Latest / Lucid Interval Podcast / Serotonin, Psychedelics, and the Pharmacology of Self - Charles Nichols, PhD
Transcript
- speaker-0: It's fascinating to me that you could study fruit flies and and learn anything about human depression. I'm really dying to know what it is that you observe with with fruit flies. 'Cause to I'm like, no way a fruit fly has a mood, but maybe they do. speaker-1: yeah, like th there there have been several studies with fruit flies and even some of the very, very early studies with serotonin were in lobsters back in the nineteen fifties and sixties. they have a lot of the same neural architecture. And then I have a colleague who studies crawfish or crayfish, crawdance. speaker-0: Crawfish. Yeah, yeah. speaker-1: And there's a lot of conserved biology for aggression, social interactions. I think that there are going to be populations where the subjective trip is going to be necessary and those where maybe not necessary, and I think most of them it's going to be necessary. Because I think if if you look at a lot of the veterans with PTSD, you look at the crack users, you look at people with major depression and other comorbid disorders. There's a lot of trauma associated with that. A lot of childhood trauma or trial trauma as an adult that has produced this dysregulation of their HPA axis and the SSRIs and whatnot aren't really very effective. So the therapies like MDMA, like psilocybin, the subjective experience allows them to really Confront, face, absorb that trauma, that history, see it from a different angle. That then subjective trip is over. The integrative therapy is crucial. MKUltra back in the day were just taking people in off the street and dosing them up. speaker-0: This was the CIA experiments with LSD. Yeah. Secret. Yeah. And what were they they were what were they doing it for? speaker-1: They were trying to develop psychedelics as a mind control agent. And one of the main leaders of that was at Tulane University and he was the chair of psychiatry at Tulane. And apparently they still have one of the bunkers they used to dose people up back in the 50s in City Park here. speaker-0: Two Lane and City Park, I believe it I was speaker-1: I was several years ago this person who shall remain unnamed, but he was in his nineties at that point, was involved in these early, early studies with LSD back in the early nineteen fifties, would talk about how they would take Amish people who would come into the big city and just bring them in off the street, put them into a dark room with no lights and dose them up with like five hundred micrograms of acid and just watch them. speaker-0: That sounds that's horrible. I shouldn't be laughing. But it th the the fact that they're Amish the fact that they're Amish is a particularly weird detail. Like the C these are the things when I heard these things in high school and college, I mean I would be like, that's preposterous. And like, you know, I mean just speaker-1: It was like can you break somebody and get them to believe things that aren't true and and this whole MKO speaker-0: Well that makes sense. So you you get someone who's a you get someone who's a true believer and see can you really change their beliefs. Okay, trying this again. Dr. Charles Nichols, thanks for joining me. speaker-1: my pleasure. Thank you for the invitation. speaker-0: So, when you meet people out in the world and they ask you, So Charles, what do you do? What's your answer for them? speaker-1: it really depends on their background, whether they're a scientist or not, or potentially even their political persuasion. so I'll my standard first answer is I study I'm a pharmacologist, I study medications to treat psychiatric diseases like depression. And then if they have a follow-up like, well what kind of medications? I said, Well, I study psychedelics. And At that point I'll I'll get, that's really interesting, tell me more. And or a lot of times people will just instantly start to try to tell me the stories of their personal experiences from back in the day. speaker-0: Reports. Right. We gotta give you trip reports. Yeah. speaker-1: Yeah. Let me tell you about that one time I was in college. So speaker-0: have so so I assume this you're saying this is what you get from lay people who are not scientists. When have you seen over the years how long have you been studying psychedelics? speaker-1: I started studying psychedelics professionally back in nineteen ninety seven, so speaker-0: Yeah, so thirty years. Yeah. Have you seen a change in how people respond when you tell them what you study? speaker-1: definitely. speaker-0: How sir? speaker-1: I first started studying them back in the late nineties and I would tell people and they would give me a skeptical look, like aren't those dangerous? What what are you studying them for? And at that point it was I was studying them to sort of understand how psychedelics work, how consciousness like the b biology of consciousness, and this was really before the therapeutic potential had become widely known. It was about another ten to fifteen years after that. speaker-0: Yeah, so you're s it was just pure scientific discovery at that point. Yeah, yeah. Yeah. What about when scientists ask you, what's how how would you your answer be different? speaker-1: if scientists a lot of times well I get a lot of the same responses if I tell a scientist, I'll go, let me tell you back in the day in the sixties when I was in graduate school or something like that. but with scientists it it gets more a bit mechanistic, like, wow. So tell me more, how do they work? What are the neural circuitries, receptors? So it gets gets a bit more detailed. But across the board, people are much more interested in actually follow-up questions, how's it working, what's it doing? so it's it's it's been going from kind of skeptical you're doing what? to that's so cool. Let me tell you about my trip. Or something like that. speaker-0: Yeah, I I mean I have you seen this was there a certain turning point at which point the, you know, scientific research into these medicines became more I guess I'd say socially acceptable, like more professionally acceptable? 'Cause I think for a while there were a lot of people in science and in academia that wouldn't wouldn't publicly admit that they were even interested in them. speaker-1: yeah, yeah. I think it was about the mid-2010s when I was a postdoc and when I was first trying to get grants as a new assistant professor here back in the early 2000s. we were studying psychedelics as tools to look at the target 5 HT2A receptor and potentially how it was involved in schizophrenia and psychosis. so we kind of had to bury, yeah, we want to know how psychedelics work and understand consciousness, but we had to wrap it in this context of using them as tools to understand what goes wrong with consciousness, like in psychosis or schizophrenia. And those studies were very helpful and informative on understanding kind of the molecular basis of psychiatric diseases. So yeah, don't don't get me wrong, but they were very valuable. But most of us in the field at that time w there were maybe I don't know, six or seven of us. we were all kind of taking the same approach because we couldn't study psychedelics to study psychedelics. speaker-0: Right, just for to understand the nature of consciousness and also I imagine that where the w your funding sources I imagine are mostly from like public s sources. speaker-1: Yeah. At that time the NIH, primarily the National Institute of Mental Health, they were funding a lot of different investigators to study five H D two A receptor pharmacology. Like the the lab I did my postdoc in, s and several others, but it was really kind of fundamental neuroscience. and how does it relate to psychiatric disease like depression or depression, substance use disorder, schizophrenia, things that serotonin were involved in, the ser the serotonin two was highly implicated. And so we were studying potentially its its dysfunction in these disorders and using psychedelics as a speaker-0: Cool. So you've you've said these letters a few times, five H T two A. Can you tell us about what the significance of those numbers and letters mean? speaker-1: So 5HT is the chemical abbreviation for the neurotransmitter serotonin. And serotonin was first discovered and isolated from something like 5,000 liters of cow blood back in the nineteen thirties as a molecule that was able to cause vascular tone. So they took the serum. They identified this factor, they didn't know what it was yet, but when they put it on, say an isolated blood vessel, it caused it to constrict. So they named it serotonin. And a few years later, they had determined what the structure was. And the structure of serotonin is five hydroxytryptamine. So the tryptamine core with the five hydroxies, so five HT. And that defines the neurotransmitter. And for serotonin, in mammals there are 14 different families of serotonin receptors, each encoded by different genes. And then there are different splice isoforms and subtypes and edited isoforms of those those all of them are what are called G protein coupled receptors, with the exception of one of them. So that means that the receptors sit on the surface of the cell. And when serotonin binds to it, they transduce a signal to the inside of the cell that then activates all kinds of enzymes on the inside of the cell to change its physiology. And there's the main families are serotonin 1, 2, 3, 4, 5, 6, and 7. And the primary target for psychedelics are serotonin 2 receptors. And in this two family, there's serotonin 2A. the B and the C. And studies in animals and humans have shown that it's the serotonin two A receptor, the 5 H T two A receptor, that is the critical one for the psychedelic behaviors of these drugs. If you block them in humans with a s a selective drug that prevents that psychedelic from binding to that receptor, you don't get any of the behavioral effects. speaker-0: So are there any other like medications that are used that would attach to the same receptor? speaker-1: yeah. So that's one of the reasons we studied the five H T two A receptor and psychedelics to study schizophrenia is because one of the primary classes of antipsychotic medications called atypical antipsychotics that were developed first in the nineteen eighties have as a major component blockade of five H T two A receptors. So the the older antipsychotic medications primarily just blocked dopamine receptors and they would they would stop a lot of the positive effects, the hallucinations. and then the next generation of antipsychotics that came along had less dopamine, but then more activity to block serotonin two A. And I think more people are taking those in the classical, they're safer. And there's even an a newer drug that's come on the market over the last couple of years called ne placid, which is a selective five H T two A blocker. It doesn't block anything else. And that's used to treat psychosis associated with Parkinson's disease. Interesting. So speaker-0: Interesting. speaker-1: you've Got evidence on one hand, if you activate the receptors, you produce these profound reality distortions, hallucinations, but if you block that receptor, you can prevent the same types of speaker-0: That's fascinating. I mean, yeah, so it's almost like a I mean, I think of it like on my iPhone when I do photography, there's a slider for contrast black point fiber and saturation, and you can just kind of dial up an effect or dial it down, and the slider appears to be this receptor, which is kind of amazing. And also with Parkinson's, I mean, my first thought with Parkinson's is dopamine. you know, you would think that that's that would be the mechanism of action. And it's interesting that serotonin also seems to be involved and with psychosis as well, I I didn't know that. speaker-1: Right. It's it's involved, I think, directly and indirectly, because one of the things about the serotonin-2 receptors is that they will modulate dopamine tone in the brain. So 5-HT2 activation leads to increased dopamine, 5-HT2C activation leads to decreased dopamine in the brain through indirect pathways. so it's a really complex pharmacology. speaker-0: Yeah, so do you I mean, do you think that like is a general matter that dopamine and serotonin kind of are work antagonistically? Or is it just at these specific receptors that they they seem to have that effect? speaker-1: they can they can act synergistically, antagonistically depending upon where they are, location in the body, the nature of the receptor. There are stimulatory and inhibitory dopamine receptors or stimulatory and inhibitory serotonin receptors. speaker-0: It's endlessly complex, right? Do you think we'll ever fully understand all of it? So we had some technical difficulties. What we were talking about was you were just saying that like, I mean, there are inhibitory and stimulatory, you know, versions of dopamine and serotonin. They work together synergistically and antagonistically. And my question was, do you think that we'll ever fully understand the neurobiology of the brain? speaker-1: do I think we'll ever fully understand it? No. speaker-0: Yeah. It's do you think there's just a theoretical limitation on our ability to do that? speaker-1: It's it's extremely complicated. And I think, you know, even if quantum AI comes online, I I think the brain is still at order orders of magnitude more complicated. It's I think we can we can model circuits, maybe at some point come up with artificial intelligence that's super intelligent, but in terms of understanding the complexity of the brain and everything that's that's there, I don't I don't think so. It's like the more we know about the brain, the more we know we we don't know about the brain. speaker-0: Yeah, 'cause I mean it's like it's like exponential complexity. So everything new that we discover comes with an exponential amount of more complexity that we don't understand, right? Yeah. So it's just I mean, there's yeah, and I'm I mean, I'm just still, you know, I've been kind of ideating about it for years, just trying to figure out the basics. I guess it's nice to be able to talk to you 'cause you can explain. you know, n the term neurotransmitter, what exactly does that mean? speaker-1: So a neurotransmitter is a chemical hormone, or it could even be a peptide, that's released from a particular type of cell or tissue in the brain that transfers information from one cell type to another cell type via a receptor. So in the case of say serotonin or dopamine. those are presynaptic, postsynaptic. There's you know like a a releaser and an acceptor. And when the say presynaptic cell receives a signal, an electrical signal to fire, it releases its neurotransmitter to the other side. And there are receptors on the other side that capture those neurotransmitters and then reinitiate signaling on the back side. speaker-0: Yeah. speaker-1: It can be. So in the as simplest you would get electrical signal would come to the presynapse, that would open voltage-gated calcium channels, calcium would come in, the calcium that comes into the presynapse would then, through a series of reactions, cause these neurotransmitter vesicles to fuse with the presynapse, they release the neurotransmitter. If it's an excitatory neurotransmitter, say it would bind to the postsynaptic neurotransmitter receptors that would then increase calcium, that increase in calcium then would continue to propagate that action potential down to the next neuron. So that's sort of simplest. But what you have is on the presynapse, you can have multiple neurotransmitters released. They can be excitatory, they can be inhibitory. You also have negative feedback on the same presynapse so that when you get a lot of neurotransmitter released you get diffusion around to the extrasynaptic area, which can then cause negative inhibition of release. And for the serotonin system, you have the excitatory or stimulatory serotonin receptors on the post