The Emerging Crisis in Non-Prescribed Ketamine Use: A Rapid Attenuation of Depression in Face of Abuse and “Chill-out” or Escapism Drug

Background: 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. Objective: This review synthesizes pivotal preclinical and clinical findings on low-dose ketamine’s rapid antidepressant effects and examines proposed mechanisms underlying its therapeutic action. Methods: This is a narrative review of key contributions in the literature addressing ketamine’s fast-acting antidepressant properties. Results: 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. Conclusions: 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.