 It's high noon. So let's see if we can get started here. Welcome everyone to the Science Circle Second Life. As you know, the Science Circle is a grant funded non-profit dedicated to the development of virtual world platforms for education. So I want to remind everyone to be on your best behavior, please. And also while I'm thinking of it, I wanted to remember next month is the Science Fair. So we have a request for submissions, I guess you call it, or for scientists to have a booth at the Science Fair. So please contact Shiloh if you have any questions or are interested in participating in the Science Fair. And with that housekeeping out of the way, our topic today is the medicinal or therapeutic use of psychedelic drugs. This is a topic I've been interested in for quite a while when we began to hear reports in recent years of some surprising clinical studies that seem to report that drugs like psilocybin and mescaline, for example, I think MDMA2, even LSD, can be therapeutically helpful for treating certain emotional or mental elements like serious depression, PTSD, I think even some elements of bipolar disorder, things like that. And one of the reasons that this has, that they have attracted attention is that they seem to have very comparable to results to traditional or well-known mood drugs or psychiatric drugs without the side effects that are often attendant with these drugs. I don't know any of you who may be taking mood drugs for depression or if anyone has been on antipsychotics, they have, I mean, antipsychotics especially have really horrible side effects. So if this bears out, it seems like it could be a very, well, it seems like a worthwhile path to pursue if they have the therapeutic benefits and the and reduced side effects. So it'll be interesting to see where these go. So to talk about this with us today, we have Dr. Robert Hendricks tagline who's going to give us a little bit of the sort of medical and biological background on these substances. And then also Steven Gager, Steven Zootply who's going to talk a little bit about the sort of the history of the use of psychedelics in medical therapies. So and I am just going to give you a brief overview of what we're going to be talking about kind of specifically the kind of drugs that have been studied. If you'll see behind me on the slide machine slide viewer there is a photograph of mushrooms. These are the psilocybin mushrooms, what are called magic mushrooms, which are the source of psilocybin. And let me see. Turns out that psilocybin, if you look to the right here in sort of the box insert the psilocybin is kind of the teal shaped molecule. You'll see it has a kind of a kind of a ring structure at one end. And then I'll show you a little bit more detail there. And you can see over on the left that the psilocybin molecule binds to the 5-ht2a receptor. This is the serotonin receptor in the brain. So that's interesting. So it binds to the serotonin receptor. And this is a PET scan image under the effects of psilocybin. And I think if you kind of go counterclockwise from the bottom right and go around you can see the increased activation in the brain and the in the bottom left quadrant. You can see that the brain is really lit up. And one hypothesis for how these drugs induce hallucinations is that they do bind to existing receptors in the brain. But the drugs of course are not the intended agonist for those receptors. And so they tend to generate sort of chaotic signaling in the brain. And it's thought that this chaotic signaling is what produces the hallucinations. And mescaline is another psychedelic that comes from the peyote cactus. And here's a picture of what a peyote cactus looks like. And this is a picture of mescaline. It has again it has a ring structure or I'm sorry this is yeah. So and the and then a bunch of methylated groups here in an amine group. Yeah, peyote buttons. Yeah, Shiloh asks what are the peyote button. The peyote buttons are those little little mushrooms that look like kind of like throw pillows. Yeah. And this is an image of mescaline. And you can see here it has this double kind of ring system here at the bottom. And oh I'm sorry a psilocybin rather. Sorry, I think I got the flip. So the psilocybin has the this double ring structure and the mescaline has the single ring. But what's interesting here or the reason I wanted to show this slide is you can see the structural similarity between psilocin and serotonin. Silicin is the metabolite of psilocybin. So psilocybin is the natural form. When you ingest it, it gets processed by the body. Some groups are cleaved off into the psilocin, which is the psychoactive form of psilocybin. And you can see how similar it is to the serotonin. So it's and psilocybin also binds to the serotonin receptor. So both of these hallucinogens bind to the serotonin receptor in the brain. A little bit surprising to me that serotonin, which is such an important molecule regulating mood and perception in the brain, is kind of nonspecific that way. And that may be fairly common because the brain sort of has endogenous forms of psychedelic drugs. There are cannabinoid receptors for naturally produced endogenous cannabinoids in the body, which the THC molecule of marijuana, also a cannabinoid, binds to those endogenous receptors. So that may be one reason why these receptors are sort of nonspecific that way, because there may be sort of endogenous versions that the body needs to be able to recognize as well. And let me see if I have, I don't know if I have one more, that might be my last slide. Yeah, so that's my last slide. So I