Advertisement

Arylcyclohexamines (Ketamine, Phencyclidine, and Analogues)

  • James H. Ho
  • Paul I. Dargan
Living reference work entry

Later version available View entry history

Abstract

Arylcyclohexamines (also known as arylcyclohexylamines) are a group of compounds that contain a cyclohexamine unit with an aryl moiety, typically a phenyl ring, attached to the same atom to which the amine group is linked (see Fig. 1). They all exhibit dissociative effects due to their antagonism of N-methyl-d-aspartate (NMDA) receptors, and many have been studied as alternatives to traditional anesthetic agents but subsequently abused recreationally in pursuit of these same effects. The most well-characterized arylcyclohexamines are phencyclidine ((1-(1-phencyclohexyl) piperidine; PCP)), ketamine, and, of the novel analogues, methoxetamine.

Keywords

Phencyclidine Ketamine Arylcyclohexamines Methoxetamine PCP Sernyl MXE NMDA receptor K-cramps K-hole M-hole 

References

  1. 1.
    Kursanov N. Phenyl derivatives of naphthenes, second paper, some derivatives of phenylcyclohexane. Zh Russ Fiz-Khim O-va. 1907;38:1295.Google Scholar
  2. 2.
    Adank K, Chiavarelli S, Pirelli AM. Studies on synthetic sympatholytics belonging to the group of ergotamine. XI. Certain derivatives with amine and mide function of 1-amino-tetraline and of cyclohexylamine. Rend Ist Sup Sanit. 1953;16(1–3):133–9.PubMedGoogle Scholar
  3. 3.
    Morris H, Wallach J. From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal. 2014;6(7–8):614–32. doi:10.1002/dta.1620.PubMedCrossRefGoogle Scholar
  4. 4.
    Lear E. Intravenous anesthesia. A survey of newer agents. Anesth Analg. 1968;47(2):154–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Maddox VH, Godefroi EF, Parcell RF. The synthesis of phencyclidine and other 1-arylcyclohexylamines. J Med Chem. 1965;8:230–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen G, Ensor CR, Russell D, Bohner B. The pharmacology of 1-(1-phenylcyclohexyl) piperidine-HCl. J Pharmacol Exp Ther. 1959;127:241–50.PubMedGoogle Scholar
  7. 7.
    Domino EF. Neurobiology of phencyclidine (Sernyl), a drug with an unusual spectrum of pharmacological activity. Int Rev Neurobiol. 1964;6:303–47.PubMedCrossRefGoogle Scholar
  8. 8.
    Greifenstein FE, Devault M, Yoshitake J, Gajewski JE. A study of a 1-aryl cyclo hexyl amine for anesthesia. Anesth Analg. 1958;37(5):283–94.PubMedCrossRefGoogle Scholar
  9. 9.
    Domino EF. Taming the ketamine tiger. 1965. Anesthesiology. 2010;113(3):678–84. doi:10.1097/ALN.0b013e3181ed09a2.PubMedGoogle Scholar
  10. 10.
    Rappolt RT, Gay GR, Farris RD. Emergency management of acute phencyclidine intoxication. JACEP. 1979;8(2):68–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Domino EF, Chodoff P, Corssen G. Pharmacologic effects of Ci-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–91.PubMedCrossRefGoogle Scholar
  12. 12.
    McCarthy DA, Chen G, Kaump DH, Ensor C. General anesthetic and other pharmacological properties of 2-(O-Chlorophenyl)-2-methylamino cyclohexanone HCL (Ci-58 l). J New Drugs. 1965;5(1):21–33.PubMedCrossRefGoogle Scholar
  13. 13.
    Stevens CL. Aminoketones and methods for their production. US3254124 A. United States Patent Office. 1966.Google Scholar
  14. 14.
    Morgan CJ, Curran HV, Independent Scientific Committee on D. Ketamine use: a review. Addiction. 2012;107(1):27–38. doi:10.1111/j.1360-0443.2011.03576.x.PubMedCrossRefGoogle Scholar
  15. 15.
    Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med. 2004;5(3):263–75. doi:10.1111/j.1526-4637.2004.04043.x.PubMedCrossRefGoogle Scholar
  16. 16.
    Lynch ME, Clark AJ, Sawynok J, Sullivan MJ. Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study. J Pain. 2005;6(10):644–9. doi:10.1016/j.jpain.2005.04.008.PubMedCrossRefGoogle Scholar
  17. 17.
    Sunder RA, Toshniwal G, Dureja GP. Ketamine as an adjuvant in sympathetic blocks for management of central sensitization following peripheral nerve injury. J Brachial Plex Peripher Nerve Inj. 2008;3:22. doi:10.1186/1749-7221-3-22.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Fujikawa DG. Neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia. 1995;36(2):186–95.PubMedCrossRefGoogle Scholar
  19. 19.
    Krystal JH. Ketamine and the potential role for rapid-acting antidepressant medications. Swiss Med Wkly. 2007;137(15–16):215–6. doi:2007/15/smw-11932.PubMedGoogle Scholar
  20. 20.
    Dorandeu F, Barbier L, Dhote F, Testylier G, Carpentier P. Ketamine combinations for the field treatment of soman-induced self-sustaining status epilepticus. Review of current data and perspectives. Chem Biol Interact. 2013;203(1):154–9. doi:10.1016/j.cbi.2012.09.013.PubMedCrossRefGoogle Scholar
  21. 21.
    Dorandeu F, Dhote F, Barbier L, Baccus B, Testylier G. Treatment of status epilepticus with ketamine, are we there yet? CNS Neurosci Ther. 2013;19(6):411–27. doi:10.1111/cns.12096.PubMedCrossRefGoogle Scholar
  22. 22.
    Andrade C. Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. J Clin Psychiatry. 2015;76(5):628–31. doi:10.4088/JCP.15f10026.PubMedCrossRefGoogle Scholar
  23. 23.
    Fang Y, Wang X. Ketamine for the treatment of refractory status epilepticus. Seizure. 2015;30:14–20. doi:10.1016/j.seizure.2015.05.010.PubMedCrossRefGoogle Scholar
  24. 24.
    Radvansky BM, Puri S, Sifonios AN, Eloy JD, Le V. Ketamine-A narrative review of its uses in medicine. Am J Ther. 2015. doi:10.1097/MJT.0000000000000257.PubMedGoogle Scholar
  25. 25.
    Scheuing L, Chiu CT, Liao HM, Chuang DM. Antidepressant mechanism of ketamine: perspective from preclinical studies. Front Neurosci. 2015;9:249. doi:10.3389/fnins.2015.00249.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Zeiler FA. Early use of the NMDA receptor antagonist ketamine in refractory and superrefractory status epilepticus. Crit Care Res Pract. 2015;2015:831260. doi:10.1155/2015/831260.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Zeiler FA, West M. Ketamine for status epilepticus: Canadian physician views and time to push forward. Can J Neurol Sci. 2015;42(2):132–4. doi:10.1017/cjn.2015.16.PubMedCrossRefGoogle Scholar
  28. 28.
    Isbister GK, Calver LA, Downes MA, Page CB. Ketamine as rescue treatment for difficult-to-sedate severe acute behavioral disturbance in the emergency department. Ann Emerg Med. 2016. doi:10.1016/j.annemergmed.2015.11.028.Google Scholar
  29. 29.
    Luisada PR, Reddick C. An epidemic of drug-induced schizophrenia. In: 128th Annual Meeting of the American Psychiatric Association. Annaheim, California. 1975.Google Scholar
  30. 30.
    Petersen RC, Stillman RC. Phencyclidine: an overview. NIDA Res Monogr. 1978;(21):1–17. Phencyclidine abuse: an appraisal.Google Scholar
  31. 31.
    Siegel RK. Phencyclidine and ketamine intoxication: a study of four populations of recreational users. NIDA Res Monogr. 1978;21:119–47.PubMedGoogle Scholar
  32. 32.
    Feldman HW. Angel dust, an ethnographic study of PCP users. Lexington: Lexington Books; 1979.Google Scholar
  33. 33.
    Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs. 2000;32(4):419–33. doi:10.1080/02791072.2000.10400244.PubMedCrossRefGoogle Scholar
  34. 34.
    Crider R. Phencyclidine: changing abuse patterns. NIDA Res Monogr. 1986;64:163–73.PubMedGoogle Scholar
  35. 35.
    Burns RS, Lerner SE, Corrado R, James SH, Schnoll SH. Phencyclidine–states of acute intoxication and fatalities. West J Med. 1975;123(5):345–9.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Lundberg GD, Gupta RC, Montgomery SH. Phencyclidine: patterns seen in street drug analysis. Clin Toxicol. 1976;9(4):503–11. doi:10.3109/15563657608988152.PubMedCrossRefGoogle Scholar
  37. 37.
    DEA. PCP tablets sold as MDMA. Information Bulletin. In: Agency, D.E., editor. Washington, DC: National Drug Intelligence Center; 2001. https://www.justice.gov/archive/ndic/pubs0/661/661p.pdf.
  38. 38.
    Flomenbaum NE, Goldfrank LR, Hoffman RS, et al. Goldfrank’s toxicologic emergencies. New York: McGraw-Hill; 2006.Google Scholar
  39. 39.
    National survey results on drug use. Monitoring the Future Study, 1975-1993. Volume II: college students and young adults.Google Scholar
  40. 40.
    ACMD. Ketamine: a review of use and harm. Department of Public Health, Home Office. 2013.Google Scholar
  41. 41.
  42. 42.
    Reier CE. Ketamine–“dissociative agent” or hallucinogen? N Engl J Med. 1971;284(14):791–2.PubMedGoogle Scholar
  43. 43.
    Dargan PI, Wood DM. Novel psychoactive substances: classification, pharmacology and toxicology. Amsterdam: Elsevier; 2013.Google Scholar
  44. 44.
    Dalgarno PJ, Shewan D. Illicit use of ketamine in Scotland. J Psychoactive Drugs. 1996;28(2):191–9. doi:10.1080/02791072.1996.10524391.PubMedCrossRefGoogle Scholar
  45. 45.
    DEA. Lists of: scheduling actions controlled substances regulated chemicals. US Department of Justice. 2015. http://www.deadiversion.usdoj.gov/schedules/orangebook/orangebook.pdf
  46. 46.
    Baumeister D, Tojo LM, Tracy DK. Legal highs: staying on top of the flood of novel psychoactive substances. Ther Adv Psychopharmacol. 2015;5(2):97–132. doi:10.1177/2045125314559539.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    DEA. Intelligence bulletin: ketamine. In: Agency, D.E., editor. Washington, DC: National Drug Intelligence Center; 2009. https://www.justice.gov/archive/ndic/pubs10/10255/10255p.pdf.
  48. 48.
    EMCDDA. EMCDDA–Europol Joint Report on a new psychoactive substance: methoxetamine (2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone). Lisbon: EMCDDA; 2014.Google Scholar
  49. 49.
    Shulgin AT, Mac Lean DE. Illicit synthesis of phencyclidine (PCP) and several of its analogs. Clin Toxicol. 1976;9(4):553–60. doi:10.3109/15563657608988157.PubMedCrossRefGoogle Scholar
  50. 50.
