Substances of Abuse and Hallucinogenic Activity: The Glutamatergic Pathway - Focus on Ketamine

  • Gian Mario Mandolini
  • Matteo Lazzaretti
  • Alfredo Carlo Altamura
  • Paolo BrambillaEmail author


This chapter analyzes the glutamatergic pathway involved in the induction of hallucinations. Indeed, the development of the so-called glutamate hypothesis of psychotic disorders arises from the evidence that glutamate signalling antagonism can induce psychotic symptoms in healthy subjects. Ketamine seems to have the capacity of inducing not only dissociative symptoms, but also psychotic symptoms such as hallucinations. The main molecular mechanism of action of ketamine is due to its glutamate-dependent property. Ketamine also has other glutamate-independent mechanisms of action which include interaction with dopaminergic receptors, as well as with opioid, muscarinic, serotonin, and noradrenaline ones. Ketamine primarily acts as a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, leading to an increase in glutamate release in prefrontal cortex. The antagonism on NMDA receptors is thought to cause the dissociative effect of the drug, engendering a disconnection between thalamus, neocortex, and limbic areas. Given that ketamine-induced symptoms resemble the positive and negative symptoms of schizophrenia, they represent a consistent and novel pharmacological model to understand the molecular basis of hallucinations.



This chapter was supported by a grant from the AIFA (Proposal AIFA-2016-02364852).


  1. 1.
    McCarthy DA, Chen G, Kaump DH, Ensor C. General anesthetic and other pharmacological properties of 2-(O-chlorophenyl)-2-methylamino cyclohexanone HCl (CI-581). J Clin Pharmacol. 1965;5:21–33.Google Scholar
  2. 2.
    Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg. 1966;45:29–40.CrossRefGoogle Scholar
  3. 3.
    Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965;6:279–91.CrossRefGoogle Scholar
  4. 4.
    Bhargava R, Young KD. Procedural pain management patterns in academic pediatric emergency departments. Acad Emerg Med. 2007;14:479–82.CrossRefGoogle Scholar
  5. 5.
    Jabre P, Combes X, Lapostolle F, Dhaouadi M, Ricard-Hibon A, Vivien B, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomized controlled trial. Lancet. 2009;374:293–300.CrossRefGoogle Scholar
  6. 6.
    Wang X, Ding X, Tong Y, Zong J, Zhao X, Ren H, et al. Ketamine does not increase intracranial pressure compared with opioids: meta-analysis of randomized controlled trials. J Anesth. 2014;28:821–7.CrossRefGoogle Scholar
  7. 7.
    Goyal S, Agrawal A. Ketamine in status asthmaticus: a review. Indian J Crit Care Med. 2013;17:154.CrossRefGoogle Scholar
  8. 8.
    Han Y, Chen J, Zou D, Zheng P, Li Q, Wang H, Xie P. Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies. Neuropsychiatr Dis Treat. 2016;12:2859.CrossRefGoogle Scholar
  9. 9.
    Permoda-Osip A, Kisielewski J, Bartkowska-Sniatkowska A, Rybakowski JK. Single ketamine infusion and neurocognitive performance in bipolar depression. Pharmacopsychiatry. 2015;48:78–9.PubMedGoogle Scholar
  10. 10.
    Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. 2016;10:612.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Koob GF. Drugs of abuse: anatomy, pharmacology and function of reward pathways. Trends Pharmacol Sci. 1992;13:177–84.CrossRefGoogle Scholar
  12. 12.
    Stevenson C. Ketamine: a review. Update Anesth. 2005;20:25–9.Google Scholar
  13. 13.
    Giorgetti R, Marcotulli D, Tagliabracci A, Schifano F. Effects of ketamine on psychomotor, sensory and cognitive functions relevant for driving ability. Forensic Sci Int. 2015;252:127–42.CrossRefGoogle Scholar
  14. 14.
    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;19:454–60.CrossRefGoogle Scholar
  15. 15.
    Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77:357–67.CrossRefGoogle Scholar
  16. 16.
    Lahti AC, Weiler MA, Tamara M, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001;25:455–67.CrossRefGoogle Scholar
  17. 17.
    Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology. 2003;169:215–33.CrossRefGoogle Scholar
  18. 18.
    Lahti AC, Koffel B, LaPorte D, Tamminga CA. Subanesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995;13:9–19.CrossRefGoogle Scholar
  19. 19.
