• Panos Zanos, Ruin Moaddel, Patrick J Morris, Lace M Riggs, Jaclyn N Highland, Polymnia Georgiou, Pereira Edna F R EFR 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.), Epidemiol, Edson X Albuquerque, Craig J Thomas, Carlos A Zarate, and 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.).
• Pharmacol. Rev. 2018 Jul 1; 70 (3): 621-660.

AbstractKetamine, 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.Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

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