    Linder RL, Lerner SE, Burns RS. PCP, the devil’s dust: recognition, management, and prevention of phencyclidine abuse. Belmont: Wadsworth Publishing Company; 1981.Google Scholar
  51. 51.
    Lerner SE, Burns RS. Phencyclidine use among youth: history, epidemiology, and acute and chronic intoxication. NIDA Res Monogr. 1978;21:66–118.PubMedGoogle Scholar
  52. 52.
    FDA. Controlled substances act. http://www.fda.gov/regulatoryinformation/legislation/ucm148726.htm. Accessed 12 Apr 2016.
  53. 53.
    Nakamura GR, Griesemer EC, Joiner LE, Noguchi TT. Determination of 1-(1-phenylcyclohexyl) pyrrolidine (PHP) in postmortem specimens: a case report. Clin Toxicol. 1979;14(4):383–8. doi:10.3109/15563657909010600.PubMedCrossRefGoogle Scholar
  54. 54.
    Smialek JE, Monforte JR, Gault R, Spitz WU. Cyclohexamine (“Rocket Fuel”)-phencyclidine’s potent analog. J Anal Toxicol. 1979;3(5):209–12. doi:10.1093/jat/3.5.209.CrossRefGoogle Scholar
  55. 55.
    Xicori. TCP synthesis. http://chemistry.mdma.ch/hiveboard/methods/000484668.html. Accessed 15 Sept 2015.
  56. 56.
    Bailey K. Identification of a street drug as N-ethyl-1-phenylcyclohexylamine, a phencyclidine analog. J Pharm Sci. 1978;67(6):885–6.PubMedCrossRefGoogle Scholar
  57. 57.
    Chen G, Ensor CR, Bohner B. The pharmacology of 2-(ethylamino)-2-(2-thienyl)-cyclohexanone-HCl (CI-634). J Pharmacol Exp Ther. 1969;168(1):171–9.PubMedGoogle Scholar
  58. 58.
    Cording CJ, DeLuca R, Camporese T, Spratt E. A fatality related to the veterinary anesthetic telazol. J Anal Toxicol. 1999;23(6):552–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Chung H, Choi H, Kim E, et al. A fatality due to injection of tiletamine and zolazepam. J Anal Toxicol. 2000;24(4):305–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Ballinger JR, Marshman JA. GLC quantification of 1-Piperidinocyclohexanecarbonitrile (PCC) in illicit phencyclidine (PCP). J Anal Toxicol. 1979;3(4):158–61. doi:10.1093/jat/3.4.158.CrossRefGoogle Scholar
  61. 61.
    Soine WH, Vincek WC, Agee DT, et al. Contamination of illicit phencyclidine with 1-piperidinocyclohexanecarbonitrile. J Anal Toxicol. 1980;4(5):217–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Reed A, Kane AW. Phencyclidine (PCP). STASH Capsules. 1970;44:1.Google Scholar
  63. 63.
    Bailey K, Chow AY, Downie RH, Pike RK. 1-Piperidinocyclohexanecarbonitrile, a toxic precursor of phencyclidine. J Pharm Pharmacol. 1976;28(9):713–4.PubMedCrossRefGoogle Scholar
  64. 64.
    Cone EJ, Vaupel DB, Buchwald WF. Phencyclidine: detection and measurement of toxic precursors and analogs in lllicit samples. J Anal Toxicol. 1980;4(3):119–23.PubMedCrossRefGoogle Scholar
  65. 65.
    Soine WH, Vincek WC, Agee DT. Phencyclidine contaminant generates cyanide. N Engl J Med. 1979;301(8):438. doi:10.1056/NEJM197908233010821.PubMedGoogle Scholar
  66. 66.
    EMCDDA. Briefing paper: online sales of new psychoactive substances/‘legal highs’: summary of results from the 2011 multilingual snapshots. 2011.Google Scholar
  67. 67.
    Ward J, Rhyee S, Plansky J, Boyer E. Methoxetamine: a novel ketamine analog and growing health-care concern. Clin Toxicol (Phila). 2011;49(9):874–5. doi:10.3109/15563650.2011.617310.CrossRefGoogle Scholar
  68. 68.
    Hofer KE, Grager B, Muller DM, et al. Ketamine-like effects after recreational use of methoxetamine. Ann Emerg Med. 2012;60(1):97–9. doi:10.1016/j.annemergmed.2011.11.018.PubMedCrossRefGoogle Scholar
  69. 69.
    Shields JE, Dargan PI, Wood DM, et al. Methoxetamine associated reversible cerebellar toxicity: three cases with analytical confirmation. Clin Toxicol (Phila). 2012;50(5):438–40. doi:10.3109/15563650.2012.683437.CrossRefGoogle Scholar
  70. 70.
    Wood DM, Davies S, Puchnarewicz M, Johnston A, Dargan PI. Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine. Eur J Clin Pharmacol. 2012;68(5):853–6. doi:10.1007/s00228-011-1199-9.PubMedCrossRefGoogle Scholar
  71. 71.
    Wikstrom M, Thelander G, Dahlgren M, Kronstrand R. An accidental fatal intoxication with methoxetamine. J Anal Toxicol. 2013;37(1):43–6. doi:10.1093/jat/bks086.PubMedCrossRefGoogle Scholar
  72. 72.
    Wiergowski M, Anand JS, Krzyzanowski M, Jankowski Z. Acute methoxetamine and amphetamine poisoning with fatal outcome: a case report. Int J Occup Med Environ Health. 2014;27(4):683–90. doi:10.2478/s13382-014-0290-8.PubMedCrossRefGoogle Scholar
  73. 73.
    Adamowicz P, Zuba D. Fatal intoxication with methoxetamine. J Forensic Sci. 2015;60 Suppl 1:S264–8. doi:10.1111/1556-4029.12594.PubMedCrossRefGoogle Scholar
  74. 74.
    Chiappini S, Claridge H, Corkery JM, et al. Methoxetamine-related deaths in the UK: an overview. Hum Psychopharmacol. 2015;30(4):244–8. doi:10.1002/hup.2422.PubMedCrossRefGoogle Scholar
  75. 75.
    ACMD. Methoxetamine report. Department of Public Health, Home Office. 2012.Google Scholar
  76. 76.
    Corazza O, Assi S, Schifano F. From “Special K” to “Special M”: the evolution of the recreational use of ketamine and methoxetamine. CNS Neurosci Ther. 2013;19(6):454–60. doi:10.1111/cns.12063.PubMedCrossRefGoogle Scholar
  77. 77.
    Menzies EL, Hudson SC, Dargan PI, et al. Characterizing metabolites and potential metabolic pathways for the novel psychoactive substance methoxetamine. Drug Test Anal. 2014;6(6):506–15. doi:10.1002/dta.1541.PubMedCrossRefGoogle Scholar
  78. 78.
    Geneste P, Kamenka JM, Ung SN, et al. Conformational determination of phencyclidine derivatives in view of structure-activity correlation. Eur J Med Chem – Chim Ther. 1979;14:301.Google Scholar
  79. 79.
    Beagle JQ. Synthesis and effects of PCP analogs. https://www.erowid.org/archive/rhodium/chemistry/pcp/. Accessed 15 Sept 2015.
  80. 80.
    Beagle JQ. 4-methoxy PCP. http://chemistry.mdma.ch/hiveboard/novel/000212050.html. Accessed 15 Sept 2015.
  81. 81.
    EMCDDA. 2011 Annual report on the state of the drugs problem in Europe, Lisbon. 2011.Google Scholar
  82. 82.
    EMCDDA. Annual report on the implementation of council decision 2005/387/JHA (New drugs in Europe, 2012), EMCDDA, Lisbon. 2012.Google Scholar
  83. 83.
    SAMHSA. Results from the 2013 National survey on drug use and health: detailed tables. In Quality, C.f.B.H.S.a., editor. Rockville: Substance Abuse and Mental Health Services Administration; 2014.Google Scholar
  84. 84.
    UNODC. United Nations Office on drugs and crime: World Drug Report 2015. Vienna: United Nations; 2015.CrossRefGoogle Scholar
  85. 85.
    Hill SL, Harbon SC, Coulson J, et al. Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK’s first Temporary Class Drug Order). Emerg Med J. 2014;31(1):45–7. doi:10.1136/emermed-2012-202251.PubMedCrossRefGoogle Scholar
  86. 86.
    UK Home Office. Drug misuse: findings from the 2013/14 Crime Survey for England and Wales. UK. 2014. https://www.gov.uk/government/publications/tables-for-drug-misuse-findings-from-the-2013-to-2014-csew. Accessed 19 Aug 2015.
  87. 87.
    UK Home Office. Illicit drug use by personal, household and area characteristics and lifestyle factors: drug misuse 2013 to 2014. 2nd ed. UK. 2014. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/344632/drug-use-personal-tabs-1314.ods. Accessed 19 Aug 2015.
  88. 88.
    UK Home Office. Illicit drug use among adults by ethnicity and sexual orientation: drug misuse 2013 to 2014. UK. 2014. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/335818/drug-use-ethnicity-tabs-1314.ods. Accessed 19 Aug 2015.
  89. 89.
    Measham F, Moore K. Repertoires of distinction: exploring the patterns of weekend polydrug use within local leisure scenes across the English night time economy. Criminol Crim Justice. 2009;9:437–64.CrossRefGoogle Scholar
  90. 90.
    Wood DM, Hunter L, Measham F, Dargan PI. Limited use of novel psychoactive substances in South London nightclubs. QJM. 2012;105(10):959–64. doi:10.1093/qjmed/hcs107.PubMedCrossRefGoogle Scholar
  91. 91.
    EMCDDA. European Drug Report: trends and developments. European Monitoring Centre for Drugs and Drug Addiction. Luxembourg: European Union; 2015.Google Scholar
  92. 92.
    SAMHSA. National household survey on drug abuse. Substance Abuse and Mental Health Services Administration. Rockville, MD; 1996.Google Scholar
  93. 93.
    DAWN. National estimates of drug-related emergency department visits, 2004–2011 – illicits (excluding alcohol). In: Services, D.o.H.a.H., editor. Rockville, MD: Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network; 2014. http://www.samhsa.gov/data/sites/default/files/Nation_2011_Illicit.xls. Accessed 6 Sept 2015.
  94. 94.
    Kandel J. Largest PCP bust uncovered in LA NBC News. Los Angeles: NBC News; 2012.Google Scholar
  95. 95.
    NIH. Monitoring the future study: trends in prevalence of various drugs. In Abuse, N.I.o.D., editor. Bethesda, MD: National Institute on Drug Abuse; 2014. https://www.drugabuse.gov/trends-statistics/monitoring-future/monitoring-future-study-trends-in-prevalence-various-drugs. Accessed 6 Sept 2015.
  96. 96.
    Mixmag. Global drugs survey: last 12 month prevalence of top 20 drugs. http://www.globaldrugsurvey.com/wp-content/uploads/2014/04/last-12-months-drug-prevalence.pdf. Accessed.
  97. 97.