    Pomarol-Clotet E, Honey GD, Murray GK, Corlett PR, Absalom AR, Lee M, Fletcher PC. Psychological effects of ketamine in healthy volunteers. Br J Psychiatry. 2006;189:173–9.CrossRefGoogle Scholar
  20. 20.
    Corlett PR, Honey GD, Krystal JH, Fletcher PC. Glutamatergic model psychoses: prediction error, learning, and inference. Neuropsychopharmacology. 2011;36:294–315.CrossRefGoogle Scholar
  21. 21.
    Xu K, Krystal JH, Ning Y, He H, Wang D, Ke X, Wang Z. Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia. J Psychiatr Res. 2015;61:64–72.CrossRefGoogle Scholar
  22. 22.
    Vollenweider FX, Leenders KL, Øye I, Hell D, Angst J. Differential psychopathology and patterns of cerebral glucose utilization produced by (S)-and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacol. 1997a;7:25–38.CrossRefGoogle Scholar
  23. 23.
    Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18 F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol. 1997b;7:9–24.CrossRefGoogle Scholar
  24. 24.
    Domino EF, Luby ED. Phencyclidine/schizophrenia: one view toward the past, the other to the future. Schizophr Bull. 2012;38:914–9.CrossRefGoogle Scholar
  25. 25.
    Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994;51:199–214.CrossRefGoogle Scholar
  26. 26.
    Frohlich J, Van Horn JD. Reviewing the ketamine model for schizophrenia. J Psychopharmacol. 2014;28:287–302.CrossRefGoogle Scholar
  27. 27.
    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;28:114–6.CrossRefGoogle Scholar
  28. 28.
    Malhotra AK, Pinals DA, Weingartner H, Sirocco K, Missar CD, Pickar D, Breier A. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology. 1996;14:301–7.CrossRefGoogle Scholar
  29. 29.
    Powers AR III, Gancsos MG, Finn ES, Morgan PT, Corlett PR. Ketamine-induced hallucinations. Psychopathology. 2015;48:376–85.CrossRefGoogle Scholar
  30. 30.
    Wolff K, Winstock AR. Ketamine. CNS Drugs. 2006;20:199–218.CrossRefGoogle Scholar
  31. 31.
    Zhang JC, Li SX, Hashimoto K. R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacol Biochem Behav. 2014;116:137–41.CrossRefGoogle Scholar
  32. 32.
    Desta Z, Moaddel R, Ogburn ET, Xu C, Ramamoorthy A, Venkata SLV, Wainer IW. Stereoselective and regiospecific hydroxylation of ketamine and norketamine. Xenobiotica. 2012;42:1076–87.CrossRefGoogle Scholar
  33. 33.
    Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19:370–80.CrossRefGoogle Scholar
  34. 34.
    Persson J. Wherefore ketamine? Curr Opin Anesthesiol. 2010;23:455–60.CrossRefGoogle Scholar
  35. 35.
    Papadia S, Hardingham GE. The dichotomy of NMDA receptor signaling. Neuroscientist. 2007;13:572–9.CrossRefGoogle Scholar
  36. 36.
    Waxman EA, Lynch DR. N-methyl-D-aspartate receptor subtypes: multiple roles in excitotoxicity and neurological disease. Neuroscientist. 2005;11:37–49.CrossRefGoogle Scholar
  37. 37.
    Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007;27:11496–500.CrossRefGoogle Scholar
  38. 38.
    Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921–7.CrossRefGoogle Scholar
  39. 39.
    White PF, Schuttler J, Shafer A, Stanski DR, Horai Y, Trevor AJ. Comparative pharmacology of the ketamine isomers. Studies in volunteers. Br J Anaesth. 1985;57:197–203.CrossRefGoogle Scholar
  40. 40.
    White PF, Way WL, Trevor WL. Ketamine: its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119–36.CrossRefGoogle Scholar
  41. 41.
    Klepstad P, Maurset A, Moberg ER, Øye I. Evidence of a role for NMDA receptors in pain perception. Eur J Pharmacol. 1990;187:513–8.CrossRefGoogle Scholar
  42. 42.
    Coyle JT, Leski M, Morrison J. Diverse role of L-glutamate acid in brain signal transduction. In: Neuropsychopharmacology: fifth generation of progress. New York: Lippincott; 2001.Google Scholar
  43. 43.
    Strasburger SE, Bhimani PM, Kaabe JH, Krysiak JT, Nanchanatt DL, Nguyen TN, Scandlen L, 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;42:147–54.CrossRefGoogle Scholar
  44. 44.
