Psychological Effects of (S)-Ketamine and N,N-Dimethyltryptamine (DMT): A Double-Blind, Cross-Over Study in Healthy Volunteers

E. Gouzoulis-Mayfrank; K. Heekeren; A. Neukirch; M. Stoll; C. Stock; M. Obradovic; K.-A. Kovar

doi:10.1055/s-2005-916185

Pharmacopsychiatry, Table of Contents

Pharmacopsychiatry 2005; 38(6): 301-311
DOI: 10.1055/s-2005-916185

Original Paper

Psychological Effects of (S)-Ketamine and N,N-Dimethyltryptamine (DMT): A Double-Blind, Cross-Over Study in Healthy Volunteers

E. Gouzoulis-Mayfrank¹ , K. Heekeren¹ ^, ² , A. Neukirch¹ ^, ² , M. Stoll² , C. Stock² , M. Obradovic³ , K.-A. Kovar³

¹Department of Psychiatry and Psychotherapy, University of Cologne, Kerpener Strasse 62, Cologne, Germany
²Department of Psychiatry and Psychotherapy, University of Technology, Aachen (RWTH), Pauwelsstrasse 30, Aachen, Germany
³Institute of Pharmacy, University of Tübingen, Auf der Morgenstelle 8, Tübingen, Germany

Abstract

Introduction: Pharmacological challenges with hallucinogens are used as models for psychosis in experimental research. The state induced by glutamate antagonists such as phencyclidine (PCP) is often considered as a more appropriate model of psychosis than the state induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and N,N-dimethyltryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design. Methods: Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT_2A agonist DMT and the glutamate N-methyl-d-aspartate (NMDA) antagonist (S)-ketamine. Results: Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia, attention deficits, body perception disturbances and catatonia-like motor phenomena were stronger after (S)-ketamine. Discussion: The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT_2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT_2A agonist state may be a better model for psychoses of the paranoid type.

