EPISODE 199: Dr. David Nichols — Psychedelics, Consciousness & the Chemistry of the Mind

[00:00] Welcome to the Human Experience Podcast, the only podcast designed to fuse your left and [00:10] right brain hemispheres and feed it the most entertaining and mentally engaging topics on [00:16] the planet. As we approach our ascent, please make sure your frontal, temporal and occipital [00:21] lobes are in their full upright position. As you take your seat of consciousness, relax your senses [00:27] and allow us to take you on a journey. We are the intimate strangers. Thank you for listening.

[00:35] Ladies and gentlemen, welcome to the show. We’ve got a tremendous program [00:39] scheduled for you today. You are listening to the Human Experience Podcast. [00:44] My name is Xavier Katana. Today, we’re joined by Dr. David Nichols. He’s a chemist and

[00:50] pharmacologist who spent more than 50 years studying how psychedelics affect the brain [00:57] and human experience. He’s a professor emeritus of pharmacology at Purdue University and the [01:04] founder of the Heffter Research Institute. His work explores how tiny changes in molecules [01:10] can lead to very different experiences. David, it’s an absolute pleasure. Welcome to HXP.

[01:18] Glad to be here. [01:19] So, David, let’s get right into it. I mean, Hamilton Morris calls you one of the greatest [01:25] chemists alive in the world today. Who, in your opinion, in the last 150 years are the [01:32] greatest chemists alive or dead?

[01:36] That would be hard to decide. I mean, you have the discoverers of the DNA. Alfred Nobel invented [01:46] dynamite, which revolutionized mining. I mean, if you go to that level, I couldn’t even begin [01:51] to name them all. I’m very complimentary of Hamilton Morris to say I’m one of the greatest

[02:00] chemists, but I’m a little more humble than that. What about in the field of psychedelics, [02:06] as far as chemists go? Albert Hofmann, Alexander Shulgin? Albert Hofmann was really [02:13] an outstanding chemist. I think people who don’t know much about his life,

[02:19] He was way beyond ordinary in terms of his talent as a chemist and his intuition, probably in the psychedelic field. [02:25] Of course, he was the pioneer. [02:28] There were people that were looking at ergot alkaloids before him. [02:31] But his work at Sandoz, the discovering of LSD, the accidental discovery, but it was based on his intuition.

[02:40] That’s an interesting story. [02:41] You know, he made a whole series of ergot alkaloids, and they’re extremely sensitive molecules to work with. [02:47] And when he went to the director, Stolen said, you know, I’d like to work with ergot.

[02:56] He was cautioned, you know, this is a very tricky molecule. [03:00] And he requisitioned, I think, something like 250 milligrams from the supply. [03:06] And they came in and said, what do you want so much ergot for? [03:12] Because it was such a touchy molecule.

[03:14] It’s light sensitive. [03:15] It’s acid sensitive. [03:17] They turned dark, just the air. [03:20] But he was really exceptional. [03:22] I’ve worked with ergot alkaloids and LSD and lysergic acid amids.

[03:26] And I can tell you, and I had the experience of what was published in literature and the knowledge of what he’d done. [03:31] And for somebody who had no clue about the chemistry of ergot alkaloids, who just started out and did what he did, I mean, it’s amazing. [03:39] He was just a fantastic, super chemist.

[03:42] And of course, he lived to be 100 and some years old, very talented. [03:46] but um and also a warm human being you know i met him on several occasions and he’s the kind of his [03:52] kind of guy of course when i met him he was older but he’s the kind of guy you want for your kids [03:57] your grandkids to have as a grandfather and just really a nice warm you know you could just the [04:03] warmth just kind of oozed off of him really outstanding so yeah i i should probably have [04:07] mentioned him in the beginning in this field though he would be you know the luminary okay [04:12] Okay, fair enough. I mean, so David, you spent more than five decades studying psychedelics, [04:19] often when much of the scientific establishment dismissed them. What do you see in these

[04:25] substances that everyone else seemed to have missed in the early stages of your career? [04:31] Well, early on, very early on, before I really had much of a scientific background, my own [04:37] sort of personal experimentation on a couple of examples. I just thought these have incredible [04:44] power, the ability to change the way you see the world. And I saw people who were taking

[04:52] psychedelics when I, you know, in the 60s, I was, I graduated my school in 1962. So I saw people who [04:59] were taking psychedelics and had very positive responses and people had very negative responses. [05:04] But I thought, you know, I’ve told and I’ve told this to people.

[05:08] I say, why? [05:08] They’d say, why do you think psychedelics are important? [05:12] And I said, well, think of the things that can change your life. [05:15] You know, you get married, you fall in love, you have a child, maybe a parent or sibling dies, or you take a dose of LSD.

[05:24] And that just doesn’t fit. [05:25] You know, when they look at you kind of funny, I said, think about you can take a tiny amount of this molecule that diffuses into your brain and stays there for a few hours and diffuses back out. [05:35] And for many people, they just never see the world again in the same way, for better, for worse.

[05:41] You know, it depends on how and why it’s done. [05:45] But some people, it’s dramatic improvement. [05:47] And for some people, it can just destroy their lives. [05:50] But, you know, how can a molecule do that? [05:52] You know, what’s in that molecule that’s so potent that it can really change the way you see things, the way you perceive the world.

[06:01] And that’s the thing that kind of attracted me to it. [06:03] I wanted to know how they worked. [06:06] Yeah. [06:06] I mean, after all these decades, what has changed about how you think about the human mind? [06:15] Well, I mean, we certainly know a lot more than we did in the very beginning.

[06:19] I mean, the kinds of tests you can do, you know, just molecular biology, you can change receptors, you can scan living human brains using different kinds of probes, you know, PET imaging and things like that. [06:37] I mean, the level of technology is just really incredible. [06:41] And, of course, we, in the beginning, no one really thought these drugs would be very useful.

[06:48] Now, shortly after they discovered, there was a lot of experimentation before we really had, you know, well-defined clinical trial procedures. [06:58] But a lot of people were taking them and just saying, wow, these are just amazing. [07:02] You know, look at what they did to Timothy Leary.

[07:04] Completely derailed his life and the people that were at Harvard with him. [07:10] So how they do that, we know more about how they work. [07:15] I mean, what kind of cells they interact with in the brain. [07:17] and that’s helping us to understand how the brain functions a little bit.

[07:21] They also seem to stimulate the growth of neurons and dendrites in brain cells. [07:27] And of course, we now know that they have tremendous therapeutic potential, [07:31] which people had speculated about in the very beginning in the 50s and early 60s, [07:36] but there were no clinical trials to really prove it. [07:39] People just had kind of a gut feeling that they were very important molecules, [07:42] which is kind of the same feeling I had.

