Evaluating the abuse liability of ketamine in the treatment of mood disorders: A systematic review.

Ketamine and its enantiomer esketamine show low risk of abuse, dependence, or misuse when administered under controlled clinical supervision, based on a systematic review of 30 studies (25 clinical and 5 preclinical). Clinical studies found minimal evidence of craving, dose escalation, or illicit use in monitored settings. Preclinical work indicated that (S)-ketamine produces reward-related behaviors, racemic ketamine shows reinforcing effects at higher doses, and (R)-ketamine has minimal reinforcing effects. Abuse risk was identified mainly in case reports lacking proper monitoring. The findings support safe incorporation of ketamine into mood disorder treatment protocols with structured administration and ongoing monitoring.

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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.