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References

1 Abi-Saab W M, D’Souza D C, Moghaddam B, Krystal J H. The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry. 1998; 31(Suppl.) 104-109
2 Adler C M, Goldberg T E, Malhotra A K, Pickar D, Breier A. Effects of ketamine on thought disorder, working memory and semantic memory in healthy volunteers. Biol Psychiatry. 1998; 43 811-816
3 Anand A, Charney D S, Oren D A, Berman R M, Hu X S, Cappiello A, Krystal J H. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of N-methyl-d-aspartate receptor antagonists. Arch Gen Psychiatry. 2000; 57 270-276
4 Andreasen N C. Scale for the assessment of positive symptoms SAPS. Dep. of Psychiatry, University of Iowa Iowa City, Copyright by Andreasen NC; 1984
5 Andreasen N C. Scale for the assessment of negative symptoms SANS. Dep. of Psychiatry, University of Iowa Iowa City, Copyright by Andreasen NC; ; 1984
6 Beringer K. Der Meskalinrausch. Heidelberg, Berlin; Springer 1927
7 Breier A, Malhotra A K, Pinals D A, Weisenfeld N I, Pickar D. Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry. 1997; 154 805-811
8 Carpenter W T. The schizophrenia ketamine challenge study debate. Biol Psychiatry. 1999; 46 1081-1091
9 Carter O L, Pettigrew J D, Burr D C, Alais D, Hasler F, Vollenweider F X. Psilocybin impairs high-level but not low-level motion perception. Neuroreport. 2004; 15 1947-1951
10 Carter O L, Pettigrew J D, Hasler F, Wallis G M, Liu G B, Hell D, Vollenweider F X. Modulating the rate and rhythmicity of perceptual rivalry alternations with the mixed 5-HT2A and 5-HT1A agonist psilocybin. Neuropsychopharmacology.. 2005; 30 1154-1162
11 Dittrich A. Aetiologie-unabhängige Strukturen veraenderter Wachbewusstseinszustaende. Stuttgart; Enke 1985
12 Dittrich A, von Arx S, Staub S. International study on altered states of consciousness (ISASC). Summary of the results. German J Psychol. 1985; 9 319-339
13 Duncan E J, Madonick S H, Parwani A, Angrist B, Rajan R, Chakravorty S, Efferen T R, Szilagyi S, Stephanides M, Chappell P B, Gonzenbach S, Ko G N, Rotrosen J P. Clinical and sensorimotor gating effects of ketamine in normals. Neuropsychopharmacology. 2001; 25 72-83
14 D’Souza D C, Berman R M, Krystal J H, Charney D S. Symptom provocation studies in psychiatric disorders: scientific value, risks, and future. Biol Psychiatry. 1999; 46 1060-1080
15 Ellis H. Mescal: A new artificial paradise. Annual report of the Smithsonian. Institution 1897: 537-548
16 Feng N, Vollenweider F X, Minder E L, Rentsch K, Grampp T, Vonderschmitt D J. Development of a gas chromatography-mass spectrometry method for determination of ketamine in plasma and its application to human samples. Ther Drug Monit. 1995; 17 95-100
17 Frecska E, White K D, Luna L E. Effects of ayahuasca on binocular rivalry with dichoptic stimulus alternation. Psychopharmacology. 2004; 173 79-87
18 Freedman B, Chapman J. Early subjective experience in schizophrenic episodes. J Abnormal Psychol. 1973; 82 46-54
19 Gouzoulis E, Hermle L, Sass H. Psychedelic experiences at the beginning of acute endogenous psychotic episodes. Nervenarzt. 1994; 65 198-201
20 Gouzoulis-Mayfrank E, Habermeyer E, Hermle L, Steinmeyer A M, Kunert J, Sass H. Hallucinogenic drug induced states resemble acute endogenous psychotic episodes: Results of an empirical study. Eur Psychiatry. 1998; 13 399-406
21 Gouzoulis-Mayfrank E, Heekeren K, Thelen B, Lindenblatt H, Kovar K A, Sass H, Geyer M A. Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle reflex in humans. Behav Pharmacol.. 1998; 9 561-566
22 Gouzoulis-Mayfrank E, Hermle L, Thelen B, Sass H. History, rationale and potential of experimental hallucinogenic drug research in psychiatry. Pharmacopsychiatry. 1998; 31(Suppl. 2) 63-68
23 Gouzoulis-Mayfrank E, Schneider F, Spitzer M, Thelen B, Sass H. Methodological issues of human experimental research with hallucinogens. Pharmacopsychiatry. 1998; 31(Suppl. 2) 114-118
24 Gouzoulis-Mayfrank E, Schreckenberger M, Sabri O, Arning C, Thelen B, Spitzer M, Kovar K A, Büll U, Sass H. Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology. 1999; 20 565-581
25 Gouzoulis-Mayfrank E, Thelen B, Habermeyer E, Kunert H J, Kovar K A, Hermle L, Spitzer M, Sass H. Psychopathological, neuroendocrine and autonomic effects of 3,4-methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy volunteers. Results of an experimental double-blind placebo-controlled study. Psychopharmacology. 1999; 142 41-50
26 Gouzoulis-Mayfrank E, Thelen B, Maier S, Habermeyer E, Kovar K -A, Sass H, Spitzer M. Effects of the hallucinogen psilocybin on covert orienting of visual attention in humans. Neuropsychobiology. 2002; 45 205-212
27 Guillermain Y, Micallef J, Possamai C, Blin O, Hasbroucq T. N-methyl-D-aspartate receptors and information processing: human choice reaction time under a subanaesthetic dose of ketamine. Neurosci Lett. 2001; 303 29-32