[07:44] I just thought these are important molecules to study. [07:47] I mean, they can change your personality after just one ingestion. [07:51] So how they did that was really interesting. [07:54] And of course, the technology available when I started was fairly simple.

[07:57] I mean, simple chemistry and simple pharmacology. [08:00] We didn’t have PET scans and MRIs and the kinds of things we can use now to look at what’s happening inside an intact living brain. [08:08] Was there a particular moment that you realized that these substances might fundamentally change our understanding of the human mind?

[08:15] excuse me um my first experience with lsd before i went to before i went to university [08:28] um i was projected outside of the well i had the vision that i was projected outside of the known [08:36] universe and i was looking in and the universe was often in the middle of nothingness which is a hard [08:43] concept to appreciate. But under the effect of LSD, I could appreciate what infinite nothingness was. [08:49] And here in the middle of infinite nothingness was this green glowing conglomeration, which was [08:54] sort of the known universe. And there was kind of a hum. And as I perceived that hum from the

[08:59] universe, it seemed to me that the function of the universe was to serve as a womb for life. [09:06] And that was why the universe was here, just to create life in all of its manifestations. [09:09] and that was a really powerful perception for me and I thought wow you know this is something I [09:15] couldn’t have thought of ordinarily I mean these things you know they open up your imagination they [09:20] give you thoughts that you ordinarily wouldn’t have now I didn’t know whether they really had [09:25] any therapeutic value I in the beginning it was just like how can they open your mind to these [09:30] kinds of perceptions how can they do that you can you normally can’t and I even today I can’t

[09:36] perceive of infinite nothingness. But I remember in that vision, the universe was in the middle of [09:42] infinite nothingness. So concepts that you just normally couldn’t understand or wouldn’t even [09:49] think of would appear under one of these psychedelics. But I didn’t appreciate the

[09:55] therapeutic value. I mean, even though I read the literature, and people would claim they’d seen [10:00] some kind of remarkable healings after people had been given psychedelics, I still couldn’t have [10:05] known or appreciated the fact that they’re useful for substance use disorders and for [10:10] depression, treatment-resistant depression, eating disorders, obsessive-compulsive disorder. [10:16] These things were just, you know, they were beyond what I could envision. I basically just

[10:21] wanted to know how they work in the brain. And of course, when I started, we didn’t even know, [10:27] you know, what the right receptors were. What does a receptor look like? What does it do? [10:33] All that functioning has been developed really since, I guess, the 80s.

[10:38] But when I started, we didn’t know any of that. [10:40] So I wanted to contribute to an understanding of what these did in the brain and how they could affect mind. [10:47] What’s something that you believed about consciousness that you no longer believe today?

[10:52] um in before uh any experience with psychedelics for me consciousness was just sort of [11:06] you know you’re when you’re awake you’re conscious that was kind of that was kind of it i wasn’t much [11:12] of a philosopher i have to say um but now the concept of of consciousness and things you know [11:19] I read stories of people who had extrasensory perception under the effect of a psychedelic. [11:27] And I thought, wow, is it possible that, you know, our consciousness can mingle or fuse with other people’s consciousness and we can get perceptions that we normally wouldn’t have. [11:38] So I think consciousness now, and when I think about things like memory, you know, I’m almost 82.

[11:48] My memory is not what it used to be. [11:50] But occasionally I’ll have flashes of things that happened to me when I was three or four or five years old. [11:55] And I think, how is this magnificent brain that we have? [11:58] How does it store all that stuff?

[12:01] And I’m sure that under hypnosis, I could probably, somebody could bring back things that I had completely forgotten from my childhood. [12:06] So consciousness, you know, does consciousness actually arise from the brain? [12:13] I’ve had discussions with people where I thought, you know, what if consciousness is just something, the brain is like a transducer that transmits our thoughts into whatever consciousness is and stored there.

[12:24] And consciousness is really a record or kind of like what people would call the soul. [12:30] Is there actually something like that that stores all of our life events that’s outside of our physical brain? [12:38] So I think about things like that sometimes.

[12:40] And I haven’t taken some psychedelics. [12:43] Those are the things that make me wonder about the nature of who we are and the nature of consciousness. [12:49] I mean, you helped found the Heffter Research Institute in 1993, long before this modern psychedelic renaissance.

[12:58] what gave you the conviction to pursue that research when so many other people had abandoned it [13:06] well i knew a lot of people that had also taken psychedelics that were scientists and uh we would [13:13] sometimes when we we would get together a scientific meeting and talk about things once in a [13:19] while um you know mark gyer was one of the people that was in Heffter and he had done research [13:24] and worked with DMT and talked about some of the unusual effects that DMT has. [13:30] And I know some other people. [13:32] And so I’d say, you know, why isn’t there any clinical research?

[13:36] You know, I could do, I was doing laboratory research and beakers and bottles and, you [13:41] know, things like that and boiling solutions and distilling stuff. [13:44] And it was just really chemistry. [13:46] And I said, the problem is nobody’s doing clinical studies.

[13:49] And the problem with that was that when the drug war started, when Nixon started the drug [13:54] in 1970, all the research was shut down. Virtually all of it would just stop. And so you had, if you [14:01] look at publications on psychedelics and LSD, you’d see this rapid rise. And in 1970, boom,

[14:08] they start dropping off again. And so they dropped down to, you know, really a low. [14:12] And I got together and I said, you know, the government’s not funding this, but I think it’s [14:17] important. Could we start an institute to raise money from philanthropists? Because we met a lot

[14:22] of philanthropists, especially in Silicon Valley, who had taken a lot of psychedelics and claimed [14:29] to have gained inspiration in terms of the design of microprocessors and so forth. And I thought, [14:35] maybe these people are willing to fund it. They weren’t as willing to fund it as I had [14:39] initially imagined, but we did get some of the Silicon Valley types to put money in.

[14:45] I think we raised about $10 million, which is not a huge amount of money. But when most of it was [14:50] going into early clinical studies, it was, you know, it was a source to fund studies that were [14:56] published in 2010 and 2011 and 2016, when nobody else was published in clinical work at all. [15:04] So if you were an academic clinician, and you were interested in psychedelics, and there were a lot, [15:08] I met him at scientific meetings, and we’d sit and talk and have a beer afterwards. And

[15:12] many of them had taken psychedelics, we all went through the 60s. So you know, a lot of us [15:17] had taken psychedelics, LSD, smoked marijuana, and so forth. So we’d sit and talk about our [15:23] experiences and just invariably we’d say, why isn’t anybody studying these things clinically [15:28] to find out? What do they do? I mean, we can look at rats and mice and, you know, chemistry and

[15:33] receptors, but we need clinical studies. And the stumbling block was there was no money. [15:39] Because if you were an academic, if you didn’t have money for your research, whether you got [15:44] from the National Institutes of Health or whoever, [15:46] if you didn’t have money for your research, [15:48] you wouldn’t be able to survive in an academic environment.