synapse But on the presynapse, you have serotonin 1B and 1A receptors, which are inhibitory. So when you get serotonin is releasing, when you've got a lot of serotonin in there, you've got the sort of auto-feedback negative regulation to then damp it back down again. So you just don't get runaway neurotransmission. And there are speaker-0: So it's almost like feedback in a microphone. Like if you have a microphone and an amp, it's just like an automatic cutoff when it knows it's escalating, it's like, yeah, we're cutting that off. Exactly. speaker-1: Yes, exactly. speaker-0: Basically. Which is appreciated when people have that. Right. and and so it's just it that's amazing. You know, it makes me wonder. At what point at what point in the evolution of life did that did that feature come along? I mean one of the things that I've found very interesting about your work is that your work in serotonin is not limited to the human species. speaker-1: No. speaker-0: yeah. tell us about that. So speaker-1: So my my PhD dissertation research was in fruit flies. And at the time I went to graduate school, it was in the late nineteen eighties. And PCR machine, gene expression, it was kind of real early days of truly understanding what genes were and elucidating how interactions between expression between genes would regulate development and brain function. So I was in the laboratory At Carnegie Mellon University, and we were studying the retina development of the eye. And the primary mechanisms involved in the retina development of the eye actually were instrumental in understanding how a lot of cancers in humans progress. And so studying the fly. Sheds a lot of information to human biology, but not necessarily like you would think. Like who would think studying the fly eye would lead to developments to treat cancer? speaker-0: That's I wouldn't I don't I I'm sure the people who started studying it probably didn't go looking for that either. You know, that's one of the reasons why people kind of lack an understanding of why we do basic research. Because you find out about stuff like that. I mean you study the f the eye of a fly. I I I don't know maybe did people go looking for cancer? Like I'm sure there's a growth factor or something. Right. speaker-1: No. It was my my dissertation advisor was John Pollack, who had done his postdoctoral work for Seymour Benzer at Caltech, and they were looking at what the signals were in the fly retina that caused this undifferentiated cellular epithelium to turn into neurons and support cells. And they elucidated this pathway called the RAS pathway that was underlying how a particular type of photoreceptor in the fly eye developed from just this undifferentiated cell to turn into a photoreceptor cell. And it required this complex signal transduction pathway of like 15 different enzymes to happen. But as it turns out, the receptor on the undifferentiated cell in the fly is the same kind of receptor in humans that mediates a lot of cell growth. And the entire pathway from that fly eye receptor receiving the signal to go tell that cell to change its developmental pathway is the RAS pathway, which was which was identified in many human cancers. And so the entire pathway of the human cancer RAS pathway was first found in the fly by not trying to study cancer, but through just basic biology. And that's how speaker-0: Understand. speaker-1: we're made. It's speaker-0: Basic science. Yeah. Yeah. And so you can do that in flies. And so I've so from your doctoral research you I guess you built an expertise in free flies? Is that the specific species? And then so where did it how did you go from there to psychedelics? I mean I can imagine, but I'd really love to hear the real story. So speaker-1: I I was really enjoying fruit flies. I learned a lot about genetics, about developmental neurobiology, development in general, really basic science, but I was not enjoying taking care of all the flies because you can't just freeze flies away, thaw them out and use them again. and I really w was just working with RNA and DNA and I wanted to do something behavioral more with mammals. So I started looking around for a postdoctoral position in some kind of mammalian behavioral biology to get away from flies. And I had looked at a few different opportunities and just through a series of serendipitous events ended up in a lab at Vanderbilt, Elaine Sanders Bush, who had been studying psychedelics since the 1960s. And she was very instrumental in understanding how the target receptor for psychedelics, the serotonin 2A receptor and 2C receptor, fundamentally function and the signaling pathways that underlie them. And the first project when I joined her lab was to investigate gene expression changes induced in the brain by LSD in rats. And I thought that was really exciting because it it really combined my knowledge of developmental neurobiology and gene expression with something that I personally thought was an interesting topic, like psychedelics. But I had never never intended to get into the field of psychedelics. that that was never in the cards. I was really interested in molecular biology, genetics, and this opportunity just just arose. speaker-0: Now your your father also is a psychedelic researcher, right? Yeah. speaker-1: Yes, yeah. speaker-0: Yeah. and so were you I mean I'm sure you were a aware of what he did at some point, but maybe wanted to differentiate yourself professionally? speaker-1: Yeah. The whole time growing up I knew he was a a chemist, a medicinal chemist. Although I wasn't quite sure exactly what he did chemistry on. when I was younger and like what kind of chemicals do you do? He would say, I work on chemicals that that make people dream. I was like, Okay and that was sufficient for somebody who was like seven or eight or ten. And it wasn't really until I was probably about a junior in high school when this is probably around eighty two, eighty three, when he was telling me okay, these are the types of chemicals that I work on. And this was back in the early Reagan era, this is your brain on drugs. so it was more I I never did get any of that negative propaganda. but it was like, my father works on these chemicals that hippies use back in the sixties. Okay. Yeah. speaker-0: And then yeah, and then so it's kind of available when it you know when you find this lab here at Vanderbilt. speaker-1: Yeah, yeah. And and wh I I did my college undergraduate. I started off as a chemistry major because I really like chemistry. And then when all the molecular biology hit and Purdue got their first like PCR machine, I I that became more attractive to me. So I switched my primary major from chemistry to biology. But I continued on the chemistry and kind of got a double major in chemistry and in and biology. But then when I when I graduated I I was really enamored with genetics and molecular biology. So I went off to do that for graduate school. speaker-0: So I there's a few terms here I've been kind of racking up in my head that we need to define. because I've heard them and I just I've never really gotten a good definition. Why don't we start with molecular biology? speaker-1: So that's kind of changed in definition over the years. molecular biology, I would say really is to the biology of molecules within a cell, enzymes, like DNA splicing, how to make transgenic cells or animals, when you're doing biology to understand how cellular components work. not like biochemistry and molecular biology have a lot of overlap. biochemistry is looking at kind of the chemistry of how these enzymes work. whereas the molecular biology can more encompass like the process of DNA replication, of cell metabolism, but it really focuses on processes that the biology of processes that happen within a cell. speaker-0: Okay. And then so the next one also is gene expression. I've heard that term a lot, but I'd I'd love to hear your explanation of what that means. speaker-1: So gene and gene expression has a a very long history. Like back until like the nineteen thirties and forties, we knew that heritable material was carried on chromosomes, but we didn't know how that material was transmitted. We didn't know whether it was on the protein that was in the chromosomes, whether it was on the DNA that was in the chromosomes. And somewhere along the line, the the the term gene Was coined for the heritable unit on a chromosome, a piece of a chromosome that transmits information from one generation to the next. And then as we became to understand that genes were encoded by DNA, then people started looking at the structure of the DNA. how the structure of the coding versus uncoat of non-coding regions on the DNA contributed to the proteins that were made. So when I'm referring to gene expression, it's like how are the proteins that are made in the cell that are relevant to the cellular function, how are they encoded in the DNA and how are they turned from kind of like beads on a string and spliced together to form an an active protein unit. speaker-0: Yeah, it's interesting. I just got the the visual metaphor of like a piano. Like there's chords that you can play. Yeah. And different chords are gonna produce different sounds. Like there's a there's a number and there's you know, not an there's not an infinite number of possibilities, but there's a lot. And if you consider all the keys on a piano that you could play and like you could select just a certain assortment of genes and they're gonna produce a very specific protein for a specific purpose. And what I've always when I've always heard gene expression is I've heard in the context diet is a common one where I've heard like you can, you know, there's a lot of talk about ketogenic diets will act will express cause different gene expression. to me, like I think growing up in the in you know, in the nineties and learning about genetics at that point in middle school, you know, you think that like you have your genes. You got them from your parents and then that's your genes. And we don't really think about them in terms of being activated or expressing or not expressing. But that's that's basically they're always in in communication with our environment, right? speaker-1: yeah, and it's very, very dynamic. so it used to be that you know there was one gene, it was expressed, it made a protein. And then we come to understand that a gene wasn't a single unit. There were introns and exons. That a gene was the terminology is a locus, that the pieces of DNA that together can be turned into protein, a functional protein, are It's tiny pieces of DNA along the locus that some of them are are turn into protein and some of them aren't. And in fact, the gene that I worked on primarily when I was a graduate student was called the Lozen's gene, had such complex genetics in splice patterns that it was one of the main genes that was used by Ed Lewis in his formulation for the hypothesis of introns and exons and gene structure. And so my dissertation research helped to sort of clarify what these advanced genetics are and how you can get a gene locus expressing from the same piece of DNA one variant of a protein in one tissue, but another variant of a protein in a different tissue that has a different function. And so you from the same gene. Right. So you can string together different components to get a protein that can have different functions. And that seems to be common with about most genes and proteins. speaker-0: So this is the the kind of the science that you were doing when you got here to Vanderbilt and were working on your postdoc was on gene expression with L S D. C what can you tell us about that? Right. speaker-1: Right. So what what we were trying to do is look to see in the rat pr prefrontal cortex, which we knew that's kind of where the the all the magic was happening with the behavior of LSD due to other e experiments from other laboratories, what kind of effects was a psychedelic like LSD having on what genes were being turned on and what genes were being turned off? And by knowing what the response was at the genes that were being turned on and turned off it to LSD, we could kind of deconstruct that to get a better idea of what LSD was doing to a cell. Because it was completely really unknown. We knew that LSD was interacting with specific 5 HT2 receptors, 5 HT1 receptors, that it was turning on certain signaling pathways, but beyond that, what what effects were it having? Was it inducing, say, genes that would indicate that there was cell damage going on or plasticity? nobody really had any idea. So it was a way of further investigating and drilling down to a deeper level of understanding of how LSD affected the cells in the brain beyond just the receptor interactions and acute effects. speaker-0: And what what what kind of discoveries did you make at that time or were made at that time when you were doing that research? So it was speaker-1: We didn't really know given all the propaganda that had been going on with this is your brain on drugs. so one of the one of the findings we might have expected were we were getting also fine kinds of toxic markers showing up, like a cell. there are certain genes and proteins that are expressed when a cell is damaged. And if those are expressed, you can say, this drug is it's toxic, it's damaging the cell, it's damaging the neuron. So that was one possibility. And we gave these rats an incredibly high dose of LSD just to make sure that we were gonna see whatever we saw. So this would be like a person maybe taking ten to twenty hits of a recreational dose of LSD. And then speaker-0: Right, which is just a yeah, yeah. So like LSD is dosed by the microgram, right? Like that it's incredibly strong. So with an e you're saying a recreational dose, maybe a hundred micrograms? speaker-1: So a recreational dose, say a hundred micrograms, so the equivalent of what we gave the rats would be like a thousand micrograms. speaker-0: That's a lot. Yeah. So that yeah. So there there's no doubt that that that they've taken L S D. Right, right, right, right. speaker-1: There's a stereotype behavior in a rat that you can tell they interesting psychedelic. speaker-0: Well and so and that's but that's part of what you were doing here is moving into the behavioral biology, right? So you're just you're literally observing behavior, which I I kind of tend to agree is is much more interesting. Yeah. to see like what and so what did you observe with rats when you said they look stoned? Do they just kinda lay on their back and like soak up the sun or almost. speaker-1: Almost. There there's a set of behaviors. one is called petosis, which is their your eyes are kind of like half closed, and the other is called hind limb abduction, which means they can't hold themselves up and they're just they kind of look like they're swimming a bit. And so it's it's very very classic of a a rat on a psychedelic. It hangs out Its eyes look stone and its body postures really kind of it it looks like it's sacked out on a beanbag. speaker-0: So it's not my first question is do you do do you th do you think they find it enjoyable? I mean if to the degree that that question makes sense with a rat, which which I think is the really the bigger question here is what is a rat consciousness really like? speaker-1: To an extent. so they don't really exhibit signs of overt stress. While they're under these states, they'll play with their cage mates, they'll eat, they'll groom. they don't really exhibit classic signs of a stressed animal. And these behaviors are transient, they go away after about half an hour. interesting. So we took the brain with speaker-0: With L S D on RAFs, is that that seems to be the primary effects for a half an hour? speaker-1: Yeah, the well, you can measure the half life of the effects of LSD in a rat are about ninety minutes. So the if you think about it, rats evolved living in refuse and garbage and trash and so they exposed to a lot of toxins. So they have a very high metabolic capability compared to humans. So