28 Hasler F, Grimberg U, Benz M A, Huber T, Vollenweider F X. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology. 2004; 172 145-156
29 Hermle L, Fünfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, Fehrenbach R A, Spitzer M. Mescaline-induced psychopathological, neuropsychological and neurometabolic effects in normal subjects. Experimental psychosis as a tool for psychiatric research. Biol Psychiatry. 1992; 32 976-991
30 Hetem L AB, Danion J M, Diemunsch P, Brandt C. Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers. Psychopharmacology. 2000; 152 283-288
31 Holcomb H H, Lahti A C, Medoff D R, Weiler M, Tamminga C A. Sequential regional cerebral blood flow brain scans using PET with H2(15)O demonstrate ketamine actions in CNS dynamically. Neuropsychopharmacology. 2001; 25 165-172
32 Hollister L E. Drug-induced psychoses and schizophrenic reactions: a critical comparison. Ann N Y Acad Sci. 1962; 96 80-92
33 Idvall J, Ahlgren I, Aronsen K R, Stenberg P. Ketamine infusions: pharmacokinetics and clinical effects. Br J Anaesth. 1979; 51 167-1173
34 Javitt D C, Zukin S R. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991; 148 1301-1308
35 Kegeles L S, Abi-Dargham A, Zea-Ponce Y, Rodenhiser-Hill J, Mann J J, Van Heertum R L, Cooper T B, Carlsson A, Laruelle M. Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia. Biol Psychiatry. 2000; 48 627-640
36 Kegeles L S, Martinez D, Kochan L D, Hwang D R, Huang Y, Mawlawi O, Suckow R F, Van Heertum R L, Laruelle M. NMDA antagonist effects on striatal dopamine release: positron emission tomography studies in humans. Synapse. 2002; 43 19-29
37 Klosterkotter J, Hellmich M, Steinmeyer E M, Schultze-Lutter F. Diagnosing schizophrenia in the initial prodromal phase. Arch Gen Psychiatry. 2001; 58 158-164
38 Kreitschmann-Andermahr I, Rosburg T, Demme U, Gaser E, Nowak H, Sauer H. Effect of ketamine on the neuromagnetic mismatch field in healthy humans. Brain Res Cogn Brain Res. 2001; 12 109-116
39 Krystal J H, Karper L P, Seibyl J P, Freeman G K, Delaney R, Bremner J D, Heninger G R, Bowers M B, Charney D S. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994; 51 199-214
40 Krystal J H, Karper L P, Bennett A, D’Souza D C, Abi-Dargham A, Morrissey K, Abi-Saab D, Bremner J D, Bowers M B, Jr., Suckow R F, Stetson P, Heninger G R, Charney D S. Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans. Psychopharmacology. 1998; 135 213-229
41 Krystal J H, Petrakis I L, Webb E, Cooney N L, Karper L P, Namanworth S, Stetson P, Trevisan L A, Charney D S. Dose-related ethanol-like effects of the NMDA antagonist, ketamine, in recently detoxified alcoholics. Arch Gen Psychiatry. 1998; 55 354-360
42 Krystal J H, Bennett A, Abi-Saab D, Belger A, Karper L P, D’Souza D C, Lipschitz D, Abi-Dargham A, Charney D S. Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions. Biol Psychiatry. 2000; 47 137-143
43 Lahti A C, Holcomb H H, Medoff D R, Tamminga C A. Ketamine activates psychosis and alters limbic blood flow in schizophrenia. NeuroReport. 1995; 6 869-872
44 Lahti A C, Koffel B, LaPorte D, Tamminga C A. Subanaesthetic doses of ketamine stimulate psychosis in schizophrenia. Neuropsychopharmacology. 1995; 13 9-19
45 Lahti A C, Weiler M A, Tamara Michaelidis B A, Parwani A, Tamminga C A. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001; 25 455-467
46 LaPorte D J, Lahti A C, Koffel B, Tamminga C A. Absence of ketamine effects on memory and other cognitive functions in schizophrenic patients. J Psychiat Res. 1996; 30 321-330
47 Luby E D, Cohen B D, Rosenbaum G, Gottlieb J S, Kelley R. Study of a new schizophrenomimetic drug - sernyl. Am Med Assoc Arch Neurological Psychiatry. 1959; 81 363-369
48 Malhotra A K, Pinals D A, Weingartner H, Sirocco K, Missar C D, Pickar D, Breier A. NMDA receptor function and human cognition: the effects of ketamine in healthy volunteers. Neuropsychopharmacology. 1996; 14 301-307
49 Malhotra A K, Adler C M, Kennison S D, Elman I, Pickar D, Breier A. Clozapine blunts N-methyl-D-aspartate antagonist-induced psychosis: a study with ketamine. Biol Psychiatry. 1997; 42 664-668
50 Medoff D R, Holcomb H H, Lahti A C, Tamminga C A. Probing the human hippocampus using rCBF: contrasts in schizophrenia. Hippocampus. 2001; 11 543-550
51 Micallef J, Guillermain Y, Tardieu S, Hasbroucq T, Possamai C, Jouve E, Blin O. Effects of subanesthetic doses of ketamine on sensorimotor information processing in healthy subjects. Clin Neuropharmacol. 2002; 25 101-106
52 Mitchell S W. The effects of Anhalonium Lewinii (the mescal button). BMJ. 1896; 2 1625-1629
53 Morgan C JA, Mofeez A, Brandne B, Bromley L, Curran H V. Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers. Neuropsychopharmacology. 2004; 29 208-218
54 Newcomer J W, Farber N B, Jevtovic-Todorovic V, Selke G, Melson A K, Hershey T, Craft S, Olney J W. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999; 20 106-118
55 Olney J W, Farber N B. Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry. 1995; 52 998-1007
