Comment by Aaron Claassens on May 25, 2009 at 5:31pm

In a paper in the latest issue of Science, Dominique Fontanilla and colleages have just reported that the psychedelic DMT acts as a regulator at the sigma-1 receptor. (Previously, research on the mechanisms of tryptamine psychedelics has focused primarily on serotonin receptors.) Among other things, they show that mice who have no sigma-1 receptor fail to show increased motor activity after DMT injection. This is fascinating for many reasons. The Sigma-1 receptor does not have a known endogenous neurotransmitter. Because DMT has been detected in human biofluids a couple times, the authors suggest DMT might be an endogenous modulator of the receptor. Whether DMT and related compounds turn out to have a significant biological role in mammals, this finding undeniably opens new vistas for understanding the mechanisms of psychedelics and may ultimately lead to novel treatments for mental illness.

The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator
D Fontanilla, M Johannessen, AR Hajipour, NV Cozzi, MB Jackson, AE Ruoho
Science, 2009, Vol. 323. (5916) pp. 934 - 937 DOI: 10.1126/science.1166127

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.


The binding, biochemical, physiological, and behavioral studies reported here all support the hypothesis that DMT acts as a ligand for the sigma-1 receptor. On the basis of our binding results and the sigma-1 receptor pharmacophore, endogenous trace amines and their N-methyl and N,N-dimethyl derivatives are likely to serve as endogenous sigma receptor regulators. Moreover, DMT, the only known mammalian N,N-dimethylated trace amine, can activate the sigma-1 receptor to modulate Na+ channels. The recent discovery that the sigma-1 receptor functions as a molecular chaperone (30) may be relevant, because sigma-1 receptors, which are observed in the endoplasmic reticulum, associate with plasma membrane Kv 1.4 channels (22) and may serve as a molecular chaperone for ion channels. Furthermore, the behavioral effect of DMT may be due to activation or inhibition of sigma-1 receptor chaperone activity instead of, or in addition to, DMT/sigma-1 receptor modulation of ion channels. These studies thus suggest that this natural hallucinogen could exert its action by binding to sigma-1 receptors, which are abundant in the brain (1, 27). This discovery may also extend to N,N-dimethylated neurotransmitters such as the psychoactive serotonin derivative N,N-dimethylserotonin (bufotenine), which has been found at elevated concentrations in the urine of schizophrenic patients (10). The finding that DMT and sigma-1 receptors act as a ligand-receptor pair provides a long-awaited connection that will enable researchers to elucidate the biological functions of both of these molecules.

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