How to Give Oral Ketamine Therapy for Treatment of Resistant Depression and Suicidality: A Critical Review

Objective: To critically review the empirical literature on oral ketamine dosing strategies and administration procedures; and provide pragmatic clinical considerations for its use in out-patient psychiatric settings for treatment-resistant depression and suicidality.Methods: A structured search of PubMed and Google Scholar was conducted to identify peer-reviewed studies published till April 2026.Studies including at least ten participants with depression or suicidality receiving oral ketamine were narratively synthesized.Results: Sixteen studies were reviewed.Dosing strategies showed substantial heterogeneity.They were broadly divided into fixed-dosing (n = 11); and individualized dose-titration (n = 5) protocols.Considerable heterogeneity was observed in patient populations, dosing regimens, treatment duration, and outcome measures.Oral ketamine was most commonly prepared by diluting injectable racemic ketamine in water or juice.Several studies employed gradual ingestion ("sipping"), although direct pharmacokinetic comparisons with bolus administration are lacking.Across study designs, oral ketamine was generally associated with clinically meaningful improvements in depressive symptoms and suicidality and demonstrated superior tolerability profile compared to intravenous ketamine.Preliminary evidence suggests that repeated treatment sessions and individualized dose-titration strategies may improve tolerability and clinical outcomes; however, these observations require confirmation in adequately powered comparative trials.Conclusion: Oral ketamine therapy appears to be a promising and safer alternative to intravenous ketamine infusion for providing rapid relief in resistant depression and suicidality.Although preliminary findings suggest efficacy comparable to other ketamine administration routes, equivalence with intravenous ketamine has not been unequivocally established.Standardized treatment protocols and high-quality randomized trials are needed before definitive clinical recommendations can be made.