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Biochemistry & Molecular Biology of Serotonin Receptors, Tryptamines & Psychedelics | Ryan Gumpper

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

Ryan Gumpper 4:44

A half years now started my official start date with may 2020. So right in the middle of the pandemic, oh, I couldn't actually get into the lab until I think it was mid June or so. So we started working in shifts And then yeah, just, you know, hit the ground running with a lot of the research that we've been doing.

Nick Jikomes 5:05

Yeah. So I mean, can you just explain what your what your PhD was in? Like what kind of scientist you are and what what level? You're thinking things that? Sure, yeah.

Ryan Gumpper 5:14

So my PhD was in actually doing research on viruses. So molecular virology, structural biology of those viruses, I did a lot of work on class of viruses called negative stranded RNA viruses. So if you think of like, you know, SARS, cov, two, that's positive stranded RNA virus, this is the opposite strand of that. So instead of using their genome to directly kind of translate proteins, for that the negative stranded RNA viruses actually have to make the mRNA transcripts from their genome, which then gets translated to proteins during the replication process. So a lot of my focus was on the structural proteins that surround the genome, and then trying to find various, you know, small molecules that would interact with this and potentially block the transcription process of that. And these are viruses, you everyone's heard of, you know, like flu, Ebola, you know, those types of viruses.

Nick Jikomes 6:18

So, so how did you get into Brian Roth's lab? Is that tied to your actual biology and the biophysics of this?

Ryan Gumpper 6:26

Yes, yeah, kinda Exactly. So actually, so my interest in psychedelics kind of goes all the way back to when I was finishing. So actually, I have two degrees in undergrad, one was in music. And then the other one is obviously in chemistry. But nearing the end of my music degree I got, I read shoguns, book, and pekao. And got really interested in kind of just overall chemistry, science behind things. And my initial thought was to try and go to med school. But then I learned, you know, I could actually get a PhD in chemistry, doing like structural biology type stuff. Within that, and I went the route to go get my PhD, though. Then after my PhD, I had taught myself like how to code and do a bunch of AI and data science type of stuff, during my PhD to do some of my research. So I actually worked as a data scientist a little bit but didn't really feel myself fitting in with that more kind of, you know, corporate type of workspace. And I have the blue is just like, you know, really want to try and study psychedelics. I know about Brian's lab from his work on solving the five ACTB LSD crystal structure. And I just reached out to Brian, and he was happened to be looking for structural biologists to work on them. So that's kind of how I got into Brian's lab.

Nick Jikomes 7:44

Interesting. So what are you working on in Brian's lab? And Can Can, can you talk about what you're working on in particular, and then just sort of give maybe give people some context as to what the lab does in general?

Ryan Gumpper 7:55

Sure. So what I'm working on in particular, is the five HTT to a receptor, I work on our large DARPA grant project that we have that's working with multiple institutions. The whole idea of that project, is to come up with non psychedelic psychedelics. So agonist, the hit the five HTT, to a receptor, but don't necessarily cause hallucinations. And that's kind of the whole premise of that grant. I also work on the five HT to see receptor. And within this, I'm very interested in the structural biology, so how all of these molecules interact with the receptor, and how those interactions interplay with the functional downstream effects of those receptors. I see. So that's, that's kind of my overarching kind of thing. I also mentioned a lot of like, computational stuff with that as well. So MD simulations, more AI machine learning stuff, as well.

Nick Jikomes 8:58

So, you know, for everyone listening, this will probably not be the best episode, if you are wanting to just start to learn about psychedelics and the underlying biology, this one might be more appropriate for someone who already knows that, and really wants to go into more detail on the small stuff, meaning literally the small stuff, the molecular biology, and the biophysics of like what is happening when classical psychedelics are doing what they do inside of the brain. But nonetheless, let's build a reasonable base for people here. So we've already started talking about five HT stuff, and, and and some detail, and we're going to elaborate all of that, but let's just let's just start out with some some pretty basic stuff here. So what are brain receptors and can you sort of maybe compare and contrast the the ion channels versus the metabotropic type receptors?

Ryan Gumpper 9:58

Yeah, sure. So There are a couple that are obviously like ion channels, and then receptors, which what's they're all like GPCRs, or G protein coupled receptors. So, ion channels kind of is exactly what you call it, they're a channel that selectively allows permeation of various different types of ions through. So you can think of sodium ions, potassium ions, calcium ions, and these can both be like voltage gated, meaning there is a charge difference between the inside and the outside of the membrane. And then that allows the channel to selectively start to open or close to allow various ions through or ligand gated, which there's some sort of ligand that binds to the outside of the cell of the membrane, which then activates or Allosteric ly, you know, modulates the channel to actually allow the permeability, then of the ions through the membrane. So the distinction between that and GPCRs. So GPCRs actually don't let anything through they act as a signal transduction modulator, essentially, so you have a ligands, that would come in and bind, which then stabilizes an active conformation of the receptor, which then causes a signal transduction cascade through that, and these can be various different things. There are multiple ones, there are excitatory ones, and also inhibitory ones that do that. And then there's also things that work directly more on transcription.

Nick Jikomes 11:25

I see. So for neurons to do what they do, it's it's all about how charged up they are or not, that determines whether or not they flare signal. So you've got ion channels, where you have ions like sodium or potassium and or other ions that literally physically flow through the channel just like water flowing through a channel in our macroscopic life. And that determines how charged up the neuron is. But then there's these other types of receptors. And that includes things like GPCRs, and there's nothing flowing through them. But something like a drug or some endogenous compound in the body binds to them, and then that on the outside of the cell, and then on the inside of the cell, stuff happens based on how everything is sort of hooked up.

Ryan Gumpper 12:10

Yeah, which in some cases, they activate ion channels, they'll inactivate ion channels, it depends on cell type, receptor type, things like that. So it's, it's a very complicated process, and there's a lot going on, but it's all kind of intertwined with each other as well.

Nick Jikomes 12:25

And so you've already mentioned, you know, you work on the 5g to a receptor, other five HT receptors, these are serotonin receptors, how many serotonin receptors are there, and which of these types are they.

Ryan Gumpper 12:39

So there are seven different serotonin receptors. Six of them are GPCRs. One is actually a ligand gated ion channel. So five HT three is a ligand gated ion channel. So there is the five HT one and five HT five, and there are various subtypes of those, but they are mostly signaling through Gi, which is an inhibitory pathway. There is the five HT to family, which for our cases in psychedelics are there are a lot of them bind to them and interact with them, the to A to B and to C receptors, and they all signal through an excitatory GQ pathway. And then five HT four, six and seven, they primarily signal through GPS pathway, which is also excited to her. And you know, these are found, you know, scattered throughout the brain and actually the whole body of all these different serotonin receptors expressed in different regions expressed in different areas, different subtypes as well, so

Nick Jikomes 13:52

and so is it is this typical? So if you have a neuromodulators, say, like serotonin or dopamine or acetylcholine or whatever, is, is it normal that you would have several different types of receptors in the brain that one would bind to or are there typically more or they're typically less.

