Ketamine in Clinical Practice: Transitioning from Anesthetic Agent to Psychiatric Therapeutic

doi:10.1017/9781009585330.007

Chapter 6 - Ketamine in Clinical Practice: Transitioning from Anesthetic Agent to Psychiatric Therapeutic

Published online by Cambridge University Press: 24 July 2026

Jose Manuel Quintero ,

Rosa Helena Bustos ,

Sharon Lechtig-Wassermann ,

Stephania Beltran and

Edited by

Michael Berk and

Seetal Dodd: Affiliation:
Deakin University, Melbourne
Michael Berk: Affiliation:
Deakin University, Melbourne
Stephen M. Stahl: Affiliation:
University of California, Riverside

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Summary

Ketamine has gained increasing attention due to its rapid and sustained antidepressant effects in treatment-resistant depression (TRD). Unlike traditional antidepressants, ketamine acts on multiple neurotransmitter systems. Beyond psychiatry, ketamine remains a valuable anesthetic and analgesic agent with applications in acute and chronic pain management.

Despite its therapeutic promise, ketamine poses challenges due to its dissociative and hallucinogenic effects, contributing to widespread recreational use. Chronic misuse is associated with adverse health outcomes. As a result, ketamine has been subject to increasing regulatory scrutiny, balancing its medical utility with concerns about abuse potential.

This chapter highlights ketamine’s multifaceted pharmacological properties, its evolution from an anesthetic to a novel psychiatric treatment, and its broader medical applications.

Keywords

anesthetic antidepressant recreational drug

Information

Type: Chapter
Information: Recreational Drugs Repurposed for Medicinal Use , pp. 112 - 134

DOI: https://doi.org/10.1017/9781009585330.007 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2026

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References

Bahji, A, Zarate, CA, Vazquez, GH. Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Expert Opin Drug Saf. 2022;21(6):853–866. doi:10.1080/14740338.2022.2047928CrossRef Google Scholar PubMed

Nikolin, S, Rodgers, A, Schwaab, A, et al. Ketamine for the treatment of major depression: a systematic review and meta-analysis. EClinicalMedicine. 2023;62:102127. doi:10.1016/j.eclinm.2023.102127CrossRef Google Scholar PubMed

Medeiros, GC, Demo, I, Goes, FS, Zarate, CA, Gould, TD. Personalized use of ketamine and esketamine for treatment-resistant depression. Transl Psychiatry. 2024;14(1):481. doi:10.1038/s41398-024-03180-8CrossRef Google Scholar PubMed

Krystal, JH, Kaye, AP, Jefferson, S, et al. Ketamine and the neurobiology of depression: toward next-generation rapid-acting antidepressant treatments. Proc Natl Acad Sci USA. 2023;120(49):e2305772120. doi:10.1073/pnas.2305772120CrossRef Google Scholar PubMed

Barrett, W, Buxhoeveden, M, Dhillon, S. Ketamine: a versatile tool for anesthesia and analgesia. Curr Opin Anaesthesiol. 2020;33(5):633–638. doi:10.1097/aco.0000000000000916CrossRef Google Scholar PubMed

Van Amsterdam, J, Van Den Brink, W. Harm related to recreational ketamine use and its relevance for the clinical use of ketamine. A systematic review and comparison study. Exp Opin Drug Saf. 2022;21(1):83–94. doi:10.1080/14740338.2021.1949454CrossRef Google Scholar PubMed

Vu, DM, Freyre, K, Opsha, O, Opsha, Y. Recreational ketamine-induced cholangiopathy and ulcerative cystitis. Am J Emerg Med. 2021;45(682):e7, e9–e682. doi:10.1016/j.ajem.2020.12.025CrossRef Google Scholar PubMed

Corazza, O, Assi, S, Schifano, F. From “Special K” to “Special M”: the evolution of the recreational use of ketamine and methoxetamine. CNS Neurosci Therap. 2013;19(6):454–460. doi:10.1111/cns.12063CrossRef Google Scholar

Rueda Carrillo, L, Garcia, KA, Yalcin, N, Shah, M. Ketamine and its emergence in the field of neurology. Cureus. 2022;14(7):e27389. doi:10.7759/cureus.27389Google Scholar PubMed

Le Daré, B, Pelletier, R, Morel, I, Gicquel, T. Histoire de la kétamine: une molécule ancienne qui a toujours la cote. Ann Pharm Fr. 2022;80(1):1–8. doi:10.1016/j.pharma.2021.04.005 CrossRef Google Scholar

Zanos, P, Gould, TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801–811. doi:10.1038/mp.2017.255CrossRef Google Scholar

Kumar, A, Kohli, A. Comeback of ketamine: resurfacing facts and dispelling myths. Korean J Anesthesiol. 2021;74(2):103–114. doi:10.4097/kja.20663CrossRef Google Scholar PubMed

Mion, G. History of anaesthesia: the ketamine story – past, present and future. Eur J Anaesthesiol. 2017;34(9):571–575. doi:10.1097/EJA.0000000000000638CrossRef Google Scholar PubMed

Powers, AR 3rd, Gancsos, MG, Finn, ES, Morgan, PT, Corlett, PR. Ketamine-induced hallucinations. Psychopathology. 2015;48(6):376–385. doi:10.1159/000438675CrossRef Google Scholar PubMed

Félix, L, Antunes, L, Campos, S, Venâncio, C, Coimbra, AM. Recreational use of ketamine and its interaction with NMDA receptors. In Preedy, VR, ed. Neuropathology of Drug Addictions and Substance Misuse. Academic Press; 2016: Chapter 62, 672–680.CrossRef Google Scholar

Zarate, CA Jr., Singh, JB, Carlson, PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856–864. doi:10.1001/arch-psyc.63.8.856CrossRef Google Scholar PubMed

Kishimoto, N, Kato, J, Suzuki, T, et al. A case of RSD with complete disappearance of symptoms following intravenous ketamine infusion combined with stellate ganglion block and continuous epidural block. Masui Jpn J Anesthesiol. 1995;44(12):1680–1684.Google Scholar PubMed

Kingery, WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain. 1997;73(2):123–139. doi:10.1016/s0304-3959(97)00049-3CrossRef Google Scholar PubMed

Sameer, M, Al Abbas, D. Clinical outcomes of ketamine in patients with traumatic brain injury: a systematic review. Int J Crit Illn Inj Sci. 2024;14(3):160–175.Google Scholar PubMed

Wang, X, Lin, C, Lan, L, JJJoca, L. Perioperative intravenous S-ketamine for acute postoperative pain in adults: a systematic review and meta-analysis. J Clin Anesth. 2021;68:110071.CrossRef Google Scholar PubMed

