A growing number of investigators are studying ketamine effects in healthy human subjects, but concerns remain about its safety as a research tool. Therefore, it is timely to revisit the safety of subanesthetic doses of ketamine in experimental psychopharmacology studies.
To report on the safety of laboratory studies with subanesthetic doses of ketamine in healthy humans using an existing dataset.
Materials and methods
Medically healthy subjects with no personal or familial Axis I psychotic spectrum disorders were administered subanesthetic doses of ketamine by intravenous infusion in a series of clinical investigations from 1989 to 2005. The safety of ketamine administration was monitored in these subjects.
Four hundred and fifty subjects received at least one dose of active ketamine. Eight hundred and thirty three active ketamine and 621 placebo infusions were administered. Ten adverse mental status events were documented in nine subjects/infusions that were deemed related to ketamine administration (2% of subjects, 1.45% of infusions). All but one adverse reaction resolved by the end of the test session. The side effects in the remaining individual were no longer clinically significant within 4 days of the test session. No residual sequelae were observed.
Ketamine administration at subanesthetic doses appears to present an acceptable level of risk for carefully screened populations of healthy human subjects in the context of clinical research programs that intensively monitor subjects throughout their study participation.
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Abi-Saab WM, D’Souza DC, Moghaddam B, Krystal JH (1998) The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 31(Suppl 2):104–109
Adler CM, Malhotra AK, Elman I, Goldberg T, Egan M, Pickar D, Breier A (1999) Comparison of ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia. Am J Psychiatry 156:1646–1649
Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A, Krystal JH (2000) Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-d-aspartate receptor antagonists. Arch Gen Psychiatry 57:270–276
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354
Carpenter WT Jr (1999) The schizophrenia ketamine challenge study debate. Biol Psychiatry 46:1081–1091
Chapman LJ, Chapman JP, Miller EN (1982) Reliabilities and intercorrelations of eight measures of proneness to psychosis. J Consult Clin Psychol 50:187–195
Cho HS, D’Souza DC, Gueorguieva R, Perry EB, Madonick S, Karper LP, Abi-Dargham A, Belger A, Abi-Saab W, Lipschitz D, Bennet A, Seibyl JP, Krystal JH (2005) Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology (Berl) 179:136–143
Corssen G, Oget S, Reed PC (1971) Computerized evaluation of psychic effects of ketamine. Anesth Analg 50:397–401
D’Souza DC, Gil R, Zuzarte E, Zimmerman L, Abi-Saab D, Damon D, White J, Krystal J (1999) Glycine-ketamine interactions in healthy humans. 6th international congress on schizophrenia research (Schizophr Res), Santa Fe, NM, pp 213
Dillon P, Copeland J, Jansen K (2003) Patterns of use and harms associated with non-medical ketamine use. Drug Alcohol Depend 69:23–28
Haas DA, Harper DG (1992) Ketamine: a review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog 39:61–68
Honey GD, Honey RA, O’Loughlin C, Sharar SR, Kumaran D, Suckling J, Menon DK, Sleator C, Bullmore ET, Fletcher PC (2005) Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: an fMRI study. Cereb Cortex 15:749–759
Karper LP, Grillon C, Charney DS, Krystal J (1994) The effect of ketamine on prepulse inhibition and attention. 33rd annual meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico
Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214
Krystal JH, Karper LP, Bennett A, D’Souza DC, Abi-Dargham A, Morrissey K, Abi-Saab D, Bremner JD, Bowers MB Jr, Suckow RF, Stetson P, Heninger GR, Charney DS (1998a) Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans. Psychopharmacology (Berl) 135:213–229
Krystal JH, Petrakis IL, Webb E, Cooney NL, Karper LP, Namanworth S, Stetson P, Trevisan LA, Charney DS (1998b) Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry 55:354–360
Krystal JH, Belger A, D’Souza DC, Anand A, Charney DS, Aghajanian GK, Moghaddam B (1999a) Therapeutic implications of the hyperglutamatergic effects of NMDA antagonists. Neuropsychopharmacology 21:S143–S157
Krystal JH, D’Souza DC, Karper LP, Bennett A, Abi-Dargham A, Abi-Saab D, Cassello K, Bowers MB Jr, Vegso S, Heninger GR, Charney DS (1999b) Interactive effects of subanesthetic ketamine and haloperidol in healthy humans. Psychopharmacology (Berl) 145:193–204
Krystal JH, D’Souza DC, Petrakis IL, Belger A, Berman RM, Charney DS, Abi-Saab W, Madonick S (1999c) NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harv Rev Psychiatry 7:125–143
Krystal JH, Bennett A, Abi-Saab D, Belger A, Karper LP, D’Souza DC, Lipschitz D, Abi-Dargham A, Charney DS (2000) Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions. Biol Psychiatry 47:137–143
Krystal JH, D’Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003a) NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 169:215–233
