ventilatory response observed during infusion. These findings indicate that low-dose esketamine is safe with respect to the hypoxic chemoreflex but has cardiovascular and psychoactive effects.
The anesthetic, analgesic, and antidepressant drug ketamine produces dissociation with symptoms of psychosis and anxiety, an effect attributed to neuronal nitric oxide depletion following N-methyl-d-aspartate blockade. There is evidence that dissociation induced by racemic ketamine, containing both ketamine enantiomers (S- and R-ketamine) but not esketamine (the S-isomer) is inhibited by nitric oxide (NO) donor sodium nitroprusside (SNP). We tested whether a similar intervention would reduce racemic and esketamine-induced analgesia in a randomized double-blind placebo-controlled trial. Seventeen healthy volunteers were treated with 0.5 μg.kg-1.
The authors respond to a critique about how to describe mind-altering drugs like ketamine, psilocybin, and cannabis. They argue that terms like "dissociative" are inadequate because these drugs produce diverse symptoms beyond disconnection from reality. They propose "psychoplastogen" as a better term, focusing on the shared mechanism of promoting rapid neural plasticity and rewiring of brain circuits, which underlies therapeutic effects such as antidepressant and pain relief actions. This term avoids the limitations of describing subjective experiences and instead highlights the neurobiological mechanism responsible for healing.