[15:51] And these were all academics for the most part. [15:53] So I said, let’s start a society or something, [15:57] a not-for-profit, and try to raise money from philanthropists [16:01] and specifically to fund some clinical studies. [16:04] And they all agreed with me, and we had an early meeting.

[16:07] We met in California at a Zen retreat, [16:12] and that was the first meeting. [16:14] And then we started to officially, [16:16] we set up a website. [16:17] My son ran the website for a long time. [16:20] He was very computer friendly.

[16:22] And we started listing publications [16:25] that we were supporting. [16:27] We still have publications [16:29] we’ve supported on our website. [16:31] Even recently, some people have acknowledged [16:34] getting support from us [16:35] and those have all gone in there.

[16:36] There’s a list of them. [16:37] People go to heffter.org [16:39] and look at the publications that we supported. [16:41] There’s quite a few there. It’s more than probably any other single organization. [16:47] Yeah, I mean, go ahead.

[16:50] Yeah. Anyway, that started it. And with a dedicated group of people that said, yes, let’s do this. [16:58] No, I mean, yeah, Heffter has done so much to advance in the study of the psilocybin, LSD, on the effects of anxiety, depression.

[17:11] And there’s so much that you guys have done. [17:13] What was the hardest part of it? [17:15] Was it raising the money, persuading institutions, or convincing other scientists that this was a legitimate field of study? [17:24] No, we knew there were scientists that wanted to do clinical studies, but they didn’t have any funding.

[17:32] And if you’re going to do a clinical study, even a small study of 30 or 40 patients, it still, depending on how you recruit, might take two or three years. [17:40] And you’d have to have a staff person dedicated to that. [17:43] In fact, Charlie Grobe, who did one of the early studies in dying patients, he did a lot of the work.

[17:49] He did clinical studies. [17:50] He did on weekends when he didn’t have his regular clinical duties at the hospital. [17:55] So people that wanted to do it, you know, if you said, how much money do you need? [18:00] Well, this is what it would cost.

[18:02] And so then we’d say, OK, let’s target for that. [18:04] I mean, the biggest study I think we supported was Michael Boganshut’s study of alcohol use disorder at New York University. [18:11] and I think we totally managed to raise two or three million dollars for that study.

[18:16] And that’s a lot of money for a nobody organization with no real infrastructure. [18:25] Looking back at your career, what single discovery surprised you the most? [18:33] Wow. [18:33] that’s really tough because i’ve done so much work um and chemically um you know

[18:45] one thing that i some of this is fairly esoteric chemistry but lsd has a group called a diethyl [18:54] amet there are two ethyl groups that can swing around freely in space and i wondered when it [19:00] because when Albert Hofmann made LSD analogs, [19:04] and we made a lot of LSD analogs too, [19:05] we reproduced some of his work, [19:07] it turns out that LSD is essentially unique. [19:10] You make almost any other derivative, [19:13] lysergic acid dimethylamide, [19:15] lysergic acid monoethylamide, [19:20] there are probably 50 or 60 you could easily envision

[19:23] where instead of the diethylamide, [19:25] you have some other kind of amide. [19:28] And LSD is unique in its potency. [19:30] All the ones we made, none of them looked as potent as LSD. [19:34] So I asked the question, why is that the case?

[19:38] Is the ethyl group doing something strange that none of the other groups can do? [19:42] And so in 2002, we made some analogs of LSD where we took the diethylamide, diethylamide, [19:51] and we locked it into a four-membered ring called an azetidine. [19:55] And then it was decorated with some methyl groups.

[19:58] And you can put them on in three different ways with them in one orientation, which we called RR, and in another orientation, which we called SS, and then in a third orientation where they’re RS. [20:10] And we tested all those in rats that had been trained to recognize the effects of LSD. [20:15] And it was only one of them, which was the SS-dimethyloazidine, which had activity comparable to LSD in the rats.

[20:23] So we published that paper and we proposed that that locked orientation of that specific part of the amide was representative of how the diethyl groups of LSD bound. [20:36] And it was 2017, 15 years later, when actually the crystal structure was determined of LSD bound to the 2B receptor by Daniel Wacker, who was working with Bryan Roth. [20:49] And that indeed is exactly where the diethyl groups were pointing.

[20:52] They were locked into an orientation that was matched to that rigid analog we’d made with the azetadine. [21:02] And it turns out that when LSD binds to the serotonin-2A receptor, which seems to be its primary target, it gets locked in. [21:11] There’s a piece of the receptor from the top of helix 4 and 5, which folds over LSD once it binds.

[21:19] and there’s a big bulky leucine amino acid residue that wedges down into the binding cavity [21:25] where LSD is and kind of locks it in. So when you look, if you looked at LSD bound to the receptor, [21:32] it would take a couple hours for it to become saturated. And then if you took all the LSD away, [21:36] it would take several hours for all the LSD to get back out because it was trapped in by this [21:41] leucine in this piece of the receptor that folded over. So we mutated that. I was working in Brian

[21:47] Ross lab, but then we mutated that to a little small alanine and all of a sudden LSD popped [21:52] right out. [21:53] So we proved that LSD had its long action, its long duration because of this one amino [21:58] acid in a loop that folded in on the top of LSD after it bound to the receptor. [22:03] So that was probably scientifically one of the most exciting things I found.

[22:08] Another thing that I did, which is not as exciting, but after MDMA became popular as [22:16] a recreational drug, Ralph Metzner decided he wanted to call it an empathogen. [22:24] And I’d done a lot of work on the chemistry of MDMA and preclinical work with rats. [22:30] And I didn’t like the word empathogen because when you say it, it sounds like pathogen, [22:35] like it’s bad stuff.

[22:36] So I coined a new word, entactogen, which meant to produce a touching within. [22:43] and within tacto touch and gen to generate. [22:47] So entactogen, I said, in pathogens, it’s not scientific. [22:51] It seems to sound like it’s toxic.

[22:54] It’s a pathogen, in pathogen. [22:56] And so I coined this term entactogen. [22:58] The last time I checked in PubMed entactogen, [23:02] there are many more references to entactogens than to in pathogen. [23:06] And people now I see, even in government writing and stuff,

[23:10] they talk about entactogens. [23:11] So that was kind of, I wouldn’t say it was exciting, [23:14] but it was nice that I could coin a term for things like MDMA that was useful [23:20] and had some meaning and get away from it. [23:22] People still talk about empathogen because Ralph Metzner was such a big name [23:26] in the psychedelic field initially because he, Metzner and Leary were together.