Orhurhu, V, Orhurhu, MS, Bhatia, A, Cohen, SP. Ketamine infusions for chronic pain: a systematic review and meta-analysis of randomized controlled trials. Anesth Analg. 2019;129(1):241–254.CrossRef Google Scholar PubMed

Church, J, Zeman, S, Lodge, D. The neuroprotective action of ketamine and MK-801 after transient cerebral ischemia in rats. Anesthesiology. 1988;69(5):702–709. doi:10.1097/00000542-198811000-00011CrossRef Google Scholar PubMed

Ornowska, M, Wormsbecker, A, Andolfatto, G, et al. The use of ketamine as a neuroprotective agent following cardiac arrest: a scoping review of current literature. CNS Neurosci Therap. 2023;29(1):104–110. doi:10.1111/cns.13983CrossRef Google Scholar PubMed

Zanos, P, Moaddel, R, Morris, PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621–660. doi:10.1124/pr.117.015198CrossRef Google Scholar PubMed

Cho, JE, Shim, JK, Choi, YS, et al. Effect of low-dose ketamine on inflammatory response in off-pump coronary artery bypass graft surgery. Br J Anaesth. 2009;102(1):23–28. doi:10.1093/bja/aen325CrossRef Google Scholar PubMed

Malsy, M, Gebhardt, K, Gruber, M, et al. Effects of ketamine, S-ketamine, and MK 801 on proliferation, apoptosis, and necrosis in pancreatic cancer cells. BMC Anesthesiol. 2015;15:111. doi:10.1186/s12871-015-0076-yCrossRef Google Scholar PubMed

Zhang, X, Zhang, Y, Du, W. Alleviating role of ketamine in breast cancer cell-induced osteoclastogenesis and tumor bone metastasis-induced bone cancer pain through an SRC/EGR1/CST6 axis. BMC Cancer. 2024;24(1):1535. doi:10.1186/s12885-024-13290-7CrossRef Google Scholar PubMed

Chaves, TV, Wilffert, B, Samcjez, X. Overdoses and deaths related to the use of ketamine and its analogues: a systematic review. Am J Drug Alcohol Abuse. 2023;49(2):141–150.CrossRef Google Scholar

Trullas, R, Skolnick, P. Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol. 1990;185(1):1–10. doi:10.1016/0014-2999(90)90204-jCrossRef Google Scholar PubMed

Shpilenia, LS. [Experience with the use of ketamine in psychiatric practice]. Zh Nevropatol Psikhiatr Im SS Korsakova. 1984;84(3):418–422. Opyt primeneniia ketamina v psikhiatricheskoĭ praktike.Google Scholar PubMed

Lv, Q, Yang, L, Li, G, et al. Large-scale persistent network reconfiguration induced by ketamine in anesthetized monkeys: relevance to mood disorders. Biol Psychiatry. 2016;79(9):765–775. doi:10.1016/j.biop-sych.2015.02.028CrossRef Google Scholar PubMed

Diazgranados, N, Ibrahim, L, Brutsche, NE, et al. A randomized add-on trial of an N-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802. doi:10.1001/arch-genpsychiatry.2010.90CrossRef Google Scholar PubMed

Zarate, CA Jr., Brutsche, NE, Ibrahim, L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71(11):939–946. doi:10.1016/j.biop-sych.2011.12.010CrossRef Google Scholar PubMed

Lally, N, Nugent, AC, Luckenbaugh, DA, et al. Anti-anhedonic effect of ketamine and its neural correlates in treatmentresistant bipolar depression. Transl Psychiatry. 2014;4(10):e469. doi:10.1038/tp.2014.105CrossRef Google Scholar PubMed

Johnston, JN, Kadriu, B, Kraus, C, Henter, ID, Zarate, CA. Ketamine in neuropsychiatric disorders: an update. Neuropsychopharmacology. 2024;49(1):23–40. doi:10.1038/s41386-023-01632-1CrossRef Google Scholar PubMed

Price, RB, Nock, MK, Charney, DS, Mathew, SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522–526. doi:10.1016/j. biopsych.2009.04.029CrossRef Google Scholar PubMed

Sepulveda Ramos, C, Thornburg, M, Long, K, et al. The therapeutic effects of ketamine in mental health disorders: a narrative review. Cureus. 2022;14(3):e23647. doi:10.7759/cureus.23647Google Scholar PubMed

Rodriguez, CI, Kegeles, LS, Levinson, A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013;38(12):2475–2483. doi:10.1038/npp.2013.150CrossRef Google Scholar PubMed

Jones, JL, Mateus, CF, Malcolm, RJ, Brady, KT, Back, SE. Efficacy of ketamine in the treatment of substance use disorders: a systematic review. Front Psychiatry. 2018;9:277. doi:10.3389/fpsyt.2018.00277CrossRef Google Scholar PubMed

Taylor, JH, Landeros-Weisenberger, A, Coughlin, C, et al. Ketamine for social anxiety disorder: a randomized, placebo-controlled crossover trial. Neuropsychopharmacology. 2018;43(2):325–333. doi:10.1038/npp.2017.194CrossRef Google Scholar PubMed

Widnyana, MG, Senapathi, TGA, Aryani, LNA, Ryalino, C. The role of ketamine as an antidepressant agent. Bali J Anesthesiol. 2023;7(2):57.Google Scholar

Yavi, M, Lee, H, Henter, ID, Park, LT, Zarate, CA Jr. Ketamine treatment for depression: a review. Discov Ment Health. 2022;2(1):9.CrossRef Google Scholar PubMed

Newport, DJ, Carpenter, LL, McDonald, WM, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950–966. doi:10.1176/appi.ajp.2015.15040465CrossRef Google Scholar PubMed

Aleksandrova, LR, Phillips, AG, Wang, YT. Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatry Neurosci: JPN. 2017;42(4):222–229. doi:10.1503/jpn.160175CrossRef Google Scholar PubMed

Rossi, GN, Hallak, JEC, Baker, G, Dursun, SM, Dos Santos, RG. The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials. Eur Arch Psychiatry Clin Neurosci. 2023;273(1):129–155. doi:10.1007/s00406-022-01460-2CrossRef Google Scholar PubMed

De Jager, JE, Boesjes, R, Roelandt, GHJ, et al. Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: a systematic review of animal models of depression. Neurosc Biobehav Rev. 2024;164:105796. doi:10.1016/j.neubiorev.2024.105796CrossRef Google Scholar PubMed

Mion, G, Villevieille, T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Therap. 2013;19(6):370–380. doi:10.1111/cns.12099CrossRef Google Scholar PubMed

Drugbank. Ketamine. 2024. https://go.drugbank.com/drugs/DB01221. Accessed November 10, 2024.Google Scholar

