Is there a risk of esketamine misuse in clinical practice?

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.