Ryan Gumpper 14:10

So I don't know about that particularly, but I think serotonin is actually the most complex out of all of them, they have the most different types. And you know, the dopamine receptors have a bunch of different types. There's also a bunch of like different opioid receptors as well. But I think off the top of my head, serotonin may have the most different receptors, and kind of the overarching family. And then if you drill down into the different subtypes, definitely for more than that, like I think five HT one has five different subtypes within that. So there's five c, one A, B, D, and E.

Nick Jikomes 14:46

I see so you could almost imagine like a family like it wouldn't be basically a literal family tree here where you've got five issue one receptors, two receptors, three receptors, but then, branching underneath each of those branches. You've got multiple Type one receptor have multiple type two receptors, and so on and so forth. Yep, exactly. And where do all these things come from, in an evolutionary sense? Are they come are there, you know, genes that encode these receptors, and they've been sort of duplicated and mutated and changed over time.

Ryan Gumpper 15:15

Yeah, so they're pretty ubiquitous, I think, throughout more complex organisms. We, yeah, the biggest, most of the organisms come more complex organisms, they. So throughout mammals, it's actually relatively conserved. I know, for the five HTT to a receptor, there are various mutations that occur, and maybe we can get into that, and how that affects Psychedelic Studies in particular. But But yeah, well conserved throughout most of the, you know, more complex animal kingdom.

Nick Jikomes 15:50

Yeah. And one more very basic question to ground people. You know, we're talking about serotonin receptors, but we keep saying five HT to five ft. One, what is the five HT part of this? And why is that serotonin,

Ryan Gumpper 16:02

so five HT is the actual it's an abbreviation for the actual chemical name, five, hydroxy tryptamine. So you can think of if you want to kind of explain it, you have one six membered ring, joined by a five membered ring kind of together. And there's a nitrogen at the point of the Pentagon on the five membered ring. And off of that you have a tail with another a carbon tail with another nitrogen. And at the five position on the six membered ring is a hydroxyl group. So an O H group, and that's what they call it, five, hydroxy tryptamine. And there are various, you know, a lot of psychedelics are in the tryptamine class. So they'll have this tryptamine core, which is that two membered ring system with the tail. And then there are various substituents off of that. So when I say five, is she serotonin or five, hydroxy tryptamine.

Nick Jikomes 16:57

I see. So tryptamines is a chemical class, you've basically got a pentagon stapled to a hexagon, you have some nitrogens in there, and, and then there's sort of variations on that basic core that give you the difference between serotonin or DMT, or psilocybin and so forth. Yeah, exactly. Okay. And so these receptors, so when we talked about the 5g to a receptor, as we will quite a bit today, this is the so called psychedelic receptor. It's the one that classical psychedelics bind to, it's obviously also a serotonin receptor. You know, before we get into the psychedelics, how selective are these ligand gated receptors and GPCRs. So, you know, endogenous Lee's is serotonin, like the only thing that binds to them is there other stuff that binds to them.

Ryan Gumpper 17:45

In dodge, honestly, I think serotonin is really the only thing that binds to them. Now, when you are talking about, you know, other psychedelic drugs, there are a lot that will bind to other types of receptors. There, a lot of them are fairly I guess you can call them nonspecific or dirty drugs. You know, LSD, will bind to not only all of the serotonin receptors, but there's evidence that it binds to the dopamine receptors as well. So there's, they're, they're very promiscuous in that sense, and bind to other receptors in the brain mediating their actions.

Nick Jikomes 18:23

I see. So the serotonin receptors themselves relatively selective for serotonin in terms of their natural ligands. But the tryptamine psychedelics tend to bind to multiple serotonin receptors, including fiber sheet to a as well as other receptors, and you know, the exact mix of things they bind to just depends on the drug.

Ryan Gumpper 18:43

Depends on the drug. Yep, depends on the substituents. Yeah, you have so I guess we can go into like, there's there's three different types of, I think, three classifications of psychedelics, you can kind of put them into these three different families. We've already talked about the tryptamines, which closely resemble serotonin, kind of underneath that you can think of Ergoline which is more rigidify tryptamine. It has extra ring systems on it. And this is a drug like LSD. So there's a whole class of LSD like drugs which have a tryptamine core that kind of come out of that based on the substituents. And then you have phenethylamines, which are actually most closely remember resembled dopamine. But these are substituted they are six member ring, and they usually have various oxygens on it and but there's still that at that tail, and then there's a free amine or nitrogen at the end of it. So a lot of these compounds will activate a lot of what they're called the M and nergic type receptors, because of this free a mean there and they interact all within a very similar manner. In that sense,

Nick Jikomes 19:56

what would be an example? What are some examples of phenethylamines

Ryan Gumpper 20:00

So you can think of mescaline. That's kind of the classic psychedelic phenethylamine. Yeah, that's kind of the classic one. MDMA would be a type of a friend methyl phenethylamine as well, although that doesn't doesn't hit any of the serotonin receptors really too much. It's quite weak in that sense.

Nick Jikomes 20:23

But yeah, okay. So in terms of 5g to a the serotonin to a receptor, the one that is famous for being activated and responsible for the psychoactive the psychedelic effects of psychedelics, walk us through, you know, start to walk us through what happens when, let's just start with serotonin. Serotonin binds to this receptor, what exactly happens to make stuff happen to make a cell do something after that happens?