speaker-0: For all and that's probably a jugs in general for the best. speaker-1: Shoo through them really fast. speaker-0: gosh, what was I about to ask? what we founded toxicity also, I was just wondering about that as well. speaker-1: So we f we first tried this technology, which turned out to be a bust, and then microarrays were in were invented. So we started, we did some of the very first microarray studies. And with those, we're able to look at like 10,000 different genes on a gene chip and look for differential expression. And what we found was really interesting, despite giving these, given this rather high dose of of LSD. The genes that were coming back as differentially expressed were primarily all increased in expression. We didn't find any that were decreased. And they were all genes involved in synaptic plasticity, like learning in memory. Genes that would be associated with when you're consolidating a memory or when you're learning something. So that was a clue that a first clue that psychedelics might. be helpful for something like the process of synaptic plasticity and learning in memory. And that was kind of the first evidence of that. And we published on that back in 2002. And if you fast forward to where we are now, LSD and these others are now psychoplastigens that enhance synaptic plasticity and learning in memory. And we first had clues of that back 25 years ago from these studies we did at Vanderbilt. speaker-0: So what i the word synaptic plastigen, synaptic plastigen. I think there's we I think synapse is the thing you've already explained. It's kind of the gap, you know, between the the space between things literally. what is a plastigen? What is plasticity? speaker-1: So when you have a neuron, it's it's imagine like a Christmas tree that's decorated with branches and on the branches you the ornaments, those would be like the the synapses that are connecting with other neurons. And this is all in three-dimensional space. when you're stressed or under certain kinds of conditions, you have a decrease in those connections. Or if you're stimulating that neuron and using it a lot, you have an increase in the connection. So that's very dynamic in the number and the nature of connections you have between the different neurons in a particular circuit. And that process is covered under the umbrella of plasticity. It's the ability of one neuron to change the nature and the number of its connections with another neuron. And those can be measured by a microscope. And literally counting the number of connections between two neurons or a functional measurement using a microelectrode that you can stick into a circuit. And there are certain like if you're getting long-term depression LTD or long-term potentiation LTP, as you're injecting current into a circuit. you can sort of have a forward feedback or negative feedback and look at the function of it, which is reflective of what's happening at the at the cellular level. So when I'm referring to plasticity, I'm referring to the ability of a drug to enhance the functional connectivity between neurons. speaker-0: It's the ability for the neurons to connect and we kind of need chains of neuronal connection, right? Neural pathways to to do things, to swing a golf club, to think, to be you know, to remember. speaker-1: When you're it's also you're you're enhancing the connectivity in those circuits underlying that behavior. And speaker-0: And so speaker-1: and in depressed individuals, stressed individuals, PTSD, major depression, they've shown that the connectivity between certain circuits in the brain is less than a healthy normal individual. So there's a a deficit of functional connectivity. And so the recent clinical studies and neuroimaging with psychedelics have shown that and in the preclinical work that's also been done that a a single administration of a psychedelic like LSD, like psilocybin, can restore the functional connectivity in these deficient brain circuits. And then the hypothesis is that's what's underlying the therapeutic effect. speaker-0: The the the r restoration of plasticity. Right. Basically. so there's also you you know, you mentioned drugs can create it, but I've I mean I've also think about exercise all the time as just a as a modulator for plasticity. And there's this neuroscientist at NYU, she's the dean of she's the arts and science college now, Wendy Suzuki. And she studies the neuroscience of exercise and she calls exercise a bubble bath for the brain. and I love that 'cause it's just it's probably highly regulating, literally, of all the neurotransmitters 'cause I've just, I think it's probably the the main thing we evolved to do is move. You know, we're distance runners, basically. And so it's interesting. I always like to to like exercise and then meditate immediately after. So my brain's you know, the most plastic for that little period after. But it's it's interesting. I mean, you're you're working with flies, you know, and or you know, you're working with rats, you find that there's these things about learning and memory, which I imagine must have been really surprising to associate that with LSD in the early two thousands. but then I mean when I think of when I'm thinking of psychedelics and also and serotonin, I think if the average person, if you did a word association between serotonin, if they provided they understood the word, they're probably gonna say something like mood or depression. And it's interesting that we're getting learning and memory and it's like, okay, well, what are the relationship to that to mood? speaker-1: Yeah, this it it's really it's complex. Serotonin regulates learning and memory, it regulates mood. And some of the work that we actually did in fruit flies several years ago here at in New Orleans was looking at the role of psychedelics and different serotonin receptors in the process of learning and memory in the fruit flies, and showed that there's a very important role that is similar to the role of serotonin in in humans. for learning in memory. speaker-0: What can you tell us about that? speaker-1: Serotonin II receptors are both intricately involved in learning in memory in both humans and mammalian systems and also social interactions. And with respect to mood, we we published a paper last year on the antidepressant-like effects of psilocybin in fruit flies. So whatever these mechanisms are that are producing long lasting effects on say mood and learning and memory are conserved very, very far back in evolution. speaker-0: Yeah, so I'm dying to know about that because I mean, I read this paper about some years ago by Charles Nagel called What is it like to be a bat? Are you familiar with this? No. it's kind of it it it kind of, I think, if if it didn't begin the field of philosophy of mind, it it changed it profoundly. Because it's just this, it's this essay about can you really imagine what it's like to be a bat? But it he kind of essentially posits this definition of consciousness, which is that for something to be conscious, it must be something to be like that. thing. Like it there must be something what it is to to be like a bat. You know, and we don't really know what that is because we're not a bat. Like we don't have the neural the neural architecture to be able to understand it. But a bat has an experience that is very bat like. and it's just kind of a a profound it's a really short little essay and it to like paper and it's like really mind-numbing. But it does make me wonder a lot about studying things like consciousness. It's fascinating to me that you could study fruit flies and and learn anything about human depression. And it's kind of wonderful and amazing that you can do that. And I'm really dying to know like what it is that you observe with with fruit flies. Because to I'm like, no way a fruit fly has a mood, but maybe they do. speaker-1: yeah, like the there there have been several studies with fruit flies and even some of the very, very early studies with serotonin were in lobsters back in the nineteen fifties and sixties. they have a lot of the same neural architecture and then I have a colleague who studies crawfish or crayfish, crawdance, looking at speaker-0: Yeah, okay. speaker-1: effects of those and there's a lot of conserved biology for say aggression social interactions like for for example in the crawfish if you've ever been to a crawfish boil and the crawfish falls out of the pot you go that's not good I want to eat you you want to put it back in the pot you reach down to get it its claws are gonna go up it's gonna pinch and it's gonna back away from you while you're trying to pick it up. That behavior is mediated by activation of serotonin-2 receptors in the crawfish. So the same receptor that is the psychedelic receptor is sort of that aggressive stance. speaker-0: So if you gave a crawfish high dose of L S D, do you assume that's what it would do? speaker-1: it might have been done. I have to look at that. speaker-0: It's and I'd be curious or would it just do it at everything and regardless of whether someone was coming? Yeah, yeah. I mean it speaker-1: A lot of the serotonin work is is is really translational. there are several labs that have looked at aggression. speaker-0: Translational means in other species and then you speaker-1: Right. What you find in in a human are I mean you find in a model organism, you also find the same fundamental mechanisms in in a human. like for speaker-0: For ethical reasons it's easier, I assume, to to do these things to rats and crawfish than it is to people. speaker-1: Right. And people think of serotonin as the had the happy drug or the happy neurotransmitter, but it's really it's the homeostasis, it's a set point. When you've got too little serotonin that might produce mood disorders, depression, anidonia. If you've got too much serotonin, that's linked to hyperaggression, aggressive outbursts. So it's really not about having the neurotransmitter there or not, it's about how much you have in How much you have can produce opposite effects on behavior. speaker-0: So one of the things I'm very interested in and have been for a while is just like with psychopharmacology are psychotropic drugs for for mood and things like that, especially antidepressants. We have a lot of antidepressant medications in this country. And going back, I think I think beginning in the seventies, there's been this idea of the chemical imbalance theory, which I d most people you talk to in medicine, if you will kind of privately admit that we know that that's not how that works really. but there's just W the way you just described it actually does seem like balance really is the relevant factor. And it's not like that I think most people think, well, your serotonin's low. You take this pill, you get some more serotonin and you feel better. And I don't know. D i is that really how it works, do you think? Or obviously it's more complicated than that. But I'm just curious about speaker-1: The serotonin deficit theory is still controversial. There have been some papers that have come out recently saying that that's not actually what happens, but then you look at the methodology and it wasn't quite right. There are those that are. And it it's not so much like if you take an SSRI like Prozac or Cetalipram, you are its primary mechanism of action is you're blocking this protein on the pre-synapse. That once serotonin is released, it's responsible for taking this free serotonin that's not bound to a postsynaptic receptor or not metabolized away to bring it back up into that presynapse and repackage it like it's a recycling. And what the SSRIs do is they block that and increase the levels of serotonin in the synapse. making making the concentration that's exposed to the postsynaptic neurotransmitters higher. But that's not all these SSRIs do. They also have affinity for other transporters. They have direct affinity for certain receptors, like 5 HT1A. So they have they're they're affecting levels of serotonin, of norepinephrine, of dopamine, and they're directly activating like serotonin 1A receptors. So it's it's not just that these SSRIs are enhancing serotonin and that's what's fixing things. That's a part of it, but they're all doing many other things. And it when it comes down to it, we have absolutely no clue what the primary mechanism of action of an SSRI is. And the FDA states that you you don't have to know how a drug works. You just have to show us that it works and it's safe. And so there are so many drugs on the market that we have no clue how they work. But they're safe and they do work. speaker-0: Right. Yeah. it so I you the way you were the what you were just describing is like re-uptake inhibition. I think a lot of people mood and mind-altering drugs seem to work that way. Yeah. Is that is is that a fair statement? I I think even like that's how amphetamines basically work with with dopaminephrine. And it's always interesting. I mean, something's always about inhibiting the inhibitor. You know, or like in it seems in medicine, like you find a way to block the thing that inhibits something or until you get more of it, or it's like these little indirect chains. Kind of I I imagine I envision like a root. Goldmer machine. You how those work where it's like, you know, the thing, it's like a cascade of things. And going back to that piano analogy with the with the genes, it's like, I mean, if you change one note in a piano chord, you get a totally different sound. Right. And a different mood of effect. So it's amazing it's almost amazing that we know anything. speaker-1: Yeah, I like really that's a really good analogy. Like the brain is the largest rube Goldberg machine that you could think in ever would exist. speaker-0: To to trillions of connections, yeah. speaker-1: You know, it goes down to the level of if you have a receptor and you have a molecule, and you change one atom on that molecule, it still activates the receptor, but now it activates that receptor differently. So instead of turning on pathway A, it turns on pathway B, and maybe turns off pathway C halfway. So even at the level of adding one methyl to a compound can completely change the output of that giant rub rub Goldberg. speaker-0: Yeah, that what you just said kind of it's kind of chilling because that's how a lot of quote unquote legal marijuana works. I mean, there's a pr a big problem with that here in Tennessee where they they we still have not allowed just natural organic cannabis to be sold. But so it's a lot of like Delta Eight THC or you which you can just go buy at some head shop. And there's a you know, what I've noticed when I moved here was something that I moved here four years ago in two thousand twenty-two. I I began to experience see a lot of something that I thought was an urban legend, which was cannabis psychosis. and I mean I'd heard of like one event from someone that had taken like spice or K two, but this is like mainstream. It's a real problem. It seems to predominate in men under twenty seven, but it it it just was not something I'd ever experienced before in the you know, in the previous decade of just using lots of real cannabis. And it just seems that people are just because in our laws we we the the statutes will ban a compound, a chemical compound. So people will just alter the chemistry. They'll add a methyl or take one away or whatever and it's like but there's really bad unintended consequences. And this is a terrible way to do drug policy, but it's it's what we have in the United States. speaker-1: That's like I there was once I think it was on a PBS, it was a special on the interaction between the plants that shaped human lives. And they talked about corn, wheat, and one of them was cannabis. And they made an interesting point that until cannabis was made illegal and scheduled, it wasn't very potent. It took a lot you know, you had speaker-0: Y you could just kinda smoke a joint for a while. Yeah. Yeah. Yeah. Yeah. speaker-1: they made it illegal that it really turned