The case for the negative
When Mikael Palner embarked on a series of experiments on rat brains last year, the question wasn’t so much whether he and his team would find N,N-dimethyltryptamine (DMT) – but where, and how much.
Since DMT is a tryptamine with similarities to serotonin (5-hydroxytryptamine), he decided to focus on serotonergic neurons. He expected to find measurable quantities of endogenous DMT, and/or meaningful storage of additional DMT his team exogenously administered to the subject rats before dispatching them for ex vivo examination.
“We did not find it, and we did not find any evidence for DMT being taken up in axons [by the serotonin transporter] or in serotonin vesicles [by the vesicular monoamine transporter],” Palner, who is an Associate Professor at the University of Southern Denmark, told Refractor over email.
The finding that DMT was “neither formed nor retained” in serotonin terminals in the rat brain came as a surprise, Palner said. DMT degrades rapidly, but by blocking its metabolization, he and his team expected to preserve detectable amounts.
The study, published in Neuropharmacology last month, concluded there was “scant evidence” for endogenous DMT in rat brains.
In defence of the affirmative
Palner’s findings appear to be at odds with a prominent 2019 study by Dean et al, which found that the rat brain “is capable of synthesizing and releasing DMT,” and showed that DMT was endogenously produced in several regions of the brain, including the visual cortex. This, the authors noted, raises “the possibility that this phenomenon may occur similarly in human brains.”
Steven Barker, a Professor Emeritus at Louisiana State University in the Department of Comparative Biomedical Sciences who co-authored the 2019 study, says he has some questions.
“While the data on the time course and distribution/elimination of DMT administration appear acceptable, the authors themselves admit several errors in their performance of their other experiments,” he said. “Most of their findings are in direct conflict with other studies that have been published regarding vesicular uptake and binding at uptake receptors.”
He also registered concerns about the study’s citations and how accurately others’ findings were represented. “The work of peer review of manuscripts is difficult but my opinion is that this manuscript required much more before being considered for publication,” Barker said.
DMT: The “Spirit Molecule”
The presence of endogenous DMT in the mammalian brain has long been hypothesised. Studies dating back decades show DMT can be detected in human and animal tissue, blood, urine and cerebrospinal fluid.
The powerful psychedelic is known for producing singularly intense experiences in users, including, but not limited to, the dissolution of space-time and the egoic self — and, not uncommonly, encounters with non-human entities including trickster “machine elves.”
The theory that DMT might be produced and/or stored in the pineal gland gained traction through the pioneering work of Rick Strassman, clinical associate professor of psychiatry at the University of New Mexico School of Medicine, and author of The Spirit Molecule.
The theory received a significant boost with the findings of the 2019 study (which Strassman also co-authored).
The 2019 study also found DMT levels were artificially spiked by inducing cardiac arrest — something which the authors said “may be related to near-death experiences.”
The debate is on
Palner says his findings don’t necessarily discount the pineal hypothesis. “Overall,” he asks us, “if DMT is not in serotonin neurons, then where is it, if it is there? I am not convinced that it is there and that it has any meaningful use. Certainly not in levels that can induce psychedelic effects [dream or near-death experiences], as much higher concentrations are needed for this.”
“While serotonin neurons were our best bet on where to look,” he continues, “the lack of DMT here is not proof that there [is] no DMT anywhere – just that it is not in the serotonin neurons or any of the brain regions we analyzed,” Palner said. “We did not look specifically in the pineal, so can’t rule this out. I guess there is still room for the hypothesis to live a bit longer.”
“Someone else really needs to try and replicate those results,” another researcher told Refractor on condition of anonymity. “Because, as Dr Palner demonstrates … there is no detectable DMT in whole-brain homogenates.”
The discrepancy could lie in the methodology, said the researcher: Palner’s study was conducted through ex vivo dissection, while the 2019 study was carried out in vivo through microdialysis, which involves inserting a minuscule probe into the rat’s brain, pumping fluids through it and analyzing what diffuses out. It could be that DMT might only be detected in specific regions of the brain where microdialysis tubes are inserted, such as the visual cortex (as in the 2019 study), and other cortical regions.
It could also be that DMT can only be detected in living animals, where samples are collected in real time, since DMT degrades quickly – however, they note Palner’s use of MAO inhibitors to block DMT degradation ought to have ruled this out.
Another possibility is that DMT could be produced in subject animals in response to the injury caused to their brain by the microdialysis procedure – since beyond its psychoactivity, DMT has neuroprotective and anti-inflammatory effects.
“Ex vivo is the only way to measure DMT [in the human brain], we can’t detect it in vivo directly,” Palner said. “But there are some limitations as well, the samples have to be handled correctly, kept on ice, and dissected quickly and without contamination from other sources.”
Barker says Palner’s conclusions stand at odds not only with the microdialysis findings of Dean et al from 2019, but results from two other laboratories which “showed that DMT in brain area perfusates was present at concentrations approaching or greater than the canonical neurotransmitters.”
Barker says that, in 50 years of analysis experience, he has learned that “developing and performing tissue isolation of endogenous DMT can be quite a challenge.”
“DMT is sensitive to light and air, it is very lipid soluble and difficult to isolate away from tissue lipids, it binds tenaciously to denatured proteins and to silicate surfaces,” he said. “I, too, have performed such negative analyses and have found that, for brain studies, perfusion techniques [such as microdialysis] are the only way to go if one wants to find DMT.”
Over the course of his five-decade career, Barker has seen massive advancements in the technology available to scientists studying this slippery molecule. For his dissertation on endogenous DMT, defended in 1978, Barker used thin layer chromatography and radiolabelled compounds to examine the metabolism of DMT in rat brain. Prior to retiring in 2016, he used advanced exact mass Fourier Transform mass spectrometry to detect picogram-level quantities of DMT and related compounds in brain tissue perfusates.
“From the earliest analytical technology of paper chromatography to the most advanced liquid chromatography high resolution mass spectrometry, our ability to detect and measure these compounds is exponentially improving,” he said.
Advances in analytical and imaging technologies … will, soon, allow us to track individual psychedelic drugs as they act in the brain.
“The advances in analytical and imaging technologies have greatly enhanced our understanding of psychedelic pharmacology and will, soon, allow us to track individual psychedelic drugs as they act in the brain,” he said. “This will advance our knowledge of diseases and disorders of the brain/mind, and enhance our understanding of perception and consciousness itself.”
The study of DMT and other hallucinogens in the United States was for decades impeded by the 1965 Congressional Amendment, and the Controlled Substances Act. These classified DMT as a Schedule-I substance, posing major challenges to researchers who wished to procure it for scientific study. Science is now playing catch-up, and psychedelics have become a major area of interest due to their therapeutic potential.
As for the future of DMT studies, Barker says there is “much left to do.”
He says there needs to be an examination of DMT levels in brain/CSF/blood over a 24-hour period, to determine if difficulties with observing DMT in body fluids are tied to circadian rhythm fluctuations. Its role in brain growth and repair, and possible links to sleep/wake cycles also need to be explored — something which could shed light on possible links to dream states.
“There are many clinical trials of psychedelics underway but new research into their therapeutic possibilities are seriously needed,” he said. “The answers we obtain from such research may inform many of our deepest questions about consciousness and the mind.”