just wanted to give you a brief, just a quick introduction to the sources and structure of the types of therapeutic psychedelics that we're going to be talking about. And Phil mentions, it's interesting not many molecules have a phosphate group, exactly. It is interesting. Okay, so tagline, Dr. Hendricks, if you're ready to proceed with that brief introduction, I'm going to remove my slide machine here and I'll hand the microphone over to you. Can you hear me? Just barely, a little bit quiet, but I can't hear you, yes. How about now? Okay, one of the things, you can hear me all right? Okay, loud and clear, good. I'm coming down crashing here. See that? That's what happens when you have your screen up high. Okay, first off, I like this picture. I took it last fall and it shows Jupiter and Saturn approaching conjunction. The important thing here for my thinking in the history of this is the term, which I coined actually in my own head, neuropsychologic malware. And that is to bring up the point of how various drugs have been presented to the public. Before I proceed, I want to just ask people to think for a moment back. It should be a memorable thing if it was very intense, but what is the longest anyone here has gone? Not really. What's the longest any of you have gone without eating, without food, without sustenance, maybe just water? And I won't talk about myself, but if you haven't, okay, I see somebody went for days. You go for days, you understand a lot. You understand a lot about what it is being human. Let's see. Primitive mankind was out there, like all the animals checking out all the plants, looking for anything to eat. And I think they were probably much more in touch with ingesting something and then having a bad effect from it than modern people in developed societies where they're eating all this processed crap, processed food, you don't know what you're eating. But some people are more sensitive or perceptive than others and will figure out I had an effect from eating something. And I wanted to touch for a moment on what an alkaloid is. We hear about alkaloids all the time or depending on where you listen to things. Alkaloid is a common term. I find most people, medical students often don't have a real good idea of what an alkaloid is. It's a class of molecules. It's a big, varied class. You think of like an alkyl carboxyl within a carboxyl group on the end of fatty acid. That's a pretty defined kind of molecule. The thing about alkaloids are generally, well, they're naturally occurring. They've 12,000 have been isolated. There's many more yet to be discovered as long as we don't burn down all the forests too quickly. But they generally have a nitrogen and an amide. That's like an ammonia group. True, they're divided into three kinds of subclasses of true alkaloids, proto alkaloids, and pseudo alkaloids. In true alkaloids, the plants derive the molecule from an amino acid such that the ammonia group is in a ring. They have these heterocyclic rings as you see with morphine here. Morphine was isolated in 1804 by a German guy about 21 years old who was an apprentice. Hardly knew what he was doing. Had really crummy equipment, but he was very curious and intelligent and he found from opiates that had been used, morphine was 10 times more potent and he studied it for a long time for his life. He died in the 1840s. So 1804 morphine emerged. When I was in medical school, they used to say if you were isolated on a desert island and you had one drug to choose to have with you, what would you take? And the answer was without question morphine. And I won't go into that, but other samples of alkaloid drugs that are shown here, they're drugs because they were derived from plants and marketed by companies, but atropine, which blocks acetylcholine receptors and when you get a depolarizing kind of paralysis, like from organophosphates, like an irresponsible people use organophosphate insecticides indiscriminately without training and they get themselves sick. Atropine is one of the first things that's used. Atropine used to be very commonly used by anesthesiologists. Quinine is used as a preventative for malaria. And so anyway, those are just three examples of these many different secondary metabolites of plants that mostly plants that have nitrogen bases. The proto alkaloids have the ammonia group from the amino acid outside of the heterocyclic ring and the pseudo alkaloids such as caffeine are not derived from an amino acid. Hang on one second. I'm sorry. I have to turn down the ambient. I have a bird screaming in my ear or something here. Okay. Maybe that'll quell it. So anyway, I think it's important to understand what alkaloids are. And they're varied and why do they exist? Well, there's evolutionary benefit for plants. You imagine a jungle in the primeval forest with all the insects and other creatures. Trees would be eaten alive if they didn't taste badly. Plants produce alkaloids because they're generally bitter tasting. And if you ever taste one, you're like, well, coffee's bitter. Cocoa is bitter, raw cocoa. And they're also fairly insoluble in water, but they are somewhat soluble in alcohol. Hence, the 19th century was full of elixirs, which were alcohol as a solvent for various alkaloids. But the plants defend themselves using these bitter tasting chemicals. And poison dart frogs, by the way, are not so good to eat as well, for obvious reasons. They have the same deal. There are alkaloids that are produced by animals. There's a few examples of that. They're also produced by bacteria and fungus. Okay. I want to zero in as quickly as I