it into like all the people who were experts in genetic engineering and plant engineering and botanics all focused on increasing the diversity of the cannabis strains and increasing the the percentage of cannabis and allowing them to grow under grow-like conditions instead. So the like the the epitome of plant genetic engineering was focused on cannabis. And if it hadn't happened, then we wouldn't have developed these super potent cannabis strains which are out there now where they're like ten times, twenty times more potent than cannabis in the sixties, like one puff now, as opposed to speaker-0: Could could have life altering effects. Yeah. It could give you a panic attack or speaker-1: The cannabis is so potent and produces a lot of these psychosis reactions because, you know, it's like having a same can be seen with caffeine. You've got these monster shot drinks with six hundred milligrams of caffeine. You're getting more and more incidence of caffeine psychosis presenting. speaker-0: Interesting. I did not know that. Caffeine psychosis. God, that sounds horrifying. speaker-1: And it's the same with like the meth caffinones and the bath salts, they make one illegal and then another one pops up. When if they just would have left it alone, we likely would have just had that original nineteen sixties cannabis that wasn't getting anybody very high. speaker-0: Yeah. well, you know, it's funny because this is like I mean, when you create a massive profit incentive, also like if you look at the flower of a from cannabis, the bud, which is you know, it's like a delivery vehicle for a drug and you're gonna charge money by weight, but you also have to move it by weight, it makes more sense to increase the concentration of the drug. Yeah. You know, it's just like in that you know, that's why cocaine is a better drug smuggling product than cannabis, 'cause it's just way more potent per per unit of weight. and so you get all the best minds in botanics and everything just working on it, like it's the cure for cancer, literally. And you know, and so this is what you get. And it is kind of like, yeah, I mean, I wonder what we would have done if we had directed that human potential towards a better use. But these are these are kind of the the unintended consequences of drug policy that, you know, I've seen ever since law school of just seeing like how, you know, and it's a lot of people We'll say, well, like, what should we just legalize everything and have a free for all? And it's kinda hard to be like, yeah, because it's like, no, that doesn't sound necessarily good either. But there's gotta be, you know, a better path than when we create these massive profit incentives, it just seems like innovation and science are much, much more nimble and faster than our legislatures and our regulators. You know what I mean? And so we're just playing whack-a-mole and it does seem like that, Probably you're probably really familiar way more familiar with this in with this than me is like the research chemicals. People will t buy research chemicals from China or India or wherever they can get them and a lot of them are like in the psychedelic realm or maybe not. I'm not really sure. They're just they're altering little things. What what can you tell us about what people are doing with that? speaker-1: Yeah. Well those I think for a long time when my father still had his laboratory active, it's like every time that he would get a publication on some molecule that he had developed, it would then show up on the research chemical market. And I think he had I had somebody ask him once, you know, shouldn't he he should be ashamed of publishing publishing knowledge because it was killing people. And he's like, you know, my job is to figure out how these receptors are working, to understand the brain. You know, it's up to every own to each individual to decide what they want to put in their body. And if they want to take a toxin into their body, that's not my fault. so it it has been an issue. and and a lot of the research chemicals were either published at PCL, TCOL, from my father's laboratory and then from a few a few underground chemists who have who have come up with stuff. But it's it's a real issue. And these are untested compounds. We don't know what their safety is. for example, the compound 25 CNN boat was a research chemical that actually my father did not invent. It was somebody in Germany who invented it. And that was making the rounds ten or fifteen years ago is the super potent LSD derivative that was killing people. And we had tested it in my lab and it was the only two A agonist that we ever tested in my lab that killed my experimental organisms. So there was a known toxicity with it. And you know it's speaker-0: Yeah. Yeah, that's something we haven't really talked about. With psychedelics, they generally, like the classic ones, don't have a lethal dose. speaker-1: The ones that are characterized, the natural ones. and they do and these these chemicals that we're coming up with, yeah, they're psychedelic, but who knows what else they're doing. Like this twenty-five CNMbo, the toxicity, I did some testing on it and it was a non five H T two A mediated effect. So it's not from the primary. It's some off target effect is being toxic. And these these research chemicals that are out there, nobody knows what else they're doing. And they could very well be producing some toxic by product or inducing a toxic effect. So it's really playing Russian roulette with these with these research chemicals. I I think speaker-0: It's also a also a a function of prohibition. Yeah. Because it's they're because they're legal. Like you can just order them on the internet. Yeah. Yeah. I want to go back to asking about, you know, the the the caffeine induced psychosis. That's fascinating. And and also with the cannabis induced psychosis, since you've studied psychosis and schizophrenia, I'm just curious like do you have any idea of like why just a large d a much larger dose of something that you would ordinarily take, like caffeine or maybe cannabis? But in a much higher dose could trigger psychosis. Do you have any sense of how that's happening mechanistically? speaker-1: so it's it's like a high dose of any kind of sympathimimetic CNS stimulant. Cocaine, amphetamine, caffeine will all produce overstimulation of the brain circuitry. And at this overstimulation it converges on these psychotic like effects of paranoia, the pounding heart, so at at higher doses, people can't would associate yeah, if you take too much meth, you have meth psychosis. You're gonna go into the psychotic break. you take too much amphetamine, you're gonna have a psychotic break. And maybe not people enough realize that if you do that with caffeine, it's the same is going to happen. And if somebody presents at the emergency room with caffeine psychosis, they're gonna have exactly overlapping symptoms as with somebody who's taken too much, say amphetamine. They're gonna have the same body symptoms are gonna have the same paranoia, mental symptoms. and it's a lot of times like people take a like a cup of coffee is like a hundred milligrams. And I just heard there was a report yesterday that came out from a group that looked at like the maximum amount of coffee intake a day for health benefits. And I think it was like five cups of coffee a day, anything more than that and it it's detrimental to your health and that's still like five hundred milligrams. But you have these monster shots, energy shots that have all these neon lettering and like marketed to to kids and they've got like five or six hundred milligrams of caffeine in it. And if you have you know it's a shot. You take one, take two, if you take three, you're gonna be having speaker-0: Yeah, you could you could literally become psychotic. And did d do these can these effects be permanent? I mean, once you kind of tip into psychosis, now you're now you're kind of a candidate, right? speaker-1: Well, I think y you just have to cool down. speaker-0: That's what antipsychotics do too, right? I they're just essentially depress everything. speaker-1: Dopamine system. But for the caffeine, if that's what it is, you just have to wait it out. It's not gonna really produce any damage. and little few people know this, but Roland Griffiths, who his claim to fame later in life was at Johns Hopkins with all the psilocybin studies. He also was one of the world's leading experts on caffeine. And when I was I I give the lecture on CNS stimulants and caffeine to the students here. and when I was putting those lectures together I noticed that a lot of the earlier caffeine studies were published by Rolland Griffiths. And I had a few conversations with him on that. And he said it was an interesting story that that he relayed to me that you know now how the amount of caffeine has to be listed on Any given drink. Like if you look at a can of Coke, can of Red Bull, it'll tell you how many milligrams of caffeine. Well, Rowland was the one who led the charge for that because he had recognized that you had all these drinks that were being marketed to children with caffeine in it, like 500 milligrams of caffeine, and nobody knew how much caffeine was in it. And so he testified before Congress on adding the amount of caffeine to to the packaging and he said he was getting death threats, he had the major beverage industry were taking out like PR hit jobs on him. it was it was quite brutal on him for a couple of years. And then finally after his congressional testimony, it was mandated that you must have the amount of caffeine on these containers for people to know what they were taking. speaker-0: Yeah. Yeah. Well well it's one of my favorite trivia questions to ask people is what's the most commonly used drug in America? And and they never they never think caffeine because they don't think it's a drug. But it it it's clearly I mean it's a stimulant, you know. I mean it it it it it kind of depends on what's your definition of a drug and for most people what's your definition of a drug is something that only bad people do. Or you know, I mean it's it's it's that's that's basically because of like that this is your brain on drugs. That if something's illegal it must be bad for you and if it's you know if it's not legal it must be good for you. But if we have the things that are legal, you know, I like alcohol and tobacco. And you nicotine and tobacco form are kind of the worst things you can do. Yeah. Just about speaker-1: You can a what I do is I go into the class and I say, Okay, we're gonna talk about caffeine today and I I I put up the statistics showing like eighty s eighty percent of adults in the US are regular caffeine users and of those eighty some percent are essentially addicted to caffeine. I said, You wanna know if you're addicted to caffeine or not? How many of you when you wake up in the morning if you don't have your cup of coffee, get irritable and grumpy or have a headache? Like More than half. speaker-0: Every caffeine user just about. Yeah. speaker-1: So you are you are dependent upon caffeine to get you back to that normal state. And one of the things that Roland had told me is like these people to to properly use caffeine, you have to not use it more than about twice a week to get to where it does enhance have that cognitive enhancing function. Because once you are dependent on caffeine, it's like the old adage with heroin, you just need that to get to feel normal again. speaker-0: Right. Well it well. speaker-1: Rollin had said to me was what these people don't realize is if they weren't dependent on con caffeine, they wouldn't need their caffeine in the morning to feel like they needed their caffeine. speaker-0: Yeah, I I gave up caffeine let let's say in October of last year. And I've actually given up all stimulants, no stimulant medication and no chocolate, which has been a hard thing to get rid of. 'cause I I used to drink ceremonial cacao and I loved it. The pharmacology of it's so cool and like a lot of serotonin precursors and I noticed after I drank it every day, I hadn't when I stopped drinking it I got a a a little lower mood after a little while. But I I just sleep so much better. I was having profound sleep disruption for years and just my body's very sensitive, but I've also noticed I have much more energy, I'm much more alert, it's much easier to focus. You know, it's just all the nootropic effects of caffeine were basically, you know, I was just in such a deficit all the time. Yeah. And you know what you were speaker-1: yeah. Yeah. It takes about six weeks. I I asked well, okay, if somebody does give up caffeine, what can I tell my students like how long will they have to basically be absent to be back to normal where it would have these neotropic effects if used properly? And he said about six weeks. so when I tell that to the class is hey and and If you want to get off caffeine to have it functional for you again, it's about six weeks and they all go, no, I can't do that. speaker-0: Too long. Yeah, if you're in medical school, there's no way you can just go six weeks without being able to think properly. You know, it's just better off staying addicted to it. You got to get back to your baseline. You're just trying to get back to normal. I mean, in principle, isn't that how all mind altering drugs work? I mean, if you take them habitually, is there any I mean, I would think that that that's an issue that I've seen with I've been on a lot of psychotropic drugs, probably fifty. and What I all I really observed was that within a few months I just would end up back to baseline and then when I then I'd have to go through the withdrawal process when I'm come off of them. And it seems to just be an inherent feature of the brain that it's it's an adaptation machine. I mean, are there any drugs for which like long term use where you would you would not expect habituation like that? speaker-1: There the the habituation is due to there's this process called desensitization and down regulation. So when your when your brain and your neurotransmitters are exposed constantly to a a ligand, in in compensation to that constant drug speaker-0: A ligand is a drug. Something that binds to your yeah. speaker-1: your your brain will reduce the amount of receptor for that drug. So then you have to take more to have that same effect. And then eventually you desensitize the system so much that it it might lose its effect completely. So Yeah, mostly speaker-0: So and that's happened to me with cannabis. She couldn't get high anymore. Yeah. speaker-1: like for L S D, if you take L S D on day one, you have a big trip, take it the second day, you have a moderate trip, you take it the third day, you won't trip at all. It's very fast with L S D if you take it like on a daily basis. But there are drugs that that have some effects that do habituate like that and others where the habituation is on a much different timeline. so like example for an opiate drug like oxycottin or something like that, the drug if you overdose on that, there there are a side effect pathway and a therapeutic pathway mediated by two different enzymes downstream of that receptor once it's activated. One of those pathways produces respiratory depression, so you stop breathing. The other pathway is that analgesia pathway. So when somebody first starts taking an opiate drug, they're at high risk of developing that respiratory depression. But then if pain goes worse, the longer they're taking that, they habituate to the respiratory depression effects. And if they're an addict, the same happens. And so the analgesic effect. speaker-0: That's interesting. Okay. speaker-1: If they then go off of the drug and they reset and they take the same amount of op opiate that they had took either as a recreational abuser or as a prescription user, they're n the they come become resensitized to the respiratory depression and then they're at risk of dying from the respiratory depression. So it's just speaker-0: is this is classic overdose. I