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Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability

Molecular Psychiatry volume 26, pages 6704–6722 (2021)Cite this article

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Abstract

Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States’ FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine’s abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.

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Fig. 1: Divergent pharmacodynamics of ketamine enantiomers.
Fig. 2: Rapid brain uptake, fast clearance, and no high-affinity target for ketamine enantiomers.
Fig. 3: Functional brain imaging reveals regional differences in the effects of ketamine enantiomers.
Fig. 4: Behavioral effects of ketamine enantiomers: locomotor activity, conditioned place preference, and drug self-administration.

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Acknowledgements

This work was supported by NIDA (ZIA000069), NIMH, and NINDS intramural funds. We thank Drs. Marisela Morales (NIDA/IRP), Dr. David White (NIDA/MDTB), Martin Pomper (Johns Hopkins University) and Robert Dannals (Johns Hopkins University) for providing resources and equipment that made this work possible. We also thank the technical support provided by Theresa Kopajtic, Hannah Korah and Sarah Applebey in helping us set up experimental procedures.

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Authors and Affiliations

  1. Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA

    Jordi Bonaventura, Sherry Lam, Meghan Carlton, Matthew A. Boehm, Juan L. Gomez, Oscar Solís & Michael Michaelides

  2. Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke Intramural Research Program, Bethesda, MD, USA

    Marta Sánchez-Soto & David R. Sibley

  3. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Rockville, MD, USA

    Patrick J. Morris & Craig J. Thomas

  4. Neurobiology of Relapse Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, USA

    Ida Fredriksson & Yavin Shaham

  5. Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Intramural Research Program, Bethesda, MD, USA

    Carlos A. Zarate Jr

  6. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Michael Michaelides

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Contributions

All authors critically reviewed the content and approved the final version before submission. JB, SL, MC, MB, JLG, OS, and MS-S performed the experiments. JB, SL, MS-S, IF, and MM analyzed the data. JB, IF, YS, and MM supervised experiments. PJM, CJT, DRS, CAZ, provided access to resources and support. JB and MM designed the study and wrote the manuscript with input from all coauthors.

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Correspondence to Jordi Bonaventura or Michael Michaelides.

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Conflict of interest

CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ is listed as co-inventor on a patent for the use of (2R,6R)- hydroxynorketamine, (S)-dehydronorketamine, and other stereo- isomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. All other authors declare no conflict of interest.

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Bonaventura, J., Lam, S., Carlton, M. et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry 26, 6704–6722 (2021). https://doi.org/10.1038/s41380-021-01093-2

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