Ryan Gumpper 20:54

Sure. So these receptors are interesting. So they so kind, let me back up here. So a lot of proteins. When you draw them in, like the scientific figures, they're normally drawn as like blobs, or just like a big blob, or a cartoon, or sometimes you'll see like transmembrane helix seems kind of coming through. And a lot of people may think of them as just the static entities, they're really not. So with the serotonin receptors, and GPCR receptors, in general, they're actually constantly moving in, they're switching between different states. So what are other multiple different states within these receptors, you can think of like an inactive state to an active state transition. Now, these molecules when they bind the receptor, they will stabilize one specific state of that receptor. In this case, serotonin will stabilize an active state, which causes a conflict, which is in a conformational, state of the GPCR that allows the transducer and this case for the five HTT to a receptor valleys T family is G alpha q, Beta Gamma heterotrimer. And then once that heterotrimer binds to the the intracellular side of the receptor, there is an exchange of GDP for GTP. And this then causes the alpha, the G, alpha and beta and gamma to dissociate from each other, and move away from one receptor and then go through their downstream signaling, occurrences here, G alpha q, then we'll go and activate a PLC, which then cleaves PIP two into its constituent parts of you know, DAG, and IP three or diacylglycerol, and icon three, that then goes to release intracellular calcium stores and you get calcium signaling that you can actually see. And then there's other PKC, that gets activated as well. And that is responsible then for all of them here, the effects of protein kinase. See that happens, then throughout the cell,

Nick Jikomes 23:10

I see. So, so there's multiple steps that happen here. So you've got a receptor, the serotonin to a receptor to GP car, which means it's not an ion channel. So it's not opening and closing to let the electricity basically flow through it, it is able to have a drug or an endogenous compound like serotonin bind to it on the outside of the cell, but it is it is going through the cell membrane itself. And on the other side, on the inside, it's hooked up to some protein machinery. And whether or not it's bound by serotonin or a drug or something determines whether that machinery is just sort of like sitting there idly on the inside stuck to the the other end of this receptor, or it gets activated and then goes on to do other things in the cell.

Ryan Gumpper 23:58

Yeah, I mean, essentially, that's what happens. So actually, in the States, the ligand binds first to the receptor, which actually Prime's it for that machinery to actually come in and bind to the receptor itself as well. So there's a myriad of like Protein Protein interactions happening, then once there's activation occurring, then there's an exchange that occurs which gives energy for them to dissociation and conformational changes and those proteins to move the Torstar down other downstream signaling effects I

Nick Jikomes 24:28

see. So instead of thinking of the receptor, as you know, just receiving signals from the outside of the cell, it's it's really receiving signals from both and when those sort of line up in the right way then interesting stuff happens happens. Yeah, I see. So okay. So, so, receptor is bound on the outside by serotonin receptor is interacting on the inside with these interesting proteins and they get activated through through various biochemical mechanisms. And then some other stuff started to happen. What walk us through the fairly basics of that other stuff, and then talk about like, what is the end goal? If we anthropomorphize here, like what what is what is the end result of this that the cell is is trying to achieve?

Ryan Gumpper 25:16

Yeah, so. So once it binds to those, I think we were talking about this before. So we have this G, Q, beta, gamma heterotrimer, these things dissociate from each other. And that GQ, then we'll go and interact with another membrane bound protein called PLC. And this is a phospho lipase. So this will go then and cleave the of the fatty acid, but it's Pip pip two. And that's it's yeah, it's essentially a fatty acid. So as a sugar group on top and along diacylglycerol, fatty chain on the bottom, which is just a bunch of carbons, you can think of down in a row. And this thing cleaves the into constitutive parts into dye subglacial on IP three. So it'd be three as a as a sugar, essentially, with three phosphate groups on it, and then that will go in IP three will go and activate various calcium channels to release and dodging endogenous intracellular calcium that's kind of stored up within the cell. And then deisel Griffes, glycerol will go and activate PKC as well as the calcium will activate protein kinase C. And that will then go and phosphorylate a lot of various things, other calcium channels within the cell, and other downstream effectors. Now, the ultimate goal of this would be the second messenger signal, which is calcium, and that acts as excitatory for neurons, so that increases their firing rings. And ultimately, also, this other phosphorylation and stuff and a lot with a lot of these trucks are finding out as their therapeutic effect actually leads to formation of spine or spinal agenesis on the neuron. So you can think of you have more interactions and networks within these neurons themselves.

Nick Jikomes 27:20

Okay, so let's break this down a little bit. So serotonin, or psychedelic binds the five HTT to a receptor, this GPCR proteins sort of hooked up to the other side of that receptor on the inside of the cell become activated. A bunch of biochemistry happens with the prime sort of primary result being calcium gets released from the inside of the cell, which also is connected to calcium may be coming inside the cell through an ion channel. And calcium is super important, right? Like, I think the average person thinks of calcium, they think of their bones or something. But it's very important for this kind of process and neurons. And it can activate different proteins inside of the cell that that do certain things, and it has the sort of excitatory effect on the cell. And then, so you said spine agenesis, but let's connect the dots here between the calcium increasing within the cell, after the GPCR is activated. And then stuff happening maybe in the nucleus of the cell.

Ryan Gumpper 28:18

Yeah, so there are various transcription factors and such that get activated from this signaling cascade, which then lead to the formation of new structures and spines within that.

Nick Jikomes 28:32

I see. So So when when people hear about something like psychedelics causing neuroplasticity, are causing new connections to form. This is what you mean by spines? Yes, yes, exactly. Exactly. And so and so literally, you know, compound binds the receptor, proteins get activated inside the cell, calcium goes up, it gets more concentrated inside the cell. And among other things, different genes get turned on, such as those that encode proteins that will actually be used to physically build new connections.

Ryan Gumpper 29:06

Yep, exactly. And that's, that's only so that's actually that's like one side of the signaling pathway of these receptors. There are a couple of other signaling pathways that actually occur as well. But this is kind of where you hear a lot about the therapeutic effect of psychedelics, their antidepressant effects, and why a lot of people are thinking about it in this way. They also coupled to another protein called the rest in which goes and that also has various signal transduction pathways as well. And then, another one that is a potential complexes PSD 95 are posted in ASIC postsynaptic density protein 95. That is also known to interact with the five HTT to a receptor in particular When it comes to psychedelics, but yeah, a lot, a lot needs to be studied about how how these different signaling pathways, whether they lead to hallucinations, whether that leads to therapeutic effects or not.

Nick Jikomes 30:11

And so, you know, so we sort of sketched out for people, one of the pathways that can be linked to 5g to a receptor activation, this is the G protein complex and the calcium effects and the stuff we were talking about. But now you're saying that there's these other protein complexes that can also be hooked up and attach this receptor on the inside of the cell? So if you've got a cell, like a neuron in the brain, just will think about one neuron is it is the five HTT to a receptor that that cell has the many of them that are in the membrane of that cell? Are all of them going to be hooked up to the G proteins, or some of the G protein some to arrested in this other thing? Or how do we think about that.

