Is There a Link Between Endogenous DMT and Schizophrenia?

Most of the “classic” psychedelics are naturally found only in a very limited number of plant or fungi species. N,N-dimethyltryptamine, more commonly known as DMT, however, is a notable exception: It’s been documented in dozens of plant species around the world, as well as some animal tissue — including, most famously, the human brain. 

DMT’s functional role in the brain, however, remains almost a total mystery. Despite some oft-repeated claims from psychedelic folklore, there’s no evidence that the compound plays any direct role in creating the dream state, or that the pineal gland releases a massive dose of it at the moment of death, eliciting some kind of mystical experience. But there’s likely some adaptive reason behind its presence in the brain; nature usually doesn’t add building blocks to such a vital organ unless it has a very good reason for doing so. Intriguingly, a 2019 paper showed that endogenous DMT levels in the brains of living rats were comparable to those of vital neurotransmitters, such as dopamine and serotonin, suggesting a critical neuromodulatory function that has yet to be teased out.

Now, a group of researchers from the nonprofit Noonautics and the University of Florida are hoping to uncover the mechanisms behind the production of endogenous DMT in the human brain, and harness them to initiate psychedelic experiences free of the messy red tape typically surrounding DMT and other tightly controlled drugs. The project also aims to identify a mysterious missing link between endogenous DMT and schizophrenia, which could in turn lead to the development of new and effective treatments for that disorder.

DMT and Schizophrenia

While scientists have long known that the human body can produce DMT, the underlying mechanisms remain unclear. One leading candidate is an enzyme called indolethylamine N-methyltransferase, or INMT, which can catalyze the biochemical process that can lead to the production of endogenous DMT. In healthy individuals, INMT is widely expressed throughout the body and may play a role in generating tightly regulated amounts of DMT. But exactly how, where, and to what extent this process occurs in the human brain remains an open question.

Nearly three-quarters of a century ago, the British psychologist Humphrey Osmond began to wonder: What happens if this engine goes haywire, and like a jammed gas pedal, produces too much endogenous DMT? And was it possible that schizophrenia, with its characteristic hallucinations, was caused by an aberrant chemical process in the brain that led to the creation of endogenous, hallucination-causing compounds? 

This was in the early 1950s, the earliest years of psychedelic research — the psychoactive properties of LSD had just been discovered less than a decade prior — and this class of compounds was then widely known as “psychotomimetics,” due to the widespread belief among experts that their subjective effects mirrored those of psychosis. (Osmond would later coin the term “psychedelic,” meaning “mind-manifesting,” and oversee research investigating the therapeutic potential of LSD for alcoholism.) It would be many years before scientists began to understand how they act in the brain; all psychiatrists like Osmond had to go on at the time was what seemed to be a direct link between the hallucinations experienced by people under the influence of psychedelics like LSD, DMT, and mescaline, and those caused by schizophrenia and other psychotic disorders.

Collaborating with the neuroscientist John Smythies, Osmond hypothesized that the schizophrenic brain was irregularly methylating (adding a methyl group to) neurochemicals like adrenaline and dopamine, producing a “schizotoxin” — an unidentified compound causing hallucinations and other sensory disturbances.

Later that decade, American biochemist and future Nobel laureate Julius Axelrod, while studying the enzymes behind the production of the amino acid tryptophan, found high concentrations of INMT in rabbit lungs. That discovery led biochemists to find the enzyme, along with DMT, in the blood, urine, and cerebrospinal fluid of human subjects. Crucially, DMT was found both in schizophrenia patients and also in human subjects who didn’t have the disease, suggesting that it wasn’t the supposed schizotoxin Osmond and Smythies had theorized. And with that, “research into DMT as a compound involved in schizophrenia just wilted on the vine,” neurochemist and pioneering DMT researcher Dr. Steven Barker told me. “But at the same time, it didn't really stimulate more research on what it’s doing there.”

To this day, the neurochemistry behind endogenous DMT is scientific terra incognita.

A “Mystery Peptide”

One major clue emerged in 1977, when scientists discovered what appeared to be a peptide — a short chain of amino acids that initiates a biological function — serving as a “possible inhibitory mechanism” that might be responsible for regulating INMT in rabbit brains.

Through his nonprofit’s research partnership with the University of Florida, Noonautics director and neuroscientist Andrew Gallimore hopes to identify that “mystery peptide,” as he describes it. “Once we uncover that mechanism, then there might be a number of ways that one could manipulate that system,” he told me. More specifically, Gallimore is interested in hacking the brain’s INMT system to naturally raise levels of DMT in the brain, thereby potentially enabling an extended DMT trip — one that’s completely noninvasive and which allows researchers to bypass the extensive regulatory red tape that surrounds psychedelic research in the U.S. and elsewhere around the world.

