Psychopharmacology (2008) 199:77–88 disorder (axis I and II according to Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV criteria) were included in the study. Subjects with a positive family history of severe psychiatric disorder in first-degree relatives, a personal history of current or previous drug abuse, or any regular medication were excluded. All subjects were screened with a medical history, a standard- ized psychiatric interview according to DSM-IV (Structured Clinical Interview for DSM) and a physical examination including a clinical test for normal hearing, electrocardio- gram, and a routine laboratory testing. Twelve subjects completed the experimental day with both doses of DMT, and ten subjects completed the day with both doses of S- ketamine. Nine subjects completed both experiments with both doses of DMT and S-ketamine. Data are presented for these nine subjects (for details on subjects and reasons for dropouts, see Gouzoulis-Mayfrank et al. 2005). Drugs DMT fumarate was synthesized in the Pharmaceutical Institute, University of Tübingen (Germany), and prepared as solution for intravenous use by Wülfing Pharma (Gronau, Germany). Two different DMT dosages were used: 1. Low DMT: a bolus injection over 5 min with 0.15– 0.2 mg/kg followed by a break of 1 min, followed by continuous infusion with 0.01125–0.015 mg/kg × min over 84 min 2. High DMT: bolus injection with 0.2–0.3 mg/kg and continuous infusion with 0.015–0.02 mg/kg ×min S-Ketamine (Ketanest® S, Parke-Davis, Karlsruhe, Ger- many) was administered in the following dosages: 1. Low S-ketamine: a bolus injection over 5 min with 0.1– 0.15 mg/kg followed by a break of 1 min, followed by continuous infusion with 0.0066–0.01 mg/kg × min over 54 min, followed by continuous infusion at a rate of 75% of the previous dose over 30 min 2. High S-ketamine: bolus injection with 0.15–0.2 mg/kg, continuous infusion with 0.01–0.015 mg/kg× min over 54 min, followed by continuous infusion at a rate of 75% of the previous dose over 30 min Due to interindividual differences in the strength of psychological effects to the same drug dose, we always started with a medium dose, which was on the maximum of the low and at the same time at the minimum of the high dose range. Depending on the intensity of effects during the first infusion period, we decided to go higher or lower for the second infusion period. This procedure leads to comparably strong psychological effects within each dose condition in spite of the interindividual differences in responsiveness to the drug. To avoid a cumulation of plasma 79 levels and clinical effects, the S-ketamine infusion rate was reduced after 60 min. Due to the fast elimination time of DMT, a reduction in the DMT dosage over the 90-min administration period was not necessary. With these doses, the psychological effects of both drugs developed fully within about 15 min and were kept relatively constant over the following period of 75 min from the start to the end of the infusion (for details on the dosage regimes, see Gouzoulis-Mayfrank et al. 2005). Study design On a separate day prior to the first experiment, all participants underwent a baseline MMN recording without drug administration. Thereafter, each subject participated in one experiment with DMT and one experiment with S- ketamine 2 to 4 weeks apart in a double-blind, crossover design and in a pseudorandomized order. On each exper- imental day, the same substance (DMT or S-ketamine) was administered in a low and a high dosage with a 2-h break between. The order of administration of the two dosages was single blind and was low–high on ten and high–low on 12 experiments. The drugs were administered by a physician, who had no other role in these experiments and did not communicate with the subjects and the other members of the research team. Both drugs were administered intrave- nously by an automatic infusion pump (Perfusor®, Braun, Melsungen, Germany). Blood pressure and heart rate were monitored automatically (Dinamap®, Critikon, Tampa, FL, USA) during the entire duration of the experiment. About 20 min after the onset of the infusion, the recording of the MMN started and lasted for about 30 min. After stopping the infusion, the psychological effects of the drugs completely vanished within 10 to 30 min. EEG recording and AX-CPT For the recording of the electroencephalogram (EEG), we used a 94-channel montage equally spaced around the reference electrode (Cz). Two additional channels were used to monitor vertical and horizontal electrooculogram (EOG). The individual position of each electrode was determined for each subject with a three-dimensional digitizer (ZEBRIS®, Isny, Germany). Electrode impedance was kept below 5 kΩ. The activity was recorded with an amplifier system (NeuroScan® Labs, El Paso, USA) and digitized continuously at a sampling rate of 1 kHz. Recording band pass was 0.3 to 250 Hz (6 dB). Three thousand auditory stimuli were presented binaurally with foam insert earphones at an intensity of 75 dB and with an interstimulus interval (ISI) of 500 ms. The acoustic stimuli consisted of 80% standard stimuli with a 50-ms duration at