Ryan Gumpper 30:55

So how we think about that is the G protein side when the shutter is activated, is actually happening over and over again, this is where you get the signal amplification. Now, at some point, the receptor will get phosphorylated. itself. And this usually happens, you know, from various other kinases, gr K's, things like that. And then once it's phosphorylated, the canonical point of view that kind of turns off, the receptor is something called a rest. And you can think of a rest and because it's called resting on the signaling, yeah. And in particular, with the five HTT to a receptor, these are the thought to then cause actual internalization of the receptor. So the receptor will then get brought in from the membrane itself. So it's no longer there. It can no longer say, actually, like, turns off the receptor and stops

Nick Jikomes 31:52

the spicy. So instead of, instead of maybe thinking about these as completely an utterly distinct serotonin to a receptor protein complexes, it's almost like it's like multiple degrees of regulation. So you know, sort of typically, you first think about the receptor getting activated and doing the G protein stuff that we talked about with calcium and all this. But if that keeps happening, so for example, if LSD is around, and we know that LSD binds to the 5g to a receptor for a long time, and causes a lot of activation, the cell, you know, as part of it sort of negative feedback loops and regulation and homeostasis, if that receptor is activated a lot and that G protein is activated and activated and activated. This other thing comes in called arrestin, which is named for the fact that it kind of kind of opposite and turns it off.

Ryan Gumpper 32:44

Yep, exactly. And there are a whole bunch of interesting things that I think are not particularly well known. Like, we know, they get internalized. But is there additional signaling that's occurring? Once it's internalized? Like, these are all questions that need to be to be answered?

Nick Jikomes 32:59

I see. So is it fair to say or it says her knowledge, currently sort of view this as any agonist, any activator, the 5g to a receptor? is going to engage the internal G protein structures and these other things? Or are there drugs that can selectively engage specific pathways inside the cell? Yeah, so

Ryan Gumpper 33:23

that's kind of the whole premise of our DARPA grant is to figure out how we can selectively design drugs to stabilize one signaling pathway over another signaling pathway. So we could potentially start to target, you know, different therapeutic effects, get rid of various side effects, or in this case, can we question I'm trying to ask is, can we get rid of hallucinations by this? So yeah, so this all comes down to the idea of potency and efficacy. So how well does this drug stabilize the active state given for like a GQ? Or how low does this drug stabilize the active state for the arresting type of pathway and signaling pathway? So what you can think about is, you know, some drugs are much more potent, meaning you need a very little bit for them to fully activate the receptor, if you think of like a dose response S curve. So where you as you increase in concentration, the activation, the receptor goes up, and at some point, you reach a plateau. And the efficacy of that is how well that actually activates it compared and we always kind of compare it to the endogenous ligand in this case. So you can compare it to like serotonin where we would say that that's something like you can say 100% And we'll say like, LSD is like 60 to 70% of that while being very potent, but it only activates the receptor 60 or 70%, as much as like the native endogenous ligand serotonin would, and these are all different for diff pathways and different drugs?

Nick Jikomes 35:03

Well, so let's let's so there's an idea here, which is very interesting. And I'm going to, I'm going to try and summarize it for people, as I understand it, and then you can comment on that. And then and then we'll sort of dig into this a little bit more. The idea is, okay, we've said that you've got these receptors 5g to a receptors, serotonin, and other drugs bind to them. But there's different sorts of information pathways that can get turned on inside of the cell, depending on all of the gory details here. Is the idea. Or are there examples where you so let's take the G protein example, the sort of canonical stuff that we think about happening inside the cell, when a GPCR, like, like serotonin to a receptor is activated, or bound by a drug? And then you mentioned this other thing called a rest in which turns it off? So my question is, are there drugs? Or do we think it's plausible that there are drugs that can not turn on the G protein complex part of this so much? And turn on something like a Rusten? And if so, is that arresting complex? Is it there simply as a homeostatic thing to turn off the G protein stuff that happens? Or does it go on and do other things and like turn on other genes in the cell or something like that?

Ryan Gumpper 36:25

Yeah, so So the resting complex, it doesn't just like necessarily turn it off, there is signaling pathways within the arrestin kind of activation, one of the more like downstream ones that everyone talks about sounds like IRQ. That's a transcription factor that will go in turn on different genes and things like that. And I do think that this needs to be kind of fleshed out further. You know, the G protein site is fairly easy, if you think about to measure because there's a whole bunch of secondary measuring downstream signaling occurring there. So in the way we measure a lot of this is through various fluorescent type assays or Brett assays, which actually looks at you can think of it it looks at proximity, so their proximity assays, like if these two proteins get together, we know that they're close to each other, and then they can move on from there. So So yeah, I mean, there's a ton of other stuff that the arrestin kind of signaling pathway is doing within that.

Nick Jikomes 37:27

And so, obviously, a lot of complexity and a lot of ambiguity inherent, like sort of ambiguity here with all of this stuff, and all the biochemistry. But if I turn this into like a simple cartoon, the idea is you've got one receptor that we're talking about privacy to a, you've got different drugs that can bind it. And the question is, you know, if you've got three sort of different skin, Scarecrow, it's different information pathways that can light up on the inside of the cell in response to something binding to the receptor on the outside of the cell. The question is, you know, some drugs might cause all three of these information, pathways to light up to some extent. And we want to know, or we're hypothesizing that perhaps, you know, labs, like yours can engineer new drugs that maybe make only one of them light up. And perhaps this is a way to get a drug, like a psychedelic or a psychedelic derived compounds that has some therapeutic efficacy, but doesn't have something like a psychoactive effect.

Ryan Gumpper 38:25

Yep. Yep, that's exactly it. And I mean, there are drugs. So this is it's very complicated. It's not super clear, right? Like, I wouldn't say that these, these pathways are, you know, they're not necessarily set in stone yet, because there are drugs that are five HT to agonist to agonists that are non psychedelic. Now, most of them are more GQ. biased in that sense, but there is some sort of arrest and signaling still occurring. So it's, I don't know if it's necessarily like, hey, on off, that's our kind of hypothesis out there. But you have drugs like lists glyceride, which is known in humans not to be psychoactive at all, to bromo LSD, so BOL, which actually only differs by one atom from LSD, and that's known to not be psychoactive at all either. While it is G, GQ biased, in that sense, is more favors the GQ pathway, there still is arrest and signaling occurring. So I think there's a specific Interplay here that we may be, you know, listen, yeah, so strange. So roughly speaking, an idea.

Nick Jikomes 39:45

This, this idea is goes something like this. There's some drugs that we know cause hallucinations, LSD, psilocybin and so forth. They tend to engage the fiber sheet to a receptor and all the other stuff such that lots of calcium gets released. In the cell, and these neurons become more active, and there's, you know, certain certain, then there's certain dynamics, that change in the brain because of how the activity of these neurons that are being stimulated, are changing their activity. But there's other drugs that we do know about, you mentioned, like lifestride, and they engage some of these serotonin receptors, they seem to do that in a way that is different, that's bias towards different types of these receptors. And with the idea be that they're turning on certain pathways in the cell, but maybe perhaps not causing the same kind of change in intracellular calcium and therefore not the same kind of change that underlies the the activity changes that give you psychedelic effects.