    Mixmag. The global drug survey 2015 findings. http://www.globaldrugsurvey.com/the-global-drug-survey-2015-findings/. Accessed.
  98. 98.
    CRDA. Central registry of drug abuse: fifty-sixth report. Narcotics Division, Security Bureau. Hong Kong Special Administrative Region; 2009. p. 70.Google Scholar
  99. 99.
    CRDA. Central registry of drug abuse: sixty-third report. Narcotics Division, Security Bureau. Hong Kong Special Administrative Region; 2015. p. 106.Google Scholar
  100. 100.
    Zawilska JB. Methoxetamine–a novel recreational drug with potent hallucinogenic properties. Toxicol Lett. 2014;230(3):402–7. doi:10.1016/j.toxlet.2014.08.011.PubMedCrossRefGoogle Scholar
  101. 101.
    Backberg M, Beck O, Helander A. Phencyclidine analog use in Sweden-intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project. Clin Toxicol (Phila). 2015;1–9. 10.3109/15563650.2015.1079325Google Scholar
  102. 102.
    Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19(6):370–80. doi:10.1111/cns.12099.PubMedCrossRefGoogle Scholar
  103. 103.
    White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. 1982;56(2):119–36.PubMedCrossRefGoogle Scholar
  104. 104.
    White PF, Schuttler J, Shafer A, et al. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth. 1985;57(2):197–203.PubMedCrossRefGoogle Scholar
  105. 105.
    Goldberg ME, Torjman MC, Schwartzman RJ, Mager DE, Wainer IW. Enantioselective pharmacokinetics of (R)- and (S)-ketamine after a 5-day infusion in patients with complex regional pain syndrome. Chirality. 2011;23(2):138–43. doi:10.1002/chir.20890.PubMedCrossRefGoogle Scholar
  106. 106.
    Ryder S, Way WL, Trevor AJ. Comparative pharmacology of the optical isomers of ketamine in mice. Eur J Pharmacol. 1978;49(1):15–23.PubMedCrossRefGoogle Scholar
  107. 107.
    Meliska CJ, Greenberg AJ, Trevor AJ. The effects of ketamine enantiomers on schedule-controlled behavior in the rat. J Pharmacol Exp Ther. 1980;212(2):198–202.PubMedGoogle Scholar
  108. 108.
    White PF, Ham J, Way WL, Trevor AJ. Pharmacology of ketamine isomers in surgical patients. Anesthesiology. 1980;52(3):231–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Cook CE, Brine DR, Jeffcoat AR, et al. Phencyclidine disposition after intravenous and oral doses. Clin Pharmacol Ther. 1982;31(5):625–34.PubMedCrossRefGoogle Scholar
  110. 110.
    Cook CE, Brine DR, Quin GD, Perez-Reyes M, Di Guiseppi SR. Phencyclidine and phenylcyclohexene disposition after smoking phencyclidine. Clin Pharmacol Ther. 1982;31(5):635–41.PubMedCrossRefGoogle Scholar
  111. 111.
    Clements JA, Nimmo WS. Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth. 1981;53(1):27–30. doi:10.1093/bja/53.1.27.PubMedCrossRefGoogle Scholar
  112. 112.
    Craven R. Ketamine. Anaesthesia. 2007;62 Suppl 1:48–53. doi:10.1111/j.1365-2044.2007.05298.x.PubMedCrossRefGoogle Scholar
  113. 113.
    Aroni F, Iacovidou N, Dontas I, Pourzitaki C, Xanthos T. Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug. J Clin Pharmacol. 2013;49:957–64. doi:10.1177/0091270009337941.CrossRefGoogle Scholar
  114. 114.
    Corazza O, Schifano F, Simonato P, et al. Phenomenon of new drugs on the Internet: the case of ketamine derivative methoxetamine. Hum Psychopharmacol. 2012;27(2):145–9. doi:10.1002/hup.1242.PubMedCrossRefGoogle Scholar
  115. 115.
    Burns RS, Lerner SE. Phencyclidine deaths. JACEP. 1978;7(4):135–41.PubMedCrossRefGoogle Scholar
  116. 116.
    EMCDDA. Report on the risk assessment of 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone (methoxetamine) in the framework of the Council Decision on new psychoactive substances. Lisbon: EMCDDA; 2014.Google Scholar
  117. 117.
    Laurenzana EM, Owens SM. Metabolism of phencyclidine by human liver microsomes. Drug Metab Dispos. 1997;25(5):557–63.PubMedGoogle Scholar
  118. 118.
    Shebley M, Jushchyshyn MI, Hollenberg PF. Selective pathways for the metabolism of phencyclidine by cytochrome p450 2b enzymes: identification of electrophilic metabolites, glutathione, and N-acetyl cysteine adducts. Drug Metab Dispos. 2006;34(3):375–83. doi:10.1124/dmd.105.007047.PubMedGoogle Scholar
  119. 119.
    Green SM, Johnson NE. Ketamine sedation for pediatric procedures: part 2, Review and implications. Ann Emerg Med. 1990;19(9):1033–46.PubMedCrossRefGoogle Scholar
  120. 120.
    Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996;77(2):203–7.PubMedCrossRefGoogle Scholar
  121. 121.
    Goldberg ME, Torjman MC, Schwartzman RJ, Mager DE, Wainer IW. Pharmacodynamic profiles of ketamine (R)- and (S)- with 5-day inpatient infusion for the treatment of complex regional pain syndrome. Pain Phys. 2010;13(4):379–87.Google Scholar
  122. 122.
    Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet. 2016. doi:10.1007/s40262-016-0383-6.PubMedGoogle Scholar
  123. 123.
    Meyer MR, Bach M, Welter J, et al. Ketamine-derived designer drug methoxetamine: metabolism including isoenzyme kinetics and toxicological detectability using GC-MS and LC-(HR-)MSn. Anal Bioanal Chem. 2013;405(19):6307–21. doi:10.1007/s00216-013-7051-6.PubMedCrossRefGoogle Scholar
  124. 124.
    Giles HG, Corrigall WA, Khouw V, Sellers EM. Plasma protein binding of phencyclidine. Clin Pharmacol Ther. 1982;31(1):77–82.PubMedCrossRefGoogle Scholar
  125. 125.
    Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol. 1983;79(2):565–75.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Lodge D, Anis NA. Effects of phencyclidine on excitatory amino acid activation of spinal interneurones in the cat. Eur J Pharmacol. 1982;77(2–3):203–4.PubMedCrossRefGoogle Scholar
  127. 127.
    Roth BL, Gibbons S, Arunotayanun W, et al. The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One. 2013;8(3), e59334. doi:10.1371/journal.pone.0059334.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966;45(1):29–40.PubMedCrossRefGoogle Scholar
  129. 129.
    Weingarten SM. Dissociation of limbic and neocortical EEG patterns in cats under ketamine anesthesia. J Neurosurg. 1972;37(4):429–33. doi:10.3171/jns.1972.37.4.0429.PubMedCrossRefGoogle Scholar
  130. 130.
    Rogers R, Wise RG, Painter DJ, Longe SE, Tracey I. An investigation to dissociate the analgesic and anesthetic properties of ketamine using functional magnetic resonance imaging. Anesthesiology. 2004;100(2):292–301.PubMedCrossRefGoogle Scholar
  131. 131.
    Sprenger T, Valet M, Woltmann R, et al. Imaging pain modulation by subanesthetic S-(+)-ketamine. Anesth Analg. 2006;103(3):729–37. doi:10.1213/01.ane.0000231635.14872.40.PubMedCrossRefGoogle Scholar
  132. 132.
    Larson AA. Interactions between ketamine and phencyclidine and dorsal root potentials (DRPs), evoked from the raphe nuclei. Neuropharmacology. 1984;23(7A):785–91.PubMedCrossRefGoogle Scholar
  133. 133.
    Okuda T. Comparison of direct and indirect depressant actions of ketamine on dorsal horn cells in rabbits. Neuropharmacology. 1986;25(4):433–40.PubMedCrossRefGoogle Scholar
  134. 134.
    Denda S, Shimoji K, Tomita M, et al. Central nuclei and spinal pathways in feedback inhibitory spinal cord potentials in ketamine-anaesthetized rats. Br J Anaesth. 1996;76(2):258–65.PubMedCrossRefGoogle Scholar
  135. 135.
    Koizuka S, Obata H, Sasaki M, Saito S, Goto F. Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats. Can J Anaesth. 2005;52(5):498–505. doi:10.1007/BF03016530.PubMedCrossRefGoogle Scholar
  136. 136.
    Lerma J, Kushner L, Zukin RS, Bennett MV. N-methyl-d-aspartate activates different channels than do kainate and quisqualate. Proc Natl Acad Sci U S A. 1989;86(6):2083–7.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Brennan TJ. AMPA/kainate receptor antagonists as novel analgesic agents. Anesthesiology. 1998;89(5):1049–51.PubMedCrossRefGoogle Scholar
  138. 138.
    Watkins JC, Jane DE. The glutamate story. Br J Pharmacol. 2006;147 Suppl 1:S100–8. doi:10.1038/sj.bjp.0706444.PubMedPubMedCentralGoogle Scholar
  139. 139.
    Lodge D, Mercier MS. Ketamine and phencyclidine: the good, the bad and the unexpected. Br J Pharmacol. 2015;172(17):4254–76. doi:10.1111/bph.13222.PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Greenamyre JT, Porter RH. Anatomy and physiology of glutamate in the CNS. Neurology. 1994;44(11 Suppl 8):S7–13.PubMedGoogle Scholar
  141. 141.
    Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol. 2007;7(1):39–47. doi:10.1016/j.coph.2006.08.011.PubMedCrossRefGoogle Scholar
  142. 142.
    Dravid SM, Erreger K, Yuan H, et al. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block. J Physiol. 2007;581(Pt 1):107–28. doi:10.1113/jphysiol.2006.124958.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Gielen M, Siegler Retchless B, Mony L, Johnson JW, Paoletti P. Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature. 2009;459(7247):703–7. doi:10.1038/nature07993.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Mony L, Kew JN, Gunthorpe MJ, Paoletti P. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential. Br J Pharmacol. 2009;157(8):1301–17. doi:10.1111/j.1476-5381.2009.00304.x.PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Herroeder S, Schonherr ME, De Hert SG, Hollmann MW. Magnesium–essentials for anesthesiologists. Anesthesiology. 2011;114(4):971–93. doi:10.1097/ALN.0b013e318210483d.PubMedCrossRefGoogle Scholar
  146. 146.
    Hollmann MW, Liu HT, Hoenemann CW, Liu WH, Durieux ME. Modulation of NMDA receptor function by ketamine and magnesium. Part II: interactions with volatile anesthetics. Anesth Analg. 2001;92(5):1182–91.PubMedCrossRefGoogle Scholar
  147. 147.
    Jentsch JD, Roth RH. The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1999;20(3):201–25. doi:10.1016/S0893-133X(98)00060-8.PubMedCrossRefGoogle Scholar
  148. 148.
    Zarate Jr CA, 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):856–64. doi:10.1001/archpsyc.63.8.856.PubMedCrossRefGoogle Scholar
  149. 149.
