When the endogenous hallucinogenic trace amine N, N-dimethyltryptamine meets the sigma-1 receptor

Introduction

Trace amines are low-abundance biogenic amine metabolites that can accumulate when monoamine oxidase is inhibited; among them, N,N-dimethyltryptamine (DMT) is a tryptamine derivative with well-documented psychedelic effects. Earlier research established DMT as an endogenous compound in rat and human brain and implicated classical serotonin 5-HT2A receptors and, more recently, the G protein–coupled trace amine-associated receptors (TAARs) in mediating some of its actions. However, some pharmacological and behavioural responses to DMT are not readily explained by 5-HT or other monoaminergic systems, leaving uncertainty about additional molecular targets and pathways that might contribute to its psychotropic profile. Su and colleagues place a new piece of evidence into this context: several studies indicate that DMT can bind the sigma-1 receptor (Sig-1R), a ligand-regulated molecular chaperone located at the mitochondria-associated endoplasmic reticulum membrane (MAM). This paper aims to synthesise the relevant biochemical, cellular, animal and clinical observations and to present a hypothetical signalling scheme by which DMT interaction with Sig-1R might contribute to its cellular and behavioural effects, including possible contributions to psychotomimetic phenomena.