Ryan Gumpper 40:44

Yeah, I would say that's, I mean, that's entirely possible. Yeah. Okay.

Nick Jikomes 40:47

So that's, that's sort of like, it's possible. We don't know the details, but like, that's sort of the space. That's the cutting edge right there.

Ryan Gumpper 40:53

Yep. That's kind of the cutting edge right there. Yeah. Okay, definitely.

Nick Jikomes 40:57

Interesting. And so what I mean, everything you just said, sort of got out it. It's pretty obvious, I think, to people why people are going after this type of question, it would, it would be very convenient for pharmaceutical companies. And for just the therapeutic side of this, it would be very convenient if you could find a drug that had the antidepressant effects and the neuro plastic effects that seem to be related to the way psychedelics work, but didn't require you to have a psychedelic trip for several hours at a time. So that's very convenient. And that is certainly you can see why that's a motivation. Can you build the case a little bit more? On just sort of the nitty gritty, mechanistic side of the science here for why we think it's plausible, and we, we will have some success if we go down this path?

Ryan Gumpper 41:49

Yeah, so I think already mentioned a couple of them with glyceride and NBO. Well, how they are more GQ brothers, LSD is more arresting, biased in that sense. There have been studies in mice, where if you knock out the arresting pathway, so if you're not gonna get arrested to and you give them like LSD or other drugs, they will head to head Twitch gets attenuated. So hedgewitch is a matter which we can measure in mice psychedelic activity, I think that's probably the strongest evidence that we have is you can start to Group A lot of these drugs into particularly like things like LSD, and to the molar rest in base, and then we see this hedgewitch attenuation, when we knock out arrest and for that. So I think that's probably the strongest scientific case. And this is you can see this pattern kind of arise.

Nick Jikomes 42:49

Yeah, you're gonna, you're gonna have to help me think about that one. So, so we said that, so drug binds to serotonin to a receptor, and let's just let's just talk about LSD. LSD binds to this receptor, G protein signal transduction pathway happens, calcium, calcium goes up inside the cell activity of the cell changes. And we think of that as being associated with the psychedelic effects. When that happens enough, this other thing called arresting comes in and sort of shuts that off. And so more arrests than doing its thing, I would think would cause less intracellular calcium and less excitability of the cell. But you just said that when you knock out arrest, then you see an attenuation of psychedelic effects. That's, that's confusing to me.

Ryan Gumpper 43:36

Yeah, I mean, so I mean, you would think that more excitability in the neurons would do that. But that's the whole idea behind this is that a lot of arrests and bias compounds tend to be hallucinogenic. Right. So I think, hallucinations, in that sense, may not entirely be regarded towards the actual I mean, I don't know, the firing of the neurons. Sure. But there is definitely I think, something going on with the arrest and pathway for hallucinogenic effects versus the the therapeutic effect for that.

Nick Jikomes 44:10

Interesting, yeah. Okay. And this is, you know, this is the cutting edge, so we really don't know what exactly is going on. Okay, so walk us through like what? Tell us a bit more about what exactly you're working on today.

Ryan Gumpper 44:26

Yeah, so I work a lot on the structural biology side of the five HTT a receptor and the five H TTC receptors. One of the main techniques I use is called cryo em, or cryogenic electron microscopy, and that allows us to resolve these receptors at the molecular level. So a lot of my research looks at Hey, can we get can we actually solve the structure at the molecular level of these compounds boundary receptors, thus we can see the interaction is with these compounds at the receptor itself. And then once we know that we can start to build up ideas is, is there any mechanistic thing can we deal with at the protein level that we can then infer at the functional level, which then we can then begin to infer at the more, you know, large scale level stuff. And these, these structures are also using like iterative drug design as well. So we can begin to actually look at the chemistry and how we can match the chemistry of the molecules, the shapes of the molecules and with the protein. And when you talk about not, and that's kind of my main study. Okay.

Nick Jikomes 45:39

And then a question I have, you know, that may connect to that is, when we think about designing novel drugs, there's, there's multiple strategies for doing that. To what extent you know, when you're making and searching for new drug in the lab, to what extent are you sort of studying the biophysics and the structural biology of receptors and stuff, and then literally engineering and architecting, like a molecule that then you go and make because you think, okay, if it has this exact shape and structure, it'll bind to the receptor in this exact way, and cause X y&z to happen. Versus you can sort of randomly generate permutations of some base structure, and then just go in and see like, which of these happens to do have the outcome that we would like?

Ryan Gumpper 46:29

I would say it's actually probably about 5050. Okay, so you can you can go in and based on the new structures that we have, you can go in and be like, Oh, look, there's, you know, a specific interaction that this truck has, it's making this hydrogen bond with the receptor itself, you know, we could change it to this analog, this, this analog, it would either, you know, we don't want that interaction or abolish it, or it will make it potentially stronger. Or you could look at the structure and be like, Hey, there's this empty pocket here. Within this space, can we design a molecule such that interacts with that pocket itself? And you go to the chemist and be like, hey, we need like a really hydrophobic region here, what are some actual substituents that then you all can put on it? Right. So it's definitely like a 5050 type of deal. Where because you have to make sure of two things, right, you have to make sure that it makes fits in with the structure, which kind of is on the structural biology side, but you have to actually make sure that it can actually be physically made by the chemists, right, you can't make every molecule necessarily very easily, or you can do a lot with chemistry, but there is certain limitations within what is, you know, theoretically, can be made and not made. So there's a lot of like, back and forth within that. It's like, hey, random, it's not random and along and what's like analog at this position, we know will fit in with the receptor based on the structures that we have. But we don't necessarily know the, you know, substituent on the molecule that we can put on it to be like, Oh, this will exactly work.

Nick Jikomes 48:06

And so, you know, when we think about something like the biological and the mechanistic basis of the hallucinogenic effects of psychedelics, we're talking about very interesting, very dramatic phenomenology. And that's sort of why people know about these compounds, and why we start studying them and why you know, people like you then, you know, dig in down to the molecular or even atomic level for how this stuff works. Is it possible to sort of think of things in the reverse direction. So for example, if you guys were studying LSD and psilocybin and the tryptamine psychedelics in the lab, but let's just say that, like, Albert, Albert Hoffman, never did his famous bicycle journey, and we had no idea these things were actually psychedelic, and psychoactive. Is there something about the way that these molecules are interacting with the five HTT to a receptor that would make a molecular structural biologist like you think, Hmm, I wonder if these will have particularly dramatic psychoactive effects because they're doing this type of thing at a receptor rather than some other type of thing that other drugs do? Or is there are the dots that connect the phenomenology of the psychoactive experience to the structural biology still still too blurry?

