The Emerging Crisis in Non-Prescribed Ketamine Use: A Rapid Attenuation of Depression in Face of Abuse and "Chill-out" or Escapism Drug.
Substance Use & Misuse February 1, 2026 Kai-Uwe Lewandrowski, Kenneth Blum, Sergio Schmidt et al.
Since 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.