can on tryptophan-derived ericot alkaloids. I have this slide just to show the range of amino acids. Ornithine is a non-protogenic amino acid. So anyway, ericots derived from tryptophan. If you look at this lower left-hand corner molecule, you'll see the same double-ring structure. It's an indole that was in mescaline that Bergon was talking about. It has a pyrrole ring with a nitrogen, and you count around counterclockwise. And two things happen to this. There's a rate limiting step in which an oxidase puts a hydroxyl group on the five position. And if you count from the nitrogen on that those lower two rings on the tryptophan, count around counterclockwise one, two, and skip the crack, three, four, five, you'll come to, and you count the end as well, you'll come to the five point where you end up with a hydroxy group. So that's the rate limiting step in making serotonin. Then the carboxyl group is removed, and a hydrogen replaces it. So you end up with tryptamine, five hydroxy tryptamine, which is serotonin. I'm going to talk a little bit about serotonin because even medical students I've talked to don't really seem to understand what serotonin does in many cases. So anyway, you think back over the history of man, there's always been a sense of wanting to expand the consciousness to seek esoteric knowledge or some kind of vision or insight about the world. And these plants can provide that in a sense, they provide at least the illusion of it. Sometimes it's bad. You have, one of the things serotonin does, it can be a vasodilator or vasoconstrictor depending on the vascular bed. And ergot, and you notice that the base of the ergot molecule is that endol, let's see, hold on a second, again, is the endol molecule, endol moiety, that has that nitrogen five atom ring attached to a benzyl group, and then you build on it. And so in ergotine, which comes from a fungus that grows on rye, you get these little black clumps of fungus, and it gets ground into the flower. And you can get people with acute and chronic ergotism think of the Salem witch trials. All these things occur in and are interpreted and managed within the culture and understanding of the times, and often religion is maybe a hindrance. The Salem witch trials, they figured, well, they had this narrow group of people from a small little diversity, and they got group think, and they got stoned with chronic ergotism from eating moldy rye bread without knowing what they were poisoning themselves with, and they started to lose it. And so they could be convinced that somebody must be a witch. There is good argument made that the Salem witch trials arose, like a lot of places, from chronic ergotism or ergot poisoning. Ergot can have hallucinatory effects, but it also causes such vasoconstriction, it can cause gangrene of the fingers and the toes and the tip of the earlobe. When you're operating on the earlobe, you can't inject it with a vasoconstrictor, because it's basically got an vascular supply, and somebody that doesn't know that injects with a vasoconstrictor and the earlobe can necrosis and slough, which is not, that's iatrogenic harm, harm caused by the treatment, which has been common in medicine, especially before 1916. At any rate, serotonin has effects on all kinds of cell types, especially neurons we're going to focus on. Platelets are a big component. Platelets help clump and cause clotting. Lucocytes, inflammatory action, enterocromophthine cells, those are lining the gut. They are derived from the neural crest cells in the embryo, and they are like short-range hormone-secreting cells, but the 90% of the serotonin is in the gut. To talk about the serotonin in the brain, there's this area in the midbrain where you have these these, especially the medial raffae nuclei. The lower ones shoot down the spinal cord. Somebody clicked me. I got a rat. And the upper ones, please don't click on the projector. I have to figure out how to protect it from being activated, but serotonin is produced almost exclusively in these cell bodies, these nuclei in the brain stem, or in the midbrain, and they have projections almost the entire brain, including cerebellum, cerebrum, basal ganglia. Every major neural pathway has adjacent serotonin neurons, almost intimately associated with it. And this is one reason why the understanding of what these drugs do is growing into studies of complexity and self-organized criticality. I'm not going to go into that, but that has to do with scale-free distributions, and it's a way of analyzing networks, and that's being applied to all kinds of things. But I wanted you to hear that and know about it and maybe check it out if you're interested. Self-organized criticality, that's been a big thing in statistics and statistical analysis that's emerged in the last 20 years. But in terms of, I don't know if you can read this well, but I have behavior effects, the CNS effects, and the drugs that are used in serotonin. Serotonin has pervasive effects on organs and in physiology. It's not a simple thing to figure out. It often modulates, it often has excitatory or inhibitory fibers, and there are 15 receptors known, seven families, and most of them, all of them have, at least, an A and a B subgroup. Also of interest is these serotonin reuptake inhibitors, SSRI, antidepressants are a big thing, and can cause problems with your serotonin system. One way to understand serotonin a little better may be to look at what happens if you have low serotonin levels and it tends to be associated with mood disorders and particularly major depressive disorder. There's some evidence that