The Analgesic and Dissociative Properties of Ketamine are Separate and Correspond to Distinct Neural Mechanisms
Noam Goldway, Talma Hendler, Itamar Jalon, Yotam Pasternak, Roi Sar-El, Dan Mirelman, Noam Sarna, Nili Green, Yara Agbaria, Haggai Sharon
bioRxiv July 31, 2025 preprint DOI: 10.1101/2025.07.25.666594 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Within-subject, placebo-controlled study |
|---|---|
| Sample size | 37 |
| Population | Healthy volunteers |
| Interventions | Ketamine Saline |
| Dose | 0.4 mg/kg bolus followed by a continuous drip of 0.4 mg/kg/h |
| Topics | Esketamine Ketamine |
| Key points | Ketamine reduced thermal pain ratings and produced dissociation, but the two effects were not correlated. It reduced pain-related activation in the insula and anterior cingulate cortex and diminished default mode network connectivity, which correlated with dissociation intensity. The authors conclude that ketamine's analgesic and dissociative effects are independent and mediated by distinct neural pathways. |
Abstract
Ketamine, a psychoactive medication, exerts both analgesic and dissociative effects. However, whether its analgesic effect stems from its dissociative properties is a topic of debate. Our study aimed to determine whether ketamine’s analgesic and dissociative effects are supported by distinct neural mechanisms. In a within-subject, placebo-controlled study, 37 healthy volunteers were administered ketamine (0.4 mg/kg bolus followed by a continuous drip of 0.4 mg/kg/h) or saline during fMRI sessions where thermal pain was induced. Our results indicate that while ketamine significantly reduced thermal pain ratings and produced robust dissociative effects, these outcomes were not correlated. Neurally, ketamine reduced pain-related brain activations across a network of regions, including the insula and anterior cingulate cortex. Additionally, ketamine significantly diminished functional connectivity between default mode network regions, and this reduction was correlated with the intensity of dissociation. These findings suggest that ketamine’s analgesic and dissociative effects are independent and mediated by distinct neural pathways.
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 |
Citations in the library
Cites 59
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs Frontiers in Human Neuroscience 2014
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics Pharmacological Reviews June 20, 2019
- A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression Archives of General Psychiatry August 1, 2010
and 54 more in the library