[23:33] You know, two of them were together, and so Metzner had a big reputation. [23:37] but being able to name a new category of psychoactive yoga as entactogen, [23:44] that was kind of satisfying. [23:46] It wasn’t a big breakthrough. [23:49] I find that fascinating.

[23:51] So leading into my questions here, [23:55] what makes the 5-HT2A receptor important to the story of classic psychedelics? [24:04] well the serotonin 2 receptor that there’s a whole there’s a family 5ht 2a 2a 2b and 2c [24:13] they’re very closely related in their um protein structure primary amino acid sequence but they’re [24:20] different and the 2a receptor but the serotonin 2 receptor in general goes way back into um [24:26] single-celled organisms so it’s a receptor that’s been important for and i don’t know why but [24:33] Things that worked have been retained through evolution. [24:38] So for some reason, the serotonin-2 receptor was important to early organisms [24:43] and was carried through in evolution up to the present time into our brains.

[24:48] And it regulates in our prefrontal cortex. [24:51] It regulates activity in our prefrontal cortex, [24:54] which is really our higher processing centers [24:57] where we produce our thought and our logic up in that area. [25:01] So they’re really important.

[25:02] They’re all throughout the brain, actually, in other parts of the body. [25:06] They’re probably the most widely distributed receptor in the human body. [25:10] But certainly in the brain, they play a major role in activating different neuronal circuits.

[25:17] And so in the prefrontal cortex is where our higher thinking occurs. [25:21] There are major players there that regulate the activity of those neurons. [25:26] So we know that now. [25:28] And, of course, now we have those receptors that are expressed in cell lines,

[25:32] and people use them routinely to understand how the drugs work and what they do. [25:36] But they’re a very important type of receptor and really modulate, you know, [25:41] what, you know, as I’m thinking and talking, [25:44] I’m sure my serotonin-2A receptors are being activated quite a bit. [25:48] Yours probably are too if you’re thinking about it.

[25:51] But, you know, it’s just one of those things of nature. [25:55] For whatever reason, those receptors have been retained throughout evolution [26:00] and expressed in higher centers in our brain. [26:03] Also in rat brain, mouse brain, etc., in the same places, [26:06] but in higher brain centers.

[26:07] So they’re very important for our cognitive function and so forth. [26:12] I mean, is it accurate that there’s only a certain number of compounds [26:16] on the planet that produce neurogenesis, [26:20] like this sort of regrowth of brain tissue? [26:23] Oh, I don’t think we know that.

[26:26] I mean, there are many of them. [26:27] certainly some of the psychedelics do. That’s a major thing that people have focused on, [26:35] dendritogenesis and spinogenesis. And I think that’s really been focused on just because [26:40] when they’ve looked at rat and mouse models after a psychedelic, they’ve seen, you know,

[26:45] increased growth of dendrites and this neurogenesis. But I don’t know if that’s [26:51] necessarily related to serotonin 2A receptor, because there are some other types of compounds [26:56] that will do that. So that’s an area that we’re just really starting to look at.

[27:03] Where do you think the chemistry of this ends and the mystery of consciousness begins? [27:10] Can you say that again? [27:12] I mean, where do you think the sort of molecules and aspects of how this affects the brain ends [27:20] and where the mystery of consciousness begins, [27:25] the experiences that people have when they’re on these compounds?

[27:34] That’s a good question. [27:39] The thing is, the brain is this marvelous biochemical computer [27:45] that’s, you know, it’s more powerful than any computer, you know, [27:50] you can manufacture with diodes and transistors and so forth. [27:55] And the idea of where is consciousness located, [27:59] some people have thought, you know, it’s located here, [28:01] some people have located here.

[28:03] I don’t really know, but I think that psychedelics will be useful tools [28:08] in understanding the origin of consciousness [28:10] because they perturb consciousness so dramatically. [28:13] So I think they will help us understand, you know, where does consciousness come from? [28:19] Is it, you know, just an overall gestalt that occurs when everything’s working right together and it’s generated?

[28:26] Or are there specific places in the brain that generates, you know, somehow generates the feeling of consciousness? [28:35] I think psychedelics will ultimately help us understand where that where the origin of consciousness lies if it’s in a single place. [28:46] But that’s a complex issue. I mean, people have been speculating about, you know, the nature of consciousness for a long time, where it comes from, how how it arises.

[28:57] So I think it’s something we’re not prepared to answer, a question we’re not prepared to answer yet. [29:04] But it’s my belief that psychedelics, because of the way they perturb consciousness, will ultimately help us answer what consciousness is. [29:13] I mean, do you think that consciousness could originate from a certain part in the brain or like the default mode network or something else?

[29:26] I kind of think that consciousness arises as a result of an interaction of different regions. [29:31] It’s not one specific one. [29:33] I mean, the default mode network obviously could be a part of it, could play a part of it. [29:40] But the way the brain is interconnected, it’s like if you, I think if you try to dissect a computer,

[29:48] just an electronic computer and say, okay, where’s the brain of the computer? [29:53] Well, you’ve got the central processing unit, but you’ve also got all the memory in there and an interaction between the central processing unit and memory. [30:04] And it does calculations. It’s stored in another part of the memory.

[30:07] So I kind of think the brain, that consciousness is kind of like that. [30:11] It’s interacting parts that work together that somehow generate consciousness, whatever consciousness is, some kind of a field. [30:19] And maybe it is actually an electrical field of some kind that we haven’t yet defined.

[30:25] That would make sense too, but I don’t think we know that. [30:30] I mean, two molecules can have relatively similar chemical structures yet produce very different subjective experiences. [30:39] What does that reveal to us about the extraordinary complexity of the brain?

[30:44] well you can take um you can take a molecule and just add a single atom to it and you can [30:55] kill the activity it had so in psychedelics you can take a molecule that’s active like [31:01] psilocybin or psilocybin and you can stick a fluorine atom onto one of the rings you kill [31:07] its activity completely because it no longer activates that receptor. So if you look at, [31:15] and Bryan Roth lab has published a huge body of data on psychedelics within the last couple of [31:20] years showing for a whole range of psychedelics, what receptors they interact with. And he’s looked [31:26] at many more receptors than just serotonin, serotonin, dopamine, and adrenergic, and [31:31] cholinergic, et cetera. And there’s no psychedelic that only activates serotonin

[31:39] to a receptor. They all activate other receptors to a lesser extent. And probably it may well be [31:47] like, you know, it’s a spice you might put into a meal. You know, you put in one spice and it [31:53] gives a certain flavor and a couple other spices and low level and it changes the flavor just a

[31:59] little bit direction in a different direction, maybe. And I think you may have the same thing [32:03] with psychedelics. You have the activation event, which I think is activation of the serotonin 2A [32:09] receptor. But then all these ancillary interactions, if it acts at norepinephrine receptors or dopamine

[32:16] receptors, different kinds of dopamine receptors, that may be influencing it. We have a study that [32:22] we have got submitted for publication now. Our collaborators at a lab in Florida have made an [32:29] LSD analog that has a hydroxy group in the 13 position.