First Hope. Ketamine hydrochloride: chemical structure, mechanism of action, structural activity relationship, synthesis, uses & side effects. 2024. www.firsthope.co.in/ketamine-hydrochloride-chemical-structure-mechanism-of-action-structural-activity-relationship-s. Accessed November 11, 2024.Google Scholar

Pai, A, Heining, M. Ketamine. Continuing Educ Anaesth Crit Care Pain. 2007;7(2):59–63. doi:10.1093/bjaceaccp/mkm008Google Scholar

Dinis-Oliveira, RJ. Metabolism and metabolomics of ketamine: a toxicological approach. Forensic Sci Res. 2017;2(1):2–10. doi:10.1080/20961790.2017.1285219CrossRef Google Scholar PubMed

Peltoniemi, MA, Hagelberg, NM, Olkkola, KT, Saari, TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet. 2016;55(9):1059–1077. doi:10.1007/s40262-016-0383-6CrossRef Google Scholar PubMed

Erstad, BL, Patanwala, AE. Ketamine for analgosedation in critically ill patients. J Crit Care. 2016;35:145–149. doi:10.1016/j.jcrc.2016.05.016CrossRef Google Scholar PubMed

Hess, EM, Riggs, LM, Michaelides, M, Gould, TD. Mechanisms of ketamine and its metabolites as antidepressants. Biochem Pharmacol. 2022;197:114892. doi:10.1016/j.bcp.2021.114892CrossRef Google Scholar PubMed

Schep, LJ, Slaughter, RJ, Watts, M, Mackenzie, E, Gee, P. The clinical toxicology of ketamine. Clin Toxicol. 2023;61(6):415–428. doi:10.1080/15563650.2023.2212125CrossRef Google Scholar PubMed

Kurato, T, Kiuchi, Y, Yasuhara, H, et al. N-methyl-d-aspartate receptor agonists and antagonists partially affect the duration of ketamine anesthesia in the rat. J Anesth.1995;9:243–246.CrossRef Google Scholar PubMed

Strasburger, S, Bhimani, P, Kaabe, J, et al. What is the mechanism of ketamine’s rapid‐onset antidepressant effect? A concise overview of the surprisingly large number of possibilities. J Clin Pharm Ther. 2017;42(2):147–154.CrossRef Google Scholar

Kang, MJY, Hawken, E, Vazquez, GH. The mechanisms behind rapid antidepressant effects of ketamine: a systematic review with a focus on molecular neuroplasticity. Front Psychiatry. 2022;13:860882. doi:10.3389/fpsyt.2022.860882CrossRef Google Scholar PubMed

Krystal, JH, Kavalali, ET, Monteggia, LM. Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms. Neuropsychopharmacology. 2024;49(1):41–50. doi:10.1038/s41386-023-01629-wCrossRef Google Scholar PubMed

Guirimand, F, Dupont, X, Brasseur, L, Chauvin, M, Bouhassira, D. The effects of ketamine on the temporal summation (wind-up) of the R(III) nociceptive flexion reflex and pain in humans. Anesth Analg. 2000;90(2):408–414. doi:10.1097/00000539-200002000-00031CrossRef Google Scholar

Wu, L-J, Zhuo, M. Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. Neurotherapeutics. 2009;6(4):693–702. doi:10.1016/j.nurt.2009.07.008 CrossRef Google Scholar PubMed

Monteggia, LM, Gideons, E, Kavalali, ET. The role of eukaryotic elongation factor 2 kinase in rapid antidepressant action of ketamine. Biol Psychiatry. 2013;73(12):1199–1203. doi:10.1016/j.biopsych.2012.09.006CrossRef Google Scholar PubMed

Mihaljević, S, Pavlović, M, Reiner, K, Ćaćić, M. Therapeutic mechanisms of ketamine. Psychiatr Danub. 2020;32(3–4):325–333. doi:10.24869/psyd.2020.325CrossRef Google Scholar PubMed

Jacob, TC, Moss, SJ, Jurd, R. GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci. 2008;9(5):331–343. doi:10.1038/nrn2370CrossRef Google Scholar PubMed

Wang, D-S, Penna, A, Orser, BA. Ketamine increases the function of γ-aminobutyric acid type A receptors in hippocampal and cortical neurons. Anesthesiology. 2017;126(4):666–677. doi:10.1097/aln.0000000000001483CrossRef Google Scholar PubMed

Williams, NR, Heifets, BD, Blasey, C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018;175(12):1205–1215. doi:10.1176/appi.ajp.2018.18020138CrossRef Google Scholar PubMed

Levinstein, MR, Budinich, RC, Bonaventura, J, et al. redefining ketamine pharmacology for antidepressant action. Synergistic NMDA and opioid receptor interactions? Am J Psychiatry. 2025;182(3):247–258. doi:10.1176/appi.ajp.20240378CrossRef Google Scholar PubMed

Berman, RM, Cappiello, A, Anand, A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351–354. doi:10.1016/s0006-3223(99)00230-9CrossRef Google Scholar PubMed

Niesters, M, Martini, C, Dahan, A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77(2):357–367. doi:10.1111/bcp.12094CrossRef Google Scholar PubMed

Jiang, C, DiLeone, RJ, Pittenger, C, Duman, RS. The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions. Transl Psychiatry. 2024;14(1):90. doi:10.1038/s41398-024-02796-0CrossRef Google Scholar PubMed

Ago, Y, Yokoyama, R, Asano, S, Hashimoto, H. Roles of the monoaminergic system in the antidepressant effects of ketamine and its metabolites. Neuropharmacology. 2023;223:109313. doi:10.1016/j.neuro-pharm.2022.109313CrossRef Google Scholar PubMed

Du, Y, Du, L, Cao, J, et al. Levo-tetrahydropalmatine inhibits the acquisition of ketamine-induced conditioned place preference by regulating the expression of ERK and CREB phosphorylation in rats. Behav Brain Res. 2017;317:367–373.CrossRef Google Scholar PubMed

Kokkinou, M, Irvine, EE, Bonsall, DR, et al. Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study. bioRxiv. 2019;748665.CrossRef Google Scholar

Belujon, P, AAJBp, G. Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity. Biol Psychiatry. 2014;76(12):927–936.CrossRef Google Scholar PubMed

Hashimoto, K, Kakiuchi, T, Ohba, H, Nishiyama, S, Tsukada, H. Reduction of dopamine D 2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: a PET study in conscious monkeys. Eur Arch Psychiatry Clin Neurosci. 2017;267:173–176.CrossRef Google Scholar

Bærentzen, SL, Thomsen, JB, Thomsen, MB, et al. Subanesthetic S‐ketamine does not acutely alter striatal dopamine transporter binding in healthy Sprague Dawley female rats. Synapse. 2024;78(4):e22294.CrossRef Google Scholar

