Ketamine, synthesized in 1962, approved in 1970, is considered safe for use in controlled conditions, mainly as an anesthetic, especially in pediatric populations and in people suffering from pulmonary diseases, as well as in emergency departments and in war situations. Dissociative states (derealization and depersonalization) produced by ketamine made it a popular recreational drug, which led to increased regulation in most countries. Intravenous application of ketamine has shown rapid, although transitory antidepressant and antisuicidal effects in patients with unipolar and bipolar depression. Esketamine, the S(+) enantiomer of ketamine, with better pharmacodynamic selectivity, has just been approved for treatment-resistant major depressive disorder, in the form of a nasal spray. Presently, the high cost of the spray not only limits its widespread use, but also makes it less prone to abuse and diversion. Additional measures are needed to hinder it from becoming a new "street drug".