Mismatch negativity generation in the human 5HT2A agonist and NMDA antagonist model of psychosis

Psychopharmacology (Berl). 2008 Jul;199(1):77-88. doi: 10.1007/s00213-008-1129-4. Epub 2008 May 18.


Rationale: Many studies have reported deficits of mismatch negativity (MMN) in schizophrenic patients. Pharmacological challenges with hallucinogens in healthy humans are used as models for psychotic states. Previous studies reported a significant reduction of MMN after ketamine (N-methyl-D-aspartate acid [NMDA] antagonist model) but not after psilocybin (5HT2A agonist model).

Objectives: The aim of the present study was to directly compare the two models of psychosis using an intraindividual crossover design.

Materials and methods: Fifteen healthy subjects participated in a randomized, double-blind, crossover study with a low and a high dose of the 5HT2A agonist dimethyltryptamine (DMT) and the NMDA antagonist S-ketamine. During electroencephalographic recording, the subjects were performing the AX-version of a continuous performance test (AX-CPT). A source analysis of MMN was performed on the basis of a four-source model of MMN generation.

Results: Nine subjects completed both experimental days with the two doses of both drugs. Overall, we found blunted MMN and performance deficits in the AX-CPT after both drugs. However, the reduction in MMN activity was overall more pronounced after S-ketamine intake, and only S-ketamine had a significant impact on the frontal source of MMN.

Conclusions: The NDMA antagonist model and the 5HT2A agonist model of psychosis display distinct neurocognitive profiles. These findings are in line with the view of the two classes of hallucinogens modeling different aspects of psychosis.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Attention / drug effects
  • Auditory Perception / drug effects
  • Brain Mapping
  • Cerebral Cortex / drug effects
  • Contingent Negative Variation / drug effects*
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Electroencephalography / drug effects
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • Humans
  • Inhibition, Psychological
  • Ketamine / pharmacology*
  • Male
  • Middle Aged
  • N,N-Dimethyltryptamine / pharmacology*
  • Orientation / drug effects
  • Pattern Recognition, Visual / drug effects
  • Psychomotor Performance / drug effects
  • Psychoses, Substance-Induced / physiopathology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Reflex, Startle / drug effects
  • Serotonin 5-HT2 Receptor Agonists*
  • Serotonin Receptor Agonists / pharmacology*
  • Signal Processing, Computer-Assisted


  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin Receptor Agonists
  • Ketamine
  • N,N-Dimethyltryptamine