Breier, A, Adler, CM, Weisenfeld, N, et al. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse. 1998;29(2):142–147. doi:10.1002/(sici)1098-2396(199806)29:2<142::Aid-syn5>3.0.Co;2-73.0.CO;2-7>CrossRef Google Scholar PubMed

Kokkinou, M, Ashok, AH, Howes, OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. 2018;23(1):59–69.CrossRef Google Scholar PubMed

Li, X, Liu, M, Li, Y, et al. Effects of ketamine on monoamine neurotransmitters and GABA in embryonic neurocytes from fetal rat. Turk J Vet Anim Sci. 2017;41(3):414–424.CrossRef Google Scholar

Ago, Y, Tanabe, W, Higuchi, M, et al. (R)-ketamine induces a greater increase in prefrontal 5-HT release than (S)-ketamine and ketamine metabolites via an AMPA receptor-independent mechanism. Int J Neuropsychopharmacol. 2019;22(10):665–674.CrossRef Google Scholar PubMed

Fukumoto, K, Iijima, M, Funakoshi, T, Shigeyuki, C. Role of 5-HT1A receptor stimulation in the medial prefrontal cortex in the sustained antidepressant effects of ketamine. Int J Neuropsychopharmacol. 2018;21(4):371–381.CrossRef Google Scholar PubMed

Sato, K, Wu, J, Kikuchi, T, et al. Differential effects of ketamine and pentobarbitone on acetylcholine release from the rat hippocampus and striatum. Br J Anaesthesia. 1996;77(3):381–384. doi:10.1093/bja/77.3.381CrossRef Google Scholar PubMed

Mimura, M, Namiki, A, Kishi, R, Ikeda, T, Miyake, H. Antagonistic effect of physostigmine on ketamine-induced anesthesia. Psychopharmacology. 1990;102(3):399–403. doi:10.1007/bf02244110CrossRef Google Scholar PubMed

Cavalleri, L, Dassieni, I, Marcotto, GS, et al. Cortisol-dependent impairment of dendrite plasticity in human dopaminergic neurons derived from hiPSCs is restored by ketamine: relevance for major depressive disorders. Neurosci Appl. 2024;3:104049. doi:10.1016/j.nsa.2024.104049 CrossRef Google Scholar

Granak, S, Hoschl, C, Ovsepian, SV. Dendritic spine remodeling and plasticity under general anesthesia. Brain Struct Funct. 2021;226(7):2001–2017. doi:10.1007/s00429-021-02308-6CrossRef Google Scholar PubMed

Siker, ES. Current usefulness of ketamine in anesthetic practice. Anesth Analg. 1971;50(6):1057.Google Scholar PubMed

Kohtala, S. Ketamine – 50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms. Pharmacol Rep: PR. 2021;73(2):323–345. doi:10.1007/s43440-021-00232-4CrossRef Google Scholar PubMed

Hirota, K, Lambert, DG. Ketamine: history and role in anesthetic pharmacology. Neuropharmacology. 2022;216:109171. doi:10.1016/j.neuro-pharm.2022.109171CrossRef Google Scholar PubMed

Thompson, J, Moppett, I, Wiles, M. Smith and Aitkenhead’s Textbook of Anaesthesia. 7th ed. Elsevier Health Sciences; 2019.Google Scholar

White Paul, F, Ham, J, Way Walter, L, Trevor, A. Pharmacology of ketamine isomers in surgical patients. Anesthesiology. 1980;52(3):231–239. doi:10.1097/00000542-198003000-00008CrossRef Google Scholar

Schroeder, KE, Irwin, ZT, Gaidica, M, et al. Disruption of corticocortical information transfer during ketamine anesthesia in the primate brain. NeuroImage. 2016;134:459–465. doi:10.1016/j.neuroimage.2016.04.039CrossRef Google Scholar PubMed

Mathew, CAZSJ, Mathew, SJ, Zarate, CA. Ketamine for Treatment-Resistant Depression. Springer; 2016.CrossRef Google Scholar

Gitlin, J, Chamadia, S, Locascio, JJ, et al. Dissociative and analgesic properties of ketamine are independent. Anesthesiology. 2020;133(5):1021–1028. doi:10.1097/ALN.0000000000003529CrossRef Google Scholar PubMed

Sleigh, J, Pullon, RM, Vlisides, PE, Warnaby, CE. Electroencephalographic slow wave dynamics and loss of behavioural responsiveness induced by ketamine in human volunteers. Br J Anaesthesia. 2019;123(5):592–600. doi:10.1016/j.bja.2019.07.021CrossRef Google Scholar PubMed

Vlisides, PE, Bel-Bahar, T, Lee, U, et al. Neurophysiologic correlates of ketamine sedation and anesthesia: a high-density electroencephalography study in healthy volunteers. Anesthesiology. 2017;127(1):58–69. doi:10.1097/ALN.0000000000001671CrossRef Google Scholar PubMed

Marland, S, Ellerton, J, Andolfatto, G, et al. Ketamine: use in anesthesia. CNS Neurosci Ther. 2013;19(6):381–389. doi:10.1111/cns.12072 CrossRef Google Scholar PubMed

White Paul, F, Way Walter, L, Trevor, AJ. Ketamine – its pharmacology and therapeutic uses. Anesthesiology. 1982;56(2):119–136. doi:10.1097/00000542-198202000-00007CrossRef Google Scholar

Gao, M, Rejaei, D, Liu, H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016;37(7):865–872. doi:10.1038/aps.2016.5CrossRef Google Scholar PubMed

Pitetti, RD, Singh, S, Pierce, MC. Safe and efficacious use of procedural sedation and analgesia by nonanesthesiologists in a pediatric emergency department. Arch Ped Adoles Med. 2003;157(11):1090–1096. doi:10.1001/archpedi.157.11.1090CrossRef Google Scholar

Motov, S, Rosenbaum, S, Vilke, GM, Nakajima, Y. Is there a role for intravenous subdissociative-dose ketamine administered as an adjunct to opioids or as a single agent for acute pain management in the emergency department? J Emerg Med. 2016;51(6):752–757. doi:10.1016/j.jemermed.2016.07.087CrossRef Google Scholar PubMed

Loftus, RW, Yeager, MP, Clark, JA, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113(3):639–646. doi:10.1097/ALN.0b013e3181e90914CrossRef Google Scholar PubMed

Brinck, EC, Tiippana, E, Heesen, M, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018;12(12):CD012033. doi:10.1002/14651858.CD012033.pub4Google Scholar PubMed

Steinberg, AC, Schimpf, MO, White, AB, et al. Preemptive analgesia for postoperative hysterectomy pain control: systematic review and clinical practice guidelines. Am J Obstetr Gynecol. 2017;217(3):303–313.e6. doi:10.1016/j.ajog.2017.03.013CrossRef Google Scholar PubMed

