Treating addiction with an addictive drug: the ketamine paradox revisited.

Background: Substance use disorders (SUDs) and treatment-resistant depression (TRD) remain a major global health challenge, marked by high relapse rates and limited long-term effectiveness of existing treatments. Ketamine, a glutamatergic modulator with rapid neuroplastic effects, has emerged as a novel intervention for TRD and is increasingly investigated as an adjunctive treatment for addiction, yet concerns about its abuse liability persist. Objective: This review critically evaluates ketamine's therapeutic potential for SUDs while examining its neurobiological mechanisms, clinical efficacy, and risk of misuse within a unified risk-benefit framework. Methods: A structured narrative review conducted in accordance with the SANRA framework using the PubMed, Scopus, PsycINFO, and Web of Science databases, covering literature published until March 2026. Eligible studies included clinical trials, experimental studies, and mechanistic investigations relevant to ketamine use in addiction and depression. Evidence was synthesized thematically across the domains of efficacy, mechanisms, and safety. Results: Across alcohol and cocaine use disorders, ketamine combined with psychotherapy has demonstrated promising reductions in craving and increases in abstinent days in small-to moderate-sized Phase 2 trials. However, findings remain difficult to generalize due to considerable variability in dosing strategies, comparator conditions, and follow-up periods. Effects on relapse prevention have been more inconsistent and less reliably positive. Mechanistically, ketamine promotes synaptic plasticity via NMDA receptor antagonism and downstream glutamatergic signaling, potentially disrupting maladaptive reward-related memories and reversing maladaptive neurocircuitry involved in both depression and addiction. While acute adverse effects are generally transient under clinical supervision, ketamine carries a well-established risk of misuse, particularly in unsupervised or high-dose settings. Conclusions: Ketamine represents a promising but still experimental intervention for both refractory depression and selected SUDs. Its clinical use depends on careful patient selection, structured delivery, and integration with psychotherapy. Although ketamine may redefine treatment paradigms for TRD and addiction, larger-scale trials and long-term safety data are essential to define its role within psychiatric and addiction treatment frameworks.