mean, I just I've been around treat the treatment world and addiction for several years and just it's the biggest thing with people that are opioid addicts coming right out of treatment. They're really vulnerable because they just you know I've even been in a I was in a treatment center where they just said look like if you relapse don't take what you were taking yeah before you got here. Like that and it's just that's just basic harm reduction is we don't want you to do it. But if you end up doing it, you're like this is how people die. And yeah I think there's kind of a common understanding of that. It's just it's like you become resensitized. that's that's you know, it's interesting that it that's separate from the analgesic effects. speaker-1: So there are there are attempts now, yeah, to make a drug that has engineered out the ability to activate that respiratory depression aspect, but to maintain the the analgesic effect. So there there's been a a few attempts at that. speaker-0: I'd like to ask about you were talking about the LSD and then the there's the rapid short-term tolerance. I mean, it's it's massive. You take it one day and then the next day, you're right, like you'd need five times more or something, and then the third day that nothing will happen. I've heard that many people make the claim that psychedelics are anti-addictive. And that was just what came to my mind when you mentioned that, because it is one thing where it's just like you it's very hard to habitually use that drug, but I know that all psychedelics don't work that way with that kind of rapid short-term tolerance. I'm just curious if like is there a definition of what anti addictive would be and and to what degree does that apply to to psychedelics speaker-1: Yeah, it's the the mechanism for that really is i is what not really known. In in terms of like substance use and addiction from a scientific standpoint, we try to model those in an animal that say you you you put a rat in a box and there's a lever in the box and every time it pushes that lever, it gets an injection of a drug. If you put heroin, cocaine, alcohol, methamphetamine, something like that in there, the rat will continue and continue to increase pressing of that drug until it essentially passes out. So that's called self administration. And so drugs that animals will self administer are almost always what become addictive in humans. but if you do that with a psychedelic, rats or mice won't do that. They'll they'll give it it's It's not something that e even if a drug produces unpleasant effects, they'll continue to do this if it's has other rewards. speaker-0: Like cocaine or methamphetamine are I'm sure very unpleasant in a certain degree, but they'll keep doing more. speaker-1: Yeah. And with psychedelics, classic five H T two A agonists, they won't do that. And they won't do that with MDMA either. So there's no self administration with psychedelics or with intactogens, which s sort of puts them in a separate class, which is kind of mirrored in in the human use. Like you give somebody a high dose of L S D for therapeutic purposes, it's like, Are you glad you did this? Yes. Would you want to do it again? No. speaker-0: It's like yeah, it's like giving birth. I mean the last I mean I I wouldn't know from experience, but I mean it's you know, I've I've had that experience where and it's like the last thing on your mind is let's do that again right now. Right. Like I mean you're just you're just kind of, you know, processing it and Yeah. speaker-1: There's very little what I would call addictive behavior associated with psychedelics. And are there people who routinely use it recreational? Yes. But that's not compulsive addictive behavior, like you would see with an opiate or with cocaine. It's that compulsion. So on one hand, LSD and psychedelics, they're not addictive. They don't produce compulsive taking behaviors. but then they're anti-addictive properties. Are that sometimes in these clinical trials for substance use disorder, like my colleague Peter Hendricks, who's up at UAB, University of Alabama, Birmingham, he just published on his study of psilocybin for essentially homeless crack addicts. there are people who have been lifelong crack users, they come in, they do their psilocybin session and never never touch it again. Yeah, one speaker-0: One time they're off crack. Yeah. Do speaker-1: It's it could be speaker-0: do we know what do we know what like a relative idea of the proportion of those people? I mean, is it is it like is it is it a substantial st statistically significant number of people or is it just kind of a noteworthy anecdote? speaker-1: I think he had at like six months, twelve months, I think there was like a sixty to seventy percent out. speaker-0: Jesus. speaker-1: And early on, like there were there was a there were a percentage that just never touched it again. There were some that maybe did it once or twice, never did it again. And going into that study, the the thing was like all of the other studies that had been done at Hopkins and NYU, those were really cherry-picked individuals to maximize success from upper middle class families who had support systems and counselors and was it really gonna work in the real world? And these people after their their therapy were going back to the streets, their lack of support systems. And so would it work? And these a number of these people, they reconnected with families, they sought out social services, they got jobs. So it really showed that in in the real world it it can't have efficacy. speaker-0: Yeah. And so like the anti addictive is not only are you not addicted to this drug, it can cancel out an addic another addiction, which is you know, the holy grail of addiction medicine. I mean, I know and there's a lot that's a lot has been made about ibogaine with that with opiate with there's there's a specific opioid pathway there, but psilocybin and crack, as far as I know, don't have much of a of a good speaker-1: You know. And with with Ibogaine, nobody's really done the studies with Ibogaine and PTSD. there's no reason to think that Ibogaine is any better than say psilocybin at reducing opiate dependence in veterans with PTSD. Those are those are studies that need to be performed. speaker-0: Yeah. Yeah. Well, now I know that there's change w in drug policy in the last few couple of months actually with with regard to Ibogaine and and bringing that in under the Trump administration. so hopefully, I mean, one of the biggest I think part of the biggest tragedies of the whole war on drugs is just the is really in a lot of ways was a war on science. Yeah. And there's all these amazing things that these medic these compounds could do, potentially. Most of it is the stuff of urban legend at this point, but it they've kind of escaped the lab again and Science is, you know, like relative to what you might get from an SSRI where there's billions of dollars of research and all this vetting and all this stuff where like we have these claims that are vetted, people are expecting the same level of certainty with regard to compounds like psilocybin and ibogaine. And it's just this weird little corner of science that's wait, that's fifty years behind everything else. speaker-1: Yeah. Yeah. It really there was a lot of research done preclinically. a lot of people assumed when the controlled scheduled act and the FDA regulation changes in 1970 that there was no research on psychedelics. That just halted preclinic I mean clinical research. So there were no more clinical studies done to looking at efficacy for treating depression, alcoholism, things like that. speaker-0: By clinical you mean on humans for a specific medical problem. Yeah. speaker-1: There were hundreds, if not thousands, of studies in the fifties and sixties. so those went went by the wayside, but there were a core number of investigators throughout the nineteen seventies, the nineteen eighties, nineties, like my postdoctoral mentor, my father, who really continued to study 5 HT2A receptors, receptor signaling. like the study of LSD acting at 5 HT2 receptors was instrumental in discovering GQ couple pathways by my postdoctoral mentors, like some basic fundamental pharmacology from these receptors. And a lot was really known preclinically about what they do in animals, the doses that they give, the types of behaviors that they elicit in mice, in rats, in cats. So there was a lot that was known preclinically which fed into why when the clinical trials resumed with psilocybin and LSD, the FDA kind of gave a pass on the safety. Because we had had all the historical data from the 50s and 60s, but then we also had this huge body of of research from animals from the seventies and eighties and the nineties feeding into what we knew about the toxicity of these compounds. speaker-0: Yeah, so like in general I one of the first things you mentioned is when people ask you about psychedelics, they'll say, Are they safe? I mean what what can you tell us about this the science of you know the safety of psychedelics? Well first maybe maybe we start with as a psychopharmacologist, how do you discuss safety when it comes to a drug? Like what are some of the metrics that you would look at? speaker-1: Yeah, so safety encompasses a rather large area. Safety refers to physical safety, mental safety, cellular safety. like is is a drug going to kill a cell? So there are tests that you would do first in the drug develop drug development pipeline where you have cells in a petri dish and you just add increasing amount of drug until those cells start to die. And then you can say what's the concentration of that cell or the drug in that cell. that starts to die, and how relevant is that to what the concentration in a person would be? And if you have to put a lot of drug in there, you can say, well, we have to put a thousand times more drug in these cells to get toxicity than we would a human. So it's it should be fairly safe. So then the next phase is you go to a whole animal and you start with low doses and you go up to very high doses to determine really what it it's called adverse events at what level are you going to start seeing adverse events, which could be say cardiovascular issues, could be seizures. It's not always death, but like what's the what's the level what you're getting an adverse event? So you'd start off with low doses and you could push it and push it and push it till you say, all right, at fifty milligrams or a hundred milligrams per kilogram of this drug, we're starting to get seizures in the animal. But if the the translated human dose would be the equivalent of say half a milligram per kilogram in that animal, you say, you have a safety margin of 200x before you start hitting these any of these adverse events. And then there are also like mental tests that you can do. There are a series of cognitive tests, activity tests that you can give increasing doses of drugs to an animal to see at what point does it now start to interfere with its ability to remember things or to find its way through maze and look to see how that compares to the the theoretical translational dose. So once you go through all these safety tests and toxicology tests to show that it's not toxic, if you pass all of those then that's the information you give to the FDA asking permission to be able to give that drug to a human. And then the FDA will evaluate all that data and say, okay, we believe that this is going to be safe for a human to do a phase one clinical trial where you now show it's safe in a human. It doesn't produce any of these effects. speaker-0: And that's the purpose of phase one is just purely safety in people, right? You're not even necessarily worried does it work? it's just is it gonna kill people or what are the adverse effects and their their incidents and things. speaker-1: Like that. Right. And if there's if there are red flags that pop up, like, it it so many drugs will say, it it it kills cancer in our in our mice, and now we put it in a petri dish at cellular cancer, now it's killing normal cells at a therapeutic dose. Or you put it in a whole animal and you find out at that point that that drug is also activating another receptor that you had no clue was activating, which is causing it to stop breathing. so most drugs will die in that phase of development where they're having these off-target toxicity events. speaker-0: Right. So and y what you were saying is with psychedelics we have so much preclinical which is in animals research for the last speaker-1: psychedelics there's been so much by so many people that we knew what what the toxic doses were in an animal we knew what the toxicity in humans were so the the FDA I don't want to say a free pass but they they let the trials proceed, but there was careful monitoring for any toxic symptoms. And to date, to my knowledge, there have been no real physical safety effects in any of the clinical trials. The s one safety issue is the safety of mental condition in You know, that gets to the the regulations in the clinical trials that people who have a a relative of with first degree psychosis probably you want to exclude them. because there is an inherent risk of a psychosis like phenotype resulting whether it's somebody's first trip or their one hundredth trip, and it seems to be a constant, like point five percent, regardless. So there is an inherent risk, but to people speaker-0: Seems to be point five percent only in people who are have a relative with psychosis, or is that in everybody? speaker-1: On everybody who takes a psychedelic, there's about a point five risk of them developing these persistent symptoms afterwards. And when when looking at that subpopulation, I would say it's highly enriched for individuals who have first degree relatives with something like psychosis or bipolar. speaker-0: So if you took okay, the half a percent of all people who have had any kind of persistent psychosis, if you were to look at those people specifically, you're gonna have a really high incidence of people with a family history of bipolar speaker-1: Right. speaker-0: disorder or schizophrenia. speaker-1: So there is almost that somebody will will mentally go crazy. And that there there are some examples of that, but from the clinical tr trials that have been well controlled, that really hasn't been an issue. speaker-0: Also that seems like just from what you I know of it from from like popular culture is there are some places and situations that are really not conducive. to taking a psychedelic like at a concert. Or or, you know, at like I mean, someone, you know, I I talked to someone yesterday who told me 'cause I told him I was talking to you today, and he's like, Yeah, man, I used to take it in high school. And I was like, Well, this is the last place in the world I would want to take a psychedelic drug. You know, I guess it would make it more interesting, but like, you know, and so there's a lot of those kind of things where you could have a panic attack. And like you could be traumatized in in those situations. And of course in a clinical setting, one of the benefits of it is that it's it's more controlled. The environment is more controlled to to eliminate something that could be terrifying. speaker-1: Yeah, I think set and setting is absolutely critical. That if you're if you're taking a medication in a bad place, you shouldn't be taking it. It's just gonna precipitate a bad trip. and for therapeutic purposes you have to really have like a a a warm, nurturing, comfortable environment. to have a positive trip. And I think that kind of goes to, you know, today they try to maximize the the real the comfort and the connectedness with the therapist so you feel you're ready for this in the therapeutic sessions. But MKUltra back in the day were just taking people in off the street and dosing them up. speaker-0: This was the CIA experiments with LSE. Yeah. Secret. Yeah. And what were they they were what were they doing it for? speaker-1: They were trying