Ketamine-induced analgesia and dissociation show distinct behavioral and neural correlates
Noam Goldway, Itamar Jalon, Yara Agbaria, Yotam Pasternak, Roi Sar-El, Dan Mirelman, Noam Sarna, Nili Green, Talma Hendler, Haggai Sharon
Neuropsychopharmacology July 20, 2026 DOI: 10.1038/s41386-026-02496-x
Summary
AI-generated from the abstractKetamine produces both pain relief and dissociation, but it remains unclear whether the two are linked. In a placebo-controlled fMRI study with 37 healthy volunteers, intravenous ketamine reduced pain and induced dissociation, yet the two effects showed distinct brain signatures. Pain was associated with activity in regions like the anterior insula and a pain-predictive brain pattern, while dissociation was linked to reduced connectivity in the default mode network. These neural markers did not correlate with each other, suggesting that ketamine's analgesic and dissociative effects arise through separate mechanisms.
Study at a glance
| Characteristics | Within-subject, placebo-controlled fMRI study Peer reviewed |
|---|---|
| Sample size | 37 |
| Population | Healthy volunteers (21 female) |
| Intervention | Ketamine |
| Dose | 0.4 mg/kg bolus over 10 min followed by 0.4 mg/kg/h continuous infusion |
| Duration | Single session per condition (ketamine or placebo), with pain stimuli and dissociation measures during scanning |
| Key finding | Ketamine-induced analgesia and dissociation show separable behavioral and neural signatures, with pain-related brain activity not covarying with dissociation-related brain connectivity. |
Abstract
Abstract 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.