    Quibell R, Prommer EE, Mihalyo M, Twycross R, Wilcock A. Ketamine*. J Pain Symptom Manag. 2011;41(3):640–9. doi:10.1016/j.jpainsymman.2011.01.001.CrossRefGoogle Scholar
  150. 150.
    Akunne HC, Reid AA, Thurkauf A, et al. [3H]1-[2-(2-thienyl)cyclohexyl]piperidine labels two high-affinity binding sites in human cortex: further evidence for phencyclidine binding sites associated with the biogenic amine reuptake complex. Synapse. 1991;8(4):289–300. doi:10.1002/syn.890080407.PubMedCrossRefGoogle Scholar
  151. 151.
    Matulewicz P, Kasicki S, Hunt MJ. The effect of dopamine receptor blockade in the rodent nucleus accumbens on local field potential oscillations and motor activity in response to ketamine. Brain Res. 2010;1366:226–32. doi:10.1016/j.brainres.2010.09.088.PubMedCrossRefGoogle Scholar
  152. 152.
    Cadoni C, Di Chiara G. Differences in dopamine responsiveness to drugs of abuse in the nucleus accumbens shell and core of Lewis and Fischer 344 rats. J Neurochem. 2007;103(2):487–99. doi:10.1111/j.1471-4159.2007.04795.x.PubMedCrossRefGoogle Scholar
  153. 153.
    Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia. Mol Psychiatry. 2002;7(8):837–44. doi:10.1038/sj.mp.4001093.PubMedCrossRefGoogle Scholar
  154. 154.
    Dursun SM. 5-HT2 receptors, hallucinations, and dementia. Br J Psychiatry. 1992;161:719.PubMedCrossRefGoogle Scholar
  155. 155.
    Wolfe Jr SA, De Souza EB. Sigma and phencyclidine receptors in the brain-endocrine-immune axis. NIDA Res Monogr. 1993;133:95–123.PubMedGoogle Scholar
  156. 156.
    Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR. Evaluation of sigma (sigma) receptors in the antidepressant-like effects of ketamine in vitro and in vivo. Eur Neuropsychopharmacol. 2012;22(4):308–17. doi:10.1016/j.euroneuro.2011.08.002.PubMedCrossRefGoogle Scholar
  157. 157.
    Vincent JP, Cavey D, Kamenka JM, Geneste P, Lazdunski M. Interaction of phencyclidines with the muscarinic and opiate receptors in the central nervous system. Brain Res. 1978;152(1):176–82.PubMedCrossRefGoogle Scholar
  158. 158.
    Rowland LM. Subanesthetic ketamine: how it alters physiology and behavior in humans. Aviat Space Environ Med. 2005;76 Suppl 7:C52–8.PubMedGoogle Scholar
  159. 159.
    Nishimura M, Sato K, Okada T, et al. Ketamine inhibits monoamine transporters expressed in human embryonic kidney 293 cells. Anesthesiology. 1998;88(3):768–74.PubMedCrossRefGoogle Scholar
  160. 160.
    Vaupel DB. Naltrexone fails to antagonize the sigma effects of PCP and SKF 10,047 in the dog. Eur J Pharmacol. 1983;92(3–4):269–74.PubMedCrossRefGoogle Scholar
  161. 161.
    Sleigh J, Harvey M, Voss L, Denny W. Ketamine – More mechanisms of action than just NMDA blockade. Trends Anaesth Crit Care. 2014;4:76–81.CrossRefGoogle Scholar
  162. 162.
    Gonzales JM, Loeb AL, Reichard PS, Irvine S. Ketamine inhibits glutamate-, N-methyl-d-aspartate-, and quisqualate-stimulated cGMP production in cultured cerebral neurons. Anesthesiology. 1995;82(1):205–13.PubMedCrossRefGoogle Scholar
  163. 163.
    Gordh T, Karlsten R, Kristensen J. Intervention with spinal NMDA, adenosine, and NO systems for pain modulation. Ann Med. 1995;27(2):229–34.PubMedCrossRefGoogle Scholar
  164. 164.
    Elliott K, Minami N, Kolesnikov YA, Pasternak GW, Inturrisi CE. The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-l-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. Pain. 1994;56(1):69–75.PubMedCrossRefGoogle Scholar
  165. 165.
    Balster RL, Chait LD. The behavioral effects of phencyclidine in animals. NIDA Res Monogr. 1978;21:53–65.PubMedGoogle Scholar
  166. 166.
    Carroll ME. A quantitative assessment of phencyclidine dependence produced by oral self-administration in rhesus monkeys. J Pharmacol Exp Ther. 1987;242(2):405–12.PubMedGoogle Scholar
  167. 167.
    Wessinger WD. Behavioral dependence on phencyclidine in rats. Life Sci. 1987;41(3):355–60.PubMedCrossRefGoogle Scholar
  168. 168.
    Carroll ME. Oral self-administration of N-allylnormetazocine (SKF-10,047) stereoisomers in rhesus monkeys: substitution during phencyclidine self-administration and withdrawal. Pharmacol Biochem Behav. 1988;30(2):493–500.PubMedCrossRefGoogle Scholar
  169. 169.
    Carroll ME, Hagen EW, Asencio M, Brauer LH. Behavioral dependence on caffeine and phencyclidine in rhesus monkeys: interactive effects. Pharmacol Biochem Behav. 1988;31(4):927–32.PubMedCrossRefGoogle Scholar
  170. 170.
    Spielewoy C, Markou A. Withdrawal from chronic phencyclidine treatment induces long-lasting depression in brain reward function. Neuropsychopharmacology. 2003;28(6):1106–16. doi:10.1038/sj.npp.1300124.PubMedGoogle Scholar
  171. 171.
    Audet MC, Goulet S, Dore FY. Enhanced anxiety follows withdrawal from subchronic exposure to phencyclidine in rats. Behav Brain Res. 2007;176(2):358–61. doi:10.1016/j.bbr.2006.10.017.PubMedCrossRefGoogle Scholar
  172. 172.
    Rawson RA, Tennant Jr FS, McCann MA. Characteristics of 68 chronic phencyclidine abusers who sought treatment. Drug Alcohol Depend. 1981;8(3):223–7.PubMedCrossRefGoogle Scholar
  173. 173.
    Jansen KL, Darracot-Cankovic R. The nonmedical use of ketamine, part two: a review of problem use and dependence. J Psychoactive Drugs. 2001;33(2):151–8. doi:10.1080/02791072.2001.10400480.PubMedCrossRefGoogle Scholar
  174. 174.
    Morgan CJ, Rees H, Curran HV. Attentional bias to incentive stimuli in frequent ketamine users. Psychol Med. 2008;38(9):1331–40. doi:10.1017/S0033291707002450.PubMedGoogle Scholar
  175. 175.
    Hurt PH, Ritchie EC. A case of ketamine dependence. Am J Psychiatry. 1994;151(5):779.PubMedGoogle Scholar
  176. 176.
    Pal HR, Berry N, Kumar R, Ray R. Ketamine dependence. Anaesth Intensive Care. 2002;30(3):382–4.PubMedGoogle Scholar
  177. 177.
    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;4:7107. doi:10.3402/ehtj.v4i0.7107.PubMedGoogle Scholar
  178. 178.
    Vidal Gine C, Fernandez Calderon F, Lopez Guerrero J. Patterns of use, harm reduction strategies, and their relation to risk behavior and harm in recreational ketamine users. Am J Drug Alcohol Abuse. 2016: 1–12. 10.3109/00952990.2016.1141211Google Scholar
  179. 179.
    Chan WH, Sun WZ, Ueng TH. Induction of rat hepatic cytochrome P-450 by ketamine and its toxicological implications. J Toxicol Environ Health A. 2005;68(17–18):1581–97. doi:10.1080/15287390590967522.PubMedCrossRefGoogle Scholar
  180. 180.
    Muetzelfeldt L, Kamboj SK, Rees H, et al. Journey through the K-hole: phenomenological aspects of ketamine use. Drug Alcohol Depend. 2008;95(3):219–29. doi:10.1016/j.drugalcdep.2008.01.024.PubMedCrossRefGoogle Scholar
  181. 181.
    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):121–33. doi:10.1111/j.1360-0443.2009.02761.x.PubMedCrossRefGoogle Scholar
  182. 182.
    Olney JW, Farber NB. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995;52(12):998–1007.PubMedCrossRefGoogle Scholar
  183. 183.
    Olney JW, Newcomer JW, Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res. 1999;33(6):523–33.PubMedCrossRefGoogle Scholar
  184. 184.
    Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr Bull. 2009;35(3):549–62. doi:10.1093/schbul/sbp006.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Frohlich J, Van Horn JD. Reviewing the ketamine model for schizophrenia. J Psychopharmacol. 2014;28(4):287–302. doi:10.1177/0269881113512909.PubMedCrossRefGoogle Scholar
  186. 186.
    Luby ED, Cohen BD, Rosenbaum G, Gottlieb JS, Kelley R. Study of a new schizophrenomimetic drug; sernyl. AMA Arch Neurol Psychiatry. 1959;81(3):363–9.PubMedCrossRefGoogle Scholar
  187. 187.
    Rosenbaum G, Cohen BD, Luby ED, Gottlieb JS, Yelen D. Comparison of sernyl with other drugs: simulation of schizophrenic performance with sernyl, LSD-25, and amobarbital (amytal) sodium; I. Attention, motor function, and proprioception. AMA Arch Gen Psychiatry. 1959;1:651–6.PubMedCrossRefGoogle Scholar
  188. 188.
    Davies BM, Beech HR. The effect of 1-arylcylohexylamine (sernyl) on twelve normal volunteers. J Ment Sci. 1960;106:912–24.PubMedGoogle Scholar
  189. 189.
    Steeds H, Carhart-Harris RL, Stone JM. Drug models of schizophrenia. Ther Adv Psychopharmacol. 2015;5(1):43–58. doi:10.1177/2045125314557797.PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Krystal JH, Karper LP, Seibyl JP, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51(3):199–214.PubMedCrossRefGoogle Scholar
  191. 191.
    Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13(1):9–19. doi:10.1016/0893-133X(94)00131-I.PubMedCrossRefGoogle Scholar
  192. 192.
    Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25(4):455–67. doi:10.1016/S0893-133X(01)00243-3.PubMedCrossRefGoogle Scholar
  193. 193.
    Snyder SH. Phencyclidine. Nature. 1980;285(5764):355–6.PubMedCrossRefGoogle Scholar
  194. 194.
    Itil T, Keskiner A, Kiremitci N, Holden JM. Effect of phencyclidine in chronic schizophrenics. Can Psychiatr Assoc J. 1967;12(2):209–12.PubMedGoogle Scholar
  195. 195.
    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):141–50. doi:10.1016/S0893-133X(97)00036-5.PubMedCrossRefGoogle Scholar
  196. 196.
    Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D. Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry. 1997;154(6):805–11.PubMedCrossRefGoogle Scholar
  197. 197.
    Holcomb HH, Lahti AC, Medoff DR, Weiler M, Tamminga CA. Sequential regional cerebral blood flow brain scans using PET with H2(15)O demonstrate ketamine actions in CNS dynamically. Neuropsychopharmacology. 2001;25(2):165–72. doi:10.1016/S0893-133X(01)00229-9.PubMedCrossRefGoogle Scholar
  198. 198.