to develop psychedelics as a mind control agent. And one of the main leaders of that was at Tulane University and he was the chair of psychiatry at Tulane, and apparently they still have one of the bunkers they used to dose people up back in the fifties in City Park here. And speaker-0: Too late in City Park, I believe it. speaker-1: I was I was several years ago this person whose shell remain unnamed, but he was in his nineties at that point. was involved in these early, early studies with LSD back in the early 1950s and he's would talk about how they would take Amish people who would come into the big city and just bring them in off the street, put them into a dark room with no lights and dose them up with like five hundred micrograms of acid and just watch them. speaker-0: What? What that sounds that's horrible. That shouldn't be laughing. But it the the the fact that they're Amish the fact that they're Amish is a particularly weird detail. Like the C these are the things when I heard these things in high school and in college. I mean I would be like, that's preposterous. speaker-1: It was like can you break somebody and get them to believe things that aren't true and and this whole MK ultra speaker-0: That makes sense. So you you get someone who's a you get someone who's a true believer and see can you really change their beliefs. Right. Right. So that's why Amish people. Okay. speaker-1: Exactly. speaker-0: You get religious fundamentalists and and okay. Yeah. And so anyway, so that's that's MK Ultra. Yeah, yeah. It's it's it's evil that the CIA did it. they they try to destroy all the records. speaker-1: You're in a you're in a horrible setting like this and you you can't help but have a bad trip. speaker-0: I've heard also there's one like kind of famous they did a lot of this in San Francisco, obviously. Yeah. And they would they would take people in and bring them into a brothel and dose them. And then I think they would they would lead them to believe they had murdered the girl. and then try to use that as a blackmail technique. and it's just like so that's that's horrifying. I mean that that's just evil to do that to someone. I mean, to to dose someone with a mind-altering drug without their knowledge or consent is just evil. but yeah, so that you were just saying like I I just had to double click on because there's probably some people watching this that would not know what MK Ultra was. It sounds like a completely insane urban legend, but we actually have document evidence from the government records that this really happened. Yeah. Right in the 60s. So yeah, I mean that obviously. probably would produce a a lasting mental effect, like a traumatizing effect because I assumed 'cause you're just these medicines it raise plasticity, right? Like to a to an extreme degree. And so plasticity is neither good nor bad. Like it's just what is it what is it that you're being impr you're going to be very impressionable, basically. Right. So what's the impression that's going to happen? Yeah. speaker-1: Yeah, so my my research we published on it in twenty twenty and other researchers like Gold Dolan have published on it as well, that there there's this window of about two to three weeks after a single dose of psychedelic, at least in our animal models, where the brain is plastic to the environment that it's in. And during that time if you put it in a stressful environment, it shapes kind of the it you you lose that antidepressant effect. So speaker-0: So the two or three weeks after are just as important arguably as the what you're doing. speaker-1: So if you take this person after two weeks, you give them the therapy, they're able to deal with things that has this positive therapeutic potential. So that's the integrative therapy. But then if you take the people during those two weeks and you put them in this mind control environment and try to control their mind, then you can reinforce whatever this paranoia and stuff. So you could either have lasting therapeutic effects or this lasting PTSD. so yeah, the plasticity. Can be for good or bad depending upon what that environment is that you're putting in. speaker-0: So I I wanna put a pin for a second in the in the role of therapy with these 'cause I want to come back and ask you about MDMA trials and and the denial of that and what you think of that. But you mentioned there's like this two or three week period and I I know about Professor Dolan's research just on like critical periods of plasticity. I if I can recall correctly, some of her research pertains to the length of the period that opens right as it pertains to the the the psychoactive effects of the drugs. Could you summarize what we know about that? speaker-1: so her her research converges a lot with our research that shows that there's there's a particular length of time after this the drug is administered where the brain remains in this plastic state that you can manipulate the environment within the first two weeks and essentially persistently affect the animal's behavior after that. But if you wait, if you manipulate the environment after those two weeks there's no lasting effect. So there's this receptivity to plasticity based on the environment in the first two weeks after giving a psychedelic. And the types of experiments that she did were a little bit different than the types of experiment that we did, but they're ax absolutely congruent in identifying that about that two-week window of availability for that brain to remain in this plastic state. speaker-0: So I'm curious about the two week period and whether or not the length of that period is dose dependent or or substance dependent. speaker-1: It it might be. we I I think that there is some data that the longer that you're you're high, maybe the longer it is, but we haven't really seen that. we've looked at the length of the experience in the animal, whether the route that we give it can govern how long that animal is subjectively high. And if we give it in a route where it's subjectively high for say ten minutes. by giving it IV or we give it IP or oral where it's subjectively high for two hours, we don't really see any difference in the long lasting antidepressant effects. speaker-0: So interesting. When you control for dose to the degree that you can do that, yeah. speaker-1: Right. So there's still it's it's it's an open question, is the time that you spend high or that's beyond the side point of s is is a subjective experience necessary for therapeutic effects or not? But speaker-0: We'll come back to that. speaker-1: for th for argument's sake here, is the time that you are high, is that really necessary or relevant for the persistence of the therapeutic effects? And the data I think is piling up that really suggests not necessarily. We've got the preclinical data that show just getting the animal to that point produces these long lasting therapeutics. The drugs the drugs like 5MEO DMT that are being used in clinical trials or DMT or the IV cellulosin, they all will have a very short duration of action, but in their phase two trials have all shown an enduring antidepressant effect. And speaker-0: Of a of approximately we think maybe the same speaker-1: A at least six weeks if if not longer. People haven't really gone out to a year more in any of these trials. So speaker-0: It's just 'cause the expense of doing that. And I guess also there's a lot more variables they can add up. speaker-1: Right. There's really only one company that's developing a long subjective trip, and that's Definium. And they they renamed themselves from MindMed a few months ago. And they're developing a a proprietary formulation of LSD for generalized anxiety. And so their method, they did a dose response of like fifty, one hundred and two hundred micrograms of LSD. And if I'm remembering correctly, found that one hundred micrograms of LSD acutely was the most effective dose to producing these long lasting therapeutic effects against generalized anxiety. So they're really the only correct speaker-0: That's interesting because I'm aware of that. LSD to me seems to be the most one of the most anxiety provoking medicines. And maybe it that's it would be interesting to know if if there's maybe a resilience that's being built to that. speaker-1: There's a story behind that involving my father on the anxiety. speaker-0: Let's hear it. So yeah. speaker-1: Some people can take LSD and they don't have any anxiety, it's fun, it's great. Other people, they take it the first few hours, it's great, but then they get all paranoid and anxious, and it becomes very unpleasant. And my my father had noticed this in his rats 30 years ago, the ones that were given LSD. repeatedly developed these real paranoid aggressive behaviors. So he formulated this hypothesis that there was a metabolite of LSD that was activating dopamine receptors so that after the the first part of the trip was over, then it transitioned over into this more dark psychotic like due to this active over activation of dopamine receptors. So he did a lot of experiments and showed that it was the dopamine D4 receptor that was reproducing those effects. He could train rats to distinguish whether they were on the early side of the trip or the later side of the trip. And the later side of the trip, if he blocked dopamine D4 receptors, he could block that. So just last year, we in collaboration were able to make that metabolite that he hypothesized decades ago. And sure enough, it's a very potent D4 agonist. So we he thinks, and we've got a manuscript that's been submitted now on the basis of the anxiety and the bad trips of LSD for some people, but not others, is that some people produce this metabolite which superactivates dopamine receptors and some people don't, which is why some people like LSD a lot more than some people don't. speaker-0: Yeah. Yeah. And presumably there's at the other end of that research some what might lead to some sort of way of inhibiting that or doing something blocking it and people that to where it could have therapeutic potential. You know, one thing that you've you've alluded to a couple of times here, and I'd love to ask you about there's now we're in my opinion, we're kind of getting into the really juicy stuff, and we're only an hour and a half in. is microdosing. Like there's that's a common practice. I mean, and there there seems to be very little, if any, research, but I think you've done some of it, right? what like what do we know about micro? producing. And what is it? And how is it you know, what's the protocol and then what do know about its effects? speaker-1: Microdosing it can mean different things to different people. one definition is a subbehavioral dose taken repeatedly over time. Another definition is one-twentieth of a behavioral dose taken over time. There's what's called the the James Fadiman protocol, which is I think taking one-twentieth of a dose every third or fourth day. there's a lot out there. There's people who are doing microdosing with psilocybin, with LSD. and there there's very little evidence supporting the claimed benefits. The claimed benefits are enhanced creativity, higher energy, a better sense of of well-being. so I was involved in a study several years ago where we had given repeated low dose of LSD over two weeks every third I think it was every third day or every fourth day at five, ten, and twenty micrograms, these are naive individuals and then did all speaker-0: Meaning they've never taken it before. speaker-1: psychedelic before. Yeah. And speaker-0: They have no expectation statement. speaker-1: No expectation it's placebo control, double blind. And cognitive testing was done across several domains, looking at you know memory, attention, proprioceptive, physical attributes. At the end, none of them could guess if they were on a drug or placebo or what dose of drug and the There were no effects on any of the cognitive measures or real physical measures. So there was nothing there. And the the purpose of this actually was not to debunk microdosing. The purpose of this study was to show that low repeated doses of LSD were safe and appropriate for a population of individuals as a safety trial. in preparation for going into Alzheimer's patients. and maybe treating MCI with LSD. And so we needed to demonstrate safety. So this demonstrated safety, but on the flip side demonstrated that there were no effects. speaker-0: Y and so if if I'm doing the math right, I mean you're saying about five re about five percent, that'd be like five micrograms of L S D. speaker-1: Five micrograms, ten micrograms, and twenty micrograms. We had three speaker-0: Crazy. So that's that's a big range. So yeah, and so and you're seeing the same thing even at twenty micrograms. speaker-1: Right. speaker-0: No. And you're you're measuring cognition. I'm wondering does that also include mood? Or things like measures of social yeah, so their social life, their their sense of connectedness, spirituality, things like that. speaker-1: Maybe i i it it had like basic mood in the question. speaker-0: Yeah, okay. So they're they're not coming in being like I found God. No. Right, right, right, right. There's nothing nothing no major change in their life. speaker-1: There have been some studies by Harriet DeWitt and her group at the University of Chicago where she was doing functional imaging in fMRI with 13 micrograms of LSD per person. And they were able to demonstrate that there were changes in connectivity that were visible with the fMRI. So at those doses, there are changes in the brain, but if they're really doing anything we we don't know. speaker-0: So well we I mean we'd want it to translate to conscious experience as the idea, right? So if it's not it's not speaker-1: So and a lot of it there's a a a term called expectational bias, which is like you know, placebo effect. And with antidepressants there's about a thirty percent placebo effect. If you give somebody a placebo, you tell them and it's antidepressant and then you test them on their depression scores a few weeks later, thirty percent of people given the placebo will say that the medicine is working. So there's a very powerful placebo effect with psychoactive drugs like this. And so if you have these people microdosing who their friends told them, it works great, take it, you know, I I think there's a huge expectancy bias on terms. speaker-0: The bias is the the cognitive element of the placebo effect is that we have this bias that we expect something to to go a certain way and so it does. speaker-1: So that's that's my take on microdosing with LSD. With psilocybin, I have now a somewhat different take. because unlike LSD, psilocybin is a pretty good anti inflammatory. whereas LSD is really not a good anti inflammatory. And the anti inflammatory capabilities of LSD are such that at the levels used in microdosing, they're having real effects in our animal models. And if any kind of mental there's neuroinflammation that's doing anything or inflammation in the body, the amounts of psilocybin that people are using may conceivably be having an anti-inflammatory effect at those levels, which could be improving the overall body or mental function. speaker-0: Right. And so you're seeing that in your research now, there's just an effect and you're I guess hypothesizing that it would be related to inflammation or speaker-1: So we we're nearly ready to submit a manuscript where we did a study using daily sub-behavioral doses of a few different psychedelics to treat rheumatoid arthritis. And each of these, included psilocybin in there, had differentiing effects, but they all had positive therapeutic effects in this model of rheumatoid arthritis at Daily sub behavioral doses. speaker-0: So you know, did you also assess for mood a alongside while you're while you're assessing for things like that? No. speaker-1: So yeah. speaker-0: I imagine if someone's rheumatoid arthritis improves, their mood's gonna get better. Right. speaker-1: Right, exactly. speaker-0: And so that