[32:33] And I’ve wondered for years, and some [32:37] earlier researchers had noticed this. People take [32:41] a psychedelic and for the first four or five hours, it’s really pleasant and [32:44] they just really enjoy it. But for most people, not all, but for most people, [32:49] the effect of LSD starts to get very dark and kind of [32:53] paranoid and it changes its nature.

[32:57] and nobody had been able to figure that out. [33:01] But we had the idea that maybe there’s a metabolite that’s formed [33:06] that could be changing that. [33:08] So we knew that LSD was metabolized into putting hydroxy groups [33:13] onto the LSD molecule.

[33:15] So we took some rats that had been trained with LSD [33:19] and we would inject them with LSD and they would press. [33:24] They have a choice between pressing two levers. [33:27] And if we gave them placebo, they’d press, say, the right lever.

[33:31] We gave them LSD, they’d press the left lever. [33:33] So we had a procedure called drug discrimination. [33:37] And we could give these rats LSD. [33:40] And if they were trained to recognize LSD, they’d always press on the LSD lever.

[33:44] If we gave them mescaline or psilocybin, they’d also press on the LSD lever. [33:48] But if we gave them something else that wasn’t psychedelic, they would press on the other lever that says, I don’t think you gave me LSD. [33:55] So I said, well, we test these rats.

[33:59] We inject them and we test the rats 30 minutes later. [34:01] What if we waited 90 minutes? [34:03] Because we knew that the response to LSD was ended by 90 minutes. [34:08] What if we give the rats LSD and then we wait 90 minutes? [34:12] And when we did that, it turned out the rats were not responding to activation of the serotonin

[34:16] 2A receptor. [34:17] By using various types of receptor blockers, we could show that LSD, whatever was happening, [34:23] was now activating a type of dopamine receptor called the dopamine D4 receptor. [34:29] And that’s where our investigation ended for a long time.

[34:33] I had some postdocs trying to make a 13-hydroxy LSD to test it and see if it had activity. [34:39] And we couldn’t get the synthesis to work. [34:42] We were following another procedure that the guy had published was bogus. [34:46] It didn’t work.

[34:47] We finally gave up, and I retired from Purdue. [34:49] And with this company that I’m with now, 2A Biosciences, we have a chemistry professor in Florida who’s been working on ergot/ergoline derivatives. [35:01] And I asked him to make 13-hydroxy LSD, which was this metabolative LSD.

[35:07] And so they were able to make it and synthesize it. [35:10] And we tested it. [35:12] And it’s an extremely potent dopamine D4 receptor stimulator. [35:18] It’s 100 times more potent than LSD at that receptor. [35:22] So then it kind of filled in our hypothesis.

[35:26] So people that take LSD, after several hours, you have your body metabolizes it. [35:34] And one of the metabolites is this hydroxy derivative of LSD. [35:37] And when that builds up, we believe that that changes the nature of the intoxication [35:41] because it’s such a potent dopamine D4 agonist.

[35:44] And the effect of LSD at the serotonin 2A receptors is fading out at the same time this metabolite is being produced. [35:52] And so you get a change in the quality of the LSD effect. [35:56] It goes from kind of psychedelic and wonderful to kind of paranoid and dark.

[36:00] And we think it’s probably related to the formation of this 13-hydroxy LSD metabolite. [36:05] Wow. [36:06] Yeah, things like that, you know, really digging in, you know, diving deeply into that and saying, well, what’s going on here?

[36:13] you know why does the effect of lsd and doesn’t change and if the other thing is for some people [36:19] lsd doesn’t change you know it’s the whole the whole eight or ten hours is just all wonderful [36:24] and lovely which made me think that maybe there was a metabolic effect because people have different [36:28] enzymes in their liver and some people don’t metabolize everybody doesn’t metabolize things [36:33] the same way so it occurred to me that maybe most people have this enzyme that puts the hydroxy group [36:38] going to the LSD molecule, but some people don’t have it. And they don’t, the LSD just doesn’t have [36:44] this two-phase intoxication. It’s just a single, you know, happy thing all the way through.

[36:50] I mean, when someone takes a psychedelic and experiences, for example, a dissolution of [36:57] their sense of self, what do we know about what’s happening neurologically in that sense? [37:03] I think the current consensus is that the default mode network kind of disintegrates. [37:12] That may be an organizing principle in the brain.

[37:16] And so you lose that and it really just become kind of undefined consciousness. [37:21] That happens with a drug called 5-methoxy DMT, which has been called a God molecule. [37:26] and it’s originally it was discovered being produced by the the desert toad [37:34] and they have these parotid glands on both sides of their head if you squeeze the parotid glands [37:41] so if if a predator like a dog would bite these toads it squishes the parotid glands on the side [37:48] of their head and they spray this toxic mixture out which has a lot of things that are will kill [37:53] the predator but if you spray it onto a glass plate and let it dry and then you shave it off [37:59] and then smoke it in a pipe the heat destroys the toxic components and the thing that’s that’s

[38:04] volatilized is this fine methoxy dmt so people talk about toad smoking or whatever that’s fine [38:10] methoxy dmt it’s extremely powerful and that will disrupt your ego and you’ve you know you’re often [38:17] And, you know, what’s called the God molecule for reason, for many people, it’s like their ego is gone and they believe they visit conversations with, say, some superior being or they went to other planets or whatever. [38:33] Very powerful perception modifying molecule. [38:38] So it’s and it has instead of just activating serotonin to a receptor, it also powerfully activates another receptor called the 1A receptor.

[38:47] serotonin 1a receptors are also localized on cortical neurons you have 2a receptors [38:54] and then at the cell body the the neurons that come out the other end have serotonin 1a receptors [39:03] so you can you can shut down that processing of cortical neurons by a serotonin 1a agonist [39:10] so there’s a complex interaction there and people who take a high dose of lsd and have this [39:16] loss of ego. LSD has effects at the 1A receptor too, but it’s much less potent than, say, 5-methoxy [39:25] DMT. So it may be the same thing that you’ve got the serotonin 2A activation and you’ve also got [39:30] the serotonin 1A activation occurring. That sounds very mechanical for talking about a loss of ego,

[39:38] and seeing God. But that’s kind of the realm of science that I’ve had to live in, [39:43] is what’s what are the mechanics of it do you think psychedelics show us something that’s [39:48] already in the mind or create something new um that’s kind of an interesting question um [39:59] you know when i perceived the universe was in the middle of infinite nothingness [40:05] That was a concept that I could have had ordinarily. [40:10] But I knew what infinity was.

