The psychedelic model of schizophrenia: the case of N,N-dimethyltryptamine

Introduction

Earlier theories that schizophrenia might be caused by an endogenous ‘‘schizotoxin’’ motivated searches for methylated psychedelic metabolites that could mimic psychotic symptoms. The transmethylation hypothesis and subsequent work led investigators to consider several candidates, including 3,4-dimethoxyphenylethylamine, bufotenine, 5‑methoxy‑DMT, and N,N‑dimethyltryptamine (DMT). The authors set out to evaluate DMT against a set of criteria (modeled on Koch’s postulates) for a putative schizotoxin: that it mimic key features of schizophrenia; be present in humans along with its precursor; be synthesised endogenously; be differentially synthesised or metabolised in schizophrenia; show incomplete tolerance; and be affected by antipsychotic drugs. Gillin and colleagues review the existing human and animal data on DMT, report their own experimental observations in normal volunteers, and examine biochemical and clinical studies that bear on each criterion. The goal is to judge whether available evidence supports DMT as a causative agent in schizophrenia or whether further data are required.