that kind of creates an interesting conundrum of like are those things separable? Doesn't matter, do we really care? But I I I do. I'm kinda curious of like what well if it's also having this other benefit if it reduces neuroinflammation, maybe their mood would get better independently. speaker-1: Right, right. So say somebody's got arthritis, they're microdosing psilocybin, which I do not advocate as a medical professional. but if for whatever reason they are, their arthritis improves, their mood is going to improve, the neuroinflammation will go down. So there might be something there and in clinical trials, that might be something to consider for a future clinical trial. looking and at inflammatory biomarkers. And a lot of clinical trials now, in in consultation with me or others, they've they've in been incorporating blood draws and other markers to look at biomarkers for for inflammation and if those are getting better or not. speaker-0: That's amazing. do we know the like the mechanism for how it reduces inflammation? Is it is it related to the serotonin pathway or is it separate or speaker-1: It's through the five H T two A pathway. If we use a genetic knockout for the receptor, we don't have anti-inflammatory effects. We block the receptor block the effects of psychedelics. So we know it's through the receptor, but the different drugs are doing different things. like in our models, DMT is not anti-inflammatory at all. LSD very weak, but psilocybin and silosin are very anti-inflammatory. And in other molecules that we've looked at the non-classic psychedelics, they're like some are treating some diseases and inflammatory pathways different than others. So we're in the process of saying, okay, they they all have some kind of protective anti-inflammatory effect, but which one works best for asthma, which one works best for arthritis, which one works best for inflammatory bowel disease? And so that gets back to how changing a given molecule. on a psychedelic will cause that receptor to turn on or off other pathways. With some psychedelics we're turning there's I think multiple anti inflammatory pathways that are being activated and some will activate some better than others. And so we're we're in the stage of sort of figuring that out now. speaker-0: That's so exciting. I mean, you talk about we we began talking about just like the unintended consequences of basic research. And I know what you're doing right now and you're describing it's not basic, but to you know, to discover, wait a minute, like you might be able to treat Crohn's disease with this. Like, you know, and s as opposed to depression, which, you know, I'm just I'm excited anything involving the mind, any kind of new drug that would help people with mood or addiction or anything of you know, mental health is exciting. But I also live with chronic inflammation. and it's just a problem I have all the time. And It just I just know the mood altering effects of it. I get anxious and irritable all the time and you know, we skin things and whatever and just it's just, you know, this kind of basic process that if I can control it with an ice bath or a or a infrared sauna or an anti inflammatory diet, it makes a massive difference just in my overall quality of life and my general sense of vitality. And so it's exciting as someone that has this, not that I, you know, I'm gonna go out and start microdosing. 'Cause I wouldn't, I wouldn't. I've tried it in you might be interested to I've tried micronosin psilocybin, it makes me reliably really irritable. and and it I mean it's it's confounding and it's been consistent across different strains over years. It's been a while since I've tried because it's like, why be in a terrible mood? It's it's just really giving you the opposite of what it was supposed to be. Yeah. So I know there's tons more research, but you might find something like a real basic mechanism and we might lead to lots of like relief for lots of people that are just kind of ailing, you know, from these inflammatory diseases. speaker-1: yeah. It's like 60 to 70 percent of people are dealing with some kind of inflammatory disorder. like I myself have degenerative spinal disc disease, and I'm in chronic back, neck, and neck and back pain. There's other people with arthritis, there's people living with eczema. there are so many people with these inflammatory diseases where the the drugs that we have, we've got like ideprofen. Which has its immune speaker-0: Or you could take an immune suppressant. speaker-1: suppressant, which then you get tuberculosis. Or speaker-0: Right. It's like yeah, I don't want to get pneumonia. Yeah, you know, I mean speaker-1: or not really good and the the ones that are becoming popular now that you see on TV commercials or for these biologics. These antibodies against, you know, IL-23 or IL-33, you have to inject those in the clinic, and those are a hundred thousand dollars a year. They're really not accessible. So what's really lacking is a truly disease modifying, safe, small molecule that somebody can take that is gonna treat their inflammation. And so far we've we see evidence in a model of cardiovascular, of inflammatory bowel, we've looked at rheumatoid arthritis, asthma. it's it's I think it's really promising. And at doses far, far below, like thirty to fifty times below a behavioral dose. speaker-0: So for one, thank you for doing this research. Like that's it, it gets me excited just to talk about it. but science in general just gets me excited. And the thing that how little information we need to make these massive breakthroughs. But we're kind of been dancing around this subject, and you you raised the the question earlier is w whether or not the psychoactive effects are are important to like the lasting mood effects. And what you're describing here, a thirtieth of a behavioral dose. Now again, like May maybe if the the I'm sure that people are gonna be in a better mood if they if they're they're in less pain, you know, but maybe there's something else that's going on more directly. What are your thoughts on whether or not the psychoactive effects are important for like th these crack addicts in in Birmingham, for example? I mean, I've heard about things like the the main variable seems to be the dissolution of the ego. Yeah. or the oceanic boundlessness and things like that. I mean, to what degree do you think that these things are separable? speaker-1: I think that there are going to be populations where the subjective trip is going to be necessary and those where maybe not necessary and I think most of them it's going to be necessary because I think if if you look at a lot of like the veterans with PTSD, you look at the crack users, you look at people with major depression and other comorbid disorders, there's a lot of trauma. associated with that. A lot of childhood trauma or trial trauma as an adult that has produced this dysregulation of their HPA axis. They've they're they're just in this rut that they can't get out of. And the SSRIs and whatnot are aren't really very effective. So the therapies like MDMA, like psilocybin, the subjective experience allows them To really Confront, face, absorb that trauma, that history, see it from a different angle. That then when the subject subjective trip is over, the integrative therapy is crucial. Like this this is what I was dealing with. I saw I saw my deceased grandmother, and she was so disappointed. in me for where I am now in my substance use. And then you explore that in in the therapy and and you realize like, my gosh, I'm not alone. I d I I talk to my mother, my grandmother, I have a family, I'm commun I have a community. They re reconnect to that. So having that subjective experience for somebody who has become disconnected, who has had some kind of trauma that they have avoided facing, or are unable to just because it's too traumatic to face, they're able to do that. if somebody doesn't have that subjective trip and have that kind of catalyst to recovery, maybe intense psychotherapy within those two weeks can get at some of those things. But I think that subjective experience is really the catalyst to the recovery. And if you have somebody who's depression this is the minor fraction of them though who are it's just idiopathic that they're happy normal people normal childhood there's no trauma but their brain neurochemistry is a little out of whack and when they get depressed they just can't come out of it and that's that's a that's a a smaller percentage. They that is the population that might benefit from the non-psychedelic psychedelics where you do have that increase in plasticity in both But in the one case, it doesn't matter if you're having a subjective experience or not, because you don't have any, you know, that's you're you you don't have these life events. But it might be enough to to renormalize some of these circuits that could be deficient because you have maybe there's a you have a undiagnosed tumor on one of your glands and that's producing a synaptic deficit in your brain. And so now you take care of that and re enhance that. So I think I think there's a role for both. But it's not not really been explored yet in clinical trials. speaker-0: Yeah, you know, that it's interesting you mentioned like these people that have this this idiopathic depression and it's and it's they're kind of stuck in it. I I've had a I had a really, really long battle with depression and and with trauma and I've been fairly public about it on this podcast. It's kind of how I've become interested in the mind. And I can imagine the the thing is what you're saying, one th I was thinking two things. One was, well, yeah, I mean, if these people could technically benefit without the subjective effects, they probably still arguably benefit more with them. Yeah. Like there doesn't seem to be any reason to exclude that. But also you still need to make sense of the depression. You still need to make sense of what you've lost and of the shame that comes from people not getting it and thinking that you're just not working hard enough or whatever. And of the life you've lost, of the experiences you've lost, the relationships you've lost. I mean, it it becomes at a certain point, it becomes its own trauma and you have to make sense with that or come to peace with it and come to love it or or whatever. I mean, it's the kind of weird thing where these compounds can facilitate connections where it's like you can anthropomorphize a disease like depression and then come to love it and give it a hug. Or things like that where it's just there there's no way to really you know, i it's it's it's I yeah, I wanna ask you about this MDMA trials. The they're the the third the phase three trials, I think it was two years ago that got rejected by the FDA for approval. What's the name of the company? Is it Lycos? speaker-1: it's now they changed from Lycos to there have been so many companies that have changed names recently. I can't I can't remember their name now. speaker-0: This was the first it was backed by maps and it was the the first the first real push for approval for MDMA. And I would love to know your opinion on just on the reasons for the denial of the of the approval by the FDA. It it to me, my layman's assa assumption or my layman's impression of it is that the FDA doesn't really understand how to standardize therapy. Like that seems to be a real sticking point that therapy seems to be an indispensable part of how this drug is meant to be used and because it's a different therapist every time, there's a different human element and that there was some lack of standardization, but maybe I'm wrong about that. speaker-1: Yeah, I'm I'm I'm not really certain of that. Yeah, they they they did ultimately release the FTA document on on the comments on why it was denied their their NDA. And I know my my personal opinion is you know there's there's a lot of opinions out there and a lot of smoke and mirrors like with what happened with the phase two trial sites up in Canada with some people being taken advantage of, but I don't ultimately think that factored into the FDA's decision. And I think a lot of what factored into the FDA's decision was that certain metrics were not gathered that are required of all psychoactive drugs. for example, the adverse events was a big one. Not all trial sites collected adverse events because I think there was maybe a misunderstanding of what Lycos thought was an adverse event versus what FDA defined as an adverse event. Whereas the FDA defines in my understanding, an adverse event is anything that's out of the realm of the ordinary, whether it's subjectively positive or negative for that person, that's an adverse event. Whereas Lycos may have been looking at it looking adverse event as something that's negative that's happening. That they had euphoria, so that euphoria wasn't counted as an adverse event. speaker-0: in my my layperson's understanding of what adverse means, I wouldn't count euphoria as a as an adverse event. It's interesting that that but they would at least need to document that because it's somehow that's not intended. speaker-1: Right. And I and then events like that are required of all CNS active drugs that the FDA goes through. so it's a bit a he said, she said from Lycos' perspective and the FDA, like Lycos say, they moved the goalpost, the FDA says no we didn't. it it ultimately comes down to I think it was it was a new company, had never gone through an approval process, it was a new type of approval for the FDA. And mistakes were made potentially on both sides. And I thought it was interesting that the FDA advisory panel, that the two people that were on it who voted for approval were the external members who were invited who said, But you we don't have anything. so it'll be speaker-0: What do you mean what do you mean they meant that they don't have anything? speaker-1: Therapies to treat PTSD. speaker-0: Right. Like right. There there's a sense of urgency that we need to bring this to market. And that that's a that's a valid, valuable perspective. I think that also should be counterbalanced with an understanding of safety 'cause right. You rush to bring things to the market 'cause we need them, you can kill people. speaker-1: Right. And I I think maybe Lycos was relying on, it's been in people for decades and and then the FDA like, Yeah, being in people and getting anecdotal reports is not the same as asking them when they're high on the drug in in your therapy session. so I I'm I'm not c quite sure what's gonna happen. I think I don't think that they are going to c do an additional trial. I think they're gonna resubmit for that NDA by trying to respond point by point to what that notice was that the FDA issued and and we'll see. Do do I think MDMA will ultimately be approved? Yes. speaker-0: Yeah, no question. speaker-1: I think it will. And I think psilocybin there's a a likely possibility that psilocybin will will be approved by the end of this year or early next year. That Compass Pathways, I think they've dosed their last patient in their phase three trial and they released their top line data a couple of weeks ago on their phase three. So they're speaker-0: What what did that data show? speaker-1: for treatment resistant depression it showed pretty impressive enduring effects for psilocybin at I think it was twelve weeks out. Yeah. So at the clinical endpoints. So they've done everything. speaker-0: From a single from a single administration, like a single dose. Yeah. So you know, that that's better than taking S SSRIs every day. speaker-1: They've got their phase three trials are now complete, so now they're putting together their new drug application package. And if everything continues to go on track for them, I would anticipate it to be submitted to the FDA by the end of the year or early next year. And then if the FDA approves it, then they have to work with the DEA to reschedule. speaker-0: think that it seems like there's a lot of political will in the Trump