Ryan Gumpper 49:21

I think they're, they're still too blurry. So what you've exactly said was kind of like a hope of mine. Coming into the lab, particularly so looking at the five HT to see receptor, I solved it with solution. And that's been published already. And you know, just looking at the interactions and stuff, it doesn't look, you know, very much different than, you know, the proposed structures of serotonin with in the actual receptor itself, and then and the known structures of serotonin with other subtypes. And also you Know the known structures that we have 582 A, with like LSD and glyceride. You know, it doesn't look that much different and like thinking about that it's like, okay, how do we then design that around that? I still think those lines are very blurry to where you can actually get to that molecular level and be like, Ah, yes, this drug will be hallucinogenic. This drug won't be you know, again, another clear to me an example of this would be less ride and bromo LSD, if you look at bromo LSD, in particular, it's exactly like LSD, except for one atom of bromine at that position at the two position. So would you say that that's hallucinogenic or not? I don't know. Right? Like, yeah, but it's not so. And how that would interact with the structure based on the given structures of that. You know, it doesn't. The it's not necessarily jiving? Quite Yeah, yeah. So not connected. Yeah. So it's much more, it's much more complicated.

Nick Jikomes 50:59

Yeah, we can't we can't just look at the structure of a compound know how it works with the receptor and say, like, that's going to be psychoactive. That's not, but But it's something that we aspire to.

Ryan Gumpper 51:08

Yes, of course, yeah. Okay. And like I said, that was kind of like, my initial hope coming into the lab is, because you would think that would be the case, right? There should be something structurally different. Because so the whole idea behind structure biology is structure begets function. Right? So there should be some information within the structure, then that could lead us to the ideas about the function of that. And you would think there'll be some sort of novel interactions that psychedelic would specifically make. But I don't think that that's the case and how it's playing out. It's more complicated, unfortunately.

Nick Jikomes 51:42

I see. And so you mentioned that most of the classic psychedelic, like, classical psychedelics, and that term is basically defined with respect to their ability to drive hallucinations and a five issue to a dependent manner. But as you mentioned, most of these drugs bind to other receptors, to some extent, other serotonin receptors, other types of receptors entirely. LSD is an example psilocybin as an example. I mean, basically, all of them bind to something other than just 5g to a, we know that if you give these drugs and you block the 5g to a receptor by using another drug, or you just get rid of that receptor, that the hallucinogenic effects seem to mostly or entirely go away. So something very important about 5g to a activation has to do with the hallucinogenic effects. Are there any drugs that are selective activators of 5g to a? And if so what do those look like?

Ryan Gumpper 52:37

I would say the most, the most potent one off top, my head is like 25, CN Embo, or Mo, is what they call it. That's extremely potent, that two A's probably the most selective at to it. But I still believe it activates, to be in to see I'd have to go and check in the literature Mark, I don't quite remember off the top of my head. But I think that would be the most potent one. And that one tends to be, I think, a rough one with a lot of, you know, adverse events that had happened is pretty, I think, popular in Europe for a while.

Nick Jikomes 53:16

So it is a solution to genetic. But the psychoactivity does differ in some way.

Ryan Gumpper 53:26

Yeah, yeah. And I think there were a lot of cardiac events that happened with that with that drug as well, which would be indication of like, you know, five HT to be receptor activation. And

Nick Jikomes 53:38

what why is that? Why do you why do you bring that up.

Ryan Gumpper 53:42

So so far, they seem to be as a is an interesting kind of off target that will occur. So if I've assumed to be into a are closely related, they're obviously within the same type of serotonin family, it's known that chronic activation of the five HTT B receptor leads to valvular cardiomyopathy. So this was actually kind of famously played out with Fanfan the diet drug that was back in the day. And that actually got removed by you know, the FDA with that, and that was because Direct Activation of five HT two B receptor, and that could be played with love these psychedelic compounds that people hear if you're taking these a lot like that, if you think a sense of maybe micro dosing. Yeah. You know, daily or however weekly basis, whatever the protocol is, you know, that could be a side effect that plays out in the long term to the user and people who might be aware about but that is kind of like an off target that you kind of want to design. For the drug perspective, drug design perspective, you want to design away from 5g

Nick Jikomes 54:57

And so with that, with that diet drug that got pulled from the Market. My guess, you know, I really know nothing about it. But my guess would be that, you know, 5g to be activation was not its sort of therapeutic Mecca mechanism of action that had been studied.

Ryan Gumpper 55:11

It was a side effect. Yeah. Yeah. So I think it was a metabolite.

Nick Jikomes 55:14

Okay. And was that a pill that people were taking daily or weekly or regularly at least?

Ryan Gumpper 55:20

Oh, yeah, yeah. People, it was a really popular drug that Fanfan combination. Okay. It's fenfluramine and something else. But yeah, they were. It was a very popular thing, I think is in the 90s. I see. That kind of came to fruition in early 2000s. I think it's so the,

Nick Jikomes 55:36

the cautionary cautionary note here slash potential buzzkill for people that are enthusiast for micro dosing on a daily or weekly basis would be that it would be so if the same thing was true with the psychedelics that also additionally bind the 5g to be receptor, that if you're taking them daily, or weekly on some regular cadence that eventually it will cause cart issues? heart issues?

Ryan Gumpper 56:03

Good. Yeah, definitely. It's so I think with a fan fan, it was about 30% of the cases. Yeah, somewhere around but it

Nick Jikomes 56:09

wasn't like they were taking this diet drug. And on day one, they had heart issues that take time to manifest.

Ryan Gumpper 56:15

Yeah, yes, it was, it was over a period of time. Yeah.

Nick Jikomes 56:19

Okay. Interesting, ya know, people have brought that up multiple times. And, you know, it is, it is related to this interesting question, I think of how much of the effects of psychedelics, the you know, the psychoactive effects, the therapeutic effects? How much of them are coming from 5g to a receptor activation itself, then how much of them are coming from other receptor interactions? Do we do we know about any other interesting reactions that, that, you know, have effects that have been worked out at all, when it comes to LSD or psilocybin or anything?

Ryan Gumpper 56:51

Do you mean, like with other receptors

Nick Jikomes 56:53

or with other receptors?

