Endogenous DMT in the Mammalian Brain | Nicolas Glynos | #142

About the Guest: Nicolas Glynos, PhD received his doctorate in Molecular & Integrative Physiology from the University of Michigan, where he studied the psychedelic drug DMT in the mammalian brain.

Episode Summary: Nick and Dr. Glynos discuss: the history of DMT research; the use of DMT in ayahuasca; whether DMT is found endogenously in animals; why plants produce DMT; pineal gland, DMT & melatonin; the latest research looking at the presence and effects of DMT in the brain; and more.

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* Episode transcript below.

Full AI-generated transcript below. Beware of typos & mistranslations!

Nicolas Glynos 4:33

Hmm, yeah, so I finished a PhD in Molecular and integrative physiology at University of Michigan last May, so almost a year ago now. And my PhD work was focused on DMT. Primarily, we looked at endogenous DMT and how its regulated in different functions of endogenous DMT. And then we also explored some different aspects of exile. Initially administered DMT in a rodent model. I also contributed a lot to psychedelic education and activism at Michigan during my PhD and published some papers on naturalistic psychedelic use and looking at interactions with healthcare providers and changes in outcomes reported by people using psychedelics naturalistically. And currently in a postdoctoral role, also at the University of Michigan, and in the chronic pain and fatigue Research Center. And there we have a group that's working on various Psychedelic Studies, and we're currently running a clinical trial with psilocybin treating patients with fibromyalgia, if.

Nick Jikomes 5:46

Interesting. So. Yeah, I read some of your work looking at DMT, endogenous DMT and the effects of exogenous DMT, and rodents, which is very interesting. Can I just want to give people a little bit of a background in terms of what DMT is and what was known about it before getting into your work? So can you give people like a cliff notes on like, what is DMT? Chemically? How is it different from other psychedelics?

Nicolas Glynos 6:15

Yeah, I think DMT is the most interesting psychedelic, and that was my passion when I came into graduate school was to get involved in DMT research. It's a pretty simple molecule. It's structurally similar to the neurotransmitter serotonin. It's also structurally similar to other psychedelics like psilocybin. And it's, it's a tryptamine and that's the chemical class that it belongs to. And it's, it's dime, it's got two methyl groups attached to the to the Amino part of the tryptamine making it Dimethyltryptamine. And it's got it's got an interesting history and actually a pretty long history in terms of terms of relative to other psychedelics. It's an active component in the hallucinogenic brew ayahuasca, which has been used across South America in various indigenous cultures for at least 1000 years. And I Alaska is a very important ceremonial and medicinal brew that's been that's been consumed widely across across South America. And DMT was brought into sort of Western science in the early 1900s. It was discovered in 1931 by a chemist named Richard Mansky, and he discovered it and it was kind of set aside before it was investigated any further. And it wasn't until I think it was 1955. Steven Psara chemist in Eastern Europe, was interested in reports of ethnographers that were studying plant based hallucinogens in South America, and they were bringing plants back and they were curious what the active compounds in the plants were that were causing these hallucinations and these psychedelic experiences, and it was found that DMT was a high a candidate for for that molecule to be the the psychoactive compound. So he administered or began the first clinical trial or the first western science research trial with DMT. And he administered it intramuscularly, first to himself and then to participants, and found that it was indeed, hallucinogenic and psychedelic

Nick Jikomes 8:30

himself with what's app, how much did he give himself?

Nicolas Glynos 8:33

I don't remember the dose exactly, but but I'm sure there was quite a bit of trial and error, because I think, you know, obviously, you would probably try an oral administration first. And I believe he did that and found that DMT wasn't orally active, and then had to go the intramuscular route to to to get the to get the effects. So that kind of brought some interest into this molecule into this compound, as a psychedelic compound. And this was also kind of occurring around the time when LSD was was being investigated in a research context, and in a clinical context, and also around the time of the discovery of serotonin as a naturally occurring endogenous compound that has has effects on mental states and mood and various other physiological and neurobiological functions. So, this, this idea of, I guess, further on that, it was also soon discovered that DMT was a naturally occurring endogenous compounds. So it was, it was found in first it was found in rodents, and then it was found to be detected and, and human bodily fluids and cerebrospinal fluid and blood and plasma.

Nick Jikomes 9:46

And when we say so, when we say it was detected, it was found to be an endogenous compound. What exactly does that mean? So I know that it means it's found in the body, but I want to make a distinction here. Between, was it? Did they figure out that it was produced in the body and doing something serving a biological function? Or was it detected at the body in very low levels, and may just have been some kind of metabolic brought byproduct? And how do we actually decide which one?

