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Ep #2 Transcript | Charles Nichols: Psilocybin, LSD, Ketamine, Inflammation & Psychedelic Medicines

Updated: Sep 6, 2021

Full episode transcript below. Beware of typos!

Nick Jikomes

Professor Nichols, thank you for joining us.

Charles Nichols 1:57

Hello, thank you for inviting me. So, um, where? Where are you calling in from today? I am calling in from New Orleans, Louisiana. And so you're a professor of pharmacology down there in New Orleans. Is that right? Right, right. Louisiana State University Health Science Center. It's one of the medical schools in the city just north of the quarter. So you've been How long? Have you been down there at LSU? I've been down here since the year before Katrina. So that would have been 2004 616 years. Okay. Wow. So you've been doing this. You've been a professor of pharmacology and you've been studying psychedelics for quite a while now longer than not everyone but but most people out there, I think. And I just want to start by saying what are having you talk about what what are psychedelics? What are the classical psychedelics? What are tryptamines? And how do they differ chemically, from non classical psychedelics, what's going on with the chemistry there? So psychedelics, terms of the terminology, the names is really kind of been fluid over the last 5060 years, for a long time, they were called hallucinogens. And hallucinogens really cover anything that

So that distinguishes it from other hallucinogens, because its main mechanism of action is through this one particular serotonin receptor, as opposed to say, ketamine, which is from a different receptor target or marijuana, which is from yet another different receptor.

Nick Jikomes 4:26

So So what are the major examples of these five htt to a receptor activating classic psychedelic,

Charles Nichols 4:32

right, the classic psychedelics are really sort of the ones that are found in nature are very closely related to the ones found in nature. So the classic psychedelic would be something like psilocybin, which is found in the magic mushrooms, mescaline, which is from the pod cactus. And LSD is also thrown in there as a classic psychedelic because it's very, very closely related to the ergot alkaloid. They're about amines. So, the classic really refers to sort of the prototype, psychedelic or psychedelic has found in nature and other one is DMT dimethyltryptamine, which is also found in several plants. So those are what we consider the classic psychedelics are really the ones that are the ones down in nature, the the prototypes for what has been modified in the subsequent decades to sort of the the new new class of psychedelics which are more like, like to CB, something like that, which is a audiogram, which is a modification of the basic structure of mescaline. And for tryptamines, you have DMT and psilocybin are tryptamines. And those are considered the classic but you have all kinds of modifications, chemical modifications, and the tryptamines. Like, for example, di PT. Or, I suppose, five methoxy DMT could be considered a classic as well, because it's also found in nature, but all the chemical modifications, these research chemicals, those are sort of the new requests, they're not really considered the classics.

Nick Jikomes 6:13

So the so the tryptamines in particular, things like LSD, psilocybin, DMT. They are, how are they made? Or how are they structurally related to neurotransmitters in the brain.

Charles Nichols 6:26

The tryptamines especially, are very closely related to serotonin, which is a dodginess neurotransmitter in in the body. It's a five hydroxy tryptamine and five ht. And the modifications of that, for example, to make psilocybin you have put a little molecule here, a molecule there, and you've got psilocybin or psilocin, which is the active metabolite.

Nick Jikomes 7:02

Gotcha. So basically, you take the, the structure of the skeleton of serotonin, you add a few atoms to one piece or another. And that's how you would get the classical psychedelic, so they're very close structurally.

Charles Nichols 7:13

Right, right. And when you have a when you have a structure like LSD, then you have you have it's, it's called an ergoline structure. And it's a little bit it's a little bit separated from from the structure of seratonin, or tryptamine. But ergoline is is more of if you can imagine the structure of seratonin has two rings on it, you got a six membered Carver ring, and then a five membered ring with a nitrogen on it, and this little tail that goes up with a nitrogen here and there's oxygen in the hydroxy up there, that's serotonin, you take that structure, you move the hydroxy, the oxygen over one, then you add a little bit more to the nitrogen, then you have silos. But with LSD, which is an ergoline, you take that same basic two ring structure, and you add another set of rings on top of that. That is the basis of the ergoline. So the ergoline, and the tryptamines all have the structure of the neurotransmitter serotonin. Because of that, the ergoline is in tryptamines like silos in DMT, five methoxy DMT, they will bind to an activates several different types of serotonin receptors. So when somebody is taking psilocybin or DMT, they're not just activating the serotonin to a receptor that produces the psychedelic effects, but they're also activating the one a type receptor, that one v type receptor, interacting with the seven serotonin seven receptor, there's actually 14 different serotonin receptors, and it probably interacted with half a dozen of them.

Nick Jikomes 9:05

So there's a lot of serotonin receptors, there's many different kinds of receptors, right? What is, how prevalent are they in the brain? are they located in one or two areas? Is it sort of throughout the whole brain? What would we know about that?

Charles Nichols 9:20

These are primarily throughout the whole brain. The thing about the target of psychedelics, the 5HT2a receptor, the highest expression of the five htt, a receptor is in the prefrontal cortex. That's the executive part of the brain, its decision its consciousness is happening there. Very, very high expression in really the higher brain centers. But there's also high expression in the visual cortex, which is sort of towards the back of the brain. And it's thought that activation of the those receptors in the visual cortex gives rise to say the geometric patterns that people will see while taking psychedelics Which is different from sort of the outright hallucinations that people will see which is more mediated from, from the, the higher brain centers. But there's also these receptors are expressed throughout the entire brain, just at higher levels in in the, in the cortex.

Nick Jikomes 10:18

And so the one that you hear most about is this five htt to a receptor. People even call it the psychedelic receptor. How do we know that's the one that primarily mediates the classical hallucinatory effects? And is it is it doing that completely? Or is there involvement from other receptors as well?

Charles Nichols 10:36

That's in in humans, it wasn't really validated until recently, we've known that in animals for a while because we've we've had drugs that will block that receptor. And if you block that receptor, say in the rat, and then give it LSD, it doesn't have the typical LSD induced behaviors. And in humans, it was a study out of Franz von biters group several years ago, where they gave a blocking drug to the to a receptor specifically, and then they showed that if they then gave psilocybin that there was no no behavioral effects.

Nick Jikomes 11:13

Gotcha. So you take psilocybin, you get the classical effects of magic mushrooms. But if you are first given a drug that blocks 5g to a, that pretty much goes away completely.

Charles Nichols 11:23

Right? Right, right. And another researcher who's been following up on a lot of those studies is Katrin preller, she's been doing functional studies by giving this drug called cancer and prior to doing lots of functional imaging and and psychological studies and demonstrating that pretty much is about all the effects of these classic psychedelics are mediated through this protein, because if she blocks it, all the effects are blocked.

Nick Jikomes 11:47

Gotcha. So, at one level, that makes a lot of sense. One thing that I've always wondered about is, if most of those classic psychedelic effects are being mediated by 5g to a receptors. How is it that a drug like say LSD versus DMT nn DMT, versus five Meo DMT have very different levels of visual hallucination?

Charles Nichols 12:13

Yeah, that's, that's the magic of pharmacology. That how how a drug interacts with the receptor, really changes the nature of how that receptor responds. So when you have a drug that even could have from the five methoxy, as opposed to a four hydroxy, that is going to engage different residues in the binding pocket of the receptor. So when it binds, it's going to induce it into a slightly different conformation. And that's going to affect how it activates or influences the activity within that cell and its neuronal firing properties. So one of the reasons is, between different psychedelics, they're, they're activating the receptor slightly differently, to reduce different effects in the cell. But they also have slightly different serotonin receptor profiles that they'll bind to, or potentially, in the case of LSD, they'll also activate dopamine receptors. So if you're pulling in slightly different subsets of receptors, you're activating receptors slightly differently. It's, it's not comparing apples to oranges, but maybe an orange to a tangerine, something like that. It's, it provides the istep pharmacology that gives the texture to the different types of experiences.

Nick Jikomes 13:26

I see. So when you think about brain receptors, and you hear about brain receptors, they're not simple on off switches, they can actually be turned on in different ways. Right? Right. And so I guess that would be, that would be why, you know, I get asked all the time, well, we have endogenous cannabinoids. How come I'm not high all the time. If these psychedelics are so close to serotonin, how can taking an SSRI? Is it making me trip? And is that is that the answer that the endogenous compounds are engaging some of the same receptors, but they're just doing it in a very different way?

Charles Nichols 13:54

Yeah, partially, partially, especially for? Like, why if you just increase serotonin levels, you can do that. by modifying your diet, you don't start hallucinating. And one of the reasons is that you're activating all the receptors, and there's a lot of some antagonism between what these receptors are doing on the cell. So if you activate one serotonin receptor to block with the other one's doing, so it part of that is going on, but also, these drugs are really, they're activating receptor differently. And that's a process called functional selectivity. So that's one of the things that we're exploring in my laboratory is how these different types of psychedelics will differentially activate recruit different different signaling pathways from the same receptor and how can we exploit that to either potentially make new drugs that will be say anti inflammatory versus more behavioral. We can engineer out some of the psychoactive effects. Or if you want to do the opposite, get rid of the anti inflammatory effects and engineering the psychoactive effects. It's really trying to understand that that's cool. What is really kind of an unknown right now?

Nick Jikomes 15:02

Gotcha. Yeah, I definitely want to ask you more about that this the the idea of engineering in or out certain components of what a psychedelic drug might do. But first, can we just talk about, you know, let's talk about serotonin generally. So you've got serotonin as this endogenous neurotransmitter that's used for lots of different stuff, you've got something like the five htt to a receptor, which is one of the most abundant receptors in the brain. It's located, as you said, throughout the cortex, what what does that receptor system and what does that transmitter system doing at you know, in an ecological terms, what is what is the natural function,

Charles Nichols 15:42

the natural function is serotonin is not like a fast neurotransmitter. When you think of neurotransmitters, people think of electrical signal causes a release of neurotransmitter from the presynaptic. And postsynaptic. NET starts another electrical signal, that's called fast neurotransmission. And that's mediated by a neurotransmitter in the brain, called glutamate. And serotonin is not really a synaptic transmitter with regards to the five htt to a receptor, it's more of a volumetric, that it's, it's sort of controlling, I like to think of serotonin sort of as a conductor of an orchestra, that you're telling this section to become louder, this section becomes softer. And it's modulating the activity of specific brain regions and circuits, it's not really causing neurons to fire or not fire, but it's enabling them to become more or less responsive. And were serotonin it to a receptors are on the neurons, they're not really on the axons are not in the synapses, they're on the what we call the apical, dendrites, and the cell body. So in the cell bodies and the little bit of the tree up to the dendrite. So when serotonin is present, what it's doing is it's making these neurons in the brain more responsive to activation when the input is releasing glutamate on them. So it's, it's kind of turning, turning up the gain of the system a little bit.

