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 via PubMed
Summary
AI-generated from the abstractSince 2000, suicide and opioid overdose rates have risen sharply. About one-third of people with major depressive disorder have treatment-resistant depression, creating an urgent need for new therapies. This narrative review synthesizes key preclinical and clinical findings on low-dose ketamine's rapid antidepressant effects. Low-dose ketamine quickly alleviates depressive symptoms, even in refractory depression. Proposed mechanisms include modulation of dopamine signaling via epigenetic neuroadaptation, interactions with D1/D2 receptor systems, optogenetic activation of D1 pathways, and changes in D2/D3 receptor availability. No consensus exists on its definitive mechanism of action. Ketamine's psychoactive properties and abuse potential underscore the need for enhanced clinical oversight and regulation.
Study at a glance
| Characteristics | Narrative review Peer reviewed |
|---|---|
| Intervention | low-dose ketamine |
| Dose | low-dose |
| Topics | Ketamine |
| Keywords | Dopamine Rapid antidepressant effect |
| Key finding | 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.