Nicolas Glynos 10:17

Yeah, that's a good point. So I think the latter is the correct so it was detected in, in human bodily fluids, blood, urine, cerebral spinal fluid, at very low levels, which are in current understanding, those levels are not recognized to be physiologically significant. So even today, after having known that DMT occurs in the body, naturally, we've known this for all 75 years, we still don't know the function of DMT. And it very much could be, like you said, a metabolic byproduct or an inactive metabolite. But there's still reason to investigate it for for reasons that it's a naturally occurring compound, and it likely does have some function, it's, it would be really surprising

Nick Jikomes 11:06

when they found it in animal tissues, did they find it at higher levels back in, like the mid 20th century?

Nicolas Glynos 11:12

Um, no, not so much. Not, there wasn't really any comparative studies to show that DMT was found at levels comparable to other, you know, active metabolites or active neurotransmitters or signaling molecules, most of the early work was actually done indirectly. So what they would do is try to try to discover or understand the biosynthetic pathway of DMT. And they would do that by taking enzyme extracts or tissue extracts and incubating them with precursor molecules like tryptamine, and then finding out whether that tryptamine can be methylated to form and methyl tryptamine, and then Dimethyltryptamine. And that's sort of an indirect measure of determining whether, you know, DMT, could be active or could be present in the body, and in the mammalian body.

Nick Jikomes 12:00

I see. So DMT is a tryptamine, which means it's probably ultimately produced from tryptophan in the body. It's similar chemically to serotonin. It's similar to other psychedelics like psilocybin and psilocin. It was, you know, it was discovered, you know, decades and decades ago, now, they, they knew it was there, they could detect tiny amounts in cerebrospinal fluid and humans, they could detect small amounts in other animal tissues. At that time, it wasn't known if the DMT was produced in order to do something important in animal tissues, or it was just sort of a byproduct, and we're just sort of detecting this inactive metabolite. When do people start figuring out that this is the component of ayahuasca and that, that this is, you know, the spirit molecules, Rick Strassman called it

Nicolas Glynos 12:52

those are sort of sort of two separate events. And when it was discovered that DMT was a component of ayahuasca, I think around the mid 20th century, so around around the 1950s or so. And that was a like I said, the result of ethno botanist and ethnographers who were studying indigenous cultures in the Amazon, and in South America, bringing back plant samples or bringing back samples of Ayahuasca or participating in Ayahuasca ceremonies, and then bringing those samples back and then using Western scientific methods to discover that that DMT was the active component. Interesting, no, that's also it's just such a cool story that the Ayahuasca story, the fact that not just one indigenous culture, but you know, dozens of indigenous cultures across many different countries across South America, independently made this discovery of the combination of different plant admixtures that can result in the hallucinogenic effects of ayahuasca. And it's not just a hallucinogenic brew, it's a really important ceremonial and medicinal concoction that's, that's widely used across many different cultures. And these two plants, it's a multiple plants that are used, but there's sort of two that are particularly important for Ayahuasca. And these plants, these combination of these plants was found amongst some of the greatest botanical diversity in the world, you know, there's 30,000 species of vascular plants in the in the Amazon. And the fact that these indigenous cultures have made this chemical discovery is kind of a feat of, of science, that's not really explainable.

Nick Jikomes 14:30

Interesting. Yeah. Because you know, if you think another way of saying what you just said is, so there are many different cultures in Central and South America, that are combining plants in a way that results in Iowa Tosca experience, so they're the combining ultimately DMT with the MAOIs that enable it to be orally active. So there's a couple of interesting things I want to ask you about here. So what do we know that they all independently discovered this or is it possible that the Ayahuasca brew was discovered a long time ago? Oh, and sort of as people spread throughout central South America, they all inherited this culturally? Or is there clear evidence that, you know, these, these cultures were in complete isolation? And they totally independently discovered this?

Nicolas Glynos 15:15

Yeah, it's a really good point, I sort of leaned toward the ladder, that it was an independent discovery. But, and I sort of I sort of hypothesize that because of the geographical separation of the groups that discovered it, and the wide geographical range of discovery. But But you're right, there could have been some some knowledge and information passed, passed among groups. So that's, that's a good point. Okay, so

Nick Jikomes 15:39

it's used in multiple cultures? That I mean, presumably, right? There's many cultural sort of in between them that don't use it. So it either had to have been lost many times or where it was independently discovered. But I think what you're saying is, this is super fascinating. How is it that people living in the jungle that don't have chemistry labs and things like this? How do they figure this out? Because there's literally like millions of plants in the Amazon jungle, if you were to just randomly start sampling them and mixing them together at random, you would probably never happen upon the exact right combinations. And yet, if multiple cultures are using this, the question is really by what method? Did they make this discovery? Is there any? Is there any information there? Like, if I have people ask them? How did you how did you guys discover this?