[40:16] I just couldn’t comprehend what it was. [40:20] So the LSD made that comprehension available. [40:25] I think we have a lot of kind of subconscious information that we don’t need for our everyday lives [40:32] that’s below the level of our awareness.

[40:35] And LSD opens that up and brings stuff out that, for the most part, we may have already had in there. [40:41] It’s not something you spend any time thinking about. [40:44] It’s not something you need for your everyday survival. [40:47] So it stays buried in your subconscious, if you will.

[40:50] You take a psychedelic, and your conscious processing is affected, but it allows these subconscious things to come up out of your mind. [40:59] So I don’t know if anything is invented or if it’s just dredged up from your subconscious by the psychedelic. [41:07] I mean, is there a compound that you think affects the mind the most out of all these different compounds?

[41:16] Well, this molecule I mentioned, 5-methoxy-DMT, is extremely powerful. [41:24] So the fact that it’s been called the God molecule tells you something about the reverence that people have for that particular molecule. [41:30] But LSD is an extremely potent compound in its own right.

[41:36] And at higher doses, people can have out-of-body experiences and, you know, see aliens and so forth. [41:45] And, you know, LSD at high doses of people to talk about that. [41:50] I think this Rolling Stones had a song, 2,000 Light Years from Home, [41:55] was supposedly a story about taking 2,000 micrograms of LSD.

[41:59] I mean, that would be, you know, a big dose. [42:01] I knew a woman who took, she said, 20 purple microdots. [42:08] Well, assuming that a microdot was 100 micrograms way back when, [42:11] 20 of those is like 2,000 micrograms. [42:14] And she said under the effects, what she saw was all the people dissolved, all the people disappeared.

[42:23] And people that she would normally have imagined had bodies were just like sparklers. [42:28] They were just sparkling electrical patterns. [42:31] And she was in that state for, I think, a couple of days, which, you know, normally LSD doesn’t last a couple of days, [42:41] but completely changed her perception of reality.

[42:45] And then had a being of light that came to her [42:51] and told her some things about her future. [42:53] So that was LSD. [42:56] So I would say offhand, probably, you know, [43:00] 5-Methex DMT does something different, [43:02] but it’s very powerful.

[43:03] And LSD is sort of the one that’s been out for a long time. [43:08] And it’s dose-dependent with LSD, of course. [43:12] You could go in a standard 100-microgram dose would not produce some of the out-of-body [43:17] stuff for most people.

[43:19] But if you go two or three or 400 micrograms, then the dose-response curve, you start getting [43:25] into different kinds of areas. [43:28] Why do some compounds, such as LSD and psilocybin, lose their dose curve after taking them in [43:36] multiple days? [43:38] versus something like ayahuasca where people take it every other day or every day and have [43:45] these mind-blowing, tremendous experiences? So if you activate the serotonin 2A receptor,

[43:54] it’s evolutionary function. It changes your ability to interact with the environment. So [44:02] if you were a caveman living in a cave and worried about bears and saber-toothed tigers [44:08] and things, if you took LSD, you wouldn’t be able to defend yourself.

[44:14] You would be totally disoriented. [44:16] And so I think the body says this receptor is so important that we can’t leave it exposed [44:22] to toxic molecules. [44:24] And so what happens is you develop tolerance. [44:27] It’s called tachyphylaxis.

[44:29] It’s a very quickly developed tolerance. [44:31] So the receptors actually become internalized. [44:34] So normally they’re expressed on the surface of the neurons where the drug can get to it. [44:39] And if you start activating, they’re pulled inside the neuron,

[44:43] so they’re not accessible in the surface anymore. [44:45] They’re still there, and eventually will return back to the surface. [44:49] But when you take, say, LSD every day, and the first day it has a good effect, [44:53] the second day the same dose will have much less of an effect, [44:57] the third day even less, and by the fourth day it won’t have much of an effect at all.

[45:01] So it’s a rapid development of tolerance. [45:04] And it’s due to the receptors, the 5-HT2A receptors being internalized into the neuron and no longer being expressed on the surface where the drug can reach it. [45:15] So it’s a protective thing.

[45:17] You know, if you were using these, you know, and like I said, as a Neanderthal or something, and you were worried about surviving or there were cave bears or saber-toothed tigers that you wanted to, you know, stay away from, you wouldn’t be able to do that if you were intoxicated with a psychedelic or something that activated the 2A receptor.

[45:38] So I think it’s a survival mechanism. [45:41] If you activate the serotonin to a receptor, too often the body says, we can’t have that. [45:47] This is unacceptable. [45:48] What’s destroying you? [45:49] It’s corrupting.

[45:50] It’s hacking in our systems, essentially. [45:53] Shut it down. [45:54] Put it inside the neuron where it can’t be reached by this toxin. [45:58] I mean, you mentioned earlier about how science has changed so much, and you’re able to map

[46:04] and image a lot of these different molecules [46:07] and what they look like [46:08] and how they biologically affect the brain. [46:11] Do you think it’s possible [46:12] that the psychedelic experience [46:15] reveals something about consciousness [46:18] that our scientific instruments [46:20] simply aren’t equipped to investigate yet? [46:25] I think that’s possible.

[46:29] Go ahead. [46:31] The idea that I mentioned earlier [46:33] that maybe consciousness was actually some kind of an electrical field [46:39] that was generated by our brain. [46:41] But we haven’t discovered that because maybe it’s at a different, [46:46] some frequency we’re not looking for.

[46:48] Maybe it’s a type of radiation that we don’t understand yet. [46:51] So you could generate consciousness could actually reside in some kind of a, [46:55] some kind of a magnetic or electrical field around the brain. [47:00] We just haven’t discovered it yet.

[47:01] I mean, how do we distinguish between a valuable psychedelic insight and a compelling illusion that merely feels profound? [47:16] There are a lot of people that have had the latter. [47:21] Yeah, you know, a validation of something, validation of an experience.

[47:31] I think if you had a perception under a psychedelic, you would have to find some way to validate it to know if it was, you know, if it was just illusory or if it was real. [47:45] And for some of these things, I don’t know how you how you could validate them. [47:49] A woman talked to me once, of course, since I work in this field, I’ve talked to a lot of people that have used psychedelics.

[47:55] and she said she was riding in a car and she was taking some she’d taken some LSD and she was [48:03] riding in a car with a couple other people she was in the back seat and they were going through [48:08] this alley and all of a sudden she jumped down on the floor and said watch out watch out and they [48:12] turn what are you talking about and just at that moment a car came from a side alley and smacked [48:17] into the side of the car she was riding in so she had had some few seconds of [48:22] of premonition that something bad was just about to happen. [48:28] So now there is a, you know, and then they ask her afterward, like, [48:32] how did you know that was going to happen? [48:33] She’s, I just knew.