Meyer-Frießem, CH, Lipke, E, Weibel, S, et al. Perioperative ketamine for postoperative pain management in patients with preoperative opioid intake: a systematic review and meta-analysis. J Clin Anesthes. 2022;78:110652. doi:10.1016/j.jclinane.2022.110652CrossRef Google Scholar PubMed

Song, JW, Shim, JK, Song, Y, et al. Effect of ketamine as an adjunct to intravenous patient-controlled analgesia, in patients at high risk of postoperative nausea and vomiting undergoing lumbar spinal surgery. BJA: Br J Anaesth. 2013;111(4):630–635. doi:10.1093/bja/aet192CrossRef Google Scholar

Mehta, SD, Smyth, D, Vasilopoulos, T, et al. Ketamine infusion reduces narcotic requirements following gastric bypass surgery: a randomized controlled trial. Surg Obes Relat Dis. 2021;17(4):737–743. doi:10.1016/j.soard.2020.11.027CrossRef Google Scholar PubMed

Mulier, JP. Is opioid-free general anesthesia for breast and gynecological surgery a viable option? Curr Opin Anaesthesiol. 2019;32(3):257–262. doi:10.1097/aco.0000000000000716CrossRef Google Scholar PubMed

Endeshaw, AS, Aligaz, EM, Molla, MT, et al. Review of clinical evidence of caudal block for postoperative analgesia in children with ketamine added local anesthetics. Ann Med Surg. 2012;75:103480. doi:10.1016/j.amsu.2022.103480Google Scholar

Dahmani, S, Michelet, D, Abback, PS, et al. Ketamine for perioperative pain management in children: a meta-analysis of published studies. Paediatr Anaesth. 2011;21(6):636–652. doi:10.1111/j.1460-9592.2011.03566.xCrossRef Google Scholar PubMed

Schnabel, A, Poepping, DM, Kranke, P, Zahn, PK, Pogatzki-Zahn, EM. Efficacy and adverse effects of ketamine as an additive for paediatric caudal anaesthesia: a quantitative systematic review of randomized controlled trials. Br J Anaesth. 2011;107(4):601–611. doi:10.1093/bja/aer258CrossRef Google Scholar

Jha, AK, Bhardwaj, N, Yaddanapudi, S, Sharma, RK, Mahajan, JK. A randomized study of surgical site infiltration with bupivacaine or ketamine for pain relief in children following cleft palate repair. Paediatr Anaesth. 2013;23(5):401–406. doi:10.1111/pan.12124CrossRef Google Scholar PubMed

Javid, MJ, Hajijafari, M, Hajipour, A, Makarem, J, Khazaeipour, Z. Evaluation of a low dose ketamine in post tonsillectomy pain relief: a randomized trial comparing intravenous and subcutaneous ketamine in pediatrics. Anesthesiol Pain Med. 2012;2(2):85–89. doi:10.5812/aapm.4399CrossRef Google Scholar PubMed

Norambuena, C, Yañez, J, Flores, V, et al. Oral ketamine and midazolam for pediatric burn patients: a prospective, randomized, double-blind study. J Pediatr Surg. 2013;48(3):629–634. doi:10.1016/j.jpedsurg.2012.08.018CrossRef Google Scholar PubMed

Ricciardelli, RM, Walters, NM, Pomerantz, M, et al. The efficacy of ketamine for postoperative pain control in adolescent patients undergoing spinal fusion surgery for idiopathic scoliosis. Spine Deform. 2020;8(3):433–440. doi:10.1007/s43390-020-00073-wCrossRef Google Scholar PubMed

Bauchat, JR, Higgins, N, Wojciechowski, KG, et al. Low-dose ketamine with multimodal postcesarean delivery analgesia: a randomized controlled trial. Int J Obstetr Anesth. 2011;20(1):3–9. doi:10.1016/j.ijoa.2010.10.002CrossRef Google Scholar PubMed

Bilgen, S, Köner, O, Türe, H, et al. Effect of three different doses of ketamine prior to general anaesthesia on postoperative pain following Caesarean delivery: a prospective randomized study. Minerva Anestesiol. 2012;78(4):442–449.Google Scholar PubMed

Leal, PC, Sakata, RK, Salomão, R, Sadatsune, EJ, Issy, AM. Assessment of the effect of ketamine in combination with remifentanil on postoperative pain. Br J Anesthesiol. 2013;63(2):178–182. doi:10.1016/s0034-7094(13)70211-3CrossRef Google Scholar PubMed

Leal, PC, Salomão, R, Brunialti, MK, Sakata, RK. Evaluation of the effect of ketamine on remifentanil-induced hyperalgesia: a double-blind, randomized study. J Clin Anesth. 2015;27(4):331–337. doi:10.1016/j.jcli-nane.2015.02.002CrossRef Google Scholar PubMed

Sahin, L, Sahin, M, Aktas, O, Kilic, E, Mandollu, E. Comparison of propofol/ketamine versus propofol/alfentanil for dilatation and curettage. Clin Exp Obstetr Gynecol. 2012;39(1):72–75.Google Scholar PubMed

Kılıc, E, Demiriz, B, Isıkay, N, et al. Alfentanil versus ketamine combined with propofol for sedation during upper gastrointestinal system endoscopy in morbidly obese patients. Saudi Med J. 2016;37(11):1191–1195. doi:10.15537/smj.2016.11.14557CrossRef Google Scholar PubMed

Volcheck, MM, Graham, SM, Fleming, KC, Mohabbat, AB, Luedtke, CA. Central sensitization, chronic pain, and other symptoms: better understanding, better management. Cleve Clin J Med. 2023;90(4):245–254. doi:10.3949/ccjm.90a.22019CrossRef Google Scholar PubMed

Finnerup, NB, Kuner, R, Jensen, TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101(1):259–301. doi:10.1152/physrev.00045.2019CrossRef Google Scholar PubMed

Pan, L, Li, T, Wang, R, et al. Roles of phosphorylation of n-methyl-d-aspartate receptor in chronic pain. Cell Mol Neurobiol. 2023;43(1):155–175. doi:10.1007/s10571-022-01188-6CrossRef Google Scholar PubMed

Culp, C, Kim, HK, Abdi, S. Ketamine use for cancer and chronic pain management. Front Pharmacol. 2020;11:599721. doi:10.3389/fphar.2020.599721CrossRef Google Scholar PubMed

Velzen, MV, Dahan, JDC, van Dorp, ELA, et al. Efficacy of ketamine in relieving neuropathic pain: a systematic review and meta-analysis of animal studies. Pain. 2021;162(9):2320–2330. doi:10.1097/j.pain.0000000000002231CrossRef Google Scholar PubMed

