Ketamine — NMDA receptor antagonist / dissociative anesthetic

The key differentiator between IV racemic ketamine (off-label, widely used) and Spravato (FDA-approved) is the regulatory framework. Spravato requires REMS certification — patients must be observed for 2 hours post-dose at the clinic. IV ketamine is prescribed off-label by anesthesiologists/psychiatrists and allows home discharge after monitoring. R-ketamine is being investigated as it may have fewer dissociative side effects while maintaining antidepressant efficacy. Ketamine's antidepressant effects typically last 2-3 weeks after single infusion; maintenance dosing schedule varies.

Overview

This page is part of Hormonaly's evidence-graded compound library. All clinical claims are linked to peer-reviewed sources via our dual-layer citation verification pipeline.

Compound Class

NMDA receptor antagonist / dissociative anesthetic

Mechanism of Action

Non-competitive NMDA glutamate receptor antagonist. At sub-anesthetic doses, produces rapid antidepressant effect via: (1) AMPA receptor throughput enhancement (glutamate burst), (2) BDNF/TrkB signaling and synaptogenesis, (3) mTOR pathway activation (rapid synapse formation in PFC), (4) inhibition of lateral habenula "anti-reward center" burst firing. Effect onset: within hours (vs weeks for SSRIs). Esketamine (S-enantiomer, Spravato) is the FDA-approved intranasal formulation — 2x more potent at NMDA receptor vs R-enantiomer; administered in certified healthcare settings due to dissociation/BP monitoring requirements. IV racemic ketamine widely used off-label at infusion clinics.

Regulatory Status

Ketamine HCl: FDA approved 1970 (anesthetic); Spravato: FDA approved 2019 (TRD, MDD with SI)

Evidence Level

High for Spravato (FDA-approved Phase 3 data); High for IV anesthesia; Moderate for off-label IV depression