78 a “preattentive” component of the auditory-evoked poten- tials (Umbricht and Krljes 2005). MMN occurs after any discriminable deviation in an ongoing repetitive acoustic stimulation with identical tones. The repetitive standard stimuli are thought to generate a memory template, and any incoming stimulus is compared against it. If the incoming stimulus does not match the template, a MMN is generated (Näätänen 1995; Ritter et al. 1995). Since MMN occurs whether or not stimuli are being attended, it is supposed to reflect an automatic, i.e., preattentive process for detecting change (Picton et al. 2000). Hence, the MMN represents context-dependent infor- mation processing at the level of the auditory sensory cortex (Näätänen et al. 2001). The main generators of the MMN lie bitemporally within the primary and secondary auditory cortices (Alho et al. 1996; Tiitinen et al. 1993). However, frontal cortical areas seem to be also involved in the generation of MMN (Rinne et al. 2000; Waberski et al. 2001). The findings of deficient MMN in schizophrenia support the hypothesis of impaired early information processing in this disorder (Umbricht and Krljes 2005). MMN deficits appear to be relatively specific for schizophrenia, since they were not observed in other mental illnesses such as major depression or bipolar disorder (Umbricht et al. 2003a; Catts 1995). Two recent studies failed to demonstrate abnormal MMN in first-episode patients; hence, it is possible that the MMN impairment develops in the ongoing course of the schizophrenia (Salisbury et al. 2002; Umbricht et al. 2006). Dopaminergic, glutamatergic, and serotoninergic sys- tems are all involved in the pathophysiology of schizo- phrenia but may modulate different symptom domains within this complex disorder. Acute dopamine receptor stimulation did not affect MMN in healthy subjects (Leung et al. 2007). In contrast, dysfunction in the N-methyl-D- aspartic acid (NMDA) receptor system is considered to play an important role in schizophrenia-related deficits in MMN (Light and Braff 2005a, b). Competitive and noncompeti- tive NMDA antagonists selectively block the generation of MMN in awake monkeys (Javitt et al. 1996). It is interesting to note that NMDA receptor antagonists such as phencyclidine and ketamine elicit psychosis-like symp- toms in humans, and pharmacological challenges with ketamine are used as a model for psychosis in human experimental research. Ketamine in subanesthetic dosages decreased MMN without affecting other event-related potential (ERP) activity in healthy humans (Umbricht et al. 2000; Kreitschmann-Andermahr et al. 2001). However, a study that used an even lower ketamine dose, which elicited only very subtle psychological effects, reported no MMN deficit (Oranje et al. 2000). The NMDA antagonist model is the most widely accepted model of psychosis, and it is thought to be an appropriate model for undifferentiated or disorganized Psychopharmacology (2008) 199:77–88 psychoses with positive and negative symptoms. However, lysergic acid diethylamide (LSD) and LSD-type hallucinogens are also used to model psychoses in animal and human experimental research. LSD-type drugs are agonists at serotonin 5HT2A receptors, and the 5HT2A agonist model of psychosis is thought to resemble more the positive symptoms of schizophrenia (Abi-Saab et al. 1998; Gouzoulis-Mayfrank et al. 2005; Vollenweider et al. 1998). It is interesting to note that a previous study of MMN in the 5HT2A agonist model of psychosis showed no significant effect of the serotonergic hallucinogen psilocybin on MMN (Umbricht et al. 2003a, b). However, acute tryptophan depletion, which reduces the brain synthesis of serotonin, did lead to increased MMN amplitude (Kähkönen et al. 2005). The aim of the present study was to investigate the effects of the 5HT2A agonist hallucinogen N,N-dimethyltryptamine (DMT) and the NMDA antagonist hallucinogen S-ketamine on the generation of MMN using two different dosages of each drug. Both drugs can be given intravenously and have similar pharmacokinetics with rapid onset at the beginning and rapid fading of action after the end of the infusion. Hence, it is possible to study the effects of the two drugs in a randomized, double-blind design. Based on the principles of model psychosis and the robust findings of diminished MMN in patients with schizophrenia, we expected a dose- dependent decrease in MMN activity after both hallucino- gens. Furthermore, this study aimed to analyze possible differences between the two hallucinogens in terms of the modulation of the frontal and temporal sources of MMN. Material and methods The present study was part of a more comprehensive investigation, which also assessed the psychological effects, spatial orienting of attention, and startle modification in healthy subjects after S-ketamine and DMT intake (for details, see Gouzoulis-Mayfrank et al. 2005, 2006; Heekeren et al. 2007). The study was carried out in accordance with the Declaration of Helsinki and was approved by the local ethics committee at the Medical Faculty of the University of Technology Aachen and the Federal Health Administration (Berlin). Written informed consent was obtained from all subjects after we described the experimental procedures in detail and explained that they might withdraw from the study at any time, if they wished so, without having to explain the reasons. Subjects Fifteen healthy volunteers (nine men, six women; mean age 38.0 years, range =28–53) with no current physical and no current or previous history of neurological or psychiatric