Nick Jikomes 17:14

I see so so when something whether it's serotonin, or a psychedelic or some other drug, when it's interacting with something like the five htt to a receptor, it's changing how entire networks of neurons respond to the signals that they're going to get anyway.

Charles Nichols 17:27

Right. Right. And that's, that's one of the things that we've looked at in our laboratory and how, how these different types of cells and networks respond at that level. And we had a paper A few years ago, where we were directly sorting and purifying the cells that were activated by psychedelics, and comparing them to the cells that weren't activated by psychedelics, to see how they were different. And then looking at how they were activated in different brain regions. So that we found that a neuron, a type of neuron, we call a pyramidal neuron, which is in layer five of the cortex, that's where the highest density of these two receptors are. But that type of neuron if it's activated by a psychedelic, say, in the prefrontal cortex, versus the somatosensory cortex, or the motor cortex, is having a different cellular response. So depending upon where a particular neuron is, in the brain, it's responding somewhat differently to the psychedelic, and how it's, it's changing how that neuron is going to respond to signals from the outside. And I think, in addition to that, we also have to a receptors that are on these cells that are connecting the neurons together called inter neurons. And a lot of those types of inter neurons are inhibitory. So they damp down the the activity of the neurons and is a particular type of inter neuron called fast spiking gabaergic parvalbumin inter neuron. And that's responsible for generating the gamma wave oscillations, which a lot of people propose, that's what really synchronizes the brain together. And we're modulating the activity of those directly with psychedelics as well. So it's not just effects on the neurons, its effects on these other accessory types of upsells in glia cells that are locally disrupting kind of the cohesion of these networks, but it's happening differently from one circuit to another.

Nick Jikomes 19:32

Gotcha. So, so this private key to a receptor system, it doesn't act locally, acts globally, right, and you can have both excitatory and inhibitory effects Is this why in a lot of the imaging and eg studies that have been done on psilocybin and other psychedelics, they're tending to see a basically a decrease in cortical activity. Is that is that linked to what you're talking about here?

Charles Nichols 19:59

It's It's It's a It's a little bit more complicated than just a decrease in cortical activity, what they're looking at is mostly blood flow. And it would you think it Okay, decreased blood flow, you have a decrease in cortical activity. But there's also some imaging studies done with flora, flora, deoxy glucose, that showed that there's increased metabolic activity sort of in these same areas. So there could be a decoupling between blood flow and metabolic activity. But psychedelics are definitely changing brain activity, either by increasing activity or decreasing activity in these really circuit and regional specific areas.

Nick Jikomes 20:37

Gotcha. So so there's this broad spectrum effect all over the place. And it's complicated. It's not it's not the same effect in every location, it's actually distinct and distinct places,

Charles Nichols 20:47

right? I think what what you're seeing at the cellular level is you're disrupting these local microcircuitry networks, through the, through the hard albumen inner neurons, the pyramidal neurons, and the somatostatin inter neurons were also disrupting. So you're you're, you're sort of dissolving the cohesion of these local net local micro networks that then spread to the more global networks. And I think that's really what's underlying what groups like Robin Carhartt, Harris and David not have seen with the disintegration of the default mode network. And it's it really is starting with these local disruptions between the inner neurons and the excitatory inner nodes. And it spreads from there but differently from different brain regions, which is why it's it's heterogeneous, you get some areas will be showing more connectivity, some less connectivity. But I think by and large, under the peak experience, there's this hyper connectivity of brain regions. I

Nick Jikomes 21:43

see. And I would imagine to there's, there's a significant time component to this. You know, the network activity will probably change a lot moment to moment, and probably different for different people. Right, right.

Interesting. So what about the other thing that I keep seeing research done around and we're links there at least trying to be made is for depression and neurogenesis. So on one hand, the sort of textbook high school level understanding of serotonin is that it's involved in mood. And that's why something like an SSRI is the quintessential antidepressant medication. And I know that there's links as well between neurogenesis and mood and depression. So what what is neurogenesis? Exactly? And what is the link between potentially psychedelics and neurogenesis with the five htt to a receptor. So neurogenesis is the process of when you have new neurons growing from neuronal stem cells in the brain. And it was really not thought to be happening in the adult brain, once your adult brain is there, it's done, you got no new brain cells. And several years ago, they discovered that SSRIs actually cause the growth of new neurons in specific brain regions like the hippocampus, and that these new neurons lead to new sprouting and new connections. And then that was associated with the antidepressant effects of SSRIs. And so that that was a quite impactful discovery. And several different groups over the last few years have looked at neurogenesis and synaptic plasticity with psychedelics, and have shown that if you stimulate the five htt to a receptor in the brain, that you will also stimulate new synapses and new neuronal connections within the brain. And in some of the work that has been done with ketamine, which does very similar things. If you block those connections from happening, you can prevent the antidepressant effects in these animal models. The current theory is really that, that ketamine and psychedelics really have this sort of convergent mechanism through a particular cellular pathway to increase synaptic density and growth in specific brain regions that are producing this anti depressant effect. Gotcha. So the the idea is, you have something like ketamine, which mechanistically It works very differently than something like psilocybin. And yet they both seem like they might have these antidepressant effects. This might be linked to neurogenesis. And so is this is this part of the thinking behind why you might be able to engineer new psychedelics that are that are not actually psychedelic. There's a component to this that's involved in like mood modulation and depression and then an components that are involved in the other stuff. Right, right. So

Charles Nichols 24:45

obviously, if you have a new antidepressant, and you've got your grandma who is very reluctant to take a psychedelic, she's depressed up you could come up with with one that is not psychoactive but would have the same Sort of synaptic increasing effects, then you could make it into, say, an ordinary medication that you could take that would be having these behavioral effects. There is some evidence that that might be possible to engineer away those. There are a few different labs who are working on that. But I think it's I'm not sure that that's ever really going to be feasible. Because if you're changing the brain, you're reducing all the synaptic plasticity and doing what it needs to do that. That you're just going to as a product of that rewiring have these subjective psychedelic effects.

Nick Jikomes 25:42

Yeah, that was that was something I was wondering about, because on the one hand, it seems like there's a lot of people trying to engineer the psychedelic component out of psychedelics, which makes sense, right? If you can have a drug that doesn't have what a clinician would probably view as a side effect. You know, ideally, you know, you don't want to treat someone where there's a requirement for them to be under supervision for eight hours, because they're going to have hallucinations. Exactly. On the other hand, if the same receptor system underlies some of the therapeutic benefits and the psychedelic effects, it might not be possible to disassociate those things. The other thing I was wondering about is, I believe, correct me if I'm wrong, that in the work of Roland Griffis and others, there actually is a there is a quite a strong correlation between the intensity of the subjective effects and the magnitude of the therapeutic outcome.

Charles Nichols 26:31

Right, right. And I think that that correlation is definitely very real, that the more intense experience that somebody has has gone through in one of the therapy sessions, the better the outcome, but rather than look at it that that experience itself is anti depressant, I would potentially argue that the more somebody has this experience, that's merely a biomarker, that they've gotten enough drug in the brain that's going to induce the plasticity that's necessary for that antidepressant effect. And along those lines, you know, how can you test if the subjective peak experience or the intensity of the experience is necessary? Some people propose looking at anesthetized people, give them psilocybin and see if that's antidepressant. nobody's done that yet. some issues with that, you know, that a lot of the cells that are affected by anesthesia are also affected by psychedelics. And there's some evidence that anesthesia itself is anti depressant.

Nick Jikomes 27:38

Yeah, I mean, ketamine is an anesthetic is

Charles Nichols 27:40

right. But even like, something like pro football, there's, there's even a or ISO floor. And there's, there's some evidence that they might be antidepressant. So if you've knock somebody out and give them suicide and depressed, so what we've done is we've generated some animal models. We've looked at the antidepressant effects of silicided in rats. And I have looked at a couple different models here. And we've shown that if we give a depressed rat, we can make a depressed rat, or there's genetically genetic models for major depression, treatment resistant depression and rat, we give it a single injection of psilocybin in these models, and then go six weeks out later. These rats are behaving like normal rats, they're not depressed, they don't have any of those depressive symptoms. We do the same model with ketamine. The antidepressant effects of ketamine were off. After about two weeks, I see, it's very similar to what is happening in in the human population where a single treatment ketamine lasts about two weeks, and psilocybin is is persistent. So we would argue if a rat really has a sense of existential existence, and anks, in it, wondering about its its own in mortality, and is that where depression is coming from? Or if not, is it really biological? So we we think that really at its core, the antidepressant effects of these classic psychedelics are really rooted in synaptic and neuronal changes within the brain due to the five htt to a receptor activation.

Nick Jikomes 29:22

And is this these long lasting antidepressant effects? At least in animals? how dependent is that? Um, dos, what what is the comparable human dose that that you're using for these rats? Is it is it a very large one, or

Charles Nichols 29:36

it's, we roughly calculated it to be around what they're using in the human, the human trials for the the effects that it's having on on the rat. The dose that we chosen is not such a large dose that it's incapacitated, it can't do anything.

Nick Jikomes 29:52

It's label. What do they do when you got a rat suicide and what do they do?

Charles Nichols 29:57

It's it's kind of funny. They They kind of hang out in their cage, they have this behavior called ptosis, which is certain receptor mediated. So their eyes are kind of half closed like this. And they like to hang out at the back of the cage where the air vent is coming in, and they'll just prop their chin up, they're kind of looking a little sleepy. So it's really easy to tell which ones we've we've given the drug to. And sometimes another behavior is a shake. So they'll have like a wet dog shake, but we don't see that very often in the rats, and the mice.

Nick Jikomes 30:31

Okay, so it clearly has a behavioral effect. Oh, yeah. And I guess one thing, that's interesting, too, is how, you know, you always wonder about how the effects that you have in a human translate to an animal and vice versa. And if you've got a lot of a lot of these psychedelic effects, mediated by receptors that are in places like the prefrontal cortex, as you said, do in animals, do they have the same distribution of 5g to a receptors? Or do we think there might be effects that are a little more unique to humans, just based on the size of our cortex and differences? Like? Yeah,

Charles Nichols 31:07

I think I think both of those are, are valid that anatomical studies looking at receptor localization in rodents versus human is very, very similar distribution in the same types of neurons. There's actually a, there's a larger difference between mice and rats, than rats and humans, and how the sort of responses to specific psychedelics are in in rats, if you give them tryptamine, psilocybin and ergoline, just about all of the behaviors shown to be to a receptor mediated. If you give the same drugs to a mouse, about half of the behavior is to a and the other half is from one a. And you also have metabolic effects to take into account that a mouse it's used to eating garbage and metabolizing things really quickly, more so than I think than a rat. So LSD and psilocybin in a mouse are gone within the half life is under 10 minutes. Oh, wow. So they're very rapidly metabolized away. Whereas in the rat are hanging around for an hour, two hours. In a human though, especially with LSD, you have a very long half life, it's hanging around much longer. So it's activating the receptors much longer. And in humans, compared to mice and rats, we have this very large neocortex comparatively large. And so we've got just a higher a higher degree of higher proportion of brain tissue for cognitive function, then did roads do this highly expressing these receptors where the drug just happens to act much longer? So I think, in humans, there are some unique properties about humans. But I think we can study the fundamental network activity, molecular and pharmacological activities in rats fairly well. mice. Okay. There's good genetic models in mice, like a knockout for the receptor. So we can do some some fancy things, but there's not any genetic tools in the rat yet.

Nick Jikomes 33:17

Gotcha. So in some ways, very, very broadly speaking, rats, rats are almost closer to humans than than mice

Charles Nichols 33:25

with psychedelics. Yeah. Wow, that's interesting. We can study a lot in them. Oh, and to even make it a further interesting story. This some manuscript we're writing out now, I also do work with fruit flies. And we've validated and looked at antidepressant effects, let's say an SSRI and a fruit fly, and silicided. And we show that a single exposure of silicided, to what we have appears sort of like a genetic model of what a depressed rat would look like in the same types of testing, that if we treat it or feed it, psilocybin for a day, and then test it a week later, for antidepressant like activity, that these fruit flies are behaving normally. As they have as if they had been given an SSRI the whole time. It has given SSRI for one day, it doesn't have that same effect.

Nick Jikomes 34:23

So in the context of treating something like depression in humans, how, how important do you think psychotherapy is in conjunction with a drug like this? Because on the one hand, there's a lot of evidence to suggest that it is important. On the other hand, when you when you describe these animal studies, you're presumably not giving the fruit flies therapy sessions, and yet are getting antidepressant effects.

Charles Nichols 34:46

Yeah, so Well, I do think that the post session, integrative therapy is really, it's necessary to maximize the full therapeutic potential. And we have some some of our animal model data that supports that. I think at its core, that this what the silicided or the psychedelics do is they open up this window of behavioral flexibility, in the days immediately following a psychedelic, that allows somebody to go in and change the way they think, change their neural network from where they've been stuck for the last so many months or years, to some new permanent state that which is which is more healthy. And we see that in one of our rat models that we use that if we give it silicides in and we just let it hang out in its cage, we have one effect. But if in the week, after within those days, the week after we expose it to additional stressors or environments, that it shapes the nature of the outcome of the antidepressant effect.

Nick Jikomes 35:47

I see. So even though critical. Okay, so you give a wrap psilocybin, and then the next day, there's no psilocybin left, it's all gone, right? going on in those days and weeks actually has a strong effect on how the animals gonna behave.

Charles Nichols 35:59

Right. Right, right, I think they're able to better adapt their behaviors, from what we see into the environments that we put them in. So I think what we're doing is acutely the civil Simon is promoting this neurogenesis, this increase in synaptic plasticity, synaptic density of specific circuits that are inherently producing an anti depressant effect on their own. But they're also opening this window of plasticity, over the next several days, where they're able to really learn new skills, learn new coping skills, learn new strategies, and integrate that into the normal behavior. Sort of, if you have somebody who's a person, and they're depressed, they've got this rigid thinking, give them a psilocybin therapy, okay, that in and of itself is going to help but then in the days after, take them back to where they were, maybe they had some insights, during the peak experience, do some integrative therapy with their trauma that they've had. And you've gotten rid of the rigid neural networks, and now they're able to readapt to what's going on into a more healthy state.

Nick Jikomes 37:15

I see. Hey, Charles, the, the mic your wire, it's rubbing against your shirt. Okay, so if you could just be mindful of that, and it's not too bad. But when you move your hands, it kind of shakes it. Okay, that's interesting. So the other thing that I think is super interesting, you mentioned that rats and mice metabolize these drugs differently than humans. But then also, within humans, you've got, you know, on one side of the spectrum, LSD, which is going to be, you know, eight or even longer hours where the effects are lasting. And on the other side of the spectrum, you've got something like DMT, where you're talking about minutes, right? What What's going on there? Why is there such a wide range of effects, both in terms of their duration and the intensity of the psychedelic effects?

Charles Nichols 37:57

Yeah, that's a good question. Those are really two polar opposites on the spectrum. It's a mixture of how the drug is interacting with the receptor, versus the metabolism of the receptor for drug like DMT. It's a small molecule, it can hop on the receptor very quickly hop off the receptor. But it's also metabolized by mono amine oxidases that are in the body within minutes. So if somebody ingest DMT orally, it won't be active because the monoamine oxidase is within the gastrointestinal system will essentially metabolize it before it gets absorbed. If it's smoked, or inhaled, it is immediately in on those getting into the blood and into the brain. But it's metabolized very quickly away. With LSD. It's a very different story because LSD, when it binds to the receptor, it changes the conformation of the receptor, to where there's this loop on to the helical membrane, spanning Hela C's that fold down in over and trap LSD in the receptor, so it can't get back out. I see. And so then you get LSD stuck in the receptor. And it's their signaling doing its thing and changing the neuron for eight to 12 hours.

Nick Jikomes 39:20

So that's why that's why it's eight to 12 hours it literally trapped at that receptor.

Charles Nichols 39:24

Right, right. This was this was on paper, just a few months ago from Brian Roth's group, I think my father was also a co author on that paper where they had the crystal structure of the to a receptor, and they showed that with LSD in there, it's just it's trapped. Can't get out.

Nick Jikomes 39:38

Oh, wow. That's cool. Yeah, I'm talking to Brian Roth in January, so I'll ask him about that. Oh, yeah. Yeah. What, um, how did you even how did you get into this? Oh, how'd you get into science and then and then this area specifically? Oh, wow. Yeah.

Charles Nichols 39:55

So it's not what most people would think. how I got into this area. So I, my father got his PhD in medicinal chemistry at University of Iowa. When I was a little kid, four or five years old, he would take me into the lab and I chemistry stuff like that. Oh, that's neat. didn't really pay much attention to it. Took chemistry class in high school. I thought that was interesting.

Nick Jikomes 40:26

But your dad, your dad wasn't just a chemist, right? Your dad is no, no, the LSD guy, basically.

Charles Nichols 40:31

Yeah. But he didn't help me get a job when I was growing up. He'd make up some stories about Oh, yeah, I'm doing this and that I'm a chemist. And he was what one point said he was trying to figure out how, you know, the molecules that make people dream, I remember was one of the cover stories that he used on me when I was about 10. Okay, so I really had no idea what he was doing. This was pre internet. Yeah, I knew he was a chemist, I knew he was pharmacologist, my mother was getting her PhD in pharmacology at the same time, at Purdue. So that around the dinner table conversations, you know, tended to go around, you know, pharmacology, drugs, receptors, experiments. But you know, it's your parents talking, you don't really pay too much attention. But I went to college. I wanted to be a chemist, not quite sure why I wanted to be a chemist, because maybe that's why my dad was a chemist. And after a couple years, I decided I didn't like chemistry. So I switched to biology, and started doing undergraduate research in a laboratory doing bacterial genetics. And this was I think, we had just gotten the first PCR machine on campus. And that was a lot of fun. And so I really, really liked biology. And genetics. didn't really know what I wanted to do for graduate school. So I, I went to a lot of Interdisciplinary Graduate Programs. And I ended up going to Carnegie Mellon for my PhD work, and it was really a focus department on developmental genetics. And I ended up working in the laboratory of dr. john Pollock, who was doing fruit fly AI research. And I remember seeing his first presentation, these beautiful, almost psychedelic pictures of these neural networks and fly brains and fly AI in different colors. And wow, that's what I want to do. So I joined his lab and spent the next several years learning about fruit fly eyes, and retina development. And after several years of just doing a lot of really hardcore genetics, developmental biology, I was like, Okay, I'm done with life. And by this time, I knew what my father did for his for his age. Yeah, that that came out a little bit later in my late teens. And, and I knew what he did when I went off to graduate school, but it didn't really interest me serotonin, okay, pharmacology, okay. But I was really fascinated by genetics. And that's the direction I went. So I wanted to get out of fruit flies in genetics, and I thought I'd go into something like a mammalian system. And just through a random set of circumstances, happened to find myself looking at an advertisement on the back of a journal for a hire for the Vanderbilt neuroscience programs. And there was an investigator on there, Elaine Sanders, Bush, who had was working on serotonin. And I had heard my I remember my father mentioned her a couple times, they were collaborating, and I thought, huh, serotonin, that could be something different. So I sent her my application, sent her an email, and almost immediately she got back. She said, I don't know. I don't know. I know. No, I don't have a position. I don't know why my name was on there. I don't have any money for it. Sorry. Okay, that was it. So then I, I was looking at other postdocs and one in a Parkinson's laboratory. So I thought, alright, I'll do dopamine and Parkinson's. It's different than flies. And then it was about two, two months later, I, you know, completely forgot about the whole Vanderbilt thing. And I got an email from Elaine, who said, oh, by the way, I've got some money. Now, if you're still interested in that postdoc, could you come interview next week? Okay. So I said, Send me your CV and everything. So she had remembered this email from somebody doing fruit fly stuff. A couple months later, went down to Vanderbilt thought it was a really fantastic environment down there in Nashville. And the lab was great. The people were great. And she said, the project I have in mind for you is to use this new technology called differential display PCR to look at what effect LSD is having on gene expression in a rat brain. Go, that sounds fun. I could do that. So I accepted the position, moved down to Nashville and started working on that project in 1997. And I think I had been in the lab, a month, a month or two, not not more than than a month or two. And she I remember very vividly, she came out of her office kind of look on her face. And she is she's

Elaine was a real firecracker. She's from Central Kentucky, probably five feet tall on a good day in real. Pull the bench comes out, looking at your CV again, and I saw that I noticed that you went to Purdue and Nichols? Do you know Dave Nichols up there? I said, Yeah, that's my dad. And she just started laughing and laughing and laughing. So at that point, she started calling me Dave, after that. So instead of Chuck, but that really, it really caught my passion, working with serotonin and neuropharmacology and serotonin to a receptors. And at that point, I knew, you know, that's what I wanted to do. And as much as I wanted to get away from fruit flies, I also got back into fruit flies when I realized that I could give drugs to fruit flies, and use that as a model system. So I had had a really fun and productive postdoc there. So I got into the field. Not because my father was in the field, I wanted to do something different. Yeah, it just sort of randomly, randomly found my way. But once once I found my way, I knew it was home.

Nick Jikomes 46:47

Okay, that's interesting. And then, you know, I think at some point, a lot of what you do is related to inflammation. Yes. So how did you get into that? And what, what are the dots that that you connect between serotonin, psychedelics, 582. A and inflammation?

Charles Nichols 47:06

Yeah, so this is people think psychedelics, they think the brain Yeah, using serotonin to AIDS in the brain. And what I that's what I was thinking. And what I came to learn is that the serotonin to a receptor is the most highly expressed serotonin receptor in the whole body. It's in every literally every tissue in your body, bone, skin, eyes, lungs, kidney, it's everywhere. And it really again, this was serendipity that we discovered this. If it had not had been for Hurricane Katrina, I don't think this would have been discovered. What do you mean? Because after Katrina, down here, we lost about half half of the faculty of the medical school. And

Nick Jikomes 47:52

I was because they moved away. They moved away,

Charles Nichols 47:54

recruited away, didn't want to live, keep living in New Orleans. And I had I had come back down after a seven month evacuation, living up in my dad's room over his garage for seven months, came back down, reestablishing my laboratory was getting ready to hire a postdoc for the laboratory, and was contacted just out of the blue by this fellow who was across the street in the pathology department banging you who his, his mentor was leaving New Orleans to go to another university and he wanted to stay is his wife was in nursing school. And he had done some research with five htt. a receptor is at the clinical level. He was an MD PhD in when he was in China getting his MD PhD and came across. He was just looking through names. Oh, I decided seratonin to a just so happened that that day, I had permission to start hiring a postdoc. He showed up in my office really as a cold call looking for a postdoc. And sure, yeah, you're hired. But his, his specialty was in blood, high blood pressure. And it was working on models of atherosclerosis and vascular inflammation. So he came in the laboratory, and I was trying to reposition him to do cellular biology, because we were trying to find an essay. So we wouldn't have to always take the brains out of the animals to study them. So we were looking at several different types of cellular outputs. We were looking at cell growth, cell division, cell death, and being named proposed, let's look at this particular essay in aortic cells, which he had been doing in his laboratory across the street, and this was an essay using smooth muscle cells from the aorta of rats,

Nick Jikomes 49:52

God, this is the heart,

Charles Nichols 49:54

the heart, and normally these cells are prohibitively expensive. You order them it's like $1,000 you get Little, little tiny amount. And so he said, well, let's let's look at it for put it in this essay for inflammation. And I was thinking, inflammation. Okay, okay. But he had the expertise, he knew what he was doing. He also happened to have the fortune at that time. That my, my daughter's mother was working in a cell culture facility where she was making the cells that we would need. So had unlimited access to this otherwise prohibitively expensive cell type, the expertise to do this inflammatory essay that wouldn't have been there if it hadn't been for Katrina. And he did the essay, where we grow these heart cells, add this inflammatory agent, and then look at inflammation in these heart cells. And, lo and behold, there was a super, super potent effect that we saw with our first drug that we looked at called DUI.

Nick Jikomes 50:57

What is that what is DUI?

Charles Nichols 50:59

DUI is to five dimethyl oxy for i o amphetamine. So if you it's an it's similar to the mescaline it's a same class of like a kind of psychedelic amphetamine. Okay, so it's not like a tryptamine or LSD. But it's it's more like mescaline in that structure. And Shogun had written a whole book on this called Pico phenethylamines. I have known and loved and this is one of those, this is

Nick Jikomes 51:29

so DUIs in there, but so it had, it had a potent anti inflammatory,

Charles Nichols 51:33

anti inflammatory effect, we didn't know what we would see. And it turns out that when we characterized everything, that this particular drug was about 100 fold more potent, as an anti inflammatory at its target than, say, dexamethasone or steroids.

Nick Jikomes 51:52

As a standard, you know, when a doctor would give someone randomly for inflammation, it's 100 times more potent, you said,

Charles Nichols 51:59

Yes. Wow. zactly. So at this point, it was Wow, we really could be on to something here, because of the levels of the potency of this drug as an anti inflammatory. It would be, you know, 50 to 100 times less of what would give somebody any kind of psychoactive effects. Not only like, like, a micro dose a micro dose,

Nick Jikomes 52:19

yeah, right. Right. So it's so potent as an anti inflammatory, you can give a tiny dose, you won't have any psychedelic or psychoactive effects, but you will have this impact on inflammation,

Charles Nichols 52:29

right. And that's what we saw with with our animal models. So we did animal models of inflammatory bowel of asthma, of atherosclerosis diabetes, so we saw really, really profound therapeutic effects in, in all of these animal models. The one we've used the most though, is asthma.

Nick Jikomes 52:53

I see. Yeah, I read about that. And I was I was fascinated when I saw it, because a it's it's this, the only example I know of where you have what you can call a micro dose of a sub psychoactive dose that's actually doing something measurable in an animal model, at least. And, and and the second thing was it I think everyone thinks about psychedelics as you know, acting on neurons in the brain, doing stuff in the brain. But as you said, these receptors are all over the place doing stuff pretty much everywhere. And it was, which is really interesting to see. Can you describe how do you do the How do you study asthma in a rat? What does that experiment look like?

Charles Nichols 53:30

Ah, so what we do is we we have a model of allergic asthma. So it's like pollen dust allergy. That's the most common kind of asthma. So what we do is we take chicken egg white protein, ovale, B chicken egg white ovalbumin. We inject it into the rat twice, and that Prime's the immune system to respond with an allergy to this antigen. That'd be like injecting yourself with pollen from ragweed or something to make yourself allergic to it. Yeah. And then we, we nebulize and give by nebulization. The same chicken egg over albumin.

Nick Jikomes 54:09

What does that mean? localization? Oh, like an inhaler. inhaler. Okay, so their inhaler

Charles Nichols 54:14

like an inhaling it. And it goes into the lungs, and then it produces this allergic response. And so after, after three days, you have basically an asthmatic rat, you have inflammation, you have mucus, you have difficulty breathing. The types of immune cells and response that are in the lung are conserved very highly with it with humans who have allergic asthma.

Nick Jikomes 54:36

And is that what asthma is basically the lungs and the airway become physically inflamed,

Charles Nichols 54:41

physically inflamed, you get inflammation of the smooth muscle cells of the endothelial cells, and then you get cells that come to the lung, around the airways that also are inflammatory so it's it's really this pathological state and then that induces remodelling of the lungs, it induces the formation of collagen and fibers and makes them stiffer. So overall, the pathology is very similar to somebody who is really having difficulty time breathing with asthma.

Nick Jikomes 55:13

I see. So if you have asthma, every time that you have an asthma attack, you actually get worse, like your lung is worse after that,

Charles Nichols 55:21

right? What can it can be, can be, and with our models, we use a particular drug to trigger the asthma attack after they inhale it and they develop the symptoms, we give them a drug that that normal, a normal person that's using people as well the same.

That will cause just a slight narrowing of the bronchioles in the lung methacholine. It's a drug

muscarinic agonist, that a normal people, it might make it like a little bit more difficult breathing. But if you have asthma and inflammation in your lungs, it's really, really going to make it difficult difficulty breathing. And that's what's called airways hyper responsiveness. And they can do that with a person, they put a person in a chamber, they expose it to the same thing, and they measure the response to this, and they can tell you how severe your asthma is. So we do that with the rats as well. Gotcha. When we treat with the drug, if we give the drug as an inhaler, to nebulize and give them the drug that way, we can both prevent the development of the asthma when we give them the allergen and we can rescue the symptoms of asthma back to normal once they've already developed those symptoms.

Nick Jikomes 56:35

So completely, it completely prevents it completely. Wow. So so you, you, you literally give them asthma, they inhale something their airways become inflamed. But before doing that, if you give them this mesclun, like drug that's very potent, and they inhale just a little bit, and they don't even have behavioral effects, that's enough to completely prevent them from having an asthmatic attack.

Charles Nichols 56:58

Yes, wow. Or if they're already having an asthmatic attack, it's not like a rescue inhaler. But they have all the inflammation there. And we give them the drug. Within a couple days after that we take the lungs out, look at them, there's no inflammation in the lung, there's no mucus, and when we test their breathing ability, it's absolutely normal. Gotcha.

Nick Jikomes 57:18

And is that? Wow. And is that a five issue to a receptor thing?

Charles Nichols 57:23

Yes, it is. I recently had a publication a couple months ago, where we looked about, I think we looked at 25, different psychedelics, to see how potent they were doing that. And the drugs like DUI and some other ones. psilocybin also was very potent at producing this anti asthma effects. And when we looked in a knockout animal, we have a mouse that doesn't have the to a receptor, there's absolutely no effect.

Nick Jikomes 57:50

Gotcha. So you can take just a small dose of a psychedelic that stimulates the five htt to a receptor, and have this really strong effect, basically, a cure for asthma, at least this form of asthma, it depends on five ht to a, it's the same receptor in humans. So is this likely to also work in humans? You think?

Charles Nichols 58:13

I think it will. Some of the cell culture data that we have is using human cells. So we're, my research is partnered with a biotech company called eleusis. That's taking some of these drugs and the IP that we've generated to develop them towards ultimately using in humans going towards human clinical trials.

Nick Jikomes 58:37

And is the idea there that you would essentially give someone a microdose a very small dose of one of these drugs, rather than trying to engineer a new drug that is structurally different?

Charles Nichols 58:47

Initially, yes. But we were also engineering new drugs. And one of the things that we did in our asthma model is we showed that the behavioral potency does not correlate with anti asthma activity at all. Like LSD, which is really super potent as a as a psychedelic at best is only weakly anti inflammatory. And I see

Nick Jikomes 59:12

is this like that functional selectivity that you're talking about before? Yes. So it can be potent at one receptor in one way in a different drug can be more potent at the same receptor and a completely different effect? Because, right, it's interacting that receptor in a different way.

Charles Nichols 59:28

Right? Wow. Like with DMT, for example, there's absolutely no anti inflammatory effects. And also code so we did a correlative analysis between 25 psychedelics, there are behavioral potency and their ability to to prevent asthma and there's there's absolutely no correlation. So we think, unlike with, say the psychiatric side, that will be able to engineer drugs that have less psycho activity, potentially even no psycho activity, but in full anti inflammatory depending upon how it activates that receptor. And we've made some progress on that we have some new chemicals now that have reduced behavior, they have, I think, two thirds less behavior induced than DUI, but they still are fully anti inflammatory.

Nick Jikomes 1:00:14

Wow, that's amazing. What, um, what what do you think about the phenomenon of micro dosing generally? Because, I mean, you're hearing I hear about all the time now, it's, it's really a cultural fad at this point. And on the one hand, you know, the work that you just described says that there could be something to it that you could have real physiological effects that might even be beneficial at a dose that's well below what would give you full blown psychoactive effects. On the other hand, it sometimes feels like it's almost flirting with homeopathy or something where people are trying to compete to say, you know, I how little they take, do you? Do you think that there's something there to micro dosing beyond the inflammatory stuff that you just described?

Charles Nichols 1:01:00

There could be that the one of the issues with that is, there have been so few really good controlled studies looking at the effects of micro dosing, I think there have been maybe only two or three over the last year or so. One, from the group, I've been involved in looking at healthy, elderly volunteers, essentially micro dosing over several weeks, and then running them through the full cognitive testing battery and whatnot, and micro dosing what LSD LSD doing 510 and 20 micrograms of LSD every third or fourth day over several weeks,

Nick Jikomes 1:01:40

and is that that's roughly like 10 times less than a recreational dose,

Charles Nichols 1:01:44

right, the threshold, the threshold dose of LSD for say, an experienced psychonaut would be about 20, micrograms. 20, somebody who's not used to used to altered states might be up to 25, or 30. So it's below the threshold, but a typical recreational dose is considered 100 micrograms. Okay, so it's about tenfold less. And we showed that there was no there were no negative effects on any cognitive measures or outcome with those tests, but on the flip side, we showed that there were there was no enhancement of any of these cognitive tests I see. And there have been a couple other studies looking at similar doses of LSD, with a few signal maybe here or there. But there's no real, real overwhelming evidence that micro dosing LSD is doing anything to cognitive function or creativity, guys on a few studies that are there, but, you know, maybe we're just looking under the wrong streetlight. Some different types of studies need to be done, because there was one study looked at some functional imaging of fMRI, or the brains after I think it was 15 or 16 micrograms of LSD or 13. And showed that there were were measurable effects on network connectivity at that level. How that would translate into behavior and cognition. I don't know. But I think I think it's certainly worth following up with, with more testing, more more controlled studies.

Nick Jikomes 1:03:22

Interesting. So it's still largely anecdotal. But but there could be something there we at least know from from the work that you're describing that small amounts of some of these drugs can have real actually very strong physiological effect. Right. Right. What about what about the link between inflammation in the brain and things like depression, I think when you describe something like asthma, and I'm imagining the airway becoming physically inflamed, that's really easy to visualize. But there's also this idea of neuro inflammation in the brain, right? What right, what is that?

Charles Nichols 1:03:56

So neuro inflammation in the brain, that's when a the brain doesn't really have an immune system, but it has, it has similar types of cells called microglia, that are in the brain that, that perform a lot of similar functions say that macrophages will in your body. So there is a kind of primitive immune system in the brain where there are inflammatory molecules and cells that will essentially treat the inflammation in the brain if it's there. And they found there was a number of years ago that people who are depressed it's not it's not everybody who has major depression, but there's a very large subset of people with major depression. When they've done biopsies of the brain and looked at biomarkers. They've seen signs of inflammation of particular inflammatory cytokines or increased, the number of actively activated microglia are increased. And they see similar neuro inflammation associated then with neurodegenerative diseases like Alzheimer's Park, Since disease, schizophrenia unmedicated schizophrenics have a significant amount of neuro inflammation. So it was maybe 10 years or so ago, this whole neuro immune hypothesis of, of psychiatric disorders was proposed. And that's become a really hot field of looking at inflammation and how it really kind of underlies a lot of a lot of psychiatric disorders. And there's inflammation in the brain associated with drug abuse as well, depression. Pretty much every everything nowadays seems to involve some aspect of inflammation.

Nick Jikomes 1:05:39

Interesting, so what, um, what other? What other areas? If any, are you working on in your lab? Or you work? What compounds are you working on? Is it all focused on inflammation? Or are there other other avenues?

Charles Nichols 1:05:52

No, I've got sort of three and a half major areas in my lab. One of them is the inflammation. And it's primarily focused on trying to identify what is going on in the cell that's producing this anti inflammatory response. We know what kinds of drugs that we can activate the receptor with, to cause either anti inflammatory response or no response we have, we have potent psychedelics that are not anti inflammatories, that we've we've identified, and we have potent psychedelics that are. So we're leveraging these kinds of tools in cell biology studies to see how they're affecting the cell differently to identify what are the molecular mechanisms. And then if we know that, we can potentially make better molecules that only activate these particular mechanisms. And another project in the laboratory is directly looking at how these different drugs are interacting with the receptor, how they're modifying the receptor to recruit different pathways. So it's more of a cell culture based receptor drug interaction project that complements what we're doing in the whole animals and the cell biology for the asthma and the inflammation. And then there's another main effort in the lab with models of depression, using psilocybin and other two way agonists to see if we can get at how these psychedelics are affecting the brain at the molecular level, to produce these persistent anti depressant effects and how that's different than ketamine because ketamine, and and psychedelics, they're both believed to activate the same molecular pathways involving mtorr and synaptogenesis. But why do psychedelics last in some cases in humans, years, this study came out like four and a half years later, 70 to 80% of the depressed individuals from the NYU study were still hadn't relapsed into depression. That was out of Steve Ross's group. But ketamine, one infusion treatment, it's gone after a couple of weeks, you have to do multiple infusions over over two weeks, and then that might last a few months, but then you have to retreat. So they have the same mechanism at the at the glutamate synaptic level. But why does psychedelics lasts so much longer, and we think that has to do with epigenetics. And some effects within within within the brain circuitry. And so we're looking at those kinds of things now within that model, further developing that model. And then the half, the three and a half the half is where we're also still doing some work with the fruit flies. Because now that we can see some interesting things with the fruit flies and silicides. And we can very quickly and rapidly get it really fundamental molecular mechanisms using the fruit fly genetics and the tools that are already already available there. Those are the really the three main areas. But we are making new new chemicals we've we've got a series of new chemicals that have a somewhat reduced behavior, but maintain anti inflammatory and we're working now on the third generation. And these are the ones that Alesis is has licensed and is trying to develop for the clinic. And that's part of the team down here at LSU is my collaborator, Tim Foster, who's up in the microbiology department, and he made an astounding discovery that psychedelics can really potently protect against a lot of the inflammation and damage produced by ocular viral infections. And so he's he's been doing a lot of really interesting work looking at the anti inflammatory effects of psychedelics in the eye as a model system.

Nick Jikomes 1:09:37

Well, is it um, I mean, most of these compounds psilocybin, various others are scheduled one. So how hard is it for you to actually do this research?

Charles Nichols 1:09:53

For me, I don't think it was as hard as it is for most what I started my own lab up back in 2004. Because I had come from the Sanders bush lab, who was already known for, I think she was one of the probably five or six labs working on psychedelics in the world at that time. And on my application to DEA for all the permits and everything I'll here's my pedigree I come from this lab, I'm moving forward. So I think I had a little bit easier time than somebody who just wants to break into it. But still, it was six months to process everything. I had site inspections, from the agents of the state and the federal.

Nick Jikomes 1:10:33

What do they actually look for? When the DEA comes in to inspect your lab? What are they looking for, they're looking for the logbooks, they use want to see the vile, every, every time every experiment, you have to write down exactly how much was taken and go to

Charles Nichols 1:10:51

that level, down to the point, point, one milligram level, everything is accounted for inventoried, and everything is kept in this giant safe. And I also, they had to come out, look at that this 500 pound triple blocking, it's a beast. But when my father retired back in 2012, I inherited his schedule one collection, should I put it that way? So he signed over all all through the DEA, and we did everything appropriately. His library of I think it was about little over 12 or 15, different schedule ones of different classes, that enabled us to really start beginning to look at some of the structural differences in a lot of these drugs.

Nick Jikomes 1:11:45

Okay, so basically, you have to take really detailed notes, people come in from the DEA to inspect the lab, and it took you about six months to get approved. What would if someone wanted to go in blind and just come in from a different field? How long do you think it would take to get approved?

Charles Nichols 1:12:02

Oh, really depends. We had the the first ever International Society for the research on psychedelics meeting here in New Orleans last fall. So we had all, you know, a meeting for scientists, by scientists, we had the Hopkins team here, people from UCSF, all around the world, from the UK, from Brazil. But also included in that were speakers from the DEA, and from the FDA. Who were all telling us that? Yes, if you can show these drugs are safe and effective, we will work with you to bring these drugs to market as medicines and the presentation from the DEA actually address this topic, how long it takes to get a license and how to really get into the field and do that it's been going down year over year, so they're fairly effective now processing it probably maybe three to four months. Okay, DEA certainly is willing to work with people now. To help them get the licenses and the paperwork done that they need to really do this type of research.

Nick Jikomes 1:13:20

I see is that because today they recognize that there's enough evidence that there's really serious work to be done. Whereas maybe in decades past, if you put in an application, they would just say, what is this? What does this guy want?

Charles Nichols 1:13:33

Yeah, yeah, yeah. I think there's there's recognition now at at that official level that there is potential medical use, and the research needs to be done in order to determine if that's true or not. So to do that, we will facilitate, you know, getting the proper licenses and paperwork done to enable you to do your research. So they're really working with the investigators now, rather than being sort of a stop, no, what do you think you're doing? So that that's been a real kind of fundamental change in the research culture over the last say, five years? Okay,

Nick Jikomes 1:14:07

well, that's that's good. I mean, what, as a scientist, and as a citizen, what do you think the appropriate legal status for these compounds is? That's a difficult question, like lower Schedule D scheduled legalized.

Charles Nichols 1:14:27

I think across the board, legalization is not the way to go. At this point. I think rescheduling them into a proper category for medicine where they can be used as a treatment, I think would be probably ideal. What would that be which

Nick Jikomes 1:14:49

which scheduling level?

Charles Nichols 1:14:51

I, I don't know. I know, I know, Matt Johnson has written about the scheduling to schedule for something like that. Unlike something like marijuana, which has become recreational across most of the country, and in, for example, in Oregon, where they decriminalized and almost legalized, if, if not legalize psychedelics. I think that what a lot of people don't realize with psychedelics is there is the potential for more harm. If you have these really powerful, powerful medicines, and if if the wrong person say they had a history of psychosis in the family, or they had a psychosis disorder, or bipolar, and got caught up with somebody who didn't know what they were doing, there's really the potential of not healing somebody but harming somebody. And so I think there has to be really a regulatory framework around how the use of these psychedelics should be moving forward. In in aspects of therapy. Yeah, therapeutic arena,

Nick Jikomes 1:16:03

you often or at least, I've often heard that, you know, when people talk about the risks for psychedelics, the one that's maybe the most common that I've heard is that they can potentially trigger psychotic episodes and people that are already predisposed to that. Is that, is there hard evidence for that? And what is, what would you say the risk is there?

Charles Nichols 1:16:23

I think it's it's fairly accepted by everyone in the field that there is a risk of that. It's documented literature on the case report of psychosis after pick the drug in PubMed, so it does happen. And I think the incidence of it is less than 1%. But it's real, it's there. It seems that up to a person, everybody who has developed these persistent psychotic disorders after a psychedelic, and it doesn't matter, it could be the first time it could be the 50th time, somewhere in there. But if they do develop these persistent psychotic disorders, that's different than hppd, which are just sort of this percents of visuals. But it was what's hppd hallucinatory post perception disorder.

Nick Jikomes 1:17:10

So maybe, maybe just Well, that's a little different.

Charles Nichols 1:17:13

So it's, that's a case where people will take a psychedelic, and they will get persistent sort of visual perturbation, sparkles or things like that, that don't go away. It's kind of like tinnitus for weeks, months, or forever. weeks, months long term. And it's kind of like you tend to this is the ringing in your ear. Yeah. But it'd be sort of like visual tinnitus is sort of how I envisioned it. Wow, the treatment for it is essentially SSRIs. So people aren't as bothered by it. I thought,

Nick Jikomes 1:17:45

that's interesting. So SSRIs, that kind of makes sense, because there's more serotonin, it's going to compete with a psychedelic for access to a receptor, I guess, people in the recreational world tend to that's the belief that I hear from people that have apparently tried it where if you're on an SSRI, it actually weakens the effects of a psychedelic.

Charles Nichols 1:18:05

It varies from person to person. I think. With some people it does with some people, it doesn't there's no sort of steadfast rule, I think that there's a potential that, that it can. And it depends on what the SSRI is, and it I think, the there's an individual variation of the expression of serotonin to a receptors. That varies a lot between individuals. And so the response to a psychedelic I think, is really more how many receptors do you have in your brain compared to the next guy over?

Nick Jikomes 1:18:40

I see, so so genetically, people can differ in terms of how much of the receptors there and right the exact structure of that receptors,

Charles Nichols 1:18:48

right, like in the psilocybin studies, sometimes they'll maybe you only need 20 milligrams of psilocybin to get somebody to that peak experience where somebody else might need 50 milligrams. Yeah. And it's not really dependent upon body weight, it's dependent upon how much receptors you have and what the occupancy needs to be. So it's, it's really complex when you're thinking about sort of SSRIs and psychedelics, and there's a lot of factors that go into it. So it's, there's no there's no real sort of negative or toxic interaction.

Nick Jikomes 1:19:22

Gotcha. And and is that also true the toxicity thing that psychedelics you know, if you have a purified compound that they have no clear evidence of toxicity in the brain or, or elsewhere? Is that true?

Charles Nichols 1:19:36

For most so for the classic psychedelics like LSD, mescaline, DMT, five, methoxy, DMT, even really, in very, very high doses, from animal studies, human studies, there's no evidence that I'm aware of that it's doing anything dangerous, or damaging in the brain. In some of my earlier studies. I was getting rats. Why doses of LSD whopping doses of LSD and analyzing the gene expression in the brain. And I didn't see a single marker of toxicity or damage and the only thing that I was seeing was upregulation of genes involved in synaptic density increases. That I think where where the issues come in are with some of these research chemicals that that haven't been tested that can produce some sort of toxicity. Like the the n n bomb series of drugs that were popular on the recreational scene a few years ago when they came out as the TOC super toxic LSD. We had somebody here in New Orleans die of booty Fest, and it was all over the news. Oh, this super toxic and bomb they took

Nick Jikomes 1:20:48

synthetics that are related but different than I

Charles Nichols 1:20:51

think there was there was a little bit of part of poly pharmacology involved in a lot of these. But I have actually done some work with some of these embalm drugs A long time ago, over 10 years ago. And when I was giving a lot of them to my fruit flies, this particular series of drugs was killing my fruit flies. And it's the first time I've ever seen a psychedelic kill a fruit fly, like an overnight Wow. And then I did some investigations in the cells. And so there this particular class of drug use recreationally does have some kind of toxicity associated with it, but we don't know what that toxicity is.

Nick Jikomes 1:21:29

Okay. But the classical psychedelics even at very high doses, there's no clear evidence that they cause any physical damage.

Charles Nichols 1:21:36

Not any physical damage. No, not that I'm aware of.

Nick Jikomes 1:21:39

Wow. Have you ever I mean, if you've studied these for a long time, have you ever wanted to try or have you ever tried any of these compounds? I had fun in college. As as most people do, but but that wasn't that wasn't actually like a triggering event for you going into this field?

Charles Nichols 1:22:00

No, no, no. interested what was for my postdoctoral mentor? Okay, Dr. Sanders, Bush. And she always told the story, she taught this psychotropic drug story and why she got into the field that she had volunteered for an LSD study back in the 1960s. Oh, wow. And before it was scheduled one Oh, yeah, it was like 67 or 68. And it was at Vanderbilt. And the way that that she told the classes, she remembers it was in a room, a pool table, there was a record player, and maybe, maybe 10 people or something like that. And they all gave him a pretty big dose of LSD and put them all in this room, and just watched them, like these two way mirrors. And, and she said, she remembers some people play pool and this one guy was freaking out. And, and for her, she had a really, really unpleasant experience. Very, very unpleasant. She said, would not want to do it again, you know, sat and said setting is critical. And it doesn't seem like it was a really good set or setting to just put a bunch of people on on acid in a room and watch them through to a mirror.

Nick Jikomes 1:23:11

But if you ever tried again, or was there the experience, so she she didn't like it, but she wanted to go study it.

Charles Nichols 1:23:17

After that, she said that, you know, it was just so amazing how such a minuscule amount of drug you know, 100 micrograms could have such a profound influence on your cognition and your your perception. And it was so fascinating to her that that's what got her studying serotonin receptors. And she was one of the real early pioneers in serotonin receptors in psychedelic drug research back in the 70s, and 80s. But that's what got her on that path was that that just one time? It was a bad experience, but she recognized the potential there.

Nick Jikomes 1:23:57

Wow. That's interesting. I remember seeing a video of your dad on YouTube or somewhere. And, you know, it's in his lab at Purdue, I think. And someone asked him basically that question, have you ever tried this? And he just sort of laughed and smiled and said, Well, I came of age in the 60s. Yeah, yeah.

And he said, He's like, I'm pretty confident that we we make the the purest LSD in my lap here, anywhere on the planet. Yeah, I think so. So that's interesting.

Charles Nichols 1:24:31

Yeah, so he's, he's still making some chemicals for me. Okay, we're collaborating, and we've come up with some some new ideas in my lab, for some of these anti inflammatories and back and forth with him and he comes up with the structure and so we were working on a couple more that he's he's gonna try to make back in sort of, ideally retires

Nick Jikomes 1:24:53

I see. So he's synthesizing brand new compounds that he's designing. well designed. Oh, that you design nice.

Charles Nichols 1:24:59

Well, And kind of together. So when he retired, my brother lives in North Carolina, and his wife daughter lives in North Carolina. And so he's got grandchildren there. So they decided to move to Chapel Hill, which is far enough away that they couldn't drop the kids off, you know, at a half hour, 10 minutes notice. And when they move down there, Brian Roth, huh, here's an opportunity. So offered my father a retirement as a professor emeritus at UNC Chapel Hill, gave him lab space in his lab. So my father is just going into a lab and helping and doing chemical synthesis. And he's synthesize the thing that the compounds that Brian was using in the crystallography structures to get the crystal structure bellus of LSD and the receptor. Wow. So he's also working with me right now, to come up with the synthesis routes of some new drugs that we've come up with that now we're working with CRS to actually just do the chemistry for us now. But he's, he's still active in drug design.

Nick Jikomes 1:26:06

Cool. Yeah, you guys wrote, he wrote a paper together that I read recently called DMT, in the mammalian brain, a critical appraisal, and you basically go through some recent studies and and he's got another paper your dad about separating facts and myths about DMT. And I read those and they were, they were really good. People ask me about DMT all the time, in my personal life and elsewhere, it's really fascinating. For those that don't know, it's Can you describe what DMT what people say DMT is like, and then I would like to maybe talk about what the pharmacology is there, and do do some of that mythbusting work with you.

Charles Nichols 1:26:47

There's two ways that you can take DMT one of them is in the the brew I Alaska, which is part of the the religious indigenous ceremonies of Peru and and the Amazon. And that is an oral formulation that normally somebody would drink. And then there's a bout of nausea and vomiting followed by several hours of a psychedelic trip. A lot of times people during that trip, they they see aspects of the jungle, jaguars snakes, in that experience. The other way for DMT is to smoke DMT. And if you smoked DMT, it very rapidly within within seconds, will, as I understand it, transport somebody from this reality to some other reality that is very different, that often has entities associated with it.

Nick Jikomes 1:27:48

So on the on the spectrum of psychedelics, it's a, it's one of the more potent experiential,

Charles Nichols 1:27:54

yes, it's one of the most potent, and it only lasts for about 10 to 15 minutes. But during that time, that there's really no perception of time, from the people who have smoked it. So they can be lost in this space internally, for a long time. But then they come back, oftentimes report having conversations with alien entities or spirits, enlightenment, but it's very subjectively different than, say, a psilocybin type peak experience where it's, it's, you're separated from the reality and your ego, but there's still something there. But the DMT or five, methoxy, DMT is even more potent, is, is qualitatively different, that takes people to other realms where they're often more often interact with, with entities and beings.

Nick Jikomes 1:28:50

So you have just a complete loss of normal perception, you're in a completely different space. It's very visual. Like there's, there's intense visual hallucinations. And it's short acting. So that goes back to maybe what you were saying earlier, so this thing looks a lot like serotonin, your body can break it down right away. It's not sticking and getting stuck in the receptor like lsda. So it's very short.

So a lot of the a lot of the stuff that you hear is, you know, you'll have people describe these experiences that are very bizarre and very profound as you as you mentioned, but then they say things like, well, maybe this is this, is the molecule involved in dreaming or near death experiences? Is that Is there any evidence for that at all?

Charles Nichols 1:29:34

I do not think there is. I think the near in the near death experience, people do see visions, they hallucinate, they communicate with deceased loved ones. There are visuals. So I can see why people would sort of confound the two there was a study survey study done. I think it was maybe a year ago, maybe two years ago, where they actually took people who had had near death experiences and were experienced Psychonauts and ask them, Okay, which one of the drugs is your near death experience most like, and by and large, the drug that they said, the near death experience was most like was ketamine. ketamine, ketamine? It wasn't DMT it was ketamine. Interesting.

Nick Jikomes 1:30:30

So it's very different. It's a dissociative, right, right. It's not a visual hallucinogen, like dmts.

Charles Nichols 1:30:37

Right. Right. So I thought that, that, that that was just a survey report, but it was people who had had actual near death experiences who were experienced with psychedelics, Pinterest, and, and the drug wasn't, you know, it wasn't a close tie between DMT Academy and it was ketamine.

Nick Jikomes 1:30:51

It was ketamine.

Charles Nichols 1:30:52

It was not DMT. So, I think there's some disconnect between what people are calling a near death experience and what they actually are subjectively, or what they would like them to be like, or what they would like to imagine a near death, like a DMT trip?

Nick Jikomes 1:31:09

And what about the idea that DMT? is an endogenous compounds in the brain or elsewhere in the body? Is that true at all? Could it be acting? Could it? Is it even feasible that it could be acting as an endogenous neurotransmitter?

Charles Nichols 1:31:25

There's a probability of not zero. There, there are small amounts of DMT that can be found in various tissues of the body in the brain. Particularly, I think the pineal gland has been the one that's been most looked at what it's doing there is is it a metabolic byproduct? Or is it actually doing something, there's, there's no evidence that I've seen, that's really convincing to me that it's actually acting as a neurotransmitter to do anything. For one, there's just not enough of it in the brain.

Nick Jikomes 1:32:03

So very, very small levels,

Charles Nichols 1:32:04

very, very small amount. And given its affinity for the receptor, or how sticky it is for the receptor, which it's not, and all the amount of serotonin that's there, it's, it's, even if you're talking about micro dosing and occupying a small fraction of the receptors, it's, it's not even that much DMT in the brain. In some some animal models in a mouse model, to get a significant amount of DMT produced in the brain that would induce a psychedelic type behavior in an in a proxy behavior in a mouse is called a head Twitch.

The stronger that a psychedelic is in humans, the stronger that drugs will give head twitches to a mouse. So it will just sit there and Twitch several times. And to get a mouse to have a statistically significant increase in head twitches from endogenous DMT. They had to do some special genetic and pharmacological tricks to shut down some enzymes in this mouse to get enough DMT to produce something that was measurable. And you're not going to be able to do that in a person. Yeah. So I yeah, the idea that it's causing dreams, for example, every night is pretty much impossible. I don't think it is. Yeah, I think from a from a receptor pharmacology standpoint, that the probability that there's enough DMT in the brain to

activate serotonin to a receptors where they need to be activated, there's, you know, many, many more simple explanations for for dreaming than endogenous DMT.

Nick Jikomes 1:33:44

And I think the last big one is this connection to the pineal gland. There's this idea out there that the pineal gland, the the so called third eye, right in the middle of the brain, its synthesizing DMT and releasing it. Is there any evidence to support that

at all?

Charles Nichols 1:34:01

There, there is evidence that the pineal gland is is making DMT a lot of a lot of that work was done by Steve Barker, who was at LSU. The other LSU in Baton Rouge for a while he done a lot of he has done a lot of really good work with looking at DMT in the pineal gland, and I think, I think it's convincingly demonstrated that there is a small amount of DMT that is produced in the pineal gland. But is that because it's a Is it a just a byproduct of metabolism of something else or I've not seen any convincing evidence that it's actually being used as a neurotransmitter because the pineal glands main function is to make melatonin that regulates the, you know, the sleep cycle. And Melatonin is very, very closely related in structure to both serotonin and DMT. In fact, Melatonin is you have to make serotonin to make melatonin. Gotcha.

Nick Jikomes 1:34:57

So just close. Maybe maybe in the process. Making melatonin you just get a tiny amount of DMT as a byproduct or something like that could be Yeah, yeah. Okay, interesting. What? I guess what, what areas are you most excited about for the next few years not necessarily that your lab is focused on but anyone working on psychedelics, what do you think is? What do you think are some of the strongest candidates for, you know, real breakthroughs between psychedelics and some sort of therapeutic application and humans that gets approved?

Charles Nichols 1:35:30

I think, considering psychedelics as to a activators, and a lot of people will put MDMA as a psychedelic, but pharmacologically, it's it's not it's entactogenic, because it doesn't work through the to a, but it oftentimes gets lumped into psychedelic therapy. I think that's very exciting. And I think we'll hopefully see that given approval. They've already done and completed phase three trials, maps has already done that. So they're, they're pretty far along, I think, for silicides. And that's going to be the next major Game Changer is when the phase three trials are completed. There are two organizations now doing the phase three trials. So as you Sona, that's out of Madison, Wisconsin, and you've got compass pathways that's out of the UK, and they're both doing phase three trials for different aspects of depression. One is treatment resistant depression, which is the compass and one is major depressive disorder, which is you Sona. And I think within the next three to five years, they finished out those phase three trials get get good data, pretty excited about that. I think one of the things I've been most excited about is some of the work of what Peter Hendricks has been doing at University of Alabama. And rather than taking sort of your middle class white millennial, or, and, and giving them antidepressant therapy, what Peter is doing is he is treating essentially homeless, African American crack addicts with psilocybin. Wow. Which is you can imagine taking people off the streets, they've been on drugs for almost their whole life hard drugs. And test results so far, have just really been astounding. Some of the these people have been have been transformed. They get themselves out of the ghetto, they're seeking social services, is this publish work yet? It's not published yet. Oh, not published yet. But it's, it's some I think, when it is published, that's, that's, I think, what I'm most excited about is not so much depression, I think, I think that's going to be a given. And it's going to help a lot of people. But the kind of people that that I'm seeing, that need the most help leaders been successful with these are the dregs of society. These are the people that have been cast out, have have been tossed away, there's nothing left for them, and they're coming back into society reconnecting with family seeking social services, staying abstinent. It's really having this transformative effect. And I think, to me, in terms of the therapy, I think that's really the most exciting to me is being able to help really this unhelpful population that's just been written off.

Nick Jikomes 1:38:41

Wow, that's amazing. So Peter Hendricks, you said,

Charles Nichols 1:38:44

Right, right. He's at the University of Alabama in Birmingham.

Nick Jikomes 1:38:47

Well, I didn't even know that was going on. That sounds really exciting.

Charles Nichols 1:38:52

Yeah, I think he's had that study going for several years now. It's hard to recruit. He's he said for that to, to get those those people to come in and actually go into therapy. But it's really fascinating. And then there's other they're using, I think psilocybin therapy out that one of the groups at UCSF for like aids survivors.

Or there's several several different areas now where it's just expanding out of major depression. I think that there's over 30 clinical trials now registered on clinical using psychedelic as usually a psilocybin.

Nick Jikomes 1:39:36

Okay, yeah, there's there's a lot going on. And like even in the private sector, you're seeing all of these companies springing up. Oh, yeah. What do you like? What do you make of the the private sector is this, you know, how much of this is legitimate? And how much is just people trying to capitalize on a hot market right now? Like, do you expect most of these companies to actually do lasting work or do you I think that there's, there's a bit of exuberance going on.

Charles Nichols 1:40:05

I think it's both. I think, the company that I'm involved with eleusis, we formed in 2013. And we were the very first company aimed at developing psychedelics for therapeutic use. And we were alone in the woods for a long time, until compass pathways came around. And then once they had success, then you had my med came around. And now it seems like every, every day, there's three or four new ones that are popping up. It's just amazing to see that where you know, 10 years ago, you tell somebody you're doing psychedelic research and they roll your eyes at Yeah, and now it's all tell me more Tell me more. But I think it's really it's the Wild West right now. It's, it's you've, you've gotten a lot of money that a lot of money from the cannabis side of things now that that's been saturated. they've they've made millions off of cannabis. Where do we go next at psychedelics? So there's a lot of Alright, here's an idea. There's an idea. A lot of different companies are springing up with different takes on things. Some of them I think will be successful. Some of them, most of them probably will not. It'll be a boom and a bust. How long that cycle is going to be? I don't know. But I think there will be at least a few that are successful. I hope we're one of them. Yeah. But I think I think it's really going to be transformative. And for for some of these smaller companies that are coming up with some some new ideas sort of thinking outside the box. It'll be interesting to see how those come up.

Nick Jikomes 1:41:36

So your company eleusis. Did you did you start that company?

Charles Nichols 1:41:39

No, no. That was founded by slummy Ross, who is a former reform, I think, reformed Wall Street banker, who contacted me gave me a call in my office to just chat about research, I think is 2013 2014. And it's turned into a real partnership where they've licensed all the anti inflammatory IP that we've been developing over the last several years. So I'm sort of been kind of the driver of the anti inflammatory research effort there, but officially, on the advisory board, chairman of the Advisory Board of eleusis, and sponsored researcher

Nick Jikomes 1:42:28

and are they focused just on inflammation treatments, or are they working on other other avenues as

Charles Nichols 1:42:33

well? Oh, other avenues as well. Recently lusas has acquired ketamine clinics in Texas in order to expand in house clinical testing facilities to do phase one, phase two clinical trials with novel formulations of ketamine and also with psilocybin. So, we believe that there's, I think, really kind of multidisciplinary we're on in wide area looking at novel formulations, ketamine and psilocybin and treating depression, looking at the use of LSD to treat Alzheimer's disease as a neurodegenerative disease and how they've already done their phase one safety trial with that. I think there's a lot of

Nick Jikomes 1:43:21

when you say novel formulations of ketamine and psilocybin, what does that actually mean?

Charles Nichols 1:43:27

Um, I think that's that's we just had a new website go up next week, and it's based on the one that we're looking at now. It's it's a formulation of ketamine that we're calling cat plus.

Nick Jikomes 1:43:41

But is it ketamine and other things? How is it different from what's already used?

Charles Nichols 1:43:47

It's a combination of ketamine with two other drugs to prevent some of the side effects. I see. I see it are often associated with the use of ketamine, that dosha bank will enhance patient response.

Nick Jikomes 1:44:02

Okay, so it's, that's it is a novel formulation. It's, it's ketamine plus these additional drugs, right, that, in this case, reduce side effects. Right, right. And then is it similar for silicided or people coming up with formulations where it's silicides and plus some other stuff?

Charles Nichols 1:44:17

There, there are a lot of people doing things with silicides out there. For example, there's one company that's developing sub sub lingual silicided where it's like silicided on a basically

one of those

Nick Jikomes 1:44:34

rattletrap dissolvable tabea

Charles Nichols 1:44:36

things there are people trying to come up with new analogues of psilocybin thinking that suicide we may not be the best drug maybe we can come up with a better drug. So there's there's a lot going on in a space right now. That it's it's it's gotten beyond my ability to keep track of how to record paces

Nick Jikomes 1:44:58

Yeah, one thing that I'm hearing The psilocybin side, which is something that you hear on the cannabis side where I work all the time is this idea of the entourage effect. So maybe one. One last area I'll ask you about is with magic mushrooms, you've got psilocybin, and then the active drug that comes from that cillessen. And is there anything else that's being produced by the mushrooms? Or is that all hypothetical right now,

Charles Nichols 1:45:24

that's pretty much hypothetical. Although within a mushroom, you are getting a half a dozen or so alkaloids that are very similar in structure. The psilocybin, for example, there's nor, nor silos, and there's based system, there's things that look very similar. But in terms of the actual, an actual drug that will produce a peak experience. So far, it's it's still a seibon and celulose. And so the other drugs that are in there, they may be adding a little bit of texture to the experience, but it's not formally been been looked at. And there's certainly not that I'm aware of any other alkaloid that seeing a mushroom that will really activate the to a receptor to produce these psychoactive events.

Nick Jikomes 1:46:12

Interesting. So are there any, are there any areas of research that you think are completely untapped yet, where no one has really looked? In regards to psychedelics, so you've got like all the depression stuff going on? You've got all this inflammation stuff that you described, you've got the end of life anxiety stuff? Is there? Is there anything? Is there anything exciting that's maybe going on quietly that that hasn't really come into the limelight yet? Oh,

Charles Nichols 1:46:41

I think it's what hasn't been done yet. My father sometimes is said of psychedelics, you know, they're their Philosopher's Stone. What do you know, what aren't they good for? We have found that there are some disease models that they don't work in. So that's a good thing. It's It's It's not going to be a panacea. But I think there are so many, so many disorders and diseases that are yet to be looked at, beyond inflammation beyond psychiatry, that they could be beneficial for we've got some evidence that it could they could be beneficial for diabetes and metabolic disorder, high cholesterol in our in our model, we reduce cholesterol, with with exposure to, to our drugs. And that's probably not through an anti inflammatory pathway,

Nick Jikomes 1:47:33

which drugs are doing that.

Charles Nichols 1:47:36

We saw that with DUI, a typical drug. And we we normalize glucose homeostasis in this model, there's, it's like a pre diabetes model. So there are there appear to be a lot of effects, not just limited to anti inflammatory, or normalizing neuronal circuits for for psychiatric disorder, that the to a receptor. It's literally on basically every cell and tissue in your body and what it's doing there. We don't know. I think there's some exploratory work now that's going into pain, looking at you know, maybe analgesia. There's just, I think so many open areas, is just waiting for somebody to look in Model X and and see if it's having a therapeutic effect or not.

Nick Jikomes 1:48:27

Yeah, well, I mean, hopefully with, you know, the DEA, working with researchers more than they have historically, with this influx of money going into research. Hopefully, that's just going to start happening more.

Charles Nichols 1:48:38

Yeah. One, one of the one of the things that hasn't really been happening that much is government sponsored research. Pretty much all of the research that's been going on all of the studies, the the MDMA studies that have happened to clinical trials, the psilocybin trials out of Hopkins, NYU, those have all been funded by private sources, private donations, private foundations. In fact, a large portion of my laboratory is funded by a private donation. Another portion is funded by eleusis. There's no NIH funding for psychedelic research per se. And I'm hopeful for that. I think that NIH is receptive, I think, once they're shown as medicines and successful, I had the director of the National Institute of Mental Health come to a presentation of mine a couple weeks ago, and we had a very nice chat about the model and psychedelics and their therapeutic effect. So I think they get it. So I think once it really comes out of the closet, psychedelic research, and we get government funding, in addition to private funding that's really going to sort of open it up to really understand the true medicinal, medicinal value of these, so we're not really dependent upon a small group of people to really drive the funding of these studies?

Nick Jikomes 1:50:05

That's great. Yeah, I hope it keeps moving in that direction. We've been talking for almost two hours, Charles, so thank you for taking the time. Is there anything, any any final words that you want to leave people with?

Charles Nichols 1:50:21

I think it's, it's, I think a lot of people don't really appreciate where we are now, today in terms of psychedelics. When I started in this field, my father told me it was going to be the kiss of death for my career, because nobody cared about it, nobody. But I persevered, kept at it, made some discoveries. And somewhere along the way, a group here therapeutic efficacy, a group there, it helps with depression. And it's really snowballed to this this point where

I think my father thought he was going to be dead before any of this would happen. And to just the way that society has changed his attitudes and becoming more open and more accepting about the use of psychedelics, and you get people's grandparents asking now about it, as opposed to what is that it's just this this fundamental shift, this paradigm shift in our culture has occurred for the better, and our understanding of psychedelics and I really do believe that there's a tremendous amount of healing opportunity to in these medicines to be developed. And whether or not I know, there's a debate now you have corporations are now developing psychedelics and taking the the magic out of it. I think that's, that's a straw man. The psychedelics are, what they are, whether they come from a laboratory or from a plant. And as Dennis McKenna said, at an event,

a couple years back, we were together, it's the magic is not from where the psychedelic comes from, they the magic is the molecule and whether that molecule comes from a laboratory, or a plant, it's the same thing. So I don't think that should really be any stigma, on you know, developing medicines, if it comes from a plant, if it comes from a laboratory, that we all want to help people. And just because, say, Reading University, or read a company, we're not just all trying to make money, we really do want to develop these medicines and help end and alleviate suffering. And so I think the community kind of needs to get over a lot of the schism that's developed and just come together and realize it's all for the greater good, and we're all trying, we're all trying to really to help each other.

Nick Jikomes 1:52:46

Well, Professor Charles Nichols, thank you for joining us. That was amazing. I hope to talk to you again at some point. And, again, just thank you. Thank you for taking the time. Thank you for inviting me. It's just a pleasure.


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