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The abuse liability of ketamine: A scoping review of preclinical and clinical studies.

Tuyen T. Le, Isabel Pazos Cordero, Muhammad Youshay Jawad, Jennifer Swainson, Joshua D. Di Vincenzo, Saja Jaberi, Lee Phan, Leanna M.W. Lui, R. Ho, Joshua D. Rosenblat, Roger S McIntyre

Journal of Psychiatric Research May 1, 2022 DOI: 10.1016/j.jpsychires.2022.04.035 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Scoping review Randomized Peer reviewed
Topics Esketamine Ketamine
Citations 82
Key findings (R)-ketamine appears to have minimal abuse liability at antidepressant-relevant doses in rodents, while (R,S)-ketamine and (S)-ketamine show greater risk for abuse in preclinical studies.

Abstract

While ketamine has been used clinically over the past decades, it has only been recently shown to be a promising therapy for treatment-resistant depression (TRD). However, ketamine and related dissociative agents may also be misused recreationally, creating significant concerns for abuse liability when prescribed for depression. Although the abuse potential of ketamine is widely recognized, there is limited evidence on the differential abuse liability of ketamine enantiomers, (S)-ketamine and (R)-ketamine. The current scoping review aims to summarize the extant literature on the abuse liability of (R,S)-ketamine and the enantiomers. A systematic search was conducted on the Embase, Medline, and APA PsycInfo databases from 1947 to July 29, 2021. Clinical and preclinical studies that assessed the abuse potential of (R,S)-ketamine, (S)-ketamine, and (R)-ketamine were screened and assessed for eligibility by two independent reviewers. A total of 65 eligible studies were identified; 55 were preclinical studies and 10 were clinical studies. Only 4 preclinical studies evaluated the abuse liability of ketamine enantiomers. Available preclinical evidence suggests that (R,S)-ketamine and (S)-ketamine have greater risk for abuse compared to (R)-ketamine. (R)-ketamine, at the antidepressant-relevant doses in rodents, appears to be safe with minimal liability for abuse. Although the abuse potential of (R,S)-ketamine is well-established in animals, limited clinical studies indicate that single or repeated ketamine administrations in professionally controlled settings did not result in misuse, dependence, diversion and/or gateway activity in patients with TRD. However, most clinical studies were retrospective and did not systematically evaluate the abuse liability of ketamine via validated psychological scales/questionnaires. Future randomized controlled trials are warranted to ascertain the abuse liability of racemic, (S)- and (R)-ketamine in TRD population, especially among patients with comorbid substance use disorders.

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 Addiction Depression