Evaluating the abuse liability of ketamine in the treatment of mood disorders: A systematic review.
Shreya Vasudeva, Gabrielle F. M. Lovell, Sabrina Wong, Gia Han Le, Diana Orsini, Sara Di Luch, Roger S McIntyre, Joshua D. Rosenblat
Journal of Psychopharmacology June 24, 2026 DOI: 10.1177/02698811261453814 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Randomized Open-label Longitudinal Peer reviewed |
|---|---|
| Population | Patients in clinical settings and preclinical models |
| Interventions | Ketamine Esketamine |
| Topics | Ketamine Esketamine |
| Keywords | Abuse Mood disorders |
| Key findings | Ketamine and esketamine carry low abuse liability when delivered in controlled, clinically supervised settings, while abuse and misuse risk was identified largely in cases without appropriate monitoring. |
Abstract
Ketamine has emerged as a promising rapid-acting treatment for mood disorders and suicidality. Notwithstanding its replicated antidepressant efficacy, ketamine-associated risk for abuse, dependence, and misuse remain. We conducted a systematic review of clinical and preclinical studies from database inception to August 2025, including randomized and observational trials, open-label extensions, case reports, and preclinical animal research, assessing ketamine or its enantiomers for outcomes related to abuse potential including craving, drug liking, tolerance, withdrawal, or dependence. A total of 30 studies (25 clinical and 5 preclinical) met the inclusion criteria. Clinical studies consistently reported minimal evidence of craving, dose escalation, misuse, or illicit use when ketamine or esketamine was administered in controlled, clinically supervised settings. Preclinical findings demonstrated that (S)-ketamine produces reward-related behaviors and locomotor sensitization, racemic ketamine shows reinforcing effects at higher doses, whereas (R)-ketamine demonstrates minimal reinforcing effects. Overall, the body of reviewed literature suggests that ketamine and esketamine carry low abuse liability when delivered in a monitored clinical setting while risk of abuse and misuse was identified largely in case reports and series in which appropriate monitoring was often not conducted. These findings support the safe incorporation of ketamine into treatment protocols for mood disorders while emphasizing the importance of structured administration and ongoing patient monitoring both throughout treatment and follow-up. Further research using longitudinal, prospective designs is warranted to assess potential misuse over extended treatment periods and across diverse patient populations, to optimize clinical safety and further inform evidence-based clinical practice guidelines.
Comparable studies
Other systematic reviews and meta-analyses on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis Depressed patients with suicidal ideation at baseline | 2017 | Systematic review and individual participant data meta-analysis | n = 167 |
| Ketamine use: a review Ketamine users | 2011 | Systematic review | |
| Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression Participants with major depression in placebo-controlled, double-blind, randomized... | 2015 | Systematic review and meta-analysis | |
| Ketamine and postoperative pain – a quantitative systematic review of randomised trials Surgical patients from 25 countries | 2004 | Systematic review | n = 2,839 |
| Side-effects associated with ketamine use in depression: a systematic review. Patients with depression | 2018 | Systematic review |
Citations in the library
Cites 31
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- 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
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial American Journal of Psychiatry December 5, 2017
- Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression The Journal of Clinical Psychiatry April 20, 2020
and 26 more in the library