    Gorelick DA, Balster RL. Phencyclidine (PCP). In: Bloom FE, Kupfer DJ, editors. Psychopharmacology, the fourth generation of progress. New York: Raven; 1994. p. 1767–76.Google Scholar
  199. 199.
    Olney JW, Labruyere J, Wang G, et al. NMDA antagonist neurotoxicity: mechanism and prevention. Science. 1991;254(5037):1515–8.PubMedCrossRefGoogle Scholar
  200. 200.
    Yonezawa Y, Kuroki T, Kawahara T, Tashiro N, Uchimura H. Involvement of gamma-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex. Eur J Pharmacol. 1998;341(1):45–56.PubMedCrossRefGoogle Scholar
  201. 201.
    Deakin JF, Lees J, McKie S, et al. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry. 2008;65(2):154–64. doi:10.1001/archgenpsychiatry.2007.37.PubMedCrossRefGoogle Scholar
  202. 202.
    Liao Y, Tang J, Ma M, et al. Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain. 2010;133(Pt 7):2115–22. doi:10.1093/brain/awq131.PubMedCrossRefGoogle Scholar
  203. 203.
    Liao Y, Tang J, Corlett PR, et al. Reduced dorsal prefrontal gray matter after chronic ketamine use. Biol Psychiatry. 2011;69(1):42–8. doi:10.1016/j.biopsych.2010.08.030.PubMedCrossRefGoogle Scholar
  204. 204.
    Verma A, Moghaddam B. NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. J Neurosci. 1996;16(1):373–9.PubMedGoogle Scholar
  205. 205.
    Smith GS, Schloesser R, Brodie JD, et al. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C-raclopride in normal human subjects. Neuropsychopharmacology. 1998;18(1):18–25. doi:10.1016/S0893-133X(97)00092-4.PubMedCrossRefGoogle Scholar
  206. 206.
    Wang JQ, Fibuch EE, Mao L. Regulation of mitogen-activated protein kinases by glutamate receptors. J Neurochem. 2007;100(1):1–11. doi:10.1111/j.1471-4159.2006.04208.x.PubMedCrossRefGoogle Scholar
  207. 207.
    Kyosseva SV, Elbein AD, Griffin WS, et al. Mitogen-activated protein kinases in schizophrenia. Biol Psychiatry. 1999;46(5):689–96.PubMedCrossRefGoogle Scholar
  208. 208.
    Arion D, Unger T, Lewis DA, Levitt P, Mirnics K. Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia. Biol Psychiatry. 2007;62(7):711–21. doi:10.1016/j.biopsych.2006.12.021.PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Morgan CJ, Monaghan L, Curran HV. Beyond the K-hole: a 3-year longitudinal investigation of the cognitive and subjective effects of ketamine in recreational users who have substantially reduced their use of the drug. Addiction. 2004;99(11):1450–61. doi:10.1111/j.1360-0443.2004.00879.x.PubMedCrossRefGoogle Scholar
  210. 210.
    Morgan CJ, Riccelli M, Maitland CH, Curran HV. Long-term effects of ketamine: evidence for a persisting impairment of source memory in recreational users. Drug Alcohol Depend. 2004;75(3):301–8. doi:10.1016/j.drugalcdep.2004.03.006.PubMedCrossRefGoogle Scholar
  211. 211.
    Hertzmann M, Reba RC, Kotlyarov EV. Single photon emission computed tomography in phencyclidine and related drug abuse. Am J Psychiatry. 1990;147(2):255–6.PubMedGoogle Scholar
  212. 212.
    Wu JC, Buchsbaum MS, Bunney WE. Positron emission tomography study of phencyclidine users as a possible drug model of schizophrenia. Yakubutsu Seishin Kodo. 1991;11(1):47–8.PubMedGoogle Scholar
  213. 213.
    Ingvar DH, Franzen G. Distribution of cerebral activity in chronic schizophrenia. Lancet. 1974;2(7895):1484–6.PubMedCrossRefGoogle Scholar
  214. 214.
    Weinberger DR, Berman KF, Zec RF. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry. 1986;43(2):114–24.PubMedCrossRefGoogle Scholar
  215. 215.
    Andreasen NC, Rezai K, Alliger R, et al. Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch Gen Psychiatry. 1992;49(12):943–58.PubMedCrossRefGoogle Scholar
  216. 216.
    Weinberger DR, Berman KF. Prefrontal function in schizophrenia: confounds and controversies. Philos Trans R Soc Lond B Biol Sci. 1996;351(1346):1495–503. doi:10.1098/rstb.1996.0135.PubMedCrossRefGoogle Scholar
  217. 217.
    Doherty JD, Simonovic M, So R, Meltzer HY. The effect of phencyclidine on dopamine synthesis and metabolic in rat striatum. Eur J Pharmacol. 1980;65(2–3):139–49.PubMedCrossRefGoogle Scholar
  218. 218.
    Jentsch JD, Elsworth JD, Redmond Jr DE, Roth RH. Phencyclidine increases forebrain monoamine metabolism in rats and monkeys: modulation by the isomers of HA966. J Neurosci. 1997;17(5):1769–75.PubMedGoogle Scholar
  219. 219.
    Jentsch JD, Redmond Jr DE, Elsworth JD, et al. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science. 1997;277(5328):953–5.PubMedCrossRefGoogle Scholar
  220. 220.
    Jentsch JD, Tran A, Le D, Youngren KD, Roth RH. Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology. 1997;17(2):92–9. doi:10.1016/S0893-133X(97)00034-1.PubMedCrossRefGoogle Scholar
  221. 221.
    Weinberger DR, Berman KF, Illowsky BP. Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia. III. A new cohort and evidence for a monoaminergic mechanism. Arch Gen Psychiatry. 1988;45(7):609–15.PubMedCrossRefGoogle Scholar
  222. 222.
    Knable MB, Weinberger DR. Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol. 1997;11(2):123–31.PubMedCrossRefGoogle Scholar
  223. 223.
    Murphy BL, Arnsten AF, Goldman-Rakic PS, Roth RH. Increased dopamine turnover in the prefrontal cortex impairs spatial working memory performance in rats and monkeys. Proc Natl Acad Sci U S A. 1996;93(3):1325–9.PubMedPubMedCentralCrossRefGoogle Scholar
  224. 224.
    Jentsch JD, Andrusiak E, Tran A, Bowers Jr MB, Roth RH. Delta 9-tetrahydrocannabinol increases prefrontal cortical catecholaminergic utilization and impairs spatial working memory in the rat: blockade of dopaminergic effects with HA966. Neuropsychopharmacology. 1997;16(6):426–32. doi:10.1016/S0893-133X(97)00018-3.PubMedCrossRefGoogle Scholar
  225. 225.
    Jentsch JD, Tran A, Taylor JR, Roth RH. Prefrontal cortical involvement in phencyclidine-induced activation of the mesolimbic dopamine system: behavioral and neurochemical evidence. Psychopharmacology (Berl). 1998;138(1):89–95.CrossRefGoogle Scholar
  226. 226.
    Sawaguchi T, Goldman-Rakic PS. D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science. 1991;251(4996):947–50.PubMedCrossRefGoogle Scholar
  227. 227.
    Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3 methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 1963;20:140–4.CrossRefGoogle Scholar
  228. 228.
    Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148(11):1474–86.PubMedCrossRefGoogle Scholar
  229. 229.
    Deutch AY. The regulation of subcortical dopamine systems by the prefrontal cortex: interactions of central dopamine systems and the pathogenesis of schizophrenia. J Neural Transm Suppl. 1992;36:61–89.PubMedGoogle Scholar
  230. 230.
    Hsu LL, Smith RC, Rolsten C, Leelavathi DE. Effects of acute and chronic phencyclidine on neurotransmitter enzymes in rat brain. Biochem Pharmacol. 1980;29(18):2524–6.PubMedCrossRefGoogle Scholar
  231. 231.
    Ilett KF, Jarrott B, O’Donnell SR, Wanstall JC. Mechanism of cardiovascular actions of 1-(1-phenylcyclohexyl)piperidine hydrochloride (phencyclidine). Br J Pharmacol Chemother. 1966;28(1):73–83.PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    McCarron MM, Schulze BW, Thompson GA, Conder MC, Goetz WA. Acute phencyclidine intoxication: incidence of clinical findings in 1,000 cases. Ann Emerg Med. 1981;10(5):237–42.PubMedCrossRefGoogle Scholar
  233. 233.
    Weiner AL, Vieira L, McKay CA, Bayer MJ. Ketamine abusers presenting to the emergency department: a case series. J Emerg Med. 2000;18(4):447–51.PubMedCrossRefGoogle Scholar
  234. 234.
    Ng SH, Tse ML, Ng HW, Lau FL. Emergency department presentation of ketamine abusers in Hong Kong: a review of 233 cases. Hong Kong Med J. 2010;16(1):6–11.PubMedGoogle Scholar
  235. 235.
    Dominici P, Kopec K, Manur R, et al. Phencyclidine intoxication case series study. J Med Toxicol. 2015;11(3):321–5. doi:10.1007/s13181-014-0453-9.PubMedCrossRefGoogle Scholar
  236. 236.
    Saegusa K, Furukawa Y, Ogiwara Y, Chiba S. Pharmacologic analysis of ketamine-induced cardiac actions in isolated, blood-perfused canine atria. J Cardiovasc Pharmacol. 1986;8(2):414–9.PubMedCrossRefGoogle Scholar
  237. 237.
    Kongsayreepong S, Cook DJ, Housmans PR. Mechanism of the direct, negative inotropic effect of ketamine in isolated ferret and frog ventricular myocardium. Anesthesiology. 1993;79(2):313–22.PubMedCrossRefGoogle Scholar
  238. 238.
    Deng CY, Yu XY, Kuang SJ, et al. Electrophysiological effects of ketamine on human atrial myocytes at therapeutically relevant concentrations. Clin Exp Pharmacol Physiol. 2008;35(12):1465–70. doi:10.1111/j.1440-1681.2008.05012.x.PubMedGoogle Scholar
  239. 239.
    Dowdy EG, Kaya K. Studies of the mechanism of cardiovascular responses to CI-581. Anesthesiology. 1968;29(5):931–43.PubMedCrossRefGoogle Scholar
  240. 240.
    Hamilton JT, Bryson JS. The effect of ketamine on transmembrane potentials of Purkinje fibres of the pig heart. Br J Anaesth. 1974;46(9):636–42.PubMedCrossRefGoogle Scholar
  241. 241.
    Koehntop DE, Liao JC, Van Bergen FH. Effects of pharmacologic alterations of adrenergic mechanisms by cocaine, tropolone, aminophylline, and ketamine on epinephrine-induced arrhythmias during halothane-nitrous oxide anesthesia. Anesthesiology. 1977;46(2):83–93.PubMedCrossRefGoogle Scholar
  242. 242.