Krystal JH, Petrakis IL, Krupitsky E, Schutz C, Trevisan L, D’Souza DC (2003b) NMDA receptor antagonism and the ethanol intoxication signal: from alcoholism risk to pharmacotherapy. Ann N Y Acad Sci 1003:176–184
Krystal JH, Petrakis IL, Limoncelli D, Webb E, Gueorgueva R, D’Souza DC, Boutros NN, Trevisan L, Charney DS (2003c) Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients. Neuropsychopharmacology 28:2020–2028
Krystal JH, Abi-Saab W, Perry E, D’Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A (2005a) Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl) 179:303–309
Krystal JH, Perry EB Jr, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, Macdougall L, Abi-Saab W, D’Souza DC (2005b) Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function. Arch Gen Psychiatry 62:985–994
Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D’Souza DC (2006) Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism. Neuropsychopharmacology 31:1793–1800
Lahti AC, Koffel B, LaPorte D, Tamminga CA (1995) Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology 13:9–19
Lahti AC, Holcomb HH, Gao X, Tamminga CA (1999) NMDA-sensitive glutamate antagonism: a human model for psychosis. Neuropsychopharmacology 21:S158–S169
Lahti AC, Warfel D, Michaelidis T, Weiler MA, Frey K, Tamminga CA (2001a) Long-term outcome of patients who receive ketamine during research. Biol Psychiatry 49:869–875
Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (2001b) Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology 25:455–467
Lipschitz DS, D’Souza DC, White JA, Charney DS, Krystal JH (1997) Clozapine blockade of ketamine effects in healthy subjects. Biol Psychiatry 41 S:23S (abstract #76)
Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A (1996) NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology 14:301–307
Miller RD (2005) Miller’s Anesthesia, 6th edn. Elsevier, Amsterdam, The Netherlands
Moretti RJ, Hassan SZ, Goodman LI, Meltzer HY (1984) Comparison of ketamine and thiopental in healthy volunteers: effects on mental status, mood, and personality. Anesth Analg 63:1087–1096
Morgan CJ, Mofeez A, Brandner B, Bromley L, Curran HV (2004a) Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers. Neuropsychopharmacology 29:208–218
Morgan CJ, Mofeez A, Brandner B, Bromley L, Curran HV (2004b) Ketamine impairs response inhibition and is positively reinforcing in healthy volunteers: a dose–response study. Psychopharmacology (Berl) 172:298–308
Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106–118
Olney JW, Farber NB (1995) Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52:998–1007
Petrakis IL, Limoncelli D, Gueorguieva R, Jatlow P, Boutros NN, Trevisan L, Gelernter J, Krystal JH (2004) Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry 161:1776–1782
Reich DL, Silvay G (1989) Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 36:186–197
Rowland LM, Astur RS, Jung RE, Bustillo JR, Lauriello J, Yeo RA (2005) Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology 30:633–639
Spitzer RL, Williams JBW, Gibbon M, First MB (1990) Structured Clinical Interview for DSM-III-R-Non-Patient Edition (SCID-NP, Version 1.0 with supplement for DSM-IV). American Psychiatric, Washington, DC
Thomson AM, West DC, Lodge D (1985) An N-methylaspartate receptor-mediated synapse in rat cerebral cortex: a site of action of ketamine? Nature 313:479–481
Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864
The authors thank Eli Lilly and Company for the provision of LY354740 and administrative and scientific support. The authors thank GlaxoSmithKline for the provision of lamotrigine and administrative and scientific support. The authors also acknowledge support from the Department of Veterans Affairs (Alcohol Research Center and Schizophrenia Biological Research Center). Lastly, the authors thank Sonah Yoo, R.Ph.; Robert Sturwold, R.Ph.; Brenda Breault, R.N., B.S.N.; Gina McManus, R.N.; Sandra Capelli, R.N.; Patricia Barry, R.N.; Cynthia D’Amico, R.N.; Willie Ford; John Roach; and Arthur Flegert of the Neurobiological Studies Unit at the VA Connecticut Healthcare System, West Haven Campus for their central contributions to the success of this project.
The members of the Yale Ketamine Study Group were as follows: Abi-Dargham, A; Abi-Saab, D; Abi-Saab, W; Ammerman, YW; Anand, A; Belger, A; Bennett, A; Berman, RM; Boutros, N; Bowers, MB; Breier, A; Bremner, JD; Brush, L; Cappiello, A; Cassello, K; Charney, DS; Cho, H; Cooney, NL; Cooper, TB; Cramer, J; Damon, D; Delaney, R; D’Souza, DC; Freeman, GK; Gelernter, J; Gil, R; Grillon, C; Gueorguieva, R; Heninger, GR; Hu, XS; Hunsberger, T; Jatlow, P; Karper, LP; Krystal, JH; Levine, L; Limoncelli, D; Lipschitz, DS; Liu, N; MacDougall, L; Madonick, SH; Morrissey, K; Namenworth, S; Oren, DA; Perry, EB; Petrakis, IL; Seibyl, JP; Stetson, P; Suckow, RF; Trevisan, LA; Vegso, S; Webb, E; White, JA; Zimmerman, L; and Zuzarte, E.
Other members of the Yale Ketamine Study Group are listed in the Acknowledgements.
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Perry, E.B., Cramer, J.A., Cho, HS. et al. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology 192, 253–260 (2007). https://doi.org/10.1007/s00213-007-0706-2
- NMDA receptor