administration to tell the DEA to cooperate, which it historically has not been willing to do. Yeah. you know, but it's also a it's a generally like I think for a long time it was just a massive waste of resources to spend more than half of their budget going after marijuana because they just refuse to reschedule it. Yeah. you know, as from schedule one. Are do you anticipate that any other psychedelics classic or otherwise would would might be approved in the next say decade? speaker-1: I think probably well COMPASS is going for treatment resistant depression. Usona is not very far behind COMPASS at all, and they would be anticipated to submit their new drug application next year as well. They're just going for major depression. so those two Definium is in the midst of their phase three for generalized anxiety and they've got breakthrough status by the FDA. So the speaker-0: That's still assignment? speaker-1: That's L S D speaker-0: LSD, right. Definitely that's the one you mentioned for speaker-1: They could be approved, say in 2028, pending positive phase three trials. Abvi bought Bretoselocin, I think, from Gilgamesh for a billion dollars earlier earlier in the year. Eli Lilly just bought a tie Beckley for their nasal DNT, fibhoxy DNT for something like two point Or three point eight billion dollars. speaker-0: That's five MEO. speaker-1: for five MEO. So both of those assets have been through phase two B, showing efficacy. So what Lily and Abby need to do now is to do a large phase three randomized controlled trial at multiple sites costing hundreds of millions of dollars. So if they get those trials going, say over the next year those trials should last about two years. So you would see within about three to four years maybe one of those assets being approved. you have there's a a company now called HELUS H E L U S which has due speaker-0: That's good name. Heal us. That's a good name. speaker-1: Yeah. Deuterated psilocybin, so it's got like heavy water hydrogens on it. speaker-0: Deuterium, yeah. speaker-1: Has a slightly different pharmacokinetic profile than psilocybin. They are now in phase three trials this year. So if they're successful, they could have something approved within the next two to three years. trying to think who else is in phase two B early phase three. I think those are the only companies that are in phase three now or would be going into phase three. there's reunion, which is developing pro drug of four hydroxy DIPT for postpartum depression. I think they've got very encouraging phase two data. I don't know if they've started their phase three yet. So I think within the next three to five years We can see several psychedelics come on the market for treatment resistant depression, major depression, postpartum depression, speaker-0: Yes, D. speaker-1: ETSD. speaker-0: Addiction? Substance use. Well the thing is w once something comes on the market for one thing, you can also kind of use it off label. speaker-1: Right. Deep deep if the FDA allows that off label use. speaker-0: Interesting. But interesting. But so there's there's a there's a list of things that are approved for off label, but that that okay, all right. speaker-1: So I think there there's there's a lot of development and excitement out there. I think what the main challenge is gonna be now is not acceptance or moving to trials, but what's the insurance reimbursable gonna be? What's the access gonna be? Is insurance gonna reimburse a psilocybin therapy course of therapy? Are they gonna reimburse for an MDMA course of therapy? it might be thirty thousand dollars. for a a still staggered course of therapy and are they gonna do that when a monthly sub prescription for Prozac is gonna cost them five dollars? speaker-0: Eight yeah, eight dollars, something like that. speaker-1: Yeah. Are are they gonna do that? And then the delivery. There is no system of care delivery. it's I don't think it's gonna be where you'll have a rescheduling across the board. I think you're gonna have a it's gonna maintain schedule one for recreational, but in certain like treatment centers it'll be descheduled to a two. speaker-0: It's like in geographic location. That's an interesting way of doing it. Yeah. speaker-1: Right designated treatment center where you're gonna have a facility that's gonna be certified to be able that none of that's out there. So we might be in the position of having psilocybin approved the DEA in the process of descheduling for therapeutic purposes or rescheduling, but there's going to be no infrastructure for that delivery. speaker-0: Yeah. speaker-1: They'll just have a psychiatrist in their office be able to get psilocybin because you're gonna have to have the the the safety. we don't know what the REMs is. The REMS is like the after safety program. You know, what are the the monitoring of the patients? How long you're gonna keep them in the clinic, what kind of clinic are you gonna have? like they have with with ketamine, the nasal spray S ketamine. Like you have to stay in the clinic for two hours, you can't take yourself home, somebody that you know has to take you home. you have to have a follow up appointment. So what are those going to be with acilocybin therapy? Those haven't been defined yet. So before speaker-0: Then they won't be until until the FDA approves it. Then that that's all to be worked out with the with the DEA. speaker-1: So you're not gonna see commercial availability until all of those are worked out. Right. And that's you know, the day that if the the new drug NDA is is issued, that's gonna be great, but that's again the start of another long process to put all these other things in place. And so it's gonna be a while between when the FDA approves it and when it's gonna be available. Because there's a lot of issues to address. speaker-0: Do you know of any research on like like medicinal benefits of other compounds we haven't mentioned, like mescaline? I think that's one of the ones that hasn't that I know of I just off the top of my head that hadn't come up. speaker-1: There are a couple organizations who are studying mescaline. one of the issues with mescaline is its low potency, its propensity to have people vomit. And it's also an issue with preservation of the peyote cactide, which is becoming an endangered species, that as mescaline become would become more popular, you get more people going in and raiding these Plans for the the the peyote cacti. So that's why in a lot of the legislation in California there's decriminalization of a lot of substances but not masculine in order to protect the the peyote cacti. So it's a little bit speaker-0: And so and just outright in the drug, because I mesaline's abundant in San Pedro cactus. It's all over the American southwest. I mean it's not it's not limited at all. and but speaker-1: Like in the early 2000s, the very first studies using psychedelics that were done by Roland Griffiths and Charlie Grob back in like 2006-2009. There was a meeting, like what drug do we use? And it was of the because the Hefty Research Institute we're funding these studies. So we were there. Do we use mescaline? We thought, no, because it's gonna make people sick and vomit. it it's not very potent. So last yeah, you don't want to give sick cancer patients something that's gonna make them feel inducing. So then is it L S D or psilocybin? LSD is gonna last just way too long and it's got such cultural baggage. Like, you know, you've got your grandmother with cancer and now you're giving her LSD. So we can't do that. So then the default it's sort of landed on psilocybin. Psilocybin it's got a a a six hour time course, it's been used by indigenous populations for decades, it's not going to make them sick. And it's easier to justify giving medicinal psilocybin to a cancer patient than it is these others. So that's kind of how psilocybin was chosen as the drug to use in these initial human studies back in the early 2000s. in the studies that were funded by the Heftar Research Institute, which really funded all of Rowland studies, the Hopkins studies, the NYU, up until very recently and still active study funding some new investigator initiatives. speaker-0: our speaking of the purging, the vomiting, our mutual friend Lorissa Carniero, who connected me to you, when my episode with her talking about sh we talked a lot about ayahuasca, which contains DMT, but it's it's a plant. It's taken, you know, ceremonially, is is known as a purgative. It will cause purging and vomiting or diarrhea. And she brought up mentioned that there's some people that think that that actually might be part of its mood altering effects, the way that affects the the bacteria in the gut that we produce most of our serotonin. in our gut. do you think that there's any any there there potentially, anything worth studying of like how the I mean it it can make people profoundly sick, but we do produce a lot of serotonin in our gut, do we not? speaker-1: Yeah. A lot of the well the purging is really what's in the intestine. It's not okay. What's in the gut. And the gut produces the serotonin from what are called enterochromophant cells and the serotonin is released directly into the enteric nervous system and the blood system. It's not released like directly into the like the lumen of the intestine. And a lot of what's believed to be one of the main purgative mechanisms of say a chemotherapy is this massive release of serotonin from these enterochromophobe cells in the gut that activate serotonin-three receptors. And serotonin three receptors signal to the vomiting center in the brain to become very nauseous and vomit. So it's this interesting that speaker-0: Serotonin does everything. Yeah. I now it's it just that that's incredible. I mean re inflammation, vomiting, mood, burning, memory. speaker-1: I think there's a single physiological behavioral process that you can think of that doesn't involve serotonin at some level. speaker-0: Wow. Yeah, that's interesting. And so and it conceivably, I mean, researching something researching psychedelics could lead to something that would help people on chemotherapy vomit less, less. Conceivably. speaker-1: Yes. speaker-0: I mean I think it would probably be a fool's errand to go looking for that, you know, maybe, but like you might you that that's conceivable at that sport. I mean that's really exciting. speaker-1: that to block chemotherapy, nausea, and vomiting on Dancitron, Zophrin is a selective serotonin-three receptor antagonist. speaker-0: Wow. Wow. Wow. so you know, I know we need to bring this conversation to a close regrettably 'cause I've really enjoyed it. I'd love to I next time I'm in New Orleans I gotta connect with we gotta go to Cafe DuMont or something. but I just wondering, I mean, after having this conversation, there's so many things I'm excited about that I've heard. I'd like to know, is there anything that we've discussed or haven't discussed that you're the most excited about coming up just in science or in medicine? speaker-1: well in in the in the field of psychedelics I'm most excited about the anti inflammatory aspects of psychedelics and I've been I've been ringing that bell for over fifteen years trying to get people to become interested that psychedelics are anti-inflammatories and like approaching colleagues. try it in your TBI models and other inflammatory models and I was just speaker-0: T B I's traumatic brain injury. speaker-1: Right. It's like, yeah, it's interesting, but we're not interested in psychedelics. And now I'm seeing psychedelics being studied for traumatic brain injury and other things. And so people are finally recognizing that psychedelics are really good for things outside the brain and the psyche. And so that's really exciting for me, seeing that the five H T two A is a target for really whole health, whole body health, not not just to treat mental like depression or PTSD. So I'm excited to see s the the use of psychedelics going off in those directions. speaker-0: It remind me, I don't r I don't know if you actually told us the story of how did you actually stumble upon the anti inflammatory effects. What was the experiment that you were doing? speaker-1: So it was it was after Hurricane Katrina and I was looking for a postdoc and this fellow whose mentor was leaving just showed up in my office one day, wanted to know if I was looking for a postdoc because his mentor was leaving and he had done research with serotonin two A receptors and hypertension when he got his MD PhD in China. And I said, Sure, I am And he had experience with with with serotonin IIA, so I hired him, and we were primarily doing cell-based assays to try to find outcomes so we wouldn't have to keep taking the brains out of animals. And his background was cell models of athosclerosis and inflammation, which I thought was interesting but had no relevance to psychedelics. And at at one point His name was Bang Ning Yu. It was had the he had the idea, let's he was an expert in this cell based athosclerosis assay. He said, I want to do this assay and test our test the psychedelic in that, see if it's anti inflammatory. I was like, That's crazy. Psychedelics the other two A's in the brain and whatnot. So I said, Go ahead, go ahead and do it. And my now ex wife at the time She was my wife at the time. She ran the cell culture facility here that routinely made these prohibitively expensive cells that we needed for that. So I got the cells, Beng Ning set up the experiment, where we added the inflammatory agent, added the psychedelic, and super, super potent anti inflammatory effects. So then I went back, I repeated it, and we knew we had something there. And then what started as kind of a curious experiment ended up now being more than half my research. But if it had not been for Hurricane Katrina My ex-wife being the director of this core and a supplier of one of the reagents we use, being able to supply a reagent we're no longer able to get, we never would have discovered this. So it was a real serendipity being in the right place in the right time at the convergence of the universe wanted this discovery to be made. So it speaker-0: That's beautiful. you know, what just when you saying that, one thing I we I we I didn't really talk about is that a lot of people w who use psychedelics will report religious experiences or spiritual experiences. And I'm wondering if do you see any divine providence in that? Or is that do you tend to look at the world that way as a scientist or do you just kind of stick to what you can measure? speaker-1: I'm I'm a fairly strict reductionist, atheist, but that being said, the universe does work in mysterious ways. so it's it's quite a coincidence. I'll I'll just leave it at that. speaker-0: Yeah, yeah. I mean I think it's really a matter of perspective of whether you're willing to be open to say, Hey, that man, that was that's incredible. That and just to basically like you said, like if it hadn't been for these things, this wouldn't have happened and you can kind of celebrate that on its own without needing to imply agency. speaker-1: Mm-hmm. speaker-0: You know, but it is it is a really remarkable thing. I mean it's one the things like I've said I love about science is just If you look at things like archaeology, just the little tiny little things that we find and we can extrapolate massive co massively consequential things from just from deduction and reduction. And it's a really cool thing. This has been I've had so much fun nerding out with you about science and just neuroscience in the mind and and psychopharmacology. And would love the chance to talk to you again sometime. And there's so much more that we There's so much more that I would love to learn. There's so many more basic questions I'd love to learn about psycho ps you know, psychodynamics and pharmacodynamics and pharmacokinetics and the differences and things like that. But I know you have to go. so thank you very much for for your time. Okay. Thanks, Charles. speaker-1: No, thank you. You're welcome.