    Bednarski RM, Sams RA, Majors LJ, Ashcraft S. Reduction of the ventricular arrhythmogenic dose of epinephrine by ketamine administration in halothane-anesthetized cats. Am J Vet Res. 1988;49(3):350–4.PubMedGoogle Scholar
  243. 243.
    Faithfull NS, Haider R. Ketamine for cardiac catheterisation. An evaluation of its use in children. Anaesthesia. 1971;26(3):318–23.PubMedCrossRefGoogle Scholar
  244. 244.
    Morray JP, Lynn AM, Stamm SJ, et al. Hemodynamic effects of ketamine in children with congenital heart disease. Anesth Analg. 1984;63(10):895–9.PubMedCrossRefGoogle Scholar
  245. 245.
    Li Y, Shi J, Yang BF, et al. Ketamine-induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol. Br J Pharmacol. 2012;165(6):1748–56. doi:10.1111/j.1476-5381.2011.01635.x.PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Bourke DL, Malit LA, Smith TC. Respiratory interactions of ketamine and morphine. Anesthesiology. 1987;66(2):153–6.PubMedCrossRefGoogle Scholar
  247. 247.
    Green SM, Clark R, Hostetler MA, et al. Inadvertent ketamine overdose in children: clinical manifestations and outcome. Ann Emerg Med. 1999;34(4 Pt 1):492–7.PubMedCrossRefGoogle Scholar
  248. 248.
    Aroni F, Iacovidou N, Dontas I, Pourzitaki C, Xanthos T. Pharmacological aspects and potential new clinical applications of ketamine: reevaluation of an old drug. J Clin Pharmacol. 2009;49(8):957–64. doi:10.1177/0091270009337941.PubMedCrossRefGoogle Scholar
  249. 249.
    Mankikian B, Cantineau JP, Sartene R, Clergue F, Viars P. Ventilatory pattern and chest wall mechanics during ketamine anesthesia in humans. Anesthesiology. 1986;65(5):492–9.PubMedCrossRefGoogle Scholar
  250. 250.
    Drummond GB. Comparison of sedation with midazolam and ketamine: effects on airway muscle activity. Br J Anaesth. 1996;76(5):663–7.PubMedCrossRefGoogle Scholar
  251. 251.
    Lau TT, Zed PJ. Does ketamine have a role in managing severe exacerbation of asthma in adults? Pharmacotherapy. 2001;21(9):1100–6.PubMedCrossRefGoogle Scholar
  252. 252.
    Chu PS, Kwok SC, Lam KM, et al. ‘Street ketamine’-associated bladder dysfunction: a report of ten cases. Hong Kong Med J. 2007;13(4):311–3.PubMedGoogle Scholar
  253. 253.
    Shahani R, Streutker C, Dickson B, Stewart RJ. Ketamine-associated ulcerative cystitis: a new clinical entity. Urology. 2007;69(5):810–2. doi:10.1016/j.urology.2007.01.038.PubMedCrossRefGoogle Scholar
  254. 254.
    Wei YB, Yang JR, Yin Z, et al. Genitourinary toxicity of ketamine. Hong Kong Med J. 2013;19(4):341–8. doi:10.12809/hkmj134013.PubMedGoogle Scholar
  255. 255.
    Chen CF, Chapman BJ, Munday KA. The effect of althesin, ketamine or pentothal on renal function in saline loaded rats. Clin Exp Pharmacol Physiol. 1985;12(2):99–105.PubMedCrossRefGoogle Scholar
  256. 256.
    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):1762–6. doi:10.1111/j.1464-410X.2012.11028.x.PubMedCrossRefGoogle Scholar
  257. 257.
    Yeung LY, Rudd JA, Lam WP, Mak YT, Yew DT. Mice are prone to kidney pathology after prolonged ketamine addiction. Toxicol Lett. 2009;191(2–3):275–8. doi:10.1016/j.toxlet.2009.09.006.PubMedCrossRefGoogle Scholar
  258. 258.
    Chu PS, Ma WK, Wong SC, et al. The destruction of the lower urinary tract by ketamine abuse: a new syndrome? BJU Int. 2008;102(11):1616–22. doi:10.1111/j.1464-410X.2008.07920.x.PubMedCrossRefGoogle Scholar
  259. 259.
    Dargan PI, Tang HC, Liang W, Wood DM, Yew DT. Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice. Clin Toxicol (Phila). 2014;52(3):176–80. doi:10.3109/15563650.2014.892605.CrossRefGoogle Scholar
  260. 260.
    Wai MS, Chan WM, Zhang AQ, Wu Y, Yew DT. Long-term ketamine and ketamine plus alcohol treatments produced damages in liver and kidney. Hum Exp Toxicol. 2012;31(9):877–86. doi:10.1177/0960327112436404.PubMedCrossRefGoogle Scholar
  261. 261.
    Hopcroft SA, Cottrell AM, Mason K, Abrams P, Oxley JD. Ureteric intestinal metaplasia in association with chronic recreational ketamine abuse. J Clin Pathol. 2011;64(6):551–2. doi:10.1136/jcp.2010.087171.PubMedCrossRefGoogle Scholar
  262. 262.
    Chen CL, Cha TL, Wu ST, et al. Renal infarction secondary to ketamine abuse. Am J Emerg Med. 2013;31(7):1153 e1153–1155. doi:10.1016/j.ajem.2013.02.036.Google Scholar
  263. 263.
    Cohen S. Angel dust. JAMA. 1977;238(6):515–6.PubMedCrossRefGoogle Scholar
  264. 264.
    Poon TL, Wong KF, Chan MY, et al. Upper gastrointestinal problems in inhalational ketamine abusers. J Dig Dis. 2010;11(2):106–10. doi:10.1111/j.1751-2980.2010.00424.x.PubMedCrossRefGoogle Scholar
  265. 265.
    Wong SW, Lee KF, Wong J, et al. Dilated common bile ducts mimicking choledochal cysts in ketamine abusers. Hong Kong Med J. 2009;15(1):53–6.PubMedGoogle Scholar
  266. 266.
    Bey T, Patel A. Phencyclidine intoxication and adverse effects: a clinical and pharmacological review of an illicit drug. Cal J Emerg Med. 2007;8(1):9–14.PubMedPubMedCentralGoogle Scholar
  267. 267.
    Pai A, Heining M. Ketamine. Continuing education in anaesthesia. Crit Care Pain. 2007;7(2):59–63. doi:10.1093/bjaceaccp/mkm008.Google Scholar
  268. 268.
    McCarron MM, Schulze BW, Thompson GA, Conder MC, Goetz WA. Acute phencyclidine intoxication: clinical patterns, complications, and treatment. Ann Emerg Med. 1981;10(6):290–7.PubMedCrossRefGoogle Scholar
  269. 269.
    Walberg CB, McCarron MM, Schulze BN. Quantitation of phencyclidine in serum by enzyme immunoassay: results in 405 patients. J Anal Toxicol. 1983;7(2):106–10.PubMedCrossRefGoogle Scholar
  270. 270.
    Östberg LL, Hultén P, Al-Saffar Y. Methoxetamine: a case series of analytically confirmed cases. Clin Toxicol (Phila). 2013;51(XXXIII International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 28–31 May 2013, Copenhagen, Denmark):257–8. doi:10.3109/15563650.2013.785188Google Scholar
  271. 271.
    Wood DM, Bishop CR, Greene SL, Dargan PI. Ketamine-related toxicology presentations to the ED. Clin Toxicol (Phila). 2008;46:630.Google Scholar
  272. 272.
    Yiu-Cheung C. Acute and chronic toxicity pattern in ketamine abusers in Hong Kong. J Med Toxicol. 2012;8(3):267–70. doi:10.1007/s13181-012-0229-z.PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    Kjellgren A, Jonsson K. Methoxetamine (MXE)–a phenomenological study of experiences induced by a “legal high” from the internet. J Psychoactive Drugs. 2013;45(3):276–86. doi:10.1080/02791072.2013.803647.PubMedPubMedCentralCrossRefGoogle Scholar
  274. 274.
    Wood DM, Dargan PI. Novel psychoactive substances: how to understand the acute toxicity associated with the use of these substances. Ther Drug Monit. 2012;34(4):363–7. doi:10.1097/FTD.0b013e31825b954b.PubMedCrossRefGoogle Scholar
  275. 275.
    Lukasik-Glebocka M, Sommerfeld K, Tezyk A, Zielinska-Psuja B, Druzdz A. Acute methoxetamine intoxication–a case report with serum and urine concentrations. Przegl Lek. 2013;70(8):671–3.PubMedGoogle Scholar
  276. 276.
    Westwell AD, Hutchings A, Caldicott DG. The identification and chemical characterization of a new arylcyclohexylamine, methoxetamine, using a novel Emergency Department toxicosurveillance tool. Drug Test Anal. 2013;5(3):203–7. doi:10.1002/dta.1375.PubMedCrossRefGoogle Scholar
  277. 277.
    Rosenbaum CD, Carreiro SP, Babu KM. Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. J Med Toxicol. 2012;8(1):15–32. doi:10.1007/s13181-011-0202-2.PubMedPubMedCentralCrossRefGoogle Scholar
  278. 278.
    Imbert L, Boucher A, Delhome G, et al. Analytical findings of an acute intoxication after inhalation of methoxetamine. J Anal Toxicol. 2014;38(7):410–5. doi:10.1093/jat/bku052.PubMedCrossRefGoogle Scholar
  279. 279.
    Clarke RS, Knox JW, Dundee JW. The effect of dosage and premedication on the action of ketamine. Br J Anaesth. 1970;42(9):799.PubMedCrossRefGoogle Scholar
  280. 280.
    Knox JW, Bovill JG, Clarke RS, Dundee JW. Clinical studies of induction agents. XXXVI: Ketamine. Br J Anaesth. 1970;42(10):875–85.PubMedCrossRefGoogle Scholar
  281. 281.
    Oduntan SA, Gool RY. Clinical trial of ketamine (CI-581): a preliminary report. Can Anaesth Soc J. 1970;17(4):411–6.PubMedCrossRefGoogle Scholar
  282. 282.
    Moore J, McNabb TG, Dundee JW. Preliminary report on ketamine in obstetrics. Br J Anaesth. 1971;43(8):779–82.PubMedCrossRefGoogle Scholar
  283. 283.
    Little B, Chang T, Chucot L, et al. Study of ketamine as an obstetric anesthetic agent. Am J Obstet Gynecol. 1972;113(2):247–60.PubMedCrossRefGoogle Scholar
  284. 284.
    Krestow M. The effect of post-anaesthetic dreaming on patient acceptance of ketamine anaesthesia: a comparison with thiopentone-nitrous oxide anaesthesia. Can Anaesth Soc J. 1974;21(4):385–9.PubMedCrossRefGoogle Scholar
  285. 285.
    Curran HV, Monaghan L. In and out of the K-hole: a comparison of the acute and residual effects of ketamine in frequent and infrequent ketamine users. Addiction. 2001;96(5):749–60. doi:10.1080/09652140020039116.PubMedCrossRefGoogle Scholar
  286. 286.
