The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator

The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma- 1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N, N- dimethyltryptamine ( DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma- 1 receptors and inhibited voltage- gated sodium ion ( Na+) channels in both native cardiac myocytes and heterologous cells that express sigma- 1 receptors. DMT induced hypermobility in wild- type mice but not in sigma- 1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma- 1 receptor.