[48:35] Well, that’s a validation of a perception she had. [48:40] And that’s a tough way to validate it, I guess. [48:43] But it would depend on what your perception, what your percept was, [48:48] I guess, in terms of how easy it would be to validate it.

[48:52] Hmm. Scientists are exploring the psychedelic-inspired drugs that might produce therapeutic benefits without the psychedelic experience itself. What’s your take on that? What’s your opinion about that? Do you think that by removing the experience that we might be removing the actual medicine, the medicinal part of it?

[49:13] So I’ve been asked that question a lot. [49:18] And I think for some indications, you absolutely need the psychedelic effect. [49:25] The reason not to have it, of course, is cost. [49:29] Insurance companies don’t want to pay. [49:30] LSD, if you get my LSD in a clinical trial, you’re going to have to keep them in the clinic all day and probably keep them overnight into the next day.

[49:38] That’s expensive. [49:39] Insurance doesn’t want to pay for that. [49:41] But if somebody can come in and have a two-hour experience, then that’s affordable. [49:47] And I don’t know if it makes any difference whether they have a psychedelic experience if it’s only two hours or not.

[49:53] You know, if they keep advertising the idea that you don’t want to have a psychedelic experience, that’s going to be a self-reinforcing idea, right? [50:00] I don’t want that to happen. [50:02] But I think there’s cases where you need it.

[50:05] Now, for someone who has simply a major depressive disorder and antidepressants just aren’t working, they’re tumor-resistant depression, I don’t think you necessarily, I don’t know that you need a psychedelic experience to cure depression.

[50:20] But I’ve seen in many of these cases where people are dying, they’ve got a terminal illness and they’re given therapy with a psychedelic. [50:30] The psychedelic experience is actually essential to their effect because what they do is we’ll have a life review. [50:38] They may even imagine some previously departed relative or parent come and tell him, don’t worry, it’s going to be fine.

[50:45] And then looking at the things that have happened in their past, one fellow that I saw that was given therapy with psilocybin, [50:55] And he said, I realized under the effect of the psilocybin that I had become estranged from my brother, who when we were little, we used to do everything together. [51:03] And I hadn’t talked to him for 10 years. [51:04] And I felt so bad.

[51:06] And after the experience was over, I sent him a note and said, I want to get together with you. [51:11] There’s no reason why we’ve been separated and get back together. [51:14] And he was reconnected with his brother. [51:17] That was part of the psychedelic effect that he had under the psilocybin.

[51:22] And so when you’re dying, I think the psychedelic effect is very beneficial. [51:28] It takes away the fear of dying for many people. [51:31] They’re not afraid to die anymore. [51:33] Whatever the psychedelics do, they make you feel like you don’t need to worry about dying.

[51:38] I’m not there yet, but, you know, it’s nice to think, well, I don’t need to worry about dying. [51:44] Well, whether it’s illusory or real, the effect is real and people are not afraid to die. [51:52] people who have become addicted. I heard a talk from a guy who was treated in New York with

[51:58] psilocybin. He had alcohol use disorder, alcoholic. And he was living with his parents. He was in his [52:04] late 20s, if I remember correctly. And he lived with his parents. He wasn’t really gainfully

[52:09] employed. And whenever he went anyplace to another city he wasn’t familiar with, he would walk around [52:14] the blocks to see where all the bars and liquor stores were. And he’s telling us this story. He [52:18] That was my life. Whenever I went someplace, I want to make sure I could get my alcohol.

[52:24] So under the effect of the psilocybin assisted therapy, he realized that his life was wasted. [52:31] He hadn’t done anything with his life. He was a parasite on his parents. [52:36] He needed to get out, get a job and get his own life.

[52:40] And after the therapy, he went back and was moving his stuff out. [52:44] He wasn’t drinking. His parents said, what happened to you? You’re not drinking anymore. [52:47] He says, I realized it was ruining my life, and I’ve got to get on with my life and do things.

[52:52] It turned his life completely around because he looked at what his life was. [52:56] Another woman, and this is a study that Michael Boganchutz did in New Mexico. [53:01] A woman came in, and I saw her on video. [53:04] They had videoed her, and she said she came in because her husband was drinking all the time,

[53:11] and she wanted to get him into the program, but he refused to come in and sign up, [53:15] So she was just coming in to tell him that he wasn’t going to come in. [53:18] And Mike said to her, he said, well, do you drink a lot? [53:21] She said, well, yeah, I drink.

[53:23] And she said, well, maybe you’re a candidate. [53:24] So they filled out a questionnaire. [53:26] And he says, you’re a candidate if you want to do the treatment. [53:28] So she did it, psilocybin-assisted therapy. [53:32] And she said, what happened under the effect of the psilocybin is I realized she had, I think, two or three children as a Hispanic woman.

[53:40] And she said, I realized I was cheating my children of their mother. [53:43] I would come home after a long day. [53:45] I was tired. [53:46] I wanted to pop open a drink right away. [53:48] And the kids would come and I’d push them away.

[53:50] And I’d just say, leave me alone. [53:52] I need to decompress. [53:53] And she’d sit and she’d drink until she was kind of wasted. [53:55] And then she’d get on with whatever the evening was. [53:58] She realized she was not having a good relationship with her children.

[54:02] She quit that. [54:03] She came home and she says, I come home now. [54:05] The first thing the kids run over, I gather them all around me. [54:08] I said, tell me about your day. [54:09] What did you do today?

[54:10] Tell me about your day. [54:11] and she spends time talking to her children. [54:14] And that psilocybin therapy had created that change in her perception [54:18] of what her life should be and her relationship with her children. [54:23] And that happens when you have the psychedelic effect.

[54:25] If you don’t have the psychedelic effect, there’s, you know, [54:28] it just happens to you and that’s it. [54:31] There’s no reflection. [54:32] There’s no integration. [54:33] There’s no awareness of what you could do better. [54:36] So for ordinary depression, I think you probably don’t need the psychedelic trip.