    Corazza O, Schifano F. Near-death states reported in a sample of 50 misusers. Subst Use Misuse. 2010;45(6):916–24. doi:10.3109/10826080903565321.PubMedCrossRefGoogle Scholar
  287. 287.
    Nelson SR, Howard RB, Cross RS, Samson F. Ketamine-induced changes in regional glucose utilization in the rat brain. Anesthesiology. 1980;52(4):330–4.PubMedCrossRefGoogle Scholar
  288. 288.
    Crosby G, Crane AM, Sokoloff L. Local changes in cerebral glucose utilization during ketamine anesthesia. Anesthesiology. 1982;56(6):437–43.PubMedCrossRefGoogle Scholar
  289. 289.
    White PF. Comparative evaluation of intravenous agents for rapid sequence induction–thiopental, ketamine, and midazolam. Anesthesiology. 1982;57(4):279–84.PubMedCrossRefGoogle Scholar
  290. 290.
    Haiden. Dry Ketamin/Ketanest S. https://drugs-forum.com/forum/showthread.php?t=137899. Accessed.
  291. 291.
    Burns RS, Lerner SE. Editorial. Phencyclidine: an emerging drug problem. Clin Toxicol. 1976;9(4):473–5. doi:10.3109/15563657608988150.PubMedCrossRefGoogle Scholar
  292. 292.
    Burns RS, Lerner SE. Perspectives: acute phencyclidine intoxication. Clin Toxicol. 1976;9(4):477–501. doi:10.3109/15563657608988151.PubMedCrossRefGoogle Scholar
  293. 293.
    Bailey DN. Phencyclidine abuse. Clinical findings and concentrations in biological fluids after nonfatal intoxication. Am J Clin Pathol. 1979;72(5):795–9.PubMedCrossRefGoogle Scholar
  294. 294.
    Bailey DN, Shaw RF, Guba JJ. Phencyclidine abuse: Plasma levels and clinical findings in casual users and in phencyclidine-related deaths. J Anal Toxicol. 1978;2:233–7.CrossRefGoogle Scholar
  295. 295.
    Poklis A, Graham M, Maginn D, Branch CA, Gantner GE. Phencyclidine and violent deaths in St. Louis, Missouri: a survey of medical examiners’ cases from 1977 through 1986. Am J Drug Alcohol Abuse. 1990;16(3–4):265–74.PubMedCrossRefGoogle Scholar
  296. 296.
    deRoux SJ, Sgarlato A, Marker E. Phencyclidine: a 5-year retrospective review from the New York City Medical Examiner’s Office. J Forensic Sci. 2011;56(3):656–9. doi:10.1111/j.1556-4029.2010.01687.x.PubMedCrossRefGoogle Scholar
  297. 297.
    Akmal M, Valdin JR, McCarron MM, Massry SG. Rhabdomyolysis with and without acute renal failure in patients with phencyclidine intoxication. Am J Nephrol. 1981;1(2):91–6.PubMedCrossRefGoogle Scholar
  298. 298.
    Fauman MA, Fauman BJ. Violence associated with phencyclidine abuse. Am J Psychiatry. 1979;136(12):1584–6.PubMedCrossRefGoogle Scholar
  299. 299.
    Moskovitz RA, Byrd T. Rescuing the angel within: PCP-related self-enucleation. Psychosomatics. 1983;24(4):402–3, 6. doi: 10.1016/S0033-3182(83)73218-4Google Scholar
  300. 300.
    Radio.com. Wu-Tang affiliated rapper who cut off his own penis was on PCP during incident Radio.com. 2014.Google Scholar
  301. 301.
    Budd RD, Liu Y. Phencyclidine concentrations in postmortem body fluids and tissues. J Toxicol Clin Toxicol. 1982;19(8):843–50.PubMedCrossRefGoogle Scholar
  302. 302.
    Burns RS, Lerner SE. Causes of phencyclidine-related deaths. Clin Toxicol. 1978;12(4):463–81. doi:10.3109/15563657809150017.PubMedCrossRefGoogle Scholar
  303. 303.
    Kessler Jr GF, Demers LM, Berlin C, Brennan RW. Letter: Phencyclidine and fatal status epilepticus. N Engl J Med. 1974;291(18):979.PubMedGoogle Scholar
  304. 304.
    Peyton SH, Couch AT, Bost RO. Tissue distribution of ketamine: two case reports. J Anal Toxicol. 1988;12(5):268–9.PubMedCrossRefGoogle Scholar
  305. 305.
    Gill JR, Stajic M. Ketamine in non-hospital and hospital deaths in New York City. J Forensic Sci. 2000;45(3):655–8.PubMedCrossRefGoogle Scholar
  306. 306.
    Schifano F, Corkery J, Oyefeso A, Tonia T, Ghodse AH. Trapped in the “K-hole”: overview of deaths associated with ketamine misuse in the UK (1993–2006). J Clin Psychopharmacol. 2008;28(1):114–6. doi:10.1097/JCP.0b013e3181612cdc.PubMedCrossRefGoogle Scholar
  307. 307.
    WHO. Ketamine: update review report. Expert Committee on Drug Dependence. Geneva: WHO; 2014.Google Scholar
  308. 308.
    Corkery J, Claridge H, Loi B, Goodair C, Schifano F. Drug-related deaths in the UK: January-December 2012. Annual Report 2013. National Programme on Substance Abuse Deaths (NPSAD), International Centre for Drug Policy (ICDP). London, UK; 2014.Google Scholar
  309. 309.
    Licata M, Pierini G, Popoli G. A fatal ketamine poisoning. J Forensic Sci. 1994;39(5):1314–20.PubMedCrossRefGoogle Scholar
  310. 310.
    Lalonde BR, Wallage HR. Postmortem blood ketamine distribution in two fatalities. J Anal Toxicol. 2004;28(1):71–4.PubMedCrossRefGoogle Scholar
  311. 311.
    Greenstein ET. Ketamine HCl, a dissociative anesthetic for squirrel monkeys (Saimiri sciureus). Lab Anim Sci. 1975;25(6):774–7.PubMedGoogle Scholar
  312. 312.
    Idvall J, Ahlgren I, Aronsen KR, Stenberg P. Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth. 1979;51(12):1167–73.PubMedCrossRefGoogle Scholar
  313. 313.
    Dallimore D, Anderson BJ, Short TG, Herd DW. Ketamine anesthesia in children–exploring infusion regimens. Paediatr Anaesth. 2008;18(8):708–14. doi:10.1111/j.1460-9592.2008.02665.x.PubMedCrossRefGoogle Scholar
  314. 314.
    Hartvig P, Larsson E, Joachimsson PO. Postoperative analgesia and sedation following pediatric cardiac surgery using a constant infusion of ketamine. J Cardiothorac Vasc Anesth. 1993;7(2):148–53.PubMedCrossRefGoogle Scholar
  315. 315.
    Herd DW, Anderson BJ, Keene NA, Holford NH. Investigating the pharmacodynamics of ketamine in children. Paediatr Anaesth. 2008;18(1):36–42. doi:10.1111/j.1460-9592.2007.02384.x.PubMedGoogle Scholar
  316. 316.
    WHO. Methoxetamine: critical review report. Expert Committee on Drug Dependence. Geneva; 2014. http://www.who.int/medicines/areas/quality_safety/4_22_review.pdf?ua=1. Accessed 4 Sept 2015.
  317. 317.
    Cheng JY, Mok VK. Rapid determination of ketamine in urine by liquid chromatography-tandem mass spectrometry for a high throughput laboratory. Forensic Sci Int. 2004;142(1):9–15. doi:10.1016/j.forsciint.2004.01.018.PubMedCrossRefGoogle Scholar
  318. 318.
    Wang KC, Shih TS, Cheng SG. Use of SPE and LC/TIS/MS/MS for rapid detection and quantitation of ketamine and its metabolite, norketamine, in urine. Forensic Sci Int. 2005;147(1):81–8. doi:10.1016/j.forsciint.2004.03.031.PubMedCrossRefGoogle Scholar
  319. 319.
    Sena SF, Kazimi S, Wu AH. False-positive phencyclidine immunoassay results caused by venlafaxine and O-desmethylvenlafaxine. Clin Chem. 2002;48(4):676–7.PubMedGoogle Scholar
  320. 320.
    Bond GR, Steele PE, Uges DR. Massive venlafaxine overdose resulted in a false positive Abbott AxSYM urine immunoassay for phencyclidine. J Toxicol Clin Toxicol. 2003;41(7):999–1002.PubMedCrossRefGoogle Scholar
  321. 321.
    Landy GL, Kripalani M. False positive phencyclidine result on urine drug testing: a little known cause. BJPsych Bull. 2015;39(1):50. doi:10.1192/pb.39.1.50.PubMedPubMedCentralCrossRefGoogle Scholar
  322. 322.
    Schier J. Avoid unfavorable consequences: dextromethorpan can bring about a false-positive phencyclidine urine drug screen. J Emerg Med. 2000;18(3):379–81.PubMedCrossRefGoogle Scholar
  323. 323.
    Budai B, Iskandar H. Dextromethorphan can produce false positive phencyclidine testing with HPLC. Am J Emerg Med. 2002;20(1):61–2.PubMedCrossRefGoogle Scholar
  324. 324.
    De Paoli G, Brandt SD, Wallach J, Archer RP, Pounder DJ. From the street to the laboratory: analytical profiles of methoxetamine, 3-methoxyeticyclidine and 3-methoxyphencyclidine and their determination in three biological matrices. J Anal Toxicol. 2013;37(5):277–83. doi:10.1093/jat/bkt023.PubMedCrossRefGoogle Scholar
  325. 325.
    Erdil F, Begec Z, Kayhan GE, et al. Effects of sevoflurane or ketamine on the QTc interval during electroconvulsive therapy. J Anesth. 2015;29(2):180–5. doi:10.1007/s00540-014-1899-2.PubMedCrossRefGoogle Scholar
  326. 326.
    Stein GY, Fradin Z, Ori Y, et al. Phencyclidine-induced multi-organ failure. Isr Med Assoc J. 2005;7(8):535–7.PubMedGoogle Scholar
  327. 327.
    Rollin A, Maury P, Guilbeau-Frugier C, Brugada J. Transient ST elevation after ketamine intoxication: a new cause of acquired brugada ECG pattern. J Cardiovasc Electrophysiol. 2011;22(1):91–4. doi:10.1111/j.1540-8167.2010.01766.x.PubMedCrossRefGoogle Scholar
  328. 328.
    Hara Y, Chugun A, Nakaya H, Kondo H. Tonic block of the sodium and calcium currents by ketamine in isolated guinea pig ventricular myocytes. J Vet Med Sci. 1998;60(4):479–83.PubMedCrossRefGoogle Scholar
  329. 329.
    Vernooy K, Delhaas T, Cremer OL, et al. Electrocardiographic changes predicting sudden death in propofol-related infusion syndrome. Heart Rhythm. 2006;3(2):131–7. doi:10.1016/j.hrthm.2005.11.005.PubMedPubMedCentralCrossRefGoogle Scholar
  330. 330.
    Rodin EA, Luby ED, Meyer JS. Electroencephalographic findings associated with sernyl infusion. Electroencephalogr Clin Neurophysiol. 1959;11:796–8.PubMedCrossRefGoogle Scholar
  331. 331.
