No one knows how dimethyltryptamine causes its hallucinogenic effects. Dimethyltryptamine structurally resembles the tryptamine neurotransmitter serotonin. In fact, there is sufficient conformational resemblance between these two molecules that DMT can dock comfortably at serotonin receptors in the brain. Thus research to date has concentrated on serotonin receptors as the key to understanding DMT.

But a recent study by Dominique Fontanilla and her colleagues at the University of Wisconsin, published this month in the prestigious journal Science, may change the direction of that research.

The Sigma-1 Receptor

The sigma-1 receptor is widely distributed throughout the body, and is found in almost all mammalian cells, including the central and peripheral nervous system. Its function has remained unclear. Stimulating the sigma-1 receptor can increase muscle tension, heart rate, breathing rate, and the size of the pupils. Drugs with a high affinity for binding at the sigma-1 receptor include the synthetic compounds cocaine, heroin, dextromethorphan, fluvoxamine, haloperidol, methamphetamine, and PCP.

Sigma-1 has long been considered an orphan receptor, without a known endogenous neurotransmitter of its own. Given the nature of the exogenous compounds that bind to the receptor, researchers took to calling the unknown sigma-1 neurotransmitter endopsychosin or, sometimes, angeldustin.

At the same time, as we have discussed before, DMT is known to be present in human blood, urine, brain tissue, and cerebrospinal fluid, and no one knew what function this endogenous DMT might have. This latest research solves both puzzles. The mysterious endogenous ligand of the sigma-1 receptor is DMT.

Several lines of reasoning — biochemical, physiological, and behavioral — led the researchers to this conclusion. They first diagrammed the chemical structures of several of the drugs known to bind to the sigma-1 receptor, reduced them to their simplest forms, and then searched for possible endogenous molecules with the same structures. Because DMT resembles these exogenous ligands — they all contain an N,N-dimethylated amine — and DMT occurs endogenously, they considered DMT a plausible candidate. The researchers were then able to demonstrate that, in rat liver homogenates, DMT could in fact bind with sigma-1 so strongly that DMT, once bound to sigma-1, could not be displaced by other high-affinity molecules.

There is a strain of mutant mice bred by scientists without sigma-1 receptors, usually called sigma-1 receptor knockout mice. When DMT is injected into nonmutant mice, it causes increased motor activity or hypermobility; when the researchers injected DMT into mutant mice, without sigma-1 receptors, no hypermobility occurred. The researchers also compared the effect of DMT on heart muscle cells from nonmutant mice with those from the genetically engineered mice. The activity of voltage-gated sodium ion channels in the cells was inhibited where sigma-1 was present, but unaffected in its absence.

Ion channels are important in cell signaling processes. These results suggest that sigma-1 receptors function to regulate ion channels in cells, and that DMT in turn is an endogenous modulator of the sigma-1 receptor.

There is further evidence for this hypothesis. Sigma-1 receptors are found in the endoplasmic reticulum inside cells. The endoplasmic reticulum is responsible for the folding and transport of proteins, which are then either secreted from the cell or used in the cell membrane. These sigma-1 receptors have been shown to function as molecular chaperones for plasma membrane ion channels in the cell, helping them fold into their functional conformations, and preventing them from folding into inactive shapes. Thus, in addition to — or instead of — affecting sigma-1 receptor modulation of ion channels, the behavioral effect of DMT may be due to activation or inhibition of sigma-1 receptor chaperone activity.

“The finding that DMT and sigma-1 receptors act as a ligand-receptor pair,” the authors conclude, “provides a long-awaited connection that will enable researchers to elucidate the biological functions of both of these molecules.”

Most commentators on this finding emphasized its practical value in studying mental illness, and therefore — this was implicit — offering an opportunity for increased research funding. James Stone of the Institute of Psychiatry in London said, “This is a very important finding and will lead to more interest in the role of DMT and the sigma-1 receptor in mental illness. People did not know what the natural ligand of sigma-1 was, and this has led to a lot of blind alleys. So this is really big news.”

Radiochemist Erik Arstad, of University College London, who has worked on sigma-1 receptors, agrees that the finding is significant. “Given the potent hallucinogenic effects of DMT, its presence in the human body has so far been a mystery. The role of the sigma-1 receptor is also poorly understood, so the suggested link between endogenous DMT levels and modulation of the sigma-1 receptor is intriguing. The findings are likely to spur considerable interest in the sigma-1 receptor, as well as trace amines, particularly in relation to mental illnesses such as schizophrenia.”

So: do we know how DMT causes hallucinations? Not yet, says senior author Arnold Ruoho, chair of pharmacology at the UW-Madison School of Medicine and Public Health. “We have no idea at present,” he said in an interview, “if or how the sigma-1 receptor may be connected to hallucinogenic activity.”