Nicolas Glynos 16:32

Yeah, it's pretty simple. They, they speak to the plants? That's, that's the answer you get, or that's the answer I've heard. There's, there's, there's a communication with, with nature in a way that is not accessible, or reasonable or normal for us, for maybe us in modern scientific labs, like, like, as you said, and, you know, there's, I'm not sure if you've read much into the ethnobotany of this, but or if your listeners have, but there's, you know, Richard Evan Shelties, was kind of the father of ethnobotany. And he talks about how this is one of the greatest mysteries of ethnobotany how this discovery was made. amongst some of the greatest botanical diversity in the world, and one of his students, Wade Davis was a person who kind of carried on that legacy of Shelties. And, and, and Wade Davis has written a few books that are just fascinating. And I'd recommend others to check out some of his work. And he is an anthropologist who studied a number of different different cultures across the world. And one of his one of his take homes that I've received from his work is, there's just many different ways of knowing there's many different ways of accessing knowledge and accessing information. And he talks about, you know, Polynesians, who were able to, you know, navigate by the stars, and by measuring the size of the waves, or the pattern of the pattern of the ocean, in ways that it's just unfathomable to, to sort of modern seafarers, I suppose, and many, many different other observations of accessing knowledge, via ways that are sort of difficult for us to understand. So so that's sort of my hypothesis with these indigenous cultures, and South America, they may have some relationship with with nature, that is sort of beyond beyond our capacity to understand. And that may have allowed them to make make this make this discovery. But that's about all I can all I can say about that.

Nick Jikomes 18:45

And so we find, obviously, DMT is found in certain plants. Psychotria Viridis, is the one that you often hear about how common is DMT? In the plant world? Because I know it's not found in just one plant, it's found in a number of them, how common is it? And do we know anything about why the plants are producing it?

Nicolas Glynos 19:06

Yeah, I think that would be such a cool study to do is to do a really thorough investigation of maybe maybe not even just individual plants, but like, large families of plants, and let's find out how many of them actually do contain DMT. Because the general notion is that people say that DMT is and everything they say that, you know, I've heard Dennis McKenna say this, it's kind of like ubiquitous, you find it you find it everywhere. And from from my reading, in my understanding, it's I generally say it's, it's found in hundreds if not 1000s of species of plants. I think there's there's research just to say it's, it's in the hundreds of plants range. But there hasn't been a thorough investigation to actually document how many plants are actually producing it. And, you know, other details about about why or where those plants are producing,

Nick Jikomes 19:52

you know, I mean, the default for me when I think about these things is in the cases where we sort of do know why a plant is producing some thing that is psychoactive and the human being more often than not, it's it's a defensive function. So you know, everything from nicotine to caffeine are produced in parts of the plants as insecticides. And these things are typically, you know, very bitter tasting alkaloids or similar compounds. And they do something like that they dissuade herbivores from eating the plant, or they literally kill insects.

Nicolas Glynos 20:23

Right, yeah, defense protection defense mechanism is a pretty pretty valid hypothesis, I would say. And I think that's, that's even come up with psilocybin and different fungi, you know, why to fungi, pretty psilocybin, likely a defense mechanism. Another interesting thing about about DMT and plants is that it's, it's, it's a metabolite of one of the most important and widely functional hormones in plants, and that's oxygen or indole, acetic acid, and indole acetic acid in plants is is kind of like serotonin in mammals, it does everything. You know, it's like it's involved in every process. And it's, it's very, it's very important. And DMT is a primary metabolite of that. So that suggests that it's likely it's likely found in and most, if not all, plant species.

Nick Jikomes 21:11

Interesting. Yeah, that's, I didn't know that. That's, that's fascinating. So it's in plants. It's an animal's at least in trace quantities, before we get to your work where, you know, we're going to be going into the mammalian brain and talking about endogenous DMT. There. Was it found at sea, you know, what we would think of as significant or potentially, you know, biologically functional levels, in any animal tissue in historical research?

Nicolas Glynos 21:38

Historical Research, I guess it depends on how you define that.

Nick Jikomes 21:41

Anything, anything before your stuff?

Nicolas Glynos 21:45

Yeah, there was at least one paper that showed that DMT was present in the rodent brain at concentrations that are pretty close to serotonin and dopamine. Yeah. And that paper was done in the in the lab that I worked in, it was published right before I joined the lab.

Nick Jikomes 22:00

Got it. Okay. Oh, I didn't actually know it was the same lab. Okay, so, yeah, I want to talk about that study. Actually, maybe before we do that, why don't we? Why don't we go back to the early 90s. So at this point, you know, we know what DMT is, we know it's found in plants. It's found in animals. We know it's part of the Ayahuasca brew that can be rendered orally active, we know that it can be injected, and you can hallucinate on it. Terence McKenna has been, you know, ranting and raving for a while by this time, so we know that you can smoke it, and that it has very potent hallucinatory effects. When did Rick Strassman start researching it? And can you summarize that body of work for people?

Nicolas Glynos 22:42

Yeah, there's, there's a little bit we skip to that I think is important to touch on the leading up to Strassman to work. So so after, after it was discovered that DNP was an endogenous compound and, and human bodily fluids, and Steven Psara started administering it to himself and others intramuscularly showing that had hallucinogenic effects. This theory arose that perhaps, if DMT is endogenous, and it causes hallucinations, perhaps it's causing psychotic disorders or schizophrenic type type hallucinations. And it was actually labeled as a schizoid toxin. So that was a hypothesis that was investigated pretty extensively between I'd say about 1960, and leading up to Strassman work in the in the late 80s, early 90s. And Steven Barker, who's kind of one of the godfathers of DMT research, published a really nice review on that. And he looked at all of the studies, and I think it's about 65 studies that had confirmed DMT and bodily fluids in humans, and looking at a comparison of psychotic versus non psychotic patients, and whether there's any kind of correlations or relationships between DMT levels and occurrences of schizophrenic type type symptoms. And it's largely come to the conclusion that there's that there's not a correlation there. But there's no, there's no evidence to support that endogenous DMT is contributing to the symptoms of schizophrenia or psychotic conditions. But it's still the hypothesis is not put to bed. In my mind, there's still there's a lot we don't know, in terms of how DMT is regulated or stored or packaged or function in different bodily tissues. So so there's still, I think, a reason to investigate that.

Nick Jikomes 24:30

But I guess the idea there was was, and there was there's a lot of this floating around in the mid 20th century, right, like in the early days of LSD research, that you know, something like schizophrenia might be explained by a molecule. For some reason the body produces something, maybe it's LSD, maybe it's DMT. Maybe it's who knows what, and this is causing the psychotic symptoms that you see in things like schizophrenia. So I guess the idea was, if that's true, if a schizophrenic is a schizophrenic because his body starts producing a bunch of DMT you would then be able to detect higher low was of DMT in something like the cerebral spinal fluid, and you're saying that people sort of checked the data there. And there wasn't obviously relationship.

Nicolas Glynos 25:09

Right? Yeah, exactly. And I think you maybe alluded to this, but it's, to me, the hypothesis comes off as a bit reductionist, you know, to, for us to come and say that this really complex psychotic disorder, this, you know, that causes hallucinations and paranoia and all sorts of different things. Is, is, you know, one month one molecule was responsible for that it's, it's a little bit reductionist, in my mind to take that stance. But, but it's not to say that that DMT or other endogenous psychoactive compounds, might be contributing to some of the symptoms like there could be a role for DMT. There. And you're right, that it has been sort of checked off of like, yet, we don't think that, that there's a correlation between DMT levels and, and psychotic symptoms. But there's baganda, there's a lot we don't know about the regulation of endogenous DMT to

Nick Jikomes 26:01

Yeah, I mean, yeah, it's perfectly conceivable that, you know, something could be synthesized, released, doing stuff that's interesting. And by the time you can detect it all the way down, you know, from the fluid you get in the spinal tap may not look different, even though it was at some intervening step in the process. Right. But anyways, okay, so anyways, there's DMT inside of us, we don't know what it's doing, we can detect it at small levels, sort of what happens next in the history of the research?

Nicolas Glynos 26:28

Yeah, thanks for summarizing all these parts as we go along. It's helpful to Yeah, so So we've got this, it's the transmit methylation hypothesis to is what we just we just summarize there. So now we've got this trans methylation hypothesis that's floating around, and some people are still interested in it. And we still still want to investigate, investigate that. And Rick Strassman comes around. And I actually, I think the story is already been told I listen to the Dave Nichols episode, and he was talking about when him and Dr. Strassman were esalaam, I think, and they had talked about, you know, initiating these DMT studies. So I think I think a lot of that did fuel statesman's interests, the transmission methylation hypothesis, this idea that we have this endogenous psychedelic compound in our bodies, and we want to know what it does. We're curious about that. That's just an interesting question. And also that it may have some sort of therapeutic benefit as well. So I think that that was that fueled some of the interest. And those guys got got a study started at the University of New Mexico, and that, and that study, they administered intravenous DMT, at a few different doses, and then just really do like kind of a basic physiological and subjective assessment. So this was actually the kind of the first, maybe not the first, but one of the first clinical trials in the modern psychedelic age, that kind of kick started the psychedelic Renaissance, it's been credited with being one of the one of the trials that that started modern psychedelic research. And through that book, or through that work, Dr. Strassman, published the DMT, the spirit molecule, and which is a documentary, you know, and a book of the same name. And he put forth a few somewhat provocative hypotheses, relating the occurrence of endogenous DMT to different processes of dying or near death experiences. And that was, yeah, I think that was kind of kind of the essence of some of that work, without going into the details too much.

Nick Jikomes 28:37

And can you give people just a sense for, you know, the time course of the effects, the nature of the hallucinations? Anything else that we know about the fit? That's just the raw physiological effects? You know, what's it doing to your heartbeat? Is there any evidence of toxicity or anything like that?

Nicolas Glynos 28:55

Yeah, so the effects are very, very short lived relative to most other psychedelics. Generally DMT, when used recreationally, it's it's vaporized and inhaled. And in the Strassman study, it was injected intravenously. And, and both of those routes of administration the effects typically last approximately 10 Minutes or Less peak effects, potentially five minutes or less. And then usually within about 15 minutes total, the effects are completely unnoticeable. So it's a very rapid acting, psychedelic and very powerful in terms of subjective effects. So users often report being sort of transported into an alternate dimension or reality, going through some sort of breaking through some sort of Portal or some sort of barrier into an alternate dimension and coupled with you know, kaleidoscopic visual effects, closed eye hallucinations, sometimes interaction As with different entities, or alien life type life forms, or maybe even, like ancestor type type forms. And then sort of returning back to back to reality after this extreme feeling of like disembodiment and being separated from your physical body, and then returning back to reality, and having the effects be almost completely subsided within, like I said, about 15 minutes. physiological effects, it's not toxic, there's no, there's hasn't been any toxicity associated with it, you know, increased increased heart rate and increased blood pressure kind of expected effects from from the from the drug.

Nick Jikomes 30:47

And it gets Yeah, in terms of the hallucinations and the subjective effects. They are both very intense, they're completely immersive as long as you take enough, you know, like you said, people report, it's as if you know, the entire world is replaced, and you're going into a different reality. So that super intense effects, they're also short lived. Do we know why these two things are true? Why is it that the effects are so short? And why is it they seem to be so intense? Does it have something to do with interacting with specific receptors in the brain beyond the classic psychedelic receptor? Does it have to do with the drug being metabolized super quickly, what explains these features?

Nicolas Glynos 31:25

I think it's, it's a couple of things. And one important thing is is the route of administration, because it's either smoked or injected intravenously. I think if you look at some of the older Saudis, when they injected psilocybin, intravenously, you also see very short effects, or shortened effects compared to the oral administration of psilocybin. And that's just because it gets absorbed super quickly through the intravenous administration, and then therefore, can get cleared quickly as well. So that causes a very rapid onset and then a short short duration. And also, the DMT is also very rapidly metabolized by monoamine oxidase is which are present widespread throughout the body. So the combination of the rods administration and rapid metabolism, I think results in the in the fast onset and the short duration. And

Nick Jikomes 32:16

so the serotonin to a receptor is the one people normally talk about when they talk about psychedelics. This is the the receptor that is necessary for the effects of most classic psychedelics, if you prevent DMT, or psilocybin or LSD from interacting with the serotonin to a receptor, most if not all, the psychedelic effects go away. However, most of the classic psychedelics are not just interacting with that receptor there and they're each interacting with a sort of a different pattern of receptors to different extents each for DMT. Beyond the five HTT to a receptor, is it interacting with other receptors? And is there anything interesting that we've learned there?

Nicolas Glynos 32:58

Yeah, so the effects of DMT are, have so far thus far been shown largely dependent on to a receptor activation, but there haven't hasn't been quite as extensive of a body of research on DMT in that regard, relative to you know, psilocybin or LSD in terms of two way activation. But it's there's a paper with two a knockout mice. And when you administer DMT, to the knockout to a knockout mice, the head Twitch responses is abolished. Head Twitch response is a kind of a behavioral proxy and rodent models for psychedelic effects. So the two way receptor is definitely important for for DMT as well. It also interacts with a number of other serotonin receptors, I think there's maybe about a dozen other serotonin receptors that DMT does interact with, again, not much is known there. There hasn't been much investigation into that. A couple other receptor groups of interest are the trace amine associated receptors or tars. Those are much less well investigated. And with respect to serotonin receptor, so we don't really even know as much about tars as we do about the serotonin receptor complex. And then finally, the, the sigma one receptors are also really important for DMT pharmacology, and those have received a little bit more attention. There's a group led by I think, and fresca in in Europe. And they've done quite a bit of work on looking at the effects of DMT on protection from hypoxia and immunological function and different and different things with respect to the sigma one receptor. So showing that the sigma one receptor is is an important component and mediating these effects when activated by by DMT.

Nick Jikomes 34:56

What's known generally about the sigma one receptor

Nicolas Glynos 35:03

You know, I don't have I don't have quite the knowledge to Yeah. To, to go into that. Got

Nick Jikomes 35:09

it. But when you said it, you said protection from hypoxia. So what was that referring to? Yeah,

Nicolas Glynos 35:15

that was that was a pretty interesting study by, by that group I mentioned. And what they did is they took they took cells and this was a in vitro experiments cells in a dish and expose them to hypoxic conditions. So reduced oxygen concentration, and supplemented the supplement of the cells with various different compounds, and one of them was was DMT. And what they found was, with increasing concentrations of DMT, they found increased cell survival. So, the DMT appeared to be hypoxia protective for the cells that were under reduced oxygen conditions. Okay, they showed you that that activity was dependent on the sigma one receptor activation.

Nick Jikomes 36:01

Got it. So hypoxia reduced oxygen, bad for cells, if you give the empty it protects the cells in those and this is on a petri dish, just just to reiterate for people not in a live animal, the cells survive more if you give them DMT. And it seems to be protecting them from some of the hypoxia that would otherwise kill them. And whatever is going on there is requires the sickness thing called the sigma one receptor. So that brings us to some other studies. Because you could look at data like that. And you might think, Ah, well, maybe if this molecule DMT is preventing cells from damage or death from hypoxia, maybe cells in the body, maybe even neurons store some DMT. And when hypoxic conditions arise, the DMT is released. And it's it's a protection mechanism for the cells so that they don't get killed or damaged in a low oxygen environment. When do you have low oxygen environment? Well, I mean, if you're having if you're dying, basically, maybe you're having trouble breathing, or something's happening to you. And I know that this is, you know, as far as I can tell, this is sort of been Rick Strassman idea for a while, perhaps the near death experience that we have often heard about. Perhaps DMT is responsible for this, perhaps the body's detecting something like low oxygen conditions, and DMT can be released under those types of conditions. So you said I guess I think you said earlier, this was actually in your lab that you did your PhD in where this this next study done a few years ago happen? So So what did they do there?

Nicolas Glynos 37:38

Yeah, there's a couple of studies we can we can mention here. And I'll just say that that's that's one of the I think the most intriguing hypotheses about endogenous DMT is that it plays some hypoxia protective role. And then perhaps as, as a byproduct, you get psychedelic effects. It could just be, you know, protecting the body from low oxygen. So I think that's definitely an interesting hypothesis worth investigating. But the study, I think, I think, that I think you're alluding to was published by John Dean, who worked in the lab and GMO origins lab where I started my PhD, he kind of finished up as I was, as I was just starting, and that paper got published right when I started. And what they did was implanted this horizontal micro dialysis probe across the occipital cortex of rats. So this is, this is much larger than a traditional micro dialysis sampling setup that you would see in most rodent studies. Most rodent studies have sort of a single probe that goes kind of vertically into the brain, and you're only sampling about like one or two millimeters of tissue, this horizontal probe actually transverse the entire occipital cortex. And I'll just mention here, and we can talk about it later. But they also took out the pineal gland of, of rats to and measured, measured DMT with and without the pineal gland. Can

Nick Jikomes 38:54

you explain that part? Like why they would have done that to begin with? Right?

Nicolas Glynos 38:58

So it's, it's, it's for a while, it's been assumed that the pineal gland is? Well, it's been hypothesized that the hypo the pineal gland might be responsible for, for DMT production. And it kind of goes it goes kind of way back to to Descartes who thought that the pineal gland was kind of the seat of the soul. And it's this interesting, it's this interesting part of the brain that there's, you know, most most brain structures have have two sides, it's two sided, but the pineal gland is just a single gland in the center of the brain. And it's, it's, it's very unique in that sense, and it plays a big role in regulating circadian circadian sleep cycles and producing melatonin. And melatonin is actually structurally quite similar to DMT. And it's got enzymes in the pineal gland contains enzymes necessary for the biosynthesis of DMT. So it had long been hypothesized that you know, Maybe the pineal gland is kind of the the central central hub of DMT production.

Nick Jikomes 40:04

Interesting. So the pineal glands in the center of the brain, I believe, I believe it's known to be the exclusive source of melatonin in the brain. Melatonin is very similar structurally to DMT. And I think you've said that the pineal gland has the enzymes that we know would be needed to make DMT. So apart from detecting DMT, there directly, all of the pieces for DMT production seem to be in that part of the brain.

Nicolas Glynos 40:27

Right? Yeah. Yeah, and the enzymes, all this many things, we can maybe talk about them later, our ADC, which is aromatic amino acid decarboxylase, that turns tryptophan into tryptamine. And then the other enzyme that's thought to be responsible for DMT production is ion Mt. And that's in the methyl amine and methyl transferase. And that turns tryptamine, into Dimethyltryptamine. So it methylated. And we can talk a bit about that too, because I have some other work that I've done to discuss that. But just to all that to say that in the study by by John Dean and 2019, they tested tested levels of DMT in the pineal intact, and then tiny, electrolyzed rats. And interesting thing is that they found that there was no difference in DMT levels between between these two groups, suggesting that the pineal gland is in fact not necessary for endogenous DMT production in the brain.

Nick Jikomes 41:22

And that's, that's DMT levels in the occipital cortex of the brain. Right.

Nicolas Glynos 41:29

So this, the pineal gland sits in the just above the occipital cortex. So this Trent, this microdialysis probe, went right through the occipital cortex and went through the pineal gland, and transverse that that whole area horizontally, and

Nick Jikomes 41:44

was that study when they're detecting DMT there with or without the pineal gland? Or is it just animals under baseline conditions that are awake? Are they asleep? Are they anesthetized? What's what are the conditions there?

Nicolas Glynos 41:57

Yeah, just just baseline conditions. Yeah, it's a pretty cool setup, where it's just an automated system, the animals are connected to the micro dialysis probes, and it feeds automatically into an HPLC, which measures the levels of DMT. And, and they were I think they were measuring measuring rats for like days at a time it they just kind of had this automated system, and it would inject into the HPLC, measure it and continue collecting, so just baseline conditions,

Nick Jikomes 42:22

and were these you know, teeny tiny levels of DMT. Or were they levels comparable to other neurotransmitters and things in the brain that we know are doing stuff

Nicolas Glynos 42:31

comparable to other levels of neurotransmitters? Yeah, this study in particular didn't actually measure the levels of serotonin or dopamine or norepinephrine or anything like that. But if you cite other research or reference other research, you'll see that the levels were were within that range, and it's in I think it's about one one to two and animal or is about the average levels that they were detecting

Nick Jikomes 42:52

it. So they detected DMT, did they do any control measurements of other endogenous compounds at all?

Nicolas Glynos 42:59

No, not that I know about to check, but I don't think they might have actually measured. Now, you know, I'm not sure.

Nick Jikomes 43:08

Yeah. Interesting. Okay. Yeah. I'll have to go back and look at that when you really want to take a look. Yeah, yeah. And then what was the other big experiment there? I believe in this one, they were basically looking at animals that were had experimentally induced cardiac arrest.

Nicolas Glynos 43:23

Right. That's kind of how we got onto all this. Yeah. So we talked about this kind of near death connection, or this dying connection to DMT. And this hypothesis that DMT might be hypoxia protective, might be released under low oxygen conditions. So they said they said to test that, and with these microdialysis probes implanted in the occipital cortex, they subjected the rats to experimental cardiac arrest, which is co2 induction. So putting co2 into the air and eliminating oxygen. And what they found there was, I think it was a about a six fold increase and DMT levels following the cardiac arrest event and in rats, and it was a significant increase statistically. So that suggests that there's suggest that DMT is responding. It's there's a physiological response that's causing DMT to increase, albeit a very intense physiological response. You know, cardiac arrest is a very stressful and intense event. But it does suggest that there's some physiologically mediated release of DMT, which is one important, which is one important component. If you were setting out to characterize DMT as a neurotransmitter or as a signaling molecule, you would want to you would want to show physiologically dependent release or activation. Yes,

Nick Jikomes 44:44

I think is an important distinction there is, you know, one of the criticisms of that work would be that this is a very intense stimulus, you're inducing cardiac arrest. And there's a difference between the regulated release say of a neurotransmitter through you know, an SNL seem dependent excitation mechanism like, you know, a normal neurotransmitter that's packaged in a vesicle sitting there, it's waiting for an action potential and it goes out like a very regulated process versus something like this, which could be, it could just be that you're basically killing the animal. Everything is getting dumped out all at once. Which would be a different thing. Right?

Nicolas Glynos 45:22

Yeah. Which, which is actually I think, which is true because the lab, GMOs lab, the lab that I'm discussing the word that published his work, did that study, and they measured a number of other neurotransmitters following cardiac arrest, you know, glutamate, GABA, serotonin, dopamine, norepinephrine, all those things, and, and they all they all spike massively after cardiac arrest. So there's, this is a, like I said, a very stressful, intense physiological event, and likely, the brain is going into some sort of protection mode, and everything is getting dumped down. Okay,

Nick Jikomes 45:56

so we know that the DMT is there, it's there. Before that happens, it goes up after that happens along with everything else going up. So we at least know that there's some amount of DMT there that, you know, we don't I don't think we know where it is, right? We don't know if it's in vesicles, or it's packaged somewhere else. But it does seem to be there.

Nicolas Glynos 46:12

Right. But I'll also say another limitation of this study is that the sampling time is 12 and a half minutes, so we're collecting a sample every 12 and a half minutes. And if you're thinking about an intense cardiac arrest event, it's probably going to happen on the scale of seconds or less, if we're grouping all that into a call and a half minute sample, then are likely missing a lot of the important nuance of that, of that process.

Nick Jikomes 46:38

So based on that evidence, would you say it shows that there is endogenous DMT in the brain under baseline conditions? Or would you like, like, what are the conclusions you would actually draw from that study that you think are rock solid?

Nicolas Glynos 46:53

I think that's the main conclusion. Yeah. And that was, that was actually the first study to show that DMT is present in the in the living rodent brain, freely behaving rodent brain, a lot of the older studies that have showed DMT in the brain, it's like post mortem tissues. So which, you know, it's still valid. But this is sort of showing that a DMT is, is present in the in the freely behaving rodent brain. So I think that's probably the the most solid takeaway from that study.

