Bifunctional Modulation of NMDA and Opioid Receptors in Ketamine Reinforcement and Misuse: Implications for Substance Use Disorder Treatment
Marjorie R. Levinstein, Ingrid Schoenborn, Peter Manza, Alan F. Schatzberg, Carlos A. Zarate, Jordi Bonaventura, Michael Michaelides
Biological Psychiatry December 4, 2025 DOI: 10.1016/j.biopsych.2025.11.021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Addiction Esketamine Ketamine |
| Citations | 5 |
| Key findings | Argues that ketamine's reinforcing properties and misuse potential arise from its bifunctional engagement with mu opioid receptors and NMDA receptors in addiction-relevant brain circuits, with the (S)-ketamine enantiomer being the primary risk driver compared with (R)-ketamine. Concludes that these mechanisms are intertwined with ketamine's antidepressant properties and its potential for substance use disorder treatment. |
Abstract
Certain medications carry a risk by providing therapeutic benefits at the expense of misuse potential. Ketamine is increasingly being used for the treatment of depression, and studies indicate that it may also have utility for substance use disorder (SUD) treatment. However, it has recreational appeal and known misuse potential. Driven by the ongoing expansion of its use in clinical settings, concerns for misuse of ketamine are escalating. In this review, we summarize neurochemical, molecular, and brain circuit mechanisms associated with ketamine reinforcement and misuse potential and discuss their relevance toward its potential for SUD treatment. We focus on ketamine's direct actions on opioid and glutamatergic systems, highlighting recent discoveries on its interactions with mu opioid receptors (MORs) and NMDA receptors (NMDARs) in addiction-relevant brain circuits. We propose that ketamine's reinforcing properties and misuse potential stem from its bifunctional engagement with these receptors, with its (S)-ketamine enantiomer, compared with (R)-ketamine, being ketamine's primary risk driver. We contextualize this bifunctional NMDAR/MOR mechanism within ketamine's known efficacy for treatment of depression and other mental health conditions, including its potential for SUD treatment. We conclude that the brain mechanisms contributing to ketamine reinforcement, its recreational appeal, and its misuse potential are intertwined with its antidepressant properties and potential for SUD treatment.
Comparable studies
Other narrative reviews on ketamine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder Patients with treatment-resistant depressive symptoms as part of major depressive... | 2018 | Narrative review | |
| Can psychedelic compounds play a part in drug dependence therapy? Patients with substance dependency | 2015 | Review | |
| Therapeutic potential of ketamine for alcohol use disorder. | 2021 | Review | |
| Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judicious Prescribing | 2022 | Review | |
| Ketamine, an Old–New Drug: Uses and Abuses | 2023 | Review |
Citations in the library
Cited by 2
- Integrating multi-receptor and neuron–glia mechanisms of ketamine's antidepressant action: a convergence framework for understanding efficacy Frontiers in Molecular Neuroscience October 21, 2026
- Treating addiction with an addictive drug: the ketamine paradox revisited Frontiers in Psychiatry July 9, 2026
Cites 64
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial American Journal of Psychiatry August 28, 2013
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
and 59 more in the library