M ajor depression is a chronic illness where almost 30%-40% of patients do not respond to conventional antidepressants, and for those who do, time to respond is often delayed for weeks to months. 1 A new paradigm of rapid-acting antidepressant (RAADs) has focused on ketamine, a glutamatergic anesthetic agent "repurposed" as a robust antidepressant and RAAD for treatment-resistant depression (TRD). 2,3 Although racemic ketamine is not Food and Drug Administration (FDA) approved for depression, the s-enantiomer of ketamine, "esketamine," received FDA approval as an adjunct with an oral antidepressant for TRD in 2019 and depressive symptoms in MDD adults with acute suicidal ideations or behaviors in 2020. This editorial centers on the clinical aspects of ketamine and esketamine in daily practice while also addressing emerging concerns associated with ketamine's unregulated use.Ketamine has been hailed as a miracle drug and is considered the flagship of the next generation of RAADs and psychedelic therapies. 4 Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist; however, the antidepressant effect of ketamine is not entirely explained by the antagonizing effect on the NMDA receptor alone. 5 The NMDA blockage has shown to trigger a complex downstream cascade leading to release of the brain-derived neurotropic factor and mammalian target of rapamycin (mTOR) activation that eventually leads to dendritic remodeling and synaptogenesis. 6,7 Ketamine has shown to increase cortical glutamate (Glu) release through inhibition of gamma-aminobutyric acid (GABA)ergic interneurons. 6 An increase in GABA and Glu levels in MDD during a ketamine infusion has been postulated as one of the mechanisms for ketamine's efficacy as well. 8,9 Ketamine has been proposed to potentially modulate opioid receptor activation as a mechanism for its antidepressant effect, 10 although conclusive evidence for this is lacking. 11,12 Animal studies suggest distinct underlying mechanisms for ketamine efficacy between sexes, as well as differences in dissociative behaviors and analgesia. Combining estrogen with ketamine or its active metabolites has shown additive effects on AMPA (α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit expression. However, post hoc analyses of human studies do not support differential efficacy or tolerability of ketamine for TRD between genders or based on menopause status among women. 13