Dr. Arnold Ruoho's lab at the University of Wisconsin has just published a paper in Science linking the endogenous hallucinogen N,N-Dimethyltryptamine (DMT) with the "orphan" (no known endogenous ligand) sigma-1 receptor.
The sigma-1 receptor was previously known to be a regulator of voltage-gated sodium, potassium, and calcium ion channels, found throughout the mammalian nervous system and periphery. While this receptor was linked with many binding partners (including cocaine, haloperidol, and fenpropimorph), its endogenous ligand was not known. DMT occurs naturally in lung and brain tissue, and had been found in human urine, blood, and cerebrospinal fluid. In some cultures, DMT is extracted from plants and used as a ceremonial hallucinogen, as in the South American sacramental tea, ayahuasca. Because it chemically resembles the known ligands of the sigma-1 receptor (they all contain an N,N-dimethylated amine) and occurs endogenously, Dr. Ruoho's group decided to investigate the binding of DMT with sigma-1 receptors.
To test DMT's affinity for the sigma-1 receptor, the researchers measured its ability to competitively bind the receptor when challenged with other sigma-1 ligands (cocaine and fenpropimorph). Rat liver homogenates containing sigma-1 receptor were allowed to bind DMT or a similar amine (tryptamine, N-methyltryptamine) before being exposed to radioactively labeled cocaine or fenpropimorph derivatives. By measuring the amount of radioactive ligand bound to the receptors after this experiment, the scientists were able to discern how well their pre-treatment with DMT and other amines had filled the receptors' binding sites. DMT was found to be the best inhibitor of cocaine and fenpropimorph binding in the rat liver homogenates, indicating that it binds strongly to sigma-1 receptors and does not allow binding of the radio-labeled drugs in this assay.
After proving that DMT and the sigma-1 receptor can bind together, Dr. Ruoho's group needed to show that DMT binding can affect the sigma-1 receptor's function as an ion channel regulator. To test this, they performed electrophyisology studies in cultured human embryonic kidney (HEK293) cells artificially expressing a cardiac voltage-gated sodium channel (hNav1.5), as well as COS-7 cells expressing the same channel, and mouse cardiac muscle cells (which contain this type of ion channel naturally). The cell culture experiments showed that in all cases, treatment with DMT decreases the activity of these ion channels, although the degree of inhibition varied between cell types (perhaps because the different cell types contain different levels of sigma-1 receptors). The mouse cardiac myocyte experiment was especially important, because it showed that normal mouse tissue responds to DMT treatment in a measurable way, indicating that further experiments in mice, including genetically modified animals, were possible.
Dr. Ruoho and his colleagues acquired a sigma-1 receptor knockout mouse for their next series of experiments. They repeated the cardiac myocyte test using tissue derived from their knockout animals and showed that while DMT decreases sodium channel current by about 29% in normal cells, the knockout cells' sodium current only decreased by about 7%. This provides further evidence that the sigma-1 receptor plays a crucial role in DMT's effect on ion channel regulation.
After completing this series of in vitro experiments, the researchers decided to test the effects of DMT in vivo. In mice, treatment with DMT and other sigma-1 receptor ligands induces hypermobility, especially if the animals are first given a monoamine oxidase inhibitor (MAOI; inhibits the naturally-occuring enzyme that breaks down DMT and other monoamines in the body). Dr. Ruoho and his team tested the behavioral effects of MAOI + DMT in wild-type and sigma-1 receptor knockout mice and found that only wild-type animals displayed characteristic hypermobility after treatment. They used methamphetamine as a positive control, showing that a drug that works through a non-sigma-1 receptor system could still induce hypermobility in the knockouts.
In their conclusions, the scientists state that "These studies thus suggest that this natural hallucinogen could exert its action by binding to sigma-1 receptors, which are abundant in the brain. 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. 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."
This study suggests that our bodies use low levels of a hallucinogenic compound to regulate normal physiological processes. I find this especially interesting, since DMT is classified as a Schedule I drug in the United States. This means that the government has decreed a naturally-occuring brain chemical to have "no currently accepted medical use" with "a lack of accepted safety for use of the drug under medical supervision." This classification implies that all of us are criminals for possessing this drug in our brains. If further studies indicate that DMT might have therapeutic promise for neurological or psychiatric diseases, one would hope that the DEA (and similar bodies around the world; DMT is a Class A drug in the UK and similarly prohibited in many other countries) would re-evaluate its status as a controlled substance. Given the way things have gone with acceptance of medicinal marijuana, though, I can't say I feel too hopeful.
Further discussion of this paper can be found at the Royal Society of Chemistry and at Psychedelic Research.
D. Fontanilla, M. Johannessen, A. R. Hajipour, N. V. Cozzi, M. B. Jackson, A. E. Ruoho (2009). The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science, 323 (5916), 934-937 DOI: 10.1126/science.1166127
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