The Emerging Crisis in Non-Prescribed Ketamine Use: A Rapid Attenuation of Depression in Face of Abuse and "Chill-out" or Escapism Drug.
Kai-Uwe Lewandrowski, Kenneth Blum, Sergio Schmidt, Rossano Kepler Alvim Fiorelli, Mark S. Gold, Kavya Mohankumar, Alireza Sharafshah, Debasis Bagchi, Albert Pinhasov, Morgan P Lorio, Edward J Modestino, Margaret A Madigan, David Baron, Alexander P L Lewandrowski, Catherine A Dennen, Panayotis K Thanos, Rajendra D Badgaiyan
Substance Use & Misuse February 1, 2026 DOI: 10.1080/10826084.2025.2612330 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Narrative review Peer reviewed |
|---|---|
| Intervention | low-dose ketamine |
| Dose | low-dose |
| Topics | Ketamine Depression Esketamine |
| Keywords | Dopamine Rapid antidepressant effect |
| Key findings | Low-dose ketamine rapidly alleviates depressive symptoms, including in treatment-resistant depression, but its definitive mechanism of action remains unknown. |
Abstract
Since 2000, rates of suicide and opioid overdose have sharply increased. Approximately one-third of individuals with major depressive disorder (MDD) experience treatment-resistant depression (TRD), highlighting the urgent need for novel therapeutic approaches. This review synthesizes pivotal preclinical and clinical findings on low-dose ketamine's rapid antidepressant effects and examines proposed mechanisms underlying its therapeutic action. This is a narrative review of key contributions in the literature addressing ketamine's fast-acting antidepressant properties. Low-dose ketamine rapidly alleviates depressive symptoms, including in refractory depression. Despite multiple hypotheses supported by preliminary data, there is no consensus regarding its definitive mechanism of action. Proposed mechanisms include modulation of dopamine signaling via epigenetic neuroadaptation, interactions with D1/D2 receptor systems, optogenetic activation of D1 pathways, and alterations in D2/D3 receptor availability. Elucidating ketamine's mechanism of action may inform the development of next-generation psychoplastogens that promote neural plasticity in TRD and unipolar MDD. However, ketamine's psychoactive properties and abuse potential, along with concerns regarding misuse and diversion, underscore the need for enhanced clinical oversight and regulatory frameworks.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |