Ketamine Dosing Across Clinical Indications: A Narrative Review Organized by Proposed NMDA-Related Mechanisms

Ketamine is a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) glutamate receptor. It was approved by the US Food and Drug Administration for anesthesia in 1970. The only other related US regulatory approval since then has been for esketamine nasal spray for depression in 2019. Over this time ketamine has been repurposed by mainly academic researchers, reporting clinical activity in diverse disorders such as status epilepticus, acute asthma, hyperactive delirium, and treatment resistant depression and anxiety. Importantly, dosing and length of treatment varies considerably by indication. Clinical indications responsive to ketamine fall into three categories: those where glutamatergic tone is normal and NMDA antagonism produces a desired effect (e.g., single bolus dosing for anesthesia, procedural sedation, and acute pain treatment); disorders where there is overactivity in glutamatergic tone and NMDA antagonism is therapeutic (e.g., prolonged infusion dosing for status epilepticus or status asthmaticus); and disorders where NMDA antagonism can enhance neuroplasticity (e.g., intermittent bolus treatment for depression/anxiety). Ketamine doses and duration of dosing differ for each of these three categories. This categorization may help generate hypotheses regarding dosing strategies for other potential novel indications such as eclampsia, anorexia nervosa, or functional neurological disorders.