Cohen, SP, Bhatia, A, Buvanendran, A, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional Anesthesia and Pain Medicine. Am Acad Pain Med Am Soc Anesthesiol. 2018;43(5):521–546. doi:10.1097/AAP.0000000000000808Google Scholar PubMed

Riccardi, A, Guarino, M, Serra, S, et al. Narrative review: low-dose ketamine for pain management. J Clin Med. 2023;12(9):3256. doi:10.3390/jcm12093256CrossRef Google Scholar PubMed

Barreveld, AM, Correll, DJ, Liu, X, et al. Ketamine decreases postoperative pain scores in patients taking opioids for chronic pain: results of a prospective, randomized, double-blind study. Pain Med. 2013;14(6):925–934. doi:10.1111/pme.12086CrossRef Google Scholar PubMed

Boenigk, K, Echevarria, GC, Nisimov, E, et al. Low-dose ketamine infusion reduces postoperative hydromorphone requirements in opioid-tolerant patients following spinal fusion: a randomised controlled trial. Eur J Anaesthesiol. 2019;36(1):8–15. doi:10.1097/eja.0000000000000877CrossRef Google Scholar PubMed

Abouarab, AH, Brülle, R, Aboukilila, MY, Weibel, S, Schnabel, A. Efficacy and safety of perioperative ketamine for the prevention of chronic postsurgical pain: a meta-analysis. Pain Pract. 2024;24(3):553–566. doi:10.1111/papr.13314CrossRef Google Scholar PubMed

Griffiths, HM. Low-dose ketamine infusions for chronic pain management: does this qualify as evidence-based practice? Bri J Pain. 2023;17(5):457–467. doi:10.1177/20494637231182804CrossRef Google Scholar PubMed

Jiao, J, Fan, J, Zhang, Y, Chen, L. Efficacy and safety of ketamine to treat cancer pain in adult patients: a systematic review. J Pain Sympt Manag. 2024;67(3):e185–e210. doi:10.1016/j.jpainsymman.2023.11.004CrossRef Google Scholar PubMed

Israel, JE, St Pierre, S, Ellis, E, et al. Ketamine for the treatment of chronic pain: a comprehensive review. Health Psychol Res. 2021;9(1):25535. doi:10.52965/001c.25535CrossRef Google Scholar PubMed

Bahji, A, Zarate, CA, Vazquez, GH. Ketamine for bipolar depression: a systematic review. Int J Neuropsychopharmacol. 2021;24(7):535–541. doi:10.1093/ijnp/pyab023CrossRef Google Scholar PubMed

Marcantoni, WS, Akoumba, BS, Wassef, M, et al. A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009–January 2019. J Affect Disord. 2020;277:831–841. doi:10.1016/j.jad.2020.09.007CrossRef Google Scholar PubMed

McIntyre, RS, Carvalho, IP, Lui, LMW, et al. The effect of intravenous, intranasal, and oral ketamine in mood disorders: a meta-analysis. J Affect Disord. 2020;276:576–584. doi:10.1016/j.jad.2020.06.050CrossRef Google Scholar PubMed

Anand, A, Mathew, SJ, Sanacora, G, et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med. 2023;388(25):2315–2325. doi:10.1056/NEJMoa2302399CrossRef Google Scholar PubMed

Monteggia, LM, Zarate, C. Antidepressant actions of ketamine: from molecular mechanisms to clinical practice. Curr Opin Neurobiol. 2015;30:139–143. doi:10.1016/j.conb.2014.12.004CrossRef Google Scholar PubMed

Murrough, JW, Perez, AM, Pillemer, S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250–256. doi:10.1016/j.biopsych.2012.06.022CrossRef Google Scholar PubMed

Gideons, ES, Kavalali, ET, Monteggia, LM. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc Natl Acad Sci U S A. 2014;111(23):8649–8654. doi:10.1073/pnas.1323920111CrossRef Google Scholar PubMed

McIntyre, RS, Rosenblat, JD, Nemeroff, CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–399. doi:10.1176/appi.ajp.2020.20081251CrossRef Google Scholar PubMed

Papakostas, GI, Salloum, NC, Hock, RS, et al. Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis. J Clin Psychiatry. 2020;81(4):19r12889. doi:10.4088/JCP.19r12889CrossRef Google Scholar PubMed

Bahji, A, Vazquez, GH, Zarate, CA. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542–555. doi:10.1016/j.jad.2020.09.071CrossRef Google Scholar PubMed

Yang, S, Wang, J, Li, X, et al. Adverse effects of esketamine for the treatment of major depression disorder: findings from randomized controlled trials. Psychiatr Quart. 2022;93(1):81–95. doi:10.1007/s11126-020-09871-xCrossRef Google Scholar PubMed

Horowitz, MA, Moncrieff, J. Are we repeating mistakes of the past? A review of the evidence for esketamine. Br J Psychiatry. 2021;219(5):614–617. doi:10.1192/bjp.2020.89CrossRef Google Scholar

Jiang, Y, Du, Z, Shen, Y, Zhou, Q, Zhu, H. The correlation of esketamine with specific adverse events: a deep dive into the FAERS database. Eur Arch Psychiatry Clin Neurosci. 2025;275(5):1373–1381. doi:10.1007/s00406-023-01732-5CrossRef Google Scholar PubMed

Wajs, E, Aluisio, L, Holder, R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891. doi:10.4088/JCP.19m12891CrossRef Google Scholar

Domany, Y, McCullumsmith, CB. Single fixed-dose intranasal ketamine for alleviation of acute suicidal ideation. An emergency department, transdiagnostic approach: a randomized, double-blind, placebo-controlled, proof-of-concept trial. Arch Suicide Res. 2022;26(3):1250–1265. doi:10.1080/13811118.2021.1878078CrossRef Google Scholar PubMed

Murrough, JW, Soleimani, L, DeWilde, KE, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial. Psychol Med. 2015;45(16):3571–3580. doi:10.1017/s0033291715001506CrossRef Google Scholar PubMed

Xiong, J, Lipsitz, O, Chen-Li, D, et al. The acute anti-suicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: a systematic review and meta-analysis. J Psychiatr Res. 2021;134:57–68. doi:10.1016/j.jpsy-chires.2020.12.038CrossRef Google Scholar

Phillips, JL, Norris, S, Talbot, J, et al. Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression. Neuropsychopharmacology. 2020;45(4):606–612. doi:10.1038/s41386-019-0570-xCrossRef Google Scholar PubMed

Witt, K, Potts, J, Hubers, A, et al. Ketamine for suicidal ideation in adults with psychiatric disorders: a systematic review and meta-analysis of treatment trials. Aust N Z J Psychiatry. 2020;54(1):29–45. doi:10.1177/0004867419883341CrossRef Google Scholar PubMed