Ryan Gumpper 56:56

Yeah. So I mean, the poly pharmacology, I think, still really needs to be played out. There is, I think, one paper that was done just on binding, where they looked at a lot of the GPS, different UPC errors with various psychedelics in that. But yeah, I mean, that's something our lab is actively working on, kind of packaging up the PI pharmacology of a lot of these different drugs. Have them all, so So yeah, it's, it's an active part of the investigation of our lab.

Nick Jikomes 57:29

One thing I want to ask about, too, that maybe ties some of the molecular details you were walking us through earlier with some interesting phenomenological differences between some of the tryptamine psychedelics is this. So we talked about the five HTT to a receptor, as a GPCR, there's G protein pathway hooked up to it, there's this arrest and pathway that's involved in sort of regulating that. We've got different types of tryptamine psychedelics in terms of the intensity and duration of their effects. So on one another spectrum, we've got something like LSD, which we know has lasts, it's the LSD experience lasts for several hours, for six, eight, even even more hours at a time. And that's because it sort of sits at in the receptor and sticks to it for a very long time. Psilocybin not quite as much, but still, you're tripping for hours at a time if you're taking a large enough dose. And then on the other end of the spectrum, you've got something like DMT, or the experience is really just on the scale of minutes. 10s of minutes, say, and there's another difference that seems to relate to those, which is how tolerance builds up and goes away. So you know, most people who've done something like LSD or psilocybin with any regularity will know that, if you take a dose on day one, you're gonna have to take a lot more on day two to get the same effect. And if you want the same effect at the same dose, you got to wait some time. And the idea there is that neurons and other cells are homeostatic, ly regulated. So if you activate a receptor for a long time, then the cell goes, Okay, there's like a lot of stuff happening there. Let's pull away those receptors to counterbalance that. And then eventually, if that drug goes away, or that activator, then things will go back to the way they were before. So in the case of something like LSD, which is short acting, because it's short acting, it doesn't trigger that sort of homeostatic internalization of receptors. And you know, you can you can do DMT multiple times in a row and still get the effects. Is that to do with the arrestin protein pathway that you talked about? Where if you're just not activating that receptor long enough, that never kicks in? And therefore,

Ryan Gumpper 59:41

the the internalization doesn't occur as much. Yeah. Yeah, I would think that that could be a plausible explanation for it. Oh, that's, you know, I don't think that that's actually been seen, and that's actually been quantified in the literature. But to me, it seems like a plausible explanation. So um, that's all Let's play down to the interactions, the atomic level interactions with the receptor. So LSD has this strong hydrophobic interaction on something we call ECL to lead, there's one amino acid on there, that's il two to nine, leucine two to nine, which is a very, you can think of as a very carbon rich amino acid, which means it's very hydrophobic, it wants to get away from water. And LSD has this area on its where it's also quite hydrophobic as well. So this interaction actually causes this lid to fold to be on top of the receptor. And it makes direct interaction with the LSD. Now, when you change this, this amino acid here, you actually change the kinetics of LSD, both the on and off kinetics from the receptor. So that leads to the direct evidence there as to why it's so long lasting for because it just sits on the receptor for a long time. Based on my father's TTC structure, I think something else may be going on. But we haven't necessarily done the kinetics data to actually dig into that at this time. Yeah. But yeah, my guess would be DMT is different than itself to and it does interact with the same type of residue that lead actually doesn't form. Come on, and the kinetics are faster the honoree and offering from this after as much as

Nick Jikomes 1:01:22

I see. Interesting. So you mentioned before, a little bit, how you got into this stuff and went in this direction was it was it literally was was the principal reason you got excited about this stuff? And wanted to understand it scientifically. trogons book?

Ryan Gumpper 1:01:40

Yes, yeah. So I started reading PCAT. And I was like, Oh, wow, this is really cool. You know, the idea of designing new drugs that can change consciousness that way, was something truly fascinating for me. And then as a structural biologist, so you can think of two other structural biologists, there's kind of been in the GPCR realm, there's kind of been two phases of things that have occurred. So initially, they were almost impossible to get structures of you had to do crystallization of these receptors. And for people, I guess, not too informed about X ray crystallography, you need a lot of protein for this to happen. And you're literally concentrating your protein and putting it in a solution, such that it forms an ordered array, and actually forms a crystal of it. And then you would take that to a synchrotron and shoot like, high powered X rays at it. And from there, you get diffraction pattern, you can actually calculate back the atomic positions, or the electron density of the protein for that, now, it turns out membrane proteins are extremely hard to crystallize, right? They're hard to isolate in and of itself, but then they're hard to crystallize, as well. So there are a handful of crystal structures out there, um, which is why it's such a big deal, when a lot of these first structure papers started to come out of the crystal structures for all of these different different types of GPCRs. So structural biologists, I wasn't necessarily, I knew it was a very hard thing to do. Then there was the kind of cryo em revolution that occurred, where both computational power and detector power kind of caught up. And now to solve these structures, we just need to be able to isolate them. So that's very different than trying to get enough protein to crystallize it. And we can start to create these protein complexes and start to, you know, play a lot more in the Crown's faces, actually, then go ahead and solve the structures. So it's become much easier. And that's why you've kind of seen, I'm sure, like the explosion of structures out there within the whole GPCR space. So I feel kind of lucky. I was kind of came in with the right interest back in the day from my undergrad degree. And then the right time, you know, terms of

Nick Jikomes 1:03:58

Yeah, yeah. Interesting. So how did you stumble into shoguns book in the first place?

Ryan Gumpper 1:04:05

My roommate actually had a copy of it. And I said, What's that? Because that's a weird name is pekao. Right? I'm like, What does that even mean? And then that's when I started to, like, look at it. And, you know, as my first kind of, I was taking, I think I was taking, like basic chemistry to at the time in my undergrad classes. So I knew you know, a little bit about this, but then I was like, Oh, wow, like he's changing molecules in these small ways and synthesizing these molecules, and they have these different effects. Like, what does that mean? Of course, it's all packaged up with a nice, you know, cool story within that, and then all the synthesis in his notes in the back of the actual durations, the amount, you know, super interesting to me at the time. So it's kind of always in the back of my head. It's like, I would like to study that. That'd be really cool to

Nick Jikomes 1:04:48

describe for people who don't know a little bit more of the structure of that book because it is a very unique book in terms of how it's structured.

