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Oral ketamine may offer a solution to the ketamine conundrum

Megan Dutton, Adem T. Can, Jim Lagopoulos, Daniel F. Hermens

Psychopharmacology December 1, 2023 DOI: 10.1007/s00213-023-06480-x (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Narrative review Peer reviewed
Intervention Ketamine
Topics Esketamine Ketamine
Key findings The authors argue that oral ketamine may be a favorable alternative to parenteral ketamine for depression, appearing to produce similarly beneficial treatment effects without the cost and medical resources required for parenteral dosing. They suggest its clinical effects may be due to the active metabolite norketamine, which reaches substantially higher levels via oral dosing, most likely through first-pass clearance, and they propose that norketamine's relevance to mental health warrants exploration.

Abstract

Abstract Ketamine has received considerable attention for its rapid and robust antidepressant response over the past decade. Current evidence, in clinical populations, predominantly relates to parenterally administered ketamine, which is reported to produce significant undesirable side effects, with additional concerns regarding long-term safety and abuse potential. Attempts to produce a similar drug to ketamine, without the psychotomimetic side effects, have proved elusive. Orally administered ketamine has a different pharmacological profile to parentally administered ketamine, suggesting it may be a viable alternative. Emerging evidence regarding the efficacy and tolerability of oral ketamine suggests that it may be a favourable route of administration, as it appears to obtain similarly beneficial treatment effects, but without the cost and medical resources required in parenteral dosing. The pharmacological effects may be due to the active metabolite norketamine, which has been found to be at substantially higher levels via oral dosing, most likely due to first-pass clearance. Despite bioavailability and peak plasma concentrations both being lower than when administered parenterally, evidence suggests that low-dose oral ketamine is clinically effective in treating pain. This may also be due to the actions of norketamine and therefore, its relevance to the mental health context is explored in this narrative review.

Comparable studies

Other narrative reviews on ketamine, most cited first.

Study Year Design Participants
Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms 2018 Review
Mechanisms of Ketamine Action as an Antidepressant 2018 Review
Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression 2021 Review
Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) 2013 Review
A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders 2017 Review and consensus statement

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Esketamine Ketamine Depression