An Oral Ketamine-Like Approach to Treatment-Resistant Obsessive-Compulsive Disorder—A Review of Mechanism, Clinical Experience, and Future Directions

Obsessive-compulsive disorder remains treatment-resistant in 40–60% of patients despite optimized serotonin-reuptake inhibitor therapy and antipsychotic augmentation. Emerging evidence points to glutamatergic dysregulation in cortico-striato-thalamo-cortical circuits as a core driver of rigid, maladaptive synaptic patterns. The Cheung Glutamatergic Regimen—a fully oral, low-cost combination of dextromethorphan, a CYP2D6 inhibitor, piracetam, and optional L-glutamine—aims to replicate the rapid neuroplastic cascade triggered by intravenous ketamine.

Study at a glance

Abstract

Obsessive-compulsive disorder (OCD) remains treatment-resistant in 40–60 % of patients despite optimised serotonin-reuptake inhibitor therapy and antipsychotic augmentation. Emerging evidence points to glutamatergic dysregulation in cortico-striato-thalamo-cortical circuits as a core driver of rigid, maladaptive synaptic patterns. The Cheung Glutamatergic Regimen (CGR)—a fully oral, low-cost combination of dextromethorphan (NMDA antagonism), a CYP2D6 inhibitor (to prolong DXM exposure), piracetam (AMPA positive allosteric modulation), and optional L-glutamine (glutamate replenishment)—aims to replicate the rapid neuroplastic cascade triggered by intravenous ketamine. Naturalistic case series and individual reports from routine practice describe rapid reductions in obsessive intensity and ritual frequency, often within days to weeks, particularly when CYP2D6 inhibition is sustained and piracetam is added. Most side effects are mild, like temporary tremors, fast heartbeats, and trouble sleeping. However, serotonin toxicity and hypomanic activation need close monitoring. The evidence is uncontrolled and only based on one clinician's experience, though it is promising.