might have something to do with autism. There's not a good support for hyperactivity, attention deficit type problems, or schizophrenia, although you often will read that serotonin and schizophrenia are related. They may be, but it's not clear how. Tagline, this is a barrigan. Do you mind if I interrupt to ask a question here real quick? Yeah, go ahead. So depressive orders may be caused by low serotonin levels. Is it thought that psychedelics basically, they bind to the serotonin receptor, so could one of the therapeutic effects be to elevate the sort of effective amount of serotonin in the brain to counteract it? You are anticipating where we're going. Okay, because my other thought was whether these psychedelic drugs sort of out-compete natural serotonin in some way. Yes, they do. That would be another thing. Okay. Yes, they do, and this is, I wanted to let you know just generally is the bigger aspect. There's so much depression in society that serotonin is associated with that. What happens if you have too much serotonin? Like if somebody changes their selective serotonin reuptake inhibitor. In other words, reuptake of the serotonin from the synapse so that it increases the activity against the receptors, stimulating the serotonergic system. What if they change medications and end up with too much serotonin, or maybe they're taking a supplement that's weird, and that can be life-threatening and agitation restlessness, headache, confusion, the heart beating, and high blood pressure. The, some of that harkens back to serotonin effects of air gut, dilated pupils, loss of muscle coordination, twitching muscles, muscle rigidity, heavy sweating, shivering, goosebumps, and because of the serotonin energy effects on the gut, diarrhea, and abdominal pain, and all those sorts of things. People on acid trips often are not bothered by it, but they will generally sweat, and they have no appetite. They're satisfied. They have no interest in food while they're tripping. So I thought this would be important to tell you about. It's, serotonin is described as the feel-good neurotransmitter, and it's, in very simplistic terms, maybe that's true, as if you don't have enough, you get depressed. Four ways you can jack up your own serotonin without having to pay anybody for drugs or therapy. One is try to adjust your attitude on a consistent basis, looking at your self in the mirror and telling yourself aloud that you're a good person and that you're doing fine and everything's going to be good, and because it's not just your brain dictating, your brain responds to everything coming in from the body, and it can include your own voice. So positive mood induction is what that's called. Bright light is important. People up in Finland know about that. Exercise, particularly aerobic, if you do that on a regular basis, that's one of the best ways to jack up good serotonin levels as well as dopaminergic circuits, which are the reward circuits like I talked about when I talked about meth, and then finally diet. We talk about there are 21 amino acids that are in the human proteins, and one is not coded directly for by transfer RNA, but that has a selenium combined with cysteine, but tryptophanes, you can't produce it in your own body. You've got to ingest it from some other source, generally plants, cheese. I tend to find animal products disgusting, so I don't, I can't think of any, I would recommend there. Okay, psychedelics. I wanted to put this in just to emphasize that these are schedule one substances, and how they became schedule one substances is kind of interesting. There is evidence that cluster headaches, substance abuse disorders, addiction, especially alcohol addiction, end of life anxiety, potential depression, obsessive compulsive disorder, which is associated with low serotonin may be helped by use of LSD. There are people taking low dose LSD every morning, which is probably not a good idea to take something like that on a daily basis. Lastly, Albert Hoffman is a fellow from Basel, Switzerland, who was really a genius, but in 1938, he isolated or derived LSD from Ergot, and five years later, he revived it and ingested it. I didn't know that LSD was derived from Ergot. I thought LSD was basically just completely chemically synthesized sort of out of thin air. I didn't realize it was derived from a natural substance. Now, most of these pharmaceuticals that are, you look at the complexity of alkaloids, it would be really hard to synthesize. Someone's asking if you could have a hallucinogenic experience without taking LSD later than these are called flashbacks. That's true, but that's not the common. Oliver Sacks took, when he was about 30 years old, took I think LSD, some cocaine and some methamphetamine and stared at a wall and imagined he wanted to see indigo on the wall and suddenly a huge blob of indigo appeared and it was beautiful to him and it disappeared and he thought that was sad, but he realized my mind can create that. Yeah, Sacks wrote a whole book about basically making the argument for therapeutic use of psychedelics and hallucinogenic. Albert Hoffman ended up taking LSD about 15 times over his lifetime as he described it and in 1958 he also was a leader in the group that derived psilocybin, isolated psilocybin. So he was quite an achiever. Now I just wanted to show here you look at the relationship of tryptophan with its indole ring there. It's a flat resonating ring and geometrically flat and attached to this three-carbon chain that has the amino group on it. It's an amino acid. Anyway, our God has that base indole ring in it and then you look