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

Fontanilla, Dominique
Johannessen, Molly
Hajipour, Abdol R.
Cozzi, Nicholas V.
Jackson, Meyer B.
Ruoho, Arnold E.

¹Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
²Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
³Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR Iran.

^*To whom correspondence should be addressed. E-mail: [email protected]

Science 323(5916):p 934-937, February 13, 2009.

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.