Both S-ketamine (an NMDA antagonist) and DMT (a 5HT2A agonist) reduced mismatch negativity (MMN) and impaired performance on a continuous performance test in healthy volunteers, but the effects differed. S-ketamine produced a more pronounced overall reduction in MMN and specifically affected the frontal source of MMN, while DMT did not. These distinct neurocognitive profiles suggest that the two classes of hallucinogens model different aspects of psychosis.
Schizophrenia patients show reduced prepulse inhibition (PPI) of the startle reflex, but hallucinogen models of psychosis in healthy volunteers do not replicate this effect. In a double-blind crossover study with 15 healthy volunteers, the serotonergic hallucinogen DMT had no significant effect on PPI, while the NMDA antagonist S-ketamine increased PPI and decreased startle magnitude. Neither drug affected the attentional modulation of PPI. These results highlight differences between human hallucinogen models and both animal models and schizophrenia itself.
Two classes of hallucinogens—serotonergic agonists like DMT and NMDA antagonists like S-ketamine—produce distinct patterns of psychosis-like symptoms, rather than one being a universally better model of schizophrenia. In a double-blind crossover study with 15 healthy volunteers, DMT more strongly induced positive symptoms such as thought disorder and inappropriate affect, while S-ketamine more strongly induced negative symptoms, attention deficits, body perception disturbances, and catatonia-like motor phenomena. The findings suggest that each drug class models different aspects or subtypes of schizophrenia, not that the NMDA antagonist model is overall superior to the 5-HT2A agonist model.