Ryan Gumpper 1:04:54

Yeah, so the first half of it is kind of like an auto biographical story of him and his wife and life. So there's a whole bunch of stories of him and him and and, and the group going and, you know, testing how different psychedelics are subjective experiences, and then various other stories of, you know, his life. And the second half is just all of these compounds, and then the synthesis of them. And then his notes at different dosages for these different compounds. So kind of, if you're working in this space, you know, pekao, and T cow, the second book that he did, which is off tryptamines. You know, there's a lot of, it's kind of a goldmine, there's a lot in there for it,

Nick Jikomes 1:05:43

ya know, they're really interesting books, if you've never read them, or looked at them, you know, literally half book like autobiography and half, half chemistry cookbook, basically. Yeah. Um, so what, so what other projects in the lab are going on just to get not necessarily that you're working on directly, but just to give people sort of an idea of all of the sort of related things that you know, Brian and other people are working on today, at the sort of cutting edge of where you guys are.

Ryan Gumpper 1:06:18

So our lab pretty much works on everything that has to do with GPCRs. So we work on a lot of what they call orphan receptors. So these are GPCRs, with no known, like, native biological ligand or no known like probe like and even so we don't even know how they're activated, what their signaling properties are. There, you can think of it if you think of like dark matter, their dark GPCRs, right, we don't know a whole lot about them, we know that they're there, but we don't know what they do. And we don't have any way to probe their their function. So that's kind of one section of our lab that we work a lot on. And with the the IDG, which is illuminating the druggable genome. So that's a lot of people kind of work on that within our lab. We will work on most of the we have people working on most of the different serotonin receptors. Besides just the five HTT to a receptor, I work on the five AC to see receptor as well. And then, we actually I'm co first author on a paper recently on dreads, where me and the other co hosts Arthur Xiang. Him and I shouldn't actually solve the structures of dreads. And we kind of did you know, I did some MD simulations, and we looked at, you know, what actually makes a dreaded dread. Like, why? Why does it not recognize the native like, and but we, you know, you can activate it with the certain chemical moieties. So, that was a really great project and fun paper to work on, as well.

Nick Jikomes 1:08:00

So what, what's, yeah, so you work on 5g to see what's interesting about that one.

Ryan Gumpper 1:08:10

Yeah, so that's a really interesting receptor. So being related to the five HTT to a receptor, it's also activated by a lot of these psychedelic drugs. But something interesting that I find with this receptor just from a basic biochemical level, and it's something we haven't talked about yet. So GPCRs, themselves, some of them actually, most of them exhibit some sort of what we call constitutive activity. So this would be spontaneous activation of the receptor and some basal level of signaling with a receptor that is independent of activation Penhaligon's. So you can think of, you know, the receptor just goes and it gets it randomly will activate with, you know, we can call the GQ pathway, or anything else. So that's called constitutive activity. Now, the five HT to see receptor in itself, I think, is super interesting in this because it has all of these different isoforms that arise from post transcriptional modifications on the actual mRNA itself, which then arise to different protein isoforms. And these isoforms arise on the specific loop where it actually interacts with the GF acute protein. And these changes in this lead to changes in constitutive activity and actual signaling of the receptor itself. And there is like 24 of them.

Nick Jikomes 1:09:46

Just just for people who don't know, alternative splicing is is sort of the thing at play there. You're saying that 5g to see comes in multiple different versions. It's a protein. And the way that works at a sort of cartoon level is you can one gene with a certain level of complexity to its structure such that the same gene can be used to make different versions of a protein.

Ryan Gumpper 1:10:13

Yes, essentially, but it's actually not alternative splicing. It's a tie. So it actually changes. So that's a to I, it's, I'm forgetting the name of it right now. It's a nucleotide. And it will cause the ribosomes actually read differently than nicer actually changes it to a G. So instead of reading as like that, you know, that single nucleotide or it actually changes the codon, right? Because the ribosomes will read in codons for each amino acid. So actually change the essential codon from it, which then allows that different amino acid to be recruited in the actual making of the protein itself. So it's not alternative splicing in that sense. It's it, you know, post transcriptional, modification of the mRNA.

Nick Jikomes 1:11:00

I see. But but the the, I guess, the point is, the cell is able to make different versions of this protein through that mechanism. And you're saying that one thing that's interesting about that is one of the differences between these different versions of 5g to see receptors is there sort of baseline level of activity,

Ryan Gumpper 1:11:17

baseline level activity and also signaling with all the different types of off because you can think of so changes based on activity, and then activation of the receptor itself. So to me, it's a super interesting problem. And one of my recent papers was kind of on that, trying to figure out the mechanism behind that itself. Finally, she she's also very interesting, there's a recent paper that came out dealing with obesity, where there are different isoforms within that are different SNPs snips, single nucleotide polymorphisms, which they have found to potentially be important for obesity. What finally, CTC is also the target of a, of an FDA approved drugs for weight loss, Lorcaserin. But that actually got pulled from the markets, I think, a couple of years ago. 2020 or 2019?

Nick Jikomes 1:12:14

For what reason, because of

Ryan Gumpper 1:12:18

increased incidence of cancer. So, you know, maybe down the line five ECCC is something we we did not want to hit with psychedelics as well. I think that's may happen or not, I don't know. But but but yeah, there's a super interesting, secondary target.

Nick Jikomes 1:12:34

Yeah, where's five HD to see expressed in the brain and body compared to say, five SD to A.

Ryan Gumpper 1:12:41

So it's espresso over the brain as well. Like, finally she too. I think it's mostly in the brain, kind of like, Finally she do it. Okay.

Nick Jikomes 1:12:49

Interesting. Well, I think there's a lot of, we covered a lot of interesting stuff. And there's certainly a lot of detail in this conversation for, for the psychedelic nerds out there to hopefully learn a little bit more at that sort of biochemical and biophysical level about how some of these things work. Is there anything else Ryan, that you want to talk about? Or that you want to reiterate from what we already discussed?

Ryan Gumpper 1:13:16

Um, not that I can think of off the top of my head.

Nick Jikomes 1:13:20

No. All right. Well, this has been fascinating. You're doing some really cool stuff. And thanks, you know, you had a nice little, they call it a snapshot that you published recently, I've posted that online, and that's in my newsletter that basically, there's one cartoon graphic that you can look up, if you look up Brian's name, Ryan's name, and Brian Roth, who he published it with. And it's sort of a really nice, relatively simple cartoon that sort of diagrams out all of the serotonin to a receptor stuff that we talked about, and all of the protein pathways and all of that stuff. So if you want to look at a picture of it, just look that up, and I'll put a link to it in the episode description as well. For those that don't know, one of my first episodes, and it might have been the second episode or something, I actually talked to Brian Roth, who was Ryan's advisor. And so we talked about some of this stuff, although obviously that was a couple of years ago, so they weren't quite as far along. So that's, that's another good episode to listen to along this with with this one. But Ryan, thank you for your time. This is really fascinating stuff and definitely good luck with the rest of your postdoc.

Ryan Gumpper 1:14:27

Thank you very much. Appreciate it.

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