    Walter M, Li S, Demenescu LR. Multistage drug effects of ketamine in the treatment of major depression. Eur Arch Psychiatry Clin Neurosci. 2014;264:55–65.CrossRefGoogle Scholar
  45. 45.
    Chen L, Malek T. Follow me down the K-hole: ketamine and its modern applications. Crit Care Nurs Q. 2015;38:211–6.CrossRefGoogle Scholar
  46. 46.
    Miller OH, Moran JT, Hall BJ. Two cellular hypotheses explaining the initiation of ketamine’s antidepressant actions: direct inhibition and disinhibition. Neuropharmacology. 2016;100:17–26.CrossRefGoogle Scholar
  47. 47.
    Quirk MC, Sosulski DL, Feierstein CE, Uchida N, Mainen ZF. A defined network of fast-spiking interneurons in orbitofrontal cortex: responses to behavioral contingencies and ketamine administration. Front Syst Neurosci. 2009;3:13.CrossRefGoogle Scholar
  48. 48.
    Rolland B, Jardri R, Amad A, Thomas P, Cottencin O, Bordet R. Pharmacology of hallucinations: several mechanisms for one single symptom? Biomed Res Int. 2014;2014:1.CrossRefGoogle Scholar
  49. 49.
    Li D, He L. Association study between the NMDA receptor 2B subunit gene (GRIN2B) and schizophrenia: aHuGE review and meta-analysis. Genet Med. 2007;9:4–8.CrossRefGoogle Scholar
  50. 50.
    Kim SY, Lee H, Kim HJ, Bang E, Lee SH, Lee DW, Choe BY. In vivo and ex vivo evidence for ketamine-induced hyperglutamatergic activity in the cerebral cortex of the rat: potential relevance to schizophrenia. NMR Biomed. 2011;24:1235–42.CrossRefGoogle Scholar
  51. 51.
    Rowland LM, Bustillo JR, Mullins PG, et al. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatr. 2005;162:394–6.CrossRefGoogle Scholar
  52. 52.
    Stone JM, Dietrich C, Edden R, Mehta MA, De Simoni S, Reed LJ, Barker GJ. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Mol Psychiatry. 2012;17(7):664.CrossRefGoogle Scholar
  53. 53.
    Boksa P. On the neurobiology of hallucinations. J Psychiatry Neurosci. 2009;34:260.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Javitt DC. Glutamate and schizophrenia: phencyclidine, N-methyl-d-aspartate receptors, and dopamine–glutamate interactions. Int Rev Neurobiol. 2007;78:69–108.CrossRefGoogle Scholar
  55. 55.
    Seeman P, Ko F, Tallerico T. Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics. Mol Psychiatry. 2005;10:877–83.CrossRefGoogle Scholar
  56. 56.
    Stoicea N, Versteeg G, Florescu D, Joseph N, Fiorda-Diaz J, Navarrete V, Bergese SD. Ketamine-based anesthetic protocols and evoked potential monitoring: a risk/benefit overview. Front Neurosci. 2016;10:37.CrossRefGoogle Scholar
  57. 57.
    Stone JM, Erlandsson K, Arstad E, Squassante L, Teneggi V, Bressan RA, Krystal JH, Ell PJ, Pilowsky LS. Relationship between ketamine-induced psychotic symptoms and NMDA receptor occupancy: a [(123)I]CNS-1261 SPET study. Psychopharmacology. 2008;197:401–8.CrossRefGoogle Scholar
  58. 58.
    Kegeles LS, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann J, Van Heertum RL, Laruelle M. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000;48:627–40.CrossRefGoogle Scholar
  59. 59.
    Zhang J, Chiodo LA, Freeman AS. Electrophysiological effects of MK-801 on rat nigrostriatal and mesoaccumbal dopaminergic neurons. Brain Res. 1992;590:153–63.CrossRefGoogle Scholar
  60. 60.
    Deutch AY, Tam SY, Freeman AS, Bowers MB, Roth RH. Mesolimbic and mesocortical dopamine activation induced by phencyclidine: contrasting pattern to striatal response. Eur J Pharmacol. 1987;134:257–64.CrossRefGoogle Scholar
  61. 61.
    Weihmuller FB, O'Dell SJ, Cole BN, Marshall JF. MK-801 attenuates the dopamine-releasing but not the behavioral effects of methamphetamine: an in vivo microdialysis study. Brain Res. 1991;549:230–5.CrossRefGoogle Scholar
  62. 62.
