Ketamine and Hydroxynorketamine as Novel Pharmacotherapies for the Treatment of Opioid Use Disorders.
Anna Onisiforou, Andria Michael, Markos Apostolakis, Elmar Mammadov, Angeliki Mitka, Maria A Kalatta, Morfeas Koumas, Andrea Georgiou, Andreas Chatzittofis, Georgia Panayiotou, Polymnia Georgiou, Carlos A. Zarate, Panos Zanos
Biological Psychiatry March 15, 2025 DOI: 10.1016/j.biopsych.2024.09.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Addiction Ketamine Esketamine |
| Keywords | Hydroxynorketamine Opioid crisis Opioid use disorders Relapse Addiction treatment Opioid therapy Ketamine research Substance abuse recovery |
| Citations | 14 |
| Key findings | Ketamine and its metabolites can effectively modulate pathophysiological processes in opioid use disorder, suggesting a promising therapeutic role in treatment and prevention of return to opioid use during abstinence. |
Abstract
Opioid use disorder (OUD) has reached epidemic proportions, with many countries facing high levels of opioid use and related fatalities. Although currently prescribed medications for OUD are considered lifesaving, they inadequately address negative affect and cognitive impairment, resulting in high relapse rates to nonmedical opioid use even years after drug cessation (protracted abstinence). Evidence supports the notion that ketamine, an anesthetic and rapid-acting antidepressant drug, holds promise as a candidate for OUD treatment, including the management of acute withdrawal somatic symptoms, negative affect during protracted opioid abstinence, and prevention of retaking nonmedical opioids. In this review, we comprehensively discuss preclinical and clinical research that has evaluated ketamine and its metabolites as potential novel therapeutic strategies for treating OUD. Furthermore, we examine evidence that supports the relevance of the molecular targets of ketamine and its metabolites in relation to their potential effects and therapeutic outcomes in OUD. Overall, existing evidence demonstrates that ketamine and its metabolites can effectively modulate pathophysiological processes affected in OUD, suggesting a promising therapeutic role in the treatment of OUD and the prevention of return to opioid use during abstinence.
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 6
- Unfolding States of Mind: A Dissociative-Psychedelic Model of Ketamine-Assisted Psychotherapy in Palliative Care. Healthcare October 27, 2025
- Treating addiction with an addictive drug: the ketamine paradox revisited Frontiers in Psychiatry July 9, 2026
- The Emerging Crisis in Non-Prescribed Ketamine Use: A Rapid Attenuation of Depression in Face of Abuse and "Chill-out" or Escapism Drug. Substance Use & Misuse February 1, 2026
- The Effects of Ketamine on Methamphetamine Withdrawal-Induced Anxiety and Drug-Seeking Behaviors in the Rat bioRxiv Preprint Server June 24, 2025
- Selective transcriptomic recovery by ( 2R,6R )-hydroxynorketamine in opioid-abstinent mice: Machine learning identifies predictive biomarkers bioRxiv (Cold Spring Harbor Laboratory) June 8, 2025
and 1 more in the library
Cites 33
- 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
- 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
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression American Journal of Psychiatry April 8, 2016
and 28 more in the library