Nick Jikomes 47:25

And so I guess the a question at this point is, is, is the DMT there? Because it's only to protect the brain from hypoxia or something like that, under special conditions? Is it some kind of, you know, stress protection type molecule? Or, you know, the more provocative the more interesting hypothesis would be? No, it's actually used as something like a neurotransmitter. And so, you know, unpack that for us, like, what, what the thinking, is there, what the hypotheses were, and how that feeds into the work that you did?

Nicolas Glynos 47:55

Yeah, so I think I think it would need a lot more evidence to be characterized as a neurotransmitter. The hypoxia hypothesis is a very interesting one. And it seems there's some data out there to suggest that it is functioning in a hypoxia protective role. But in order to characterize a molecule as a neurotransmitter, there's, there's a number of criteria that have to be met. And if you look at some of the canonical neurotransmitters like serotonin, you'll see that there's, there's specialized neurons for their synthesis. So we have serotonergic neurons, and those neurons have the enzymes necessary for the biosynthesis of serotonin. So we would need that need that for DMT, we would need DMT yogic neurons, which, which which there may be another another finding of that study by John Dean is the CO localization of those two enzymes, IMT. And ADC was found in a number of different brain regions, and I think in the cortex in the choroid plexus, and in the pineal gland, as well, so that that those can be areas where there are, quote, unquote, DMT ergic neurons. So that's one criteria for for a neurotransmitter. Another criteria is that there's a mechanism to package and store a neurotransmitter and vesicles. That's generally done to protect the neurotransmitter from metabolic degradation, and to sort of store and sequester it so that it can be released via excise exocytosis in a concentrated package. Another criteria is that once that vesicle was released, via access exocytosis that the the neurotransmitter activates a postsynaptic receptor, there's some receptor on the other side of that presynaptic neuron that gets activated and causes a downstream physiological response. Another criteria is that after that postsynaptic receptor has been activated, the molecule would need to be recycled or metabolized in some way, and often that's a rehab Take mechanism like for serotonin insert. It's the serotonin transporter that can take serotonin back into that serotonergic neuron, and then either metabolize it or package it back into a vesicle. And that exocytosis has to be activity dependent, there has to be some, some physiological response that's causing that access to exocytosis. So those characteristics still need to be worked out, if we're going to start to call DMT, a neurotransmitter or a neuro signaling molecule even. And there's a bit of evidence, kind of for each of those. So you could, you could very loosely kind of put together a hypothesis that that suggests that DMT is a neurotransmitter, but it's but it's not. It's not quite solid. And a lot of it's from from pre 1980. So there hasn't been much, much modern investigation into

Nick Jikomes 50:52

it. So is a fair summary. So so all those criteria need to be met? Before you can say something as a bonafide neurotransmitter. In an animal brain? We know that there's some DMT there, we don't know how it's packaged. Is it in a synaptic vesicle? Is it packaged some other way? We know that obviously, DMT can activate postsynaptic receptors in right, like there's five HTT to a receptors in the brain, if it is being packaged like a neurotransmitter, which no one has proven yet. You know, there would be receptors there for it to activate. But, you know, we we don't have those other pieces, right. We don't know if it's in vesicles. We don't know if there's neuronal activity dependent release. We don't know if there's a reuptake mechanism. So, you know, the jury's still out.

Nicolas Glynos 51:35

Right? Yeah. And like I said, there's some loose evidence like, there's hyper but a paper by Nick cozy, and he showed that DMT acts at both the serotonin transporter at cert. And also at V mat two and V mat two is a circular transport vesicular transport transporter, so it can act as the DMT into into vesicles. But we're not sure whether that the mat two or cert colocalized with ion, MT and ADC to produce these DMT ergic neurons. So yeah, there's still there's still quite a bit of work to do in that field. Okay,

Nick Jikomes 52:11

cool. So then we've got your work on endogenous DMT. Can you just set that work up for us? And describe like, what motivated it and what the what you set out to look for?

Nicolas Glynos 52:25

Hmm, huh? Yeah, we. So it had pretty long been assumed, based on the work by by Dean, and all that I that I mentioned before, because that because that work showed that I NMT, and ADC are colocalizing, and different cortical neurons and different regions of the brain. So basically, everybody in the field is assuming that I NMT is the is the critical enzyme for DMT biosynthesis. And we're basically using that as an anatomical marker of where DMT might be produced. So we're saying if we can, if we can isolate ion, MT, or if we can show where it is expressed, that's likely a region where DMT is being produced. So we wanted to investigate that we wanted to look into the enzyme I NMT. And find out a little bit more about it. So So we developed an IMT knockout rat model. And if we're if we're operating under the assumption that IMT is the key enzyme for DMT biosynthesis, then the standard hypothesis, the obvious hypothesis, is that an ion empty