Ketamine Effects on Memory Reconsolidation Favor a Learning Model of Delusions
Philip R. Corlett, Victoria C. Cambridge, Jennifer M. Gardner, Jennifer S. Piggot, Danielle C. Turner, Jessica S. Everitt, F. Sergio Arana, Hannah L. Morgan, Amy Milton, Jonathan K. Lee, Michael R. F. Aitken, Anthony Dickinson, Barry J. Everitt, Anthony Absalom, Ram Adapa, Naresh Subramanian, Jane R. Taylor, John H. Krystal, Paul C. Fletcher
PLoS One June 12, 2013 DOI: 10.1371/journal.pone.0065088 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Placebo-controlled within-subjects study Peer reviewed |
|---|---|
| Sample size | 18 |
| Population | Human subjects (8 female) |
| Intervention | Ketamine |
| Duration | 72 hours |
| Topics | Esketamine Ketamine |
| Keywords | Memory consolidation Placebo Cognitive psychology Classical conditioning Nmda receptor Psychosis Developmental psychology Audiology Hippocampus |
| Citations | 104 |
| Key points | Re-presentation of a conditioned stimulus under ketamine led to stronger subsequent memory than under placebo, correlating with vulnerability to psychotogenic effects and prediction error brain signal. |
Abstract
Delusions are the persistent and often bizarre beliefs that characterise psychosis. Previous studies have suggested that their emergence may be explained by disturbances in prediction error-dependent learning. Here we set up complementary studies in order to examine whether such a disturbance also modulates memory reconsolidation and hence explains their remarkable persistence. First, we quantified individual brain responses to prediction error in a causal learning task in 18 human subjects (8 female). Next, a placebo-controlled within-subjects study of the impact of ketamine was set up on the same individuals. We determined the influence of this NMDA receptor antagonist (previously shown to induce aberrant prediction error signal and lead to transient alterations in perception and belief) on the evolution of a fear memory over a 72 hour period: they initially underwent Pavlovian fear conditioning; 24 hours later, during ketamine or placebo administration, the conditioned stimulus (CS) was presented once, without reinforcement; memory strength was then tested again 24 hours later. Re-presentation of the CS under ketamine led to a stronger subsequent memory than under placebo. Moreover, the degree of strengthening correlated with individual vulnerability to ketamine's psychotogenic effects and with prediction error brain signal. This finding was partially replicated in an independent sample with an appetitive learning procedure (in 8 human subjects, 4 female). These results suggest a link between altered prediction error, memory strength and psychosis. They point to a core disruption that may explain not only the emergence of delusional beliefs but also their persistence.
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
Cited by 14
- The Predictive Coding Account of Psychosis. Biological Psychiatry May 25, 2018
- Ketamine-From an Anesthetic to a Psychiatric Drug: Mechanisms of Action, Clinical Applications and Potential Risks. Molecules June 30, 2025
- [Ketamine Augmented Psychotherapy (KAP) in mood disorder: User guide]. L'Encephale June 1, 2022
- Therapeutic benefit versus epistemic risk: Need for empirical research in psychedelic epistemology. Journal of Psychiatric Research August 1, 2025
- The Causal Role of Consciousness in Psychedelic Therapy for Treatment-Resistant Depression: Hypothesis and Proposal ACS Pharmacology & Translational Science July 16, 2025
and 9 more in the library
Cites 18
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. American Journal of Psychiatry 2003
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Measurement of dissociative states with the Clinician‐Administered Dissociative States Scale (CADSS) Journal of Traumatic Stress 1998
- Attenuation of the Neuropsychiatric Effects of Ketamine With Lamotrigine Archives of General Psychiatry March 1, 2000
and 13 more in the library