Ketamine-induced analgesia and dissociation show distinct behavioral and neural correlates.

Ketamine produces both analgesic and dissociative effects, but whether analgesia depends on dissociation remains debated. This question is part of a broader discussion on whether the subjective experiences elicited by psychoactive drugs are necessary for their therapeutic benefits. Here, we tested whether ketamine-induced analgesia and dissociation show separable behavioral and neural signatures. In a within-subject, placebo-controlled fMRI study, 37 healthy volunteers (21 female) underwent two sessions: intravenous ketamine (0.4 mg/kg bolus over 10 min followed by 0.4 mg/kg/h continuous infusion) or saline placebo. Individually calibrated thermal pain stimuli were applied to the right leg during scanning. Dissociative states were measured repeatedly using the Clinician-Administered Dissociative States Scale. Whole-brain univariate and multivariate analyses, as well as network-based functional connectivity analyses, were performed. Ketamine induced both analgesia (session × pain intensity interaction: F(1,54) = 11.22, p = 0.001) and dissociation (main effect of session: F(1,32) = 57.44, p < 0.001), and the two corresponded to distinct neural indices. Greater pain was associated with increased univariate activity in regions such as the anterior insula, as well as with stronger expression of a pain-predictive multivoxel pattern (ρ = 0.6, p < 0.001), whereas higher dissociation intensity was selectively associated with reduced default mode network connectivity (ρ = .49, p < 0.01). Neurobehavioral markers of pain and dissociation did not covary (ρ = -0.24 to 0.32, all p > 0.09), consistent with distinct neural correlates of ketamine's analgesic and dissociative effects.