Evaluation of Current Evidence on the Efficacy of Esketamine in Treating Substance-Use Disorders in Patients With Treatment-Resistant Depression (TRD): A Narrative Review
Cureus March 14, 2026 Suneha Shelke, Rusheeth Thummalapally
Treatment-resistant depression (TRD) affects up to a third of people with major depressive disorder who do not respond to standard antidepressants. Esketamine, a nasal spray approved for TRD in 2019, blocks NMDA receptors and may also reduce compulsive and addictive behaviors in patients whose depression and substance use disorders are linked. This review of randomized trials, cohort studies, systematic reviews, and animal research suggests that esketamine can reduce drug-seeking behavior, lessen cravings, and improve outcomes when paired with behavioral therapies like mindfulness. In rodent studies, esketamine reduced cocaine-seeking after abstinence, and clinical data hint at benefits for alcohol misuse. Esketamine may offer a dual treatment for depression and addiction, but larger studies are needed to confirm its effects and safety.