56 Oranje B, van Berckel B N, Kemner C, van Ree J M, Kahn R S, Verbaten M N. The effects of a sub-anaesthetic dose of ketamine on human selective attention. Neuropsychopharmacology. 2000; 22 293-302
57 Øye N, Hustveit O, Moberg E R, Pausen O, Skoglund L A. The chiral forms of ketamine as probes for NMDA receptor function in humans. In Kameyama T, Nabeshima T, Domino ES, editors NMDA receptor related agents: Biochemistry, Pharmacology and Behavior. Ann Arbor; NPP Books 1991: p 381-389
58 Øye N, Paulsen O, Maurset A. Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors. Journal of Pharmacology and Experimental Therapeutics. 1992; 260 1209-1213
59 Pechnick R N, Ungerleider J T. Hallucinogens. In Lowinson JH, Ruiz P, Millman RB, Langrod JG, editors Substance Abuse. A comprehensive textbook, 3rd ed. Baltimore, Maryland:; Williams and Wilkins 1997: p 230-238
60 Rosenbaum G, Cohen B D, Luby E D, Gottlieb J S, Yelen D. Comparison of Sernyl with other drugs. Arch Gen Psychiatry. 1959; 1 113-118
61 Riba J, Rodriguez-Fornells A, Urbano G, Morte A, Antonijoan R, Montero M, Callaway J C, Barbanoj M J. Subjective effects and tolerability of the South American psychoactive beverage Ayahuasca in healthy volunteers. Psychopharmacology. 2001; 154 85-95
62 Riba J, Anderer P, Jané F, Saletu B, Barbanoj M J. Effects of the South American psychoactive beverage ayahuasca on regional brain electrical activity in humans: a functional neuroimaging study using low-resolution electromagnetic tomography. Neuropsychobiology. 2004; 50 89-101
63 Smith G S, Schloesser R, Brodie J D, Dewey S L, Logan J, Vitkun S A, Simkowitz P, Hurley A, Cooper T, Volkow N D, 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
64 Snyder S H. Psychotogenic drugs as models for schizophrenia. Neuropsychopharmacology. 1988; 1 197-199
65 Spitzer M, Thimm M, Hermle L, Holzman P, Schneider F, Gouzoulis-Mayfrank E, Kischka U, Kovar K -A. Increased activation of indirect semantic associations under psilocybin. Biol Psychiatry. 1996; 39 1055-1057
66 Stockings G T. A clinical study of the mescaline psychosis, with special reference to the mechanism of the genesis of schizophrenic and other psychotic states. J Ment Sci. 1940; 86 29-47
67 Strassman R J, Qualls C R. Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic and cardiovascular effects. Arch Gen Psychiatry. 1994; 51 85-97
68 Strassman R J, Qualls C R, Uhlenhuth E H, Kellner R. Dose-response study of N,N-dimethyltryptamine in humans. II. Subjective effects and preliminary results of a new rating scale. Arch Gen Psychiatry. 1994; 51 98-108
69 Strassman R J, Qualls C R, Berg L M. Differential tolerance to biological and subjective effects of four closely spaced doses of N,N-dimethyltryptamine in humans. Biol Psychiatry. 1996; 39 784-795
70 Umbricht D, Schmid L, Koller R, Vollenweider F X, Hell D, Javitt D C. Ketamine-induced deficits in auditory and visual context-dependent processing in healthy volunteers: implications for models of cognitive deficits in schizophrenia. Arch Gen Psychiatry. 2000; 57 1139-1147
71 Umbricht D, Koller R, Vollenweider F X, Schmid L. Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers. Biol Psychiatry. 2002; 51 400-406
72 Umbricht D, Vollenweider F X, Schmid L, Grubel C, Skrabo A, Huber T, Koller R. Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology. 2003; 28 170-181
73 Vollenweider F X. Advances and pathophysiological models of hallucinogenic drug actions in humans: a preamble to schizophrenia research. Pharmacopsychiatry. 1998; 31 ( 2) 92-103
74 Vollenweider F X, Geyer M A. A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull. 2001; 56 495-507
75 Vollenweider F X, Antonini A, Leenders K L, Oye I, Hell D, Angst J. Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). Eur Neuropsychopharmacology. 1997; 7 25-38
76 Vollenweider F X, Leenders K L, 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 [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacology. 1997; 7 9-24
77 Vollenweider F X, Leenders K L, Scharfetter C, Maguire P, Stadelmann O, Angst J. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology. 1997; 16 357-372
78 Vollenweider F X, Vollenweider-Scherpenhuyzen M F, Babler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 1998; 9 3897-3902
79 Vollenweider F X, Vontobel P, Hell D, Leenders K L. 5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man - a PET study with [11C]raclopride. Neuropsychopharmacology. 1999; 20 424-433
80 Vollenweider F X, Vontobel P, Oye I, Hell D, Leenders K L. Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res. 2000; 34 35-43
81 Weiler M A, Thaker G K, Lahti A C, Tamminga C A. Ketamine effects on eye movements. Neuropsychopharmacology. 2000; 23 645-653

Professor Euphrosyne Gouzoulis-Mayfrank, MD

Department of Psychiatry and Psychotherapy

University of Cologne

Kerpener Straße 62

50924 Cologne

Germany

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