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Is there a risk of esketamine misuse in clinical practice?

Carlos Roncero, Milton Merizalde-Torres, Néstor Szerman, Marta Torrens, Pablo Vega, Pilar Andres-Olivera, Francisco Javier Álvarez

Therapeutic advances in drug safety 2025 DOI: 10.1177/20420986241310685 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Review Case report Peer reviewed
Intervention Intranasal esketamine
Duration Nearly 4.5 years
Topics Addiction Depression Esketamine Ketamine
Keywords High-risk populations Risk of abuse Treatment-resistant depression trd Refractory depression Ketamine therapy Clinical safety Drug dependence
Citations 11
Key findings Esketamine is safe across diverse patient populations, with no documented abuse, misuse, addiction, or withdrawal in long-term studies, including high-risk groups with substance use disorder or alcohol use disorder.

Abstract

In 2019, intranasal esketamine gained approval as a promising therapy for those individuals grappling with treatment-resistant depression. Both clinical trials and real-world studies have underscored its efficacy in alleviating and remitting depressive symptoms, with sustained benefits observed for nearly 4.5 years. As the S-enantiomer of ketamine, esketamine's dosing guidelines and strict medical supervision stem from prior research on ketamine's use in depression and history as a recreational drug. Despite initial concerns, long-term clinical studies have not documented instances of abuse, misuse, addiction or withdrawal, and the same was found in case reports or subsamples of high-risk populations with comorbidities such as substance use disorder or alcohol use disorder. Esketamine has proven to be safe and well tolerated without fostering new-onset substance use in vulnerable groups. Real-world studies reinforced these observations, reporting no adverse events (AEs) related to pharmacological interactions of esketamine with any other substance, and no new-onset drug or alcohol misuse, craving, misuse or diversion of use. Reports of esketamine craving remain rare, with only one case report documented in 2022. Most drug-related AEs reported in pharmacovigilance databases are those identified in the product's technical data sheet and with known reported frequency. More importantly, no register of illicit acquisition of esketamine or its tampering for obtaining ketamine or other altered products was found in our search. Overall, our review confirms esketamine's safety across diverse patient populations, reassuring its responsible use and the scarcity of reports of abuse or misuse since its introduction to the market.

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

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Addiction Depression Esketamine Ketamine

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