at LSD and you see the modification that or modifications that lead to its structure. Now because it tends to, I think one, it adheres to serotonin receptor types one, five, I'm sorry, one, two, five and seven. One, five and seven have been difficult to study. The two-way receptor seems to be the biggest actor. In the two-way receptor it gets caught in there inside the receptor and there is a chemical lid as it's described that was picked up by a crystallography by a researcher at University of North Carolina that protects the LSD so it stays in this receptor because one of the interesting things I always wondered about was how is this thing so potent? How does it last so long? LSD trips last for hours. It's thought that the molecule is caught in the receptor for about 40 minutes. That's wild. Just one last thing. It takes so the active dose, what's called a moderate dose of LSD is like 50 to 250 milligrams. I think that Hoffman on his first trip took 200 or more, I'm sorry, micrograms. We're talking micrograms. 50 to 200 micrograms would be, 200 might be the high end of a, yes I misspoke, Shalu, a good dose. He took a whopping dose and he got afraid. He was afraid he was losing his mind and the sensitivity is because it has such focal adherence particularly to these serotonin type 2A receptors that seem to be the activator but as you recall from the diagram of all these projections throughout the brain of serotonin tracks, what does that mean? How does it get these effects? It's really hard to describe. Robert, I'm really sorry. I'm afraid I really do have to cut you off because we only have about 15 minutes left and we still need to get Steven in. I do want to let everyone know of course that taglines that slides are available on the Google Drive. Really, really sorry and we hopefully, we're planning to have a fireside chat later this week I think Wednesday evening so we have, we'll have another opportunity to dig into this some more. One lessons. 1957 of an essay was written by a guy named Wasson who went down to Oaxaca, Mexico and partook of mushrooms that were used. It was in tribal use. They didn't even speak Spanish and then he wrote an essay there and it became a high point of interest. Eventually, meanwhile, the US government, the CIA, started using LSD to give to lawmen and suspects, subjects rather, who were unaware that they were being stoned with it and these were generally paranoid rednecks who carried guns and things and so they had bad trips and so I think a lot of the junk that was fed to the gray-haired congressmen and senators who knew nothing about this was about how this was a psychotoxic drug rather than psychotropic drug. There's a very troubling history to have some of these drugs came to be schedule one drugs. There's a troubling history of racism, for example, that marijuana in particular, but I think also peyote were tagged as used by Mexicans and so forth and racist congressmen used them to barrage ethnic groups, Native Americans also and so forth and one reason they were scheduled to schedule one so that they could put all these ethnic groups in jail. So it's very troubling. Yes, it was used as a weapon to suppress people. So my slide thing is going high again. All right. Well, thanks very much, Robert. I appreciate that but I do want to give Stephen a chance to for his presentation also. So Stephen, the mic is yours. All right. Thanks, Matt. Thanks for all that background. So, you know, I am not a professional when it comes to thinking about psychology, psychiatry or these types of molecules. Again, I have a background about chemistry. I used to teach human anatomy and when it came across my desk a few years ago listening to Michael Pollan on the interview circuit talk about his book, How to Change Your Mind but the science of psychedelics teaches us about consciousness, dine, addiction, depression and transcendence. I was like, this is amazing. Because one of the things that I advise younger people these days when I think about profession and biology is that you really want to be at a place where there are new technologies, new theories and funding and an application. And so the new ways of studying neurobiology with positronic emission topography, much better double blind research studies, this is a great place to be. And I think the impact of this will be rather amazing. I think Michael Pollan in his book does a really good job of conveying that. And so I really recommend and this is what I kind of crash read over the past. So let me give a couple quick summaries from his points. And that, yeah, he kind of talks about the LSD invention with Albert Hoffman. And what's kind of amazing about this, this was a strategy that was common among pharmaceutical companies was to kind of search the library of plant chemicals and then try and synthesize them to have them be pure and then useful in studies. And so LSD was something I think meant for like an analgesic. And it didn't work that way when they studied it in animals. And as a tagline mentioned, it was five years later, he brings it out of the lab, he's thinking, oh, this is an interesting molecule. And he accidentally doses himself. So this is one of the great stories of an accidental discovery. But it was very obvious that it's something that had very powerful effects. And then also just if you ever see this come across your calendar, April 19th is called Bicycle Day to celebrate this. Michael Pollan went to an anniversary of Bicycle Day where Hoffman was actually there. I think this was back in 2006 and he describes it. Now we're on the same time. Well, a little bit