    Whitton PS, Biggs CS, Pearce BR, Fowler LJ. Regional effects of MK-801 on dopamine and its metabolites studied by in vivo microdialysis. Neurosci Lett. 1992;142:5–8.CrossRefGoogle Scholar
  63. 63.
    Murase S, Mathe JM, Grenhoff J, Svensson TH. Effects of dizocilpine (MK-801) on rat midbrain dopamine cell activity: differential actions on firing pattern related to anatomical localization. J Neural Transm. 1993;91:13–25.CrossRefGoogle Scholar
  64. 64.
    Adams BW, Bradberry CW, Moghaddam B. NMDA antagonist effects on striatal dopamine release: microdialysis studies in awake monkeys. Synapse. 2002;43:12–8.CrossRefGoogle Scholar
  65. 65.
    Kegeles LS, Martinez D, Kochan LD, Hwang D-R, Huang Y, Mawlawi O, Suckow RF, Van Heertum RL, Laruelle M. NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans. Synapse. 2002;43:19–29.CrossRefGoogle Scholar
  66. 66.
    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;16:373–9.CrossRefGoogle Scholar
  67. 67.
    Witkin JM, Monn JA, Schoepp DD, Li X, Overshiner C, Mitchell SN, Rorick-Kehn LM. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J Pharmacol Exp Ther. 2016;358:71–82.CrossRefGoogle Scholar
  68. 68.
    Rao TS, Kim HS, Lehmann J, Martin LL, Wood PL. Differential effects of phencyclidine (PCP) and ketamine on mesocortical and mesostriatal dopamine release in vivo. Life Sci. 1989;45:1065–72.CrossRefGoogle Scholar
  69. 69.
    Lannes B, Micheletti G, Warter JM, Kempf E, Di Scala G. Behavioural, pharmacological and biochemical effects of acute and chronic administration of ketamine in the rat. Neurosci Lett. 1991;128:177–81.CrossRefGoogle Scholar
  70. 70.
    Micheletti G, Lannes B, Haby C, Borrelli E, Kempf E, Warter JM, Zwiller J. Chronic administration of NMDA antagonists induces D 2 receptor synthesis in rat striatum. Mol Brain Res. 1992;14:363–8.CrossRefGoogle Scholar
  71. 71.
    Breier A, Adler CM, Weisenfeld N, Su TP, Elman I, Picken L, Malhotra AK, Pickar D. Effects of NMDA antagonism on striatal dopamine release in healthy subjects: application of a novel PET approach. Synapse. 1998;29:142–7.CrossRefGoogle Scholar
  72. 72.
    Smith GS, Schloesser R, Brodie JD, Dewey SL, Logan J, Vitkun SA, Simkowitz P, Hurley A, Cooper T, Volkow ND, Cancro R. Glutamate modulation of dopamine measured in vivo with positron emission tomography (PET) and 11C±raclopride in normal human subjects. Neuropsychopharmacology. 1998;18:18–25.CrossRefGoogle Scholar
  73. 73.
    Vollenweider FX, Vontobel P, Øye I, Hell D, Leenders KL. Effects of (S)-ketamine on striatal dopamine: a [11 C] raclopride PET study of a model psychosis in humans. J Psychiatr Res. 2000;34:35–43.CrossRefGoogle Scholar
  74. 74.
    Krystal JH, D’Souza DC, Karper LP, Bennett A, Abi-Dargham A, Abi-Saab D, Charney DS. Interactive effects of subanesthetic ketamine and haloperidol in healthy humans. Psychopharmacology. 1999;145:193–204.CrossRefGoogle Scholar
  75. 75.
    Kantrowitz J, Javitt D. Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models. Clin Schizophr Relat Psychoses. 2010;4:189–200.CrossRefGoogle Scholar
  76. 76.
    Pitcher GM, Kalia LV, Ng D, Goodfellow NM, Yee KT, Lambe EK, Salter MW. Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. Nat Med. 2011;17:470–8.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Gian Mario Mandolini
    • 1
  • Matteo Lazzaretti
    • 1
  • Alfredo Carlo Altamura
    • 1
  • Paolo Brambilla
    • 1
    • 2
    Email author
  1. 1.Department of Neurosciences and Mental Health, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoUniversity of MilanMilanItaly
  2. 2.Department of Psychiatry and Behavioural NeurosciencesUniversity of Texas at HoustonHoustonUSA

Personalised recommendations