Is there a risk of addiction to ketamine during the treatment of depression? A systematic review of available literature.
Gianmarco Ingrosso, Anthony J. Cleare, Mario F Juruena
Journal of Psychopharmacology 2025 DOI: 10.1177/02698811241303597 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Open-label Case report Peer reviewed |
|---|---|
| Sample size | 2,174 |
| Population | Adult patients with depression |
| Interventions | Ketamine Esketamine |
| Topics | Addiction Depression Esketamine Ketamine |
| Keywords | Ketamine therapy Depression treatment Addiction risk Mental health research Drug safety |
| Citations | 20 |
| Key findings | Only 4 out of 2,174 patients showed clear signs of tolerance or dependence on ketamine during depression treatment. |
Abstract
Ketamine has demonstrated both rapid and sustained efficacy in treating depression, especially in treatment-resistant cases. However, concerns regarding the addictive potential of ketamine during long-term depression treatment persist among clinicians. This review aimed to summarise the evidence on addiction phenomena associated with ketamine treatment of depression. A comprehensive search was conducted in MEDLINE, Embase, PsycInfo and Global Health databases, with additional relevant studies identified through reference lists. Sixteen studies were included, comprising six randomised controlled trials, three single-arm open-label studies, one retrospective study, three case series and three case reports, for a total of 2174 patients. The studies employed various routes of administration, including intravenous, intramuscular, intranasal, oral and sublingual. Ketamine was administered in the racemic form, except for the studies that utilised intranasal esketamine. Among the included population, four patients were reported to exhibit clear signs of tolerance to the antidepressant effect of ketamine or dependence on the drug, while the majority did not. Cases of addiction phenomena reported in studies that did not meet the inclusion criteria are also discussed. Despite the heterogeneity in study designs and outcome assessment methods, the review underscores the relative safety of ketamine treatment for adult patients with depression, emphasising the importance of medically supervised administration, vigilant monitoring and judicious dosing. Future long-term studies employing quantitative scales to assess dependence phenomena could contribute to strengthening the evidence for the safe and effective use of ketamine in the treatment of depression.
Comparable studies
Other systematic reviews and meta-analyses on ketamine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine use: a review Ketamine users | 2011 | Systematic review | |
| Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review | 2021 | Systematic review | |
| Therapeutic Potentials of Ketamine and Esketamine in Obsessive–Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature | 2021 | Systematic review | |
| Efficacy of ketamine intervention to decrease alcohol use, cravings, and withdrawal symptoms in adults with problematic alcohol use or alcohol use disorder: A systematic review and comprehensive analysis of mechanism of actions. People with harmful alcohol use, alcohol craving, or alcohol withdrawal states,... | 2022 | Systematic review | n = 634 |
| Ketamine Treatment for Alcohol Use Disorder: A Systematic Review. Adult patients with alcohol use disorder, heavy drinkers, or those undergoing alcohol... | 2023 | Systematic review | n = 854 |
Citations in the library
Cited by 18
- Role of ketamine in the treatment of substance use disorders: A systematic review. Journal of Substance Use and Addiction Treatment August 1, 2025
- Advances in the study of NMDA receptors in depression pathogenesis and the antidepressant efficacy of their antagonists. Asian Journal of Psychiatry June 1, 2025
- Ketamine's Role in Neuroinflammation and Neuroprotection Across Neurological and Psychiatric Disorders: A Narrative Review. Pharmaceuticals August 29, 2025
- Novel psychedelic interventions for post-traumatic stress disorder and their promise for precision medicine. Therapeutic Advances in Psychopharmacology December 4, 2025
- A randomized, double-blind, placebo-controlled, Phase 1 study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of an immediate-release oral ketamine capsule in healthy volunteers. Journal of Psychopharmacology June 20, 2025
and 13 more in the library
Cites 29
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression JAMA Psychiatry June 5, 2019
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
- Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism American Journal of Psychiatry August 29, 2018
and 24 more in the library