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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 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
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
Topics Esketamine Ketamine
Key points 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.

Comparable studies

Other randomized controlled trials on ketamine, most cited first.

Study Year Design Participants
Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community 1994 Randomized controlled trial n = 19
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery 2005 Randomized controlled trial n = 75
Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures 2014 Randomized controlled trial n = 41
Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers 2000 Single-blind placebo-controlled study n = 20

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Esketamine Ketamine Addiction Default mode network