Vitek, G, Langenfeld, R, Walters, RW, et al. Therapeutic and safety outcomes of intravenous ketamine for treatment-refractory depression in a veteran population: a case series. Mil Med. 2022;188(7–8):e2242–e2248. doi:10.1093/milmed/usac395CrossRef Google Scholar

Lee, Y, Syeda, K, Maruschak, NA, et al. A new perspective on the anti-suicide effects with ketamine treatment: a procognitive effect. J Clin Psychopharmacol. 2016;36(1):50–56. doi:10.1097/jcp.0000000000000441CrossRef Google Scholar PubMed

Wilkinson, ST, Ballard, ED, Bloch, MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175(2):150–158. doi:10.1176/appi.ajp.2017.17040472CrossRef Google Scholar PubMed

Vieira, F, Correia-Melo, FS, Santos-Lima, C, et al. Ketamine and esketamine augmentation for suicidal ideation: a randomized, double-blinded clinical trial. Gen Hosp Psychiatry. 2021;68:97–99. doi:10.1016/j.genhospp-sych.2020.12.011CrossRef Google Scholar PubMed

Kumari, S, Chaudhry, HA, Sagot, A, et al. Exploring esketamine’s therapeutic outcomes as an FDA-designated breakthrough for treatment-resistant depression and major depressive disorder with suicidal intent. A narrative review. Cureus. 2024;16(2):e53987. doi:10.7759/cureus.53987Google Scholar

Fu, DJ, Ionescu, DF, Li, X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191. doi:10.4088/JCP.19m13191CrossRef Google Scholar PubMed

Ionescu, DF, Fu, DJ, Qiu, X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22–31. doi:10.1093/ijnp/pyaa068CrossRef Google Scholar PubMed

Jollant, F, Colle, R, Nguyen, TML, et al. Ketamine and esketamine in suicidal thoughts and behaviors: a systematic review. Therap Adv Psychopharmacol. 2023;13:20451253231151327. doi:10.1177/20451253231151327CrossRef Google Scholar PubMed

Evers, AG, Murrough, JW, Charney, DS, Costi, S. Ketamine as a prophylactic resilience-enhancing agent. Front Psychiatry. 2022;13:833259. doi:10.3389/fpsyt.2022.833259CrossRef Google Scholar PubMed

McGowan, JC, LaGamma, CT, Lim, SC, et al. Prophylactic ketamine attenuates learned fear. Neuropsychopharmacology. 2017;42(8):1577–1589. doi:10.1038/npp.2017.19CrossRef Google Scholar PubMed

Parise, EM, Parise, LF, Sial, OK, et al. The resilient phenotype induced by prophylactic ketamine exposure during adolescence is mediated by the ventral tegmental area-nucleus accumbens pathway. Biol Psychiatry. 2021;90(7):482–493. doi:10.1016/j.biopsych.2021.05.002CrossRef Google Scholar PubMed

Allen, CA, Ivester, JR. Ketamine for pain management – side effects & potential adverse events. Pain Manag Nurs. 2017;18(6):372–377. doi:10.1016/j.pmn.2017.05.006CrossRef Google Scholar PubMed

Short, B, Fong, J, Galvez, V, Shelker, W, Loo, CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5(1):65–78. doi:10.1016/s2215-0366(17)30272-9CrossRef Google Scholar PubMed

Acevedo-Diaz, EE, Cavanaugh, GW, Greenstein, D, et al. Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression. J Affect Disord. 2020;263:568–575. doi:10.1016/j.jad.2019.11.028CrossRef Google Scholar PubMed

Elia, N, Tramèr, MR. Ketamine and postoperative pain – a quantitative systematic review of randomised trials. Pain. 2005;113(1–2):61–70. doi:10.1016/j.pain.2004.09.036CrossRef Google Scholar PubMed

Stoker, AD, Rosenfeld, DM, Buras, MR, Alvord, JM, Gorlin, AW. Evaluation of clinical factors associated with adverse drug events in patients receiving sub-anesthetic ketamine infusions. J Pain Res. 2019;12:3413–3421. doi:10.2147/jpr.S217005CrossRef Google Scholar PubMed

Grabski, M, Borissova, A, Marsh, B, Morgan, CJA, Curran, HV. Ketamine as a mental health treatment: are acute psychoactive effects associated with outcomes? A systematic review. Behav Brain Res. 2020;392:112629. doi:10.1016/j.bbr.2020.112629CrossRef Google Scholar PubMed

Lineham, A, Avila-Quintero, VJ, Bloch, MH, Dwyer, J. The relationship between acute dissociative effects induced by ketamine and treatment response in adolescent patients with treatment-resistant depression. J Child Adolesc Psychopharmacol. 2023;33(1):20–26. doi:10.1089/cap.2022.0086CrossRef Google Scholar PubMed

Bayes, A, Short, B, Zarate, CA, et al. The Ketamine Side Effect Tool (KSET): a comprehensive measurement-based safety tool for ketamine treatment in psychiatry. J Affect Disord. 2022;308:44–46. doi:10.1016/j.jad.2022.04.020CrossRef Google Scholar PubMed

van Schalkwyk, GI, Wilkinson, ST, Davidson, L, Silverman, WK, Sanacora, G. Acute psychoactive effects of intravenous ketamine during treatment of mood disorders: analysis of the Clinician Administered Dissociative State Scale. J Affect Disord. 2018;227:11–16. doi:10.1016/j.jad.2017.09.023CrossRef Google Scholar PubMed

Stefanovic, A, Brandner, B, Klaassen, E, et al. Acute and chronic effects of ketamine on semantic priming: modeling schizophrenia? J Clin Psychopharmacol. 2009;29(2):124–133. doi:10.1097/JCP.0b013e31819a4b91CrossRef Google Scholar PubMed

Honey, GD, O’Loughlin, C, Turner, DC, et al. The effects of a subpsychotic dose of ketamine on recognition and source memory for agency: implications for pharmacological modelling of core symptoms of schizophrenia. Neuropsychopharmacology. 2006;31(2):413–423. doi:10.1038/sj.npp.1300846CrossRef Google Scholar PubMed

Pennybaker, SJ, Luckenbaugh, DA, Park, LT, Marquardt, CA, Zarate, CA. Ketamine and psychosis history: antidepressant efficacy and psychotomimetic effects postinfusion. Biol Psychiatry. 2017;82(5):e35–e36. doi:10.1016/j.biopsych.2016.08.041CrossRef Google Scholar PubMed

Malhotra, AK, Pinals, DA, Adler, CM, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology. 1997;17(3):141–150. doi:10.1016/s0893-133x(97)00036-5CrossRef Google Scholar PubMed

