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Review ArticleReview Article

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Panos Zanos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna F. R. Pereira, Edson X. Albuquerque, Craig J. Thomas, Carlos A. Zarate Jr. and Todd D. Gould
Jeffrey M. Witkin, ASSOCIATE EDITOR
Pharmacological Reviews July 2018, 70 (3) 621-660; DOI: https://doi.org/10.1124/pr.117.015198
Panos Zanos
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Ruin Moaddel
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Patrick J. Morris
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Lace M. Riggs
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Jaclyn N. Highland
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Polymnia Georgiou
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Edna F. R. Pereira
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Edson X. Albuquerque
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Craig J. Thomas
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Carlos A. Zarate Jr.
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Todd D. Gould
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Jeffrey M. Witkin
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This article has a correction. Please see:

  • Correction to “Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms” - October 01, 2018

Abstract

Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine’s pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

Footnotes

  • This work is supported by a National Institutes of Health (NIH) Grant MH107615 and a Harrington Discovery Institute Scholar-Innovator Grant to T.D.G., a National Association for Research on Schizophrenia and Depression Young Investigator Award to P.Z., and the National Institute of Aging (R.M.), National Institute of Mental Health (C.A.Z.), and National Center for Advancing Translational Sciences (C.J.T.) NIH intramural research programs.

  • The authors declare competing financial interests: R.M. and C.A.Z. are listed as coinventors on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro- and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.J.M., C.J.T., C.A.Z., and T.D.G. are listed as coinventors 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 post-traumatic stress disorders. R.M., P.J.M., C.A.Z., and C.J.T. have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. P.Z. and T.D.G. have assigned their patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland, Baltimore. All other authors declare no competing interests.

  • https://doi.org/10.1124/pr.117.015198.

  • U.S. Government work not protected by U.S. copyright
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Pharmacological Reviews: 70 (3)
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Review ArticleReview Article

Ketamine and Ketamine Metabolite Pharmacology

Panos Zanos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna F. R. Pereira, Edson X. Albuquerque, Craig J. Thomas, Carlos A. Zarate and Todd D. Gould
Pharmacological Reviews July 1, 2018, 70 (3) 621-660; DOI: https://doi.org/10.1124/pr.117.015198

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Review ArticleReview Article

Ketamine and Ketamine Metabolite Pharmacology

Panos Zanos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna F. R. Pereira, Edson X. Albuquerque, Craig J. Thomas, Carlos A. Zarate and Todd D. Gould
Pharmacological Reviews July 1, 2018, 70 (3) 621-660; DOI: https://doi.org/10.1124/pr.117.015198
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