later, tagline mentions the seeking the macadamia mushroom, which was a photo spread, an essay in life. And again, amateur mycologist Robert Gordon Watson managed to over several trips get the confidence of a shaman down in Mexico, because this was very secretive. There was actually very few people in Western society outside of Mexico knew about psilocybin and much magic mushrooms. But again, this hit the scene. And I think if you go back and look historically, and this is what Pollan talks about, is that people were really excited about this. And these very immediately were seen as helpful people were happy after using them. And so the applications them to treating addiction, again, it wasn't called PTSD at the time. And depression and anxiety were all immediately realized. And so there was a flowering of research that's actually occurring. And the company that Hoffman worked for actually made it free for people. Again, I don't want to talk about other people are not good at keeping track of names. So I can't really go too much about what the book said. But as an example here, I just mentioned the spring Grove experiment in Maryland. But again, this was an NIH funded research. Another person that you may have heard about is Timothy Leary. So here's someone who's very famous because he's very outspoken about mind altering drugs. In particular, the idea that they kind of undermine the way we think about the mind works and maybe about how society I think that is one of the major contributing factors to what you might call the reversal of society to these being useful drugs. And of course, you know, as they reached a lot of the counterculture outside of the medical clinic, that's where people got very worried about it. But again, up through this late 60s, there was a lot of government funding for this. There were a lot of people seeing positive effects. And there's a lot of publications. But because of the outspokenness partly of Timothy Leary, and then people really looking at bad behavior by these medical researchers, right? So one thing that Timothy Leary did and Richard Albert did at Harvard, like all these practices of getting consent, of having patients knowing what they're doing was not very well followed. And then the other thing is very few of these studies were done in a kind of golden classic way of doing it with double blind studies. And so the actual value of research, as people look back on it, you know, from a statistical standpoint of view, they may or may not have really been accomplishing their goals of convincing people these are very useful for therapy. And so that's really, I mean, the context that I grew up in is that LSD is a horrible thing. You don't want to take it. It's obviously a legal molecule. You can go federal jail for it. And that was kind of the sense of it. And certainly very little research. With one exception, at least in the western hemisphere up in Saskatchewan, they were still working on for alcohol addiction. And they were seeing really good results with that. But otherwise pretty much cleared out. Now what pollen does go on to say is that there was a big underground for this. And so in San Francisco in particular, there were a lot of shamans who still did LSD psilocybin treatments with individual people. And that ultimately is something where pollen goes through a personal experience. He's a six year old man. He felt maybe he could learn from this and writing about it. And he did basically three trips, one with LSD, one psilocybin, and another one called the toad. And that's what he kind of details a lot in his book after he goes through the history of all this. And then the final part of the book really focuses on this modern revival of actual good research when it comes to understanding how these molecules can be used for therapy. And kind of the landmark paper is from the Roland Griffiths lab out of Johns Hopkins, where they kind of took an interesting different tactic where normally in this type of medical physiology research, you would try to kind of have a lot of physiological markers and outcomes and whatnot. In this case, they really just focus more on the experiential patient things that happened and try and publish that. And then to make the case that, look, you know, particularly people are dealing with, say, end of life decisions, depression about life threatening diseases or pathologies, this has value. Now, they weren't trying to make the case that has long out-term effects right away, but that's ultimately what's happened. Where Roland Griffiths has thought of several publications showing that there's about an 80% effectiveness in treating depression and anxiety for people with diseases. People are seeing good results with addiction, especially alcohol addiction. The guy who actually found it, Apolyx Anonymous, used LSD to help him get past his addictions. And so the kind of current state of things, and this is what I think is amazing at how to advise young people, and Paul goes through some of this too, there's some other researchers that are now doing a lot of brain scanning technology, really trying to understand the chemistry as Aragon showed that we actually are understanding these molecules, how they're interacting from the clinical standpoint. And so the kind of thing that I think Paul makes a very good case, although it's a little bit less scientific as a way to, you know, talk about this, is that what is the meaning of the mind? Right? So when people have descriptions, and scientists kind of dance around this issue, people have mystical experiences, and they're commonly seen God, or