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Science 323 (5916): 934-937

Copyright © 2009 by the American Association for the Advancement of Science

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

Dominique Fontanilla,1 Molly Johannessen,2 Abdol R. Hajipour,3 Nicholas V. Cozzi,1 Meyer B. Jackson,2 Arnold E. Ruoho1*

Abstract: 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.

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

* To whom correspondence should be addressed. E-mail: aeruoho{at}wisc.edu


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