    Stockard JJ, Werner SS, Aalbers JA, Chiappa KH. Electroencephalographic findings in phencyclidine intoxication. Arch Neurol. 1976;33(3):200–3.PubMedCrossRefGoogle Scholar
  332. 332.
    Cogen FC, Rigg G, Simmons JL, Domino EF. Phencyclidine-associated acute rhabdomyolysis. Ann Intern Med. 1978;88(2):210–2.PubMedCrossRefGoogle Scholar
  333. 333.
    Patel R, Connor G. A review of thirty cases of rhabdomyolysis-associated acute renal failure among phencyclidine users. J Toxicol Clin Toxicol. 1985;23(7–8):547–56.PubMedGoogle Scholar
  334. 334.
    Diringer MN, Reaven NL, Funk SE, Uman GC. Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients. Crit Care Med. 2004;32(7):1489–95.PubMedCrossRefGoogle Scholar
  335. 335.
    Young PJ, Saxena M, Beasley R, et al. Early peak temperature and mortality in critically ill patients with or without infection. Intensive Care Med. 2012. doi:10.1007/s00134-012-2478-3.Google Scholar
  336. 336.
    Vooturi S, Jayalakshmi S, Sahu S, Mohandas S. Prognosis and predictors of outcome of refractory generalized convulsive status epilepticus in adults treated in neurointensive care unit. Clin Neurol Neurosurg. 2014;126:7–10. doi:10.1016/j.clineuro.2014.07.038.PubMedCrossRefGoogle Scholar
  337. 337.
    Stanek B, Zimpfer M, Fitzal S, Raberger G. Plasma catecholamines, plasma renin activity and haemodynamics during sodium nitroprusside-induced hypotension and additional beta-blockage with bunitrolol. Eur J Clin Pharmacol. 1981;19(5):317–22.PubMedCrossRefGoogle Scholar
  338. 338.
    Kumai T, Tanaka M, Tateishi T, Asoh M, Kobayashi S. Effects of sodium nitroprusside on the catecholamine synthetic pathway in the adrenal medulla of rats. Jpn J Pharmacol. 1998;77(3):205–10.PubMedCrossRefGoogle Scholar
  339. 339.
    Cohen BD, Luby ED, Rosenbaum G, Gottlieb JS. Combined sernyl and sensory deprivation. Compr Psychiatry. 1960;1:345–8.PubMedCrossRefGoogle Scholar
  340. 340.
    Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: a review. Br Med Bull. 2015;114(1):169–79. doi:10.1093/bmb/ldv017.PubMedCrossRefGoogle Scholar
  341. 341.
    Picchioni AL, Consroe PF. Activated charcoal–a phencyclidine antidote, or hog in dogs. N Engl J Med. 1979;300(4):202. doi:10.1056/NEJM197901253000423.PubMedGoogle Scholar
  342. 342.
    Aronow R, Done AK. Phencyclidine overdose: an emerging concept of management. JACEP. 1978;7(2):56–9.PubMedCrossRefGoogle Scholar
  343. 343.
    Barton CH, Sterling ML, Vaziri ND. Phencyclidine intoxication: clinical experience in 27 cases confirmed by urine assay. Ann Emerg Med. 1981;10(5):243–6.PubMedCrossRefGoogle Scholar
  344. 344.
    Aronow R, Miceli JN, Done AK. Clinical observations during phencyclidine intoxication and treatment based on ion-trapping. NIDA Res Monogr. 1978;21:218–28.PubMedGoogle Scholar
  345. 345.
    Allen WR, O’Barr TP, Corby DG. Hemoperfusion of phencyclidine in the dog. Int J Artif Organs. 1985;8(2):101–4.PubMedGoogle Scholar
  346. 346.
    Bovill JG, Coppel DL, Dundee JW, Moore J. Current status of ketamine anaesthesia. Lancet. 1971;1(7712):1285–8.PubMedCrossRefGoogle Scholar
  347. 347.
    Bovill JG, Clarke RS, Dundee JW, Pandit SK, Moore J. Clinical studies of induction agents. 38. Effect of premedicants and supplements on ketamine anaesthesia. Br J Anaesth. 1971;43(6):600–8.PubMedCrossRefGoogle Scholar
  348. 348.
    Sadove MS, Hatano S, Redlin T, et al. Clinical study of droperidol in the prevention of the side-effects of ketamine anesthesia: a progress report. Anesth Analg. 1971;50(4):526–32.PubMedCrossRefGoogle Scholar
  349. 349.
    Sadove MS, Hatano S, Zahed B, et al. Clinical study of droperidol in the prevention of the side effects of ketamine anesthesia: a preliminary report. Anesth Analg. 1971;50(3):388–93.PubMedGoogle Scholar
  350. 350.
    Erbguth PH, Reiman B, Klein RL. The influence of chlorpromazine, diazepam, and droperidol on emergence from ketamine. Anesth Analg. 1972;51(5):693–700.PubMedCrossRefGoogle Scholar
  351. 351.
    Lilburn JK, Dundee JW, Nair SG, Fee JP, Johnston HM. Ketamine sequelae. Evaluation of the ability of various premedicants to attenuate its psychic actions. Anaesthesia. 1978;33(4):307–11.PubMedCrossRefGoogle Scholar
  352. 352.
    Dundee JW, Lilburn JK. Ketamine-lorazepam. Attenuation of psychic sequelae of ketamine by lorazepam. Anaesthesia. 1978;33(4):312–4.PubMedCrossRefGoogle Scholar
  353. 353.
    Mattila MA, Larni HM, Nummi SE, Pekkola PO. Effect of diazepam on emergence from ketamine anaesthesia. A double-blind study. Anaesthesist. 1979;28(1):20–3.PubMedGoogle Scholar
  354. 354.
    Cartwright PD, Pingel SM. Midazolam and diazepam in ketamine anaesthesia. Anaesthesia. 1984;39(5):439–42.PubMedCrossRefGoogle Scholar
  355. 355.
    Toft P, Romer U. Comparison of midazolam and diazepam to supplement total intravenous anaesthesia with ketamine for endoscopy. Can J Anaesth. 1987;34(5):466–9. doi:10.1007/BF03014351.PubMedCrossRefGoogle Scholar
  356. 356.
    Kolhe EP, Dhumal PR, Kurhekar VA. Comparative study of midazolam and diazepam to supplement ketamine as total intravenous anaesthesia in short orthopedic procedures. Int J Pharm Biomed Res. 2013;4(1):15–20.Google Scholar
  357. 357.
    Ayim EN, Makatia FX. The effects of diazepam on ketamine anaesthesia. East Afr Med J. 1976;53(7):377–82.PubMedGoogle Scholar
  358. 358.
    Levanen J, Makela ML, Scheinin H. Dexmedetomidine premedication attenuates ketamine-induced cardiostimulatory effects and postanesthetic delirium. Anesthesiology. 1995;82(5):1117–25.PubMedCrossRefGoogle Scholar
  359. 359.
    Gupta K, Gupta A, Gupta PK, et al. Dexmedetomidine premedication in relevance to ketamine anesthesia: a prospective study. Anesth Essays Res. 2011;5(1):87–91. doi:10.4103/0259-1162.84193.PubMedPubMedCentralCrossRefGoogle Scholar
  360. 360.
    Brechner M, Wang B, Wong H, Morgan J. Phencyclidine and violence: clinical and legal issues. J Clin Psychopharmacol. 1988;8:397–401.Google Scholar
  361. 361.
    Kinlock T. Does phencyclidine (PCP) use increase violent crime? J Drug Issues. 1991;21:795–816.CrossRefGoogle Scholar
  362. 362.
    Weiss K. “Wet” and wild: PCP and criminal responsibility. J Psychiatry Law. 2004;32:361–84.Google Scholar
  363. 363.
    Crane CA, Easton CJ, Devine S. The association between phencyclidine use and partner violence: an initial examination. J Addict Dis. 2013;32(2):150–7. doi:10.1080/10550887.2013.797279.PubMedPubMedCentralCrossRefGoogle Scholar
  364. 364.
    Welch MJ, Correa GA. PCP intoxication in young children and infants. Clin Pediatr (Phila). 1980;19(8):510–4.CrossRefGoogle Scholar
  365. 365.
    Schwartz RH, Einhorn A. PCP intoxication in seven young children. Pediatr Emerg Care. 1986;2(4):238–41.PubMedCrossRefGoogle Scholar
  366. 366.
    Karp HN, Kaufman ND, Anand SK. Phencyclidine poisoning in young children. J Pediatr. 1980;97(6):1006–9.PubMedCrossRefGoogle Scholar
  367. 367.
    Strauss AA, Modaniou HD, Bosu SK. Neonatal manifestations of maternal phencyclidine (PCP) abuse. Pediatrics. 1981;68(4):550–2.PubMedGoogle Scholar
  368. 368.
    Briggs GG. Drugs in pregnancy and lactation. Baltimore: Lippincott, Williams & Wilkins; 1998.Google Scholar
  369. 369.
    Nicholas JM, Lipshitz J, Schreiber EC. Phencyclidine: its transfer across the placenta as well as into breast milk. Am J Obstet Gynecol. 1982;143(2):143–6.PubMedCrossRefGoogle Scholar
  370. 370.
    Kaufman KR, Petrucha RA, Pitts Jr FN, Weekes ME. PCP in amniotic fluid and breast milk: case report. J Clin Psychiatry. 1983;44(7):269–70.PubMedGoogle Scholar
  371. 371.
    Wachsman L, Schuetz S, Chan LS, Wingert WA. What happens to babies exposed to phencyclidine (PCP) in utero? Am J Drug Alcohol Abuse. 1989;15(1):31–9.PubMedCrossRefGoogle Scholar
  372. 372.
    Rahbar F, Fomufod A, White D, Westney LS. Impact of intrauterine exposure to phencyclidine (PCP) and cocaine on neonates. J Natl Med Assoc. 1993;85(5):349–52.PubMedPubMedCentralGoogle Scholar
  373. 373.
    Heesen M, Bohmer J, Brinck EC, et al. Intravenous ketamine during spinal and general anaesthesia for caesarean section: systematic review and meta-analysis. Acta Anaesthesiol Scand. 2015;59(4):414–26. doi:10.1111/aas.12468.PubMedCrossRefGoogle Scholar
  374. 374.
    EMEA. Ketamine summary report document EMEA/MRL/315/97-FINAL. European Agency for the Evaluation of Medicinal Products. London: EMEA; 1997. http://www.ema.europa.eu/docs/en_GB/document_library/Maximum_Residue_Limits_-_Report/2009/11/WC500014539.pdf
  375. 375.
    Abdel-Rahman MS, Ismail EE. Teratogenic effect of ketamine and cocaine in CF-1 mice. Teratology. 2000;61(4):291–6. doi:10.1002/(SICI)1096-9926(200004)61:4<291::AID-TERA8>3.0.CO;2-Q.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Clinical ToxicologyGuy’s and St Thomas’ NHS Foundation TrustLondonUK

Personalised recommendations