Psychopathological effects of S-ketamine and dimethyltryptamine (DMT) in humans: a double-blind, cross-over human experimental study of the NMDA antagonist and the 5HT2A agonist model of psychosis

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.

Study at a glance

Abstract

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 (LSD), psilocybin and dimethyltryptamine (DMT). However, so far, this question has never been addressed directly in an experimental study. Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the 5-HT2A agonist DMT and the NMDA antagonist S-ketamine. Overall, the intensity of the hallucinogenic drug effects was similar for DMT and S-ketamine. 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. The present study demonstrates that the NMDA antagonist model of psychosis is not overall superior to the 5-HT2A agonist model. Rather, the two classes of drugs model different aspects or types of schizophrenia.