sometimes they actually are seeing their own birth, or they're seeing the universe in amazing things, they're not interpreted as God, or some other sort of mystical being guiding them and giving them an advice, and seeing dead people, and people take it that way. That's how they will actually interpret it. But is it that way? But what does it mean to have a mind? And the final thing I'll say is that Paulin's kind of main description about how he thinks this works, and he's getting this from a conversation with scientists, is that these drugs cause an ego dissolution. That when you think about anxiety, you're a person who you can conceive of that as something where you're getting so self centered about what may happen. You're getting freaked out about the future and how it affects you. And so if you have this chemical compound that does something to your neurophysiology, affects certain parts of brain centers that dissolve this sense of self as being very and extremely self centered, then you can actually deal with addictions or anxieties because you don't have the sense of you. And what's really important, of course, and this is where the 1960s-70s got it wrong, is that when you think about these as a therapy, you don't want to just think of this as a pill. It's extremely important to have a context, a setting, and a guide, and kind of some mantras or a plan of how to deal with the things you're going to see. So one of the things that got Timotheiler in trouble was that people were being described as undergoing psychoses after taking these drugs during their studies. It probably actually wasn't psychoses as we would clinically pathologically describe it. People were probably just very super anxious and freaked out from what they couldn't understand and had no context or understanding of how to deal with it. So I think that that's an important context of it as well. That when we think about how we say this, that guidance is very important. But that's actually one of the things that undermines the research as well, is that you don't know what the influence of that context and your guides might be. That's one thing that, you know, Pollan makes very clear, is that some of his guidance very much influenced the way and the things that he saw in terms of treatment. But what seems to be relatively clear is that statistically as people study this, people have good outcomes. And now that we have a more statistically rigorous experimental design way of doing it, and we can also correlate this with physiology things that we can study, with brain scans, etc., follow-up studies, this is a great time to be trying to understand. So there's a lot of promise for this to happen. On the other hand, again, one of the main things it's doing is taking people's egos away from theirs from themselves. And you can imagine that when you think about that very widespread thing, you can imagine there are companies or governments who would also try and suppress that to some degree. Again, I don't want to make a big case about that. But I think that this book was a great description. And it really hits on this interesting topic where there's increasing amounts of anxiety, increasing amounts of depression, but the ability to study this and to revive an old thing that seemed to be working is just a great place to be at. At that point, I'll just take any questions. You look at that local chat. Yeah, Stephen, I think it was in the same book you're talking about. I'm not sure. It may have been one of his other books, but Pauline does make an interesting argument that certain plants, well, as Tagline mentioned, plants develop alkaloids to taste bad as a defense mechanism. But the opposite can also be true, that plants can develop chemicals that are pleasurable to us in order to attract us to them and make themselves valuable to us. He makes the argument that marijuana, for example, he's kind of anthropomorphizing here, but essentially marijuana wants to create a pleasant effect so that we'll cultivate it and protect it and domesticate it, which is exactly what we've done by creating a chemical that we like. We protect it. So plants can use a number of different strategies to survive, one of which is to be appealing to humans. Yeah, that's a very good example. One of the best examples I have is mistletoe, where it's a nice red berry, birds eat it, and in fact, for those seeds to germinate, you actually have to go through the acidic environments of the birds' guts, but that helps it disperse wider. That way, the new mistletoe plants are not competing with their paramistotoe plants. I think that type of interaction is fascinating. It wasn't clear for me from Paulin in doing some quick surveys if they've really discovered kind of like the real target in nature or what animal would help with the disbursement or what is the natural selection advantage for plants. It's not clear, but mushrooms are fun stuff. They do crazy stuff. Okay, let's see if we have any other questions here. Earlier on, Shiloh had asked about addiction. It's my understanding that psychedelics are really not that addictive. I suppose their recreational effects can induce one to want to do them a lot, but I don't think that's the same thing as addiction. I sort of have the impression that it's drugs that affect the dopamine system, reward center of the brain that tend to be more addictive. Cocaine, for example, affects dopamine, but drugs that affect the serotonin system tend to be less addictive. Is that fair to say? No, that's actually very fair. A lot of people who are studying this in the 50s, 60s, 70s, there were