Target-Controlled Intravenous Infusion

The concept of Endo-DMTx builds upon Gallimore’s earlier work with the psychiatrist Rick Strassman, known for his landmark experiments administering intravenous DMT to humans in the 1990s, and subsequently recording their trip reports in his 2000 book DMT: The Spirit Molecule. 

In 2016, Gallimore and Strassman published a paper making the case that DMT, unlike other psychedelic compounds, was amenable to a medical technology called target-controlled intravenous infusion, which is used during surgery to maintain consistent levels of anesthetic drugs in the brain. For reasons that aren’t entirely clear, regular usage of DMT doesn’t result in the building of tolerance in the human body (though this may depend on the method of administration). If you take 100 micrograms of LSD two days in a row, the second experience will probably be more muted than the first. Not so with DMT. The latter is also unique among the psychedelics in that its onset and duration, at least when it’s smoked (or vaporized, technically), are both incredibly quick: just a few seconds and around fifteen minutes, respectively. Although volunteers in Strassman’s study often returned from the DMT state with vivid descriptions, they were — as is typical of the DMT experience — often too bewildered to make any real sense of what they’d just been through: a function both of the intensity and the brevity of the experience.

Gallimore and Strassman envisioned a technology, dubbed DMTx, which could modulate the injection of the drug into human subjects, adjusting drug levels in their brains over time and “potentially allowing more detailed analysis and even mapping of the DMT space’s structure and content, performing experiments, as well as establishing stable communication with the entities that reside within the space,” as Gallimore writes in his latest book, Death by Astonishment. (The title is a nod to the late Terence McKenna, who once used that phrase, probably only half-jokingly, to describe what he considered to be the only real danger of using DMT.)

Meanwhile, Gallimore and Strassman proposed, researchers would closely monitor subjects’ DMT levels from the outside, like NASA mission control keeping an eye on a spaceship’s telemetry as it observes the surface of an alien planet from orbit. “Such methods could be used to control the depth of the experience during a DMT session, moving the subject into more intense levels of DMT intoxication or lowering them back into more manageable levels to provide both respite and easier communication with the research team,” they wrote in their 2016 paper. 

This could also enable a more flexible means of psychedelic-assisted therapy, giving mental health professionals the ability to adjust DMT levels depending on which particular disorder they’re trying to address, or on the stage of treatment. “Using this model, patients could be ‘titrated’ for both the duration and intensity of the DMT state that was most useful for augmenting the psychotherapeutic process,” Gallimore and Strassman wrote. “For example, in the case of working through trauma, re-experiencing the feared stimulus in the altered state might be initiated with induction into a mildly altered state of relatively brief duration. In the course of treatment, a more prolonged and intense altered level of consciousness could be applied to a more extensive working through process, broadening and deepening the therapeutic gains begun with shorter and lighter exposures.”

“We Just Don’t Understand What Drives the Disease”

Both Noonautics and the University of Florida researchers behind Endo-DMTx want to identify the “mystery peptide” that seems to lie behind INMT and, thus, potentially develop a means of manipulating the human brain’s endogenous DMT system — albeit for different reasons.

While Gallimore is looking for a way to artificially ramp up natural DMT production in the brain, Christopher McCurdy, a medicinal chemist at the University of Florida, is returning to Osmond’s transmethylation hypothesis of schizophrenia: the theory that schizophrenia is a byproduct of an aberrant and intoxicating methylation process in the brain.

Like the role of endogenous DMT in animals, schizophrenia largely remains a scientific mystery, which has precluded the possibility of creating effective pharmacological interventions. “We just don’t understand what drives the disease,” McCurdy told me. “And so really trying to understand where [it] comes from is at the root of the question of how we develop better treatments.” Previous research has shown that INMT activity was higher in people with schizophrenia than in a control group without the disease, and that in the schizophrenic subjects, the enzyme’s activity correlated with the severity of symptoms. McCurdy now aims to identify the “mystery peptide” in order to artificially downregulate INMT in the brains of people with schizophrenia, which he says “would be a totally novel way of looking at treating” the disease.

As a first step, McCurdy and his team have set out to replicate the 1977 study that first identified the inhibitor peptide. They’ve already detected it in rabbit lungs, and the next step will be looking for it in human cerebrospinal fluid. If the peptide shows up, they’ll need to map out its constituent amino acids. It could turn out that the peptide is one already known to medical science, but McCurdy is hoping, as every scientist does, to discover something completely new: a previously unknown peptide that could lead to new treatment options for people with schizophrenia.

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