Subjective effects of psychedelics like ketamine and psilocybin appear to play a modest role in their therapeutic outcomes for depression and substance use disorder. A meta-analysis of 23 ketamine studies (471 patients) and 8 psilocybin studies (183 patients) found that subjective experiences explained 5–10% of therapeutic improvement for ketamine and 24% for psilocybin. Psilocybin showed a greater mediating effect than ketamine, especially for depression. Substance use disorder treatment showed a larger mediating effect than depression, regardless of the drug.
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.