very clear animal models that you can give animals stuff that's addictive and they get addicted to it. They'll ignore their environments, they'll ignore each other. And there was no indication of that for LSD or psilocybin. Right, right. There's the famous rat study where they would just constantly push the button to get more cocaine, just obsessively, but you just don't see that behavior with psychedelics where people just will just obsess over getting more. Comment, can you hear me? Yes. I agree that with the dopaminergic circuits, you tend to get addictive behavior because you're getting reward. Serotonin circuits, when they're stimulated just right, you get a warm benevolent euphoria. The people that tripped when they were not crazy to begin with or they generally didn't want to leave it, they enjoyed it so much, they felt wonderful. Now, there was a, I'm trying to remember the details, an experiment in which epinephrine, slow-acting epinephrine, was given years ago and people didn't know it and they studied them and they had somebody next to them who complained and then somebody that bragged or spoke up about how great something was and whatever the tone of the thing was, the response of the individual on epinephrine tended to be amplified. The epinephrine didn't make them crazy. It made it more intense and I think that because the, in a sense, I had mentioned about the way the brain works and this self-organized criticality, it's been likened to a resonant plate or a resonant instrument and it breaks down barriers between parts of the brain for focus, problem-solving, and sense of self so that the possible resonance that can happen within the network is expanded and people can have new experience. Yeah, that seems related to this notion of sort of ego dissolution which can be highly beneficial for anxiety disorders. PTSD, which make you completely self-centered and focused on yourself and if you can escape the trap of being completely absorbed in yourself, it seems like that would really be eye-opening, be a relief. Yeah, I had one other comment I wanted to make and then I'll shut up if I may. The original legislature against LSD and POD and such was thrown in with barbiturates and amphetamines and if they found somebody that had done something that had some of that substance with them, they called up those circumstances and even with the barbiturates and especially meth, they had very few, they had like 13 out of 125,000 potential cases that they called up as justification for all these laws. Not that meth particularly or amphetamines can't be harmful with chronic use but I wanted to make a point and they swept this up because the youth culture scared these old guys and believe me, I showed you a picture when I was in Oaxaca in, I was 16, a buddy of mine and he had a car. We went down there and went to all these ruins. He ended up getting shot to death in a robbery in his truck in New Orleans so these are people that died as the song goes but at any rate, how many people have died of marijuana overdose? How many people have died really of LSD overdose or POD overdose? I've looked up some figures just real quickly in 2019 in the United States, 39,707 deaths from firearms occurred. 60% were suicides. In 2021 thus far, 17,749 deaths from firearms have occurred. 7,915 were murders, 9,384 were suicides, 234 mass shootings in the United States so far this year, 15 mass murders, 124 children, 0 to 11 years old killed and in 2019 I have numbers that 85,688 people died liver deaths from alcohol and aside from there is a certain number of people that died from alcohol overdose. These are legal. I remember Chris Christofferson, the actor-singer said, man, I didn't even know this FTA, the firearms tobacco and alcohol organization existed. This was after they killed all those people in Waco, Texas. He says, damn those are some of my favorite things. And so these are the things that American society anyway, I know this is an international group, but I'm speaking from this perspective seem to think is fine to have legal and some states are encouraging it further like Texas, which is taking away any waiting periods or screening or anything for anyone who wants any firearm. Constitutional carry baby, that's what it's about here. So let's continue this discussion Wednesday at the fireside chat. I really want to draw this to a close now so we're not running too far over time. So thank you tagline and thank you Stephen. I really appreciate you stepping up to be so well prepared at such short notice for this topic today. So really, really, really appreciate it. And just as one final closing thought I would like to mention that Lucy in the Sky with Diamonds is not about LSD. It was inspired by a drawing that Julian did when he was like seven years old and the imagery in the song does not depict a acid trip. The imagery in the song is actually inspired by Alice in Wonderland, which is a favorite book that of John Lennon when he was a kid and completely nothing to do with LSD. So would you would you argue that John Lennon had never had LSD before he wrote Lucy? Pretty sure he had done a lot of LSD when he wrote Lucy, yeah. I think so. So I think there may have been an influence. There may have been an influence. I'll grant that. All right you guys thanks so much and thanks to everyone for attending today. Really appreciate it and I hope you can join us Wednesday evening for the fireside chat and with that I'll gabble us to a close. Thanks again everyone. Thanks Bergon. Thanks for coming everyone. Thanks for me as well. I hope everyone has a wonderful weekend.