Tashakkori, M, Ford, A, Dragovic, M, Gabriel, L, Waters, F. The time course of psychotic symptom side effects of ketamine in the treatment of depressive disorders: a systematic review and meta-analysis. Australas Psychiatry. 2021;29(1):80–87. doi:10.1177/1039856220961642CrossRef Google Scholar PubMed

Bartova, L, Papageorgiou, K, Milenkovic, I, et al. Rapid antidepressant effect of S-ketamine in schizophrenia. Eur Neuropsychopharmacol. 2018;28(8):980–982. doi:10.1016/j.euroneuro.2018.05.007CrossRef Google Scholar PubMed

Morgan, CJ, Muetzelfeldt, L, Curran, HV. Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: a 1-year longitudinal study. Addiction. 2010;105(1):121–133. doi:10.1111/j.1360-0443.2009.02761.xCrossRef Google Scholar PubMed

Morrison, RL, Fedgchin, M, Singh, J, et al. Effect of intranasal esketamine on cognitive functioning in healthy participants: a randomized, double-blind, placebo-controlled study. Psychopharmacology. 2018;235(4):1107–1119. doi:10.1007/s00213-018-4828-5CrossRef Google Scholar PubMed

Gill, H, Gill, B, Rodrigues, NB, et al. The effects of ketamine on cognition in treatment-resistant depression: a systematic review and priority avenues for future research. Neurosci Biobehav Rev. 2021;120:78–85. doi:10.1016/j.neubiorev.2020.11.020CrossRef Google Scholar PubMed

Sigtermans, M, Dahan, A, Mooren, R, et al. S(+)-ketamine effect on experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers. Anesthesiology. 2009;111(4):892–903. doi:10.1097/ALN.0b013e3181b437b1CrossRef Google Scholar PubMed

Gelissen, HP, Epema, AH, Henning, RH, et al. Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle. Anesthesiology. 1996;84(2):397–403. doi:10.1097/00000542-199602000-00019CrossRef Google Scholar PubMed

Kalsi, SS, Wood, DM, Dargan, PI. The epidemiology and patterns of acute and chronic toxicity associated with recreational ketamine use. Emerg Health Threats J. 2011;15:7107. doi:10.3402/ehtj.v4i0.7107CrossRef Google Scholar

Szarmach, J, Cubała, WJ, Włodarczyk, A, Wiglusz, MS. Short-term ketamine administration in treatment-resistant depression: focus on cardiovascular safety. Psychiatr Danub. 2019;31(Suppl 3):585–590.Google Scholar PubMed

Riva-Posse, P, Reiff, CM, Edwards, JA, et al. Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions. J Affect Disorders. 2018;236:291–297. doi:10.1016/j.jad.2018.02.025CrossRef Google Scholar PubMed

Rodrigues, NB, McIntyre, RS, Lipsitz, O, et al. Safety and tolerability of IV ketamine in adults with major depressive or bipolar disorder: results from the Canadian Rapid Treatment Center of Excellence. Exp Opin Drug Saf. 2020;19(8):1031–1040. doi:10.1080/14740338.2020.1776699CrossRef Google Scholar PubMed

Doherty, T, Wajs, E, Melkote, R, et al. Cardiac safety of esketamine nasal spray in treatment-resistant depression: results from the clinical development program. CNS Drugs. 2020;34(3):299–310. doi:10.1007/s40263-020-00699-4CrossRef Google Scholar PubMed

Mak, SK, Chan, MT, Bower, WF, et al. Lower urinary tract changes in young adults using ketamine. J Urol. 2011;186(2):610–614. doi:10.1016/j.juro.2011.03.108CrossRef Google Scholar

Findeis, H, Sauer, C, Cleare, A, Bauer, M, Ritter, P. Urothelial toxicity of esketamine in the treatment of depression. Psychopharmacology. 2020;237(11):3295–3302. doi:10.1007/s00213-020-05611-yCrossRef Google Scholar PubMed

Jhang, JF, Hsu, YH, Kuo, HC. Possible pathophysiology of ketamine-related cystitis and associated treatment strategies. Int J Urol. 2015;22(9):816–825. doi:10.1111/iju.12841CrossRef Google Scholar PubMed

Wei, YB, Yang, JR, Yin, Z, et al. Genitourinary toxicity of ketamine. Hong Kong Med J. 2013;19(4):341–348. doi:10.12809/hkmj134013Google Scholar PubMed

Winstock, AR, Mitcheson, L, Gillatt, DA, Cottrell, AM. The prevalence and natural history of urinary symptoms among recreational ketamine users. BJU Int. 2012;110(11):1762–1766. doi:10.1111/j.1464-410X.2012.11028.xCrossRef Google Scholar PubMed

Shahani, R, Streutker, C, Dickson, B, Stewart, RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 2007;69(5):810–812. doi:10.1016/j.urology.2007.01.038CrossRef Google Scholar PubMed

Cheung, RY, Chan, SS, Lee, JH, et al. Urinary symptoms and impaired quality of life in female ketamine users: persistence after cessation of use. Hong Kong Med J. 2011;17(4):267–273.Google Scholar PubMed

Ng, J, Lui, LMW, Rosenblat, JD, et al. Ketamine-induced urological toxicity: potential mechanisms and translation for adults with mood disorders receiving ketamine treatment. Psychopharmacology. 2021;238(4):917–926. doi:10.1007/s00213-021-05767-1CrossRef Google Scholar PubMed

Wolff, K, Winstock, AR. Ketamine: from medicine to misuse. CNS Drugs. 2006;20(3):199–218. doi:10.2165/00023210-200620030-00003CrossRef Google Scholar PubMed

Zhang, MW, Harris, KM, Ho, RC. Is off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications. BMC Med Ethics. 2016;17:4. doi:10.1186/s12910-016-0087-3CrossRef Google Scholar PubMed

Morgan, CJ, Mofeez, A, Brandner, B, Bromley, L, Curran, HV. Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose-response study. Psychopharmacology. 2004;172(3):298–308. doi:10.1007/s00213-003-1656-yGoogle Scholar PubMed

Corkery, JM, Hung, WC, Claridge, H, et al. Recreational ketamine-related deaths notified to the National Programme on Substance Abuse Deaths, England, 1997–2019. J Psychopharmacol. 2021;35(11):1324–1348. doi:10.1177/02698811211021588CrossRef Google Scholar

Liu, Y, Lin, D, Wu, B, Zhou, W. Ketamine abuse potential and use disorder. Brain Res Bull. 2016;126(Pt 1):68–73. doi:10.1016/j.brainres-bull.2016.05.016CrossRef Google Scholar PubMed

Savić Vujović, K, Jotić, A, Medić, B, et al. Ketamine, an old-new drug: uses and abuses. Pharmaceuticals. 2023;17(1):16. doi:10.3390/ph17010016CrossRef Google Scholar

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