Psychological Effects of (S)-Ketamine and N,N-Dimethyltryptamine (DMT): A Double-Blind, Cross-Over Study in Healthy Volunteers

Two classes of hallucinogenic drugs model different aspects of schizophrenia-like symptoms. In a double-blind crossover study, fifteen healthy volunteers received both the serotonin 5-HT2A agonist DMT and the glutamate NMDA antagonist (S)-ketamine. Nine subjects completed both sessions. DMT produced stronger positive symptoms resembling schizophrenia, such as formal thought disorder and inappropriate affect. (S)-ketamine produced stronger negative symptoms, attention deficits, body perception disturbances, and catatonia-like motor phenomena. The findings suggest neither drug model is overall superior; rather, each models distinct symptom profiles: DMT models paranoid-type psychoses, while (S)-ketamine models psychoses with prominent negative and catatonic features.

Study at a glance

Abstract

INTRODUCTION: 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 diethylamide (LSD), psilocybin and N,N-dimethyltryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design. METHODS: Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT2A agonist DMT and the glutamate N-methyl-D-aspartate (NMDA) antagonist (S)-ketamine. RESULTS: Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, 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. DISCUSSION: The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A agonist state may be a better model for psychoses of the paranoid type.