[54:40] But for disorders, mood disorder, eating disorders, alcohol use disorders, any kind of drug use disorders, eating disorders, the classic was to put someone and take a psilocybin in front of a mirror who’s got an eating disorder. [55:00] And, you know, these are some of the most fatal disorders and they affect mostly young women, anorexia. [55:07] And there’s a study now that’s, this is one of the first studies that I wanted to have to do, [55:11] but we couldn’t find a way to do it, was to get eating disorder patients and then put them in [55:17] front of a mirror and say, what do you see? And under those conditions, they would probably see

[55:23] their body as a skeleton that you’re killing yourself, you’re dying. And that impression is [55:28] what would be the thing that would change them. And that doesn’t, if you just gave them a pill, [55:32] it’s not going to happen. So I think without the psychedelic effects, maybe major depressive

[55:39] disorder, you can develop something that would treat that. But for eating disorders, [55:45] substance use disorders, existential distress, I think the psychedelic effect is a necessary part [55:51] of it. Now, whether you need it for the antidepressant effect, I don’t know. But I don’t

[55:56] think if you just look at it rationally, there’s no reason why you would need to have the [56:02] psychedelic experience just to treat ordinary major depressive disorder. [56:07] But for some of these others, you get insight into it. [56:11] One of the earliest studies I saw was published years ago by Brandup and Vanguard.

[56:16] It was a 10-year follow-up of a guy who had developed severe obsessive compulsive disorder. [56:21] I think he lived in Sweden or Norway, one of those countries. [56:26] I don’t remember all the details now. [56:28] But it was a case report that they were reporting.

[56:30] and he had been an executive, mid-level executive in a big corporation, [56:37] and he developed obsessive-compulsive disorder. [56:40] It became so bad that if he’d hear a toilet flush, [56:42] he’d have to wash his hands 10 or 15 times. [56:45] His body was chafed because he had taken so many showers [56:50] and washed himself so much.

[56:51] His fear of contamination had gone on and on and on [56:55] to the point where it would take him four hours to get ready for work in the morning. [56:59] He had to go through a whole ritual of things to clean himself, et cetera. [57:03] He lost his job.

[57:04] So he was taken in and given LSD once a week with just a nurse sitting by him. [57:09] And they said he described these things from his childhood. [57:13] He could go back and pinpoint the time at which he developed the OCD, the obsessive compulsive disorder.

[57:19] He’d stepped off a bus one night coming home from work, and it stepped in a pile of dog poop. [57:25] And that’s the point at which he could target. [57:27] That’s where it started. [57:28] but he would do a debriefing with the psychiatrist who was running this program.

[57:34] He’d come in afterward and say, well, what did you see? [57:36] What did you think about? [57:37] And he would tell him all these things he went through about his life and this disorder, etc. [57:42] But after a year, he was completely normal.

[57:44] He went back to his company, got a job, became a regional manager, [57:49] became a big executive in the company. [57:52] And that was the case where the psychedelic experience was part of his treatment, [57:57] was going through and spending once a month going through looking at all these things. [58:02] Obviously, there was some pharmacology going on behind it.

[58:05] Receptors were changing, dendrites were growing, whatever. [58:08] But we don’t understand. [58:11] Obviously, we don’t understand completely what’s going on. [58:14] I mean, this is a fairly new area. [58:18] I mean, we published the studies of psilocybin in dying people in 2016

[58:25] from New York University and Johns Hopkins. [58:28] That’s only been 10 years. [58:30] And the number of publications now is just out of control. [58:33] I used to keep all the publications that came out about psychedelics. [58:37] I’d store them in a folder.

[58:38] And now I put a few in there. [58:40] But there’s 4,000 documents in there now. [58:43] So you just can’t keep up with it. [58:45] The science is moving so quickly. [58:47] And there’s still not any real significant government funding for this,

[58:51] Even though, you know, Nora Volkov, the head of NIDA, she was opposed to these drugs. [58:57] And now she’s a supporter and advocate for psychedelics. [59:01] So, but there’s no, still, there’s still not enough funding for this. [59:05] And we probably won’t have more funding until we get a new administration in.

[59:08] But I think the field still has so much to develop and so many discoveries to make. [59:16] David that’s the first part of our conversation the first half uh there’s a bonus episode which [59:24] is 30 minutes but for the people listening right now where can people find your work [59:29] and I know you’ve got a new book coming out when is that out um well I’ve got a book called [59:36] The Accidental Professor which is my it’s a memoir it’s a little vignettes for my life [59:42] which may or may not be that interesting. [59:45] I paid a vanity publisher to do it.

[59:47] It’s four, I think 400 pages. [59:49] It’ll be out next year sometime. [59:51] Probably it’ll show up on the Amazon. [59:53] And I just wrote a science fiction book [59:55] called the Talotians. [59:57] I just finished editing the final draft

[59:59] of the manuscript [1:00:00] and it’ll probably appear [1:00:01] sometime in the next six months [1:00:03] on Amazon and Barnes and Noble [1:00:05] and some of these book places. [1:00:08] So, but I had a website at Purdue [1:00:11] but there’s not much about it. If people just go on and Google David E. Nichols, they’ll find a

[1:00:17] bunch of talks that I’ve given, links to things that I’ve done. That’s probably the best way. I [1:00:23] don’t really have a website where they can go and find all the stuff I’ve done. They probably have [1:00:27] to do a little bit of extra work on their own. Guys, we’ll make all the links available that

[1:00:33] we can to find David’s work that you can find in the show notes for this episode. [1:00:38] we’re going to move over to the bonus round. If you want to get to that, go to the human xp.com [1:00:45] slash membership and you can access the rest of this conversation. That’s how we fund

[1:00:52] conversations like these. And if you made it this far, thank you so much for listening. [1:00:57] We’re going to move over to the bonus episode right now. Otherwise, we will see you guys next [1:01:02] week. David, welcome to the bonus episode round that we do with our guests. I mean,

[1:01:11] it really just breaks down the person behind the microphone as much as we can. But I wanted [1:01:19] to finish our conversation because there’s so much I had in my notes that we didn’t get [1:01:24] to cover. I wanted to cover, you published a book with Alexander Shulgin. What was it

[1:01:31] like working with him? Oh, Sasha, Sasha Shulgin, he was, he was one of a kind. [1:01:42] You know, he, he, I knew of his work because when I was a graduate student, I started graduate [1:01:48] school in 1969. And he had just published a paper on some of the work he’d done from the previous

[1:01:55] years, he worked at Dow Chemical Company. And then at a certain point, he decided to separate [1:02:01] from Dow. And it was either his decision, according to him, or was the company’s decision, [1:02:07] according to people I knew who were at Dow in Walnut Creek. But he had a laboratory. There

[1:02:13] had been a barn behind his house. His parents had emigrated from, I believe, Russia. And he and his [1:02:22] mother and father had lived in this really house in outside of Walnut Creek, California. [1:02:30] And the house, they had a barn behind the house, which had burned down. And so Sasha had

[1:02:38] put a roof over it and made it into a home lab. And I had visited him many times, [1:02:44] but he was the only one publishing anything really that was interesting, [1:02:48] especially after the Controlled Substances Act was passed in 1970 [1:02:53] there was no money for academics [1:02:55] so almost all the academics got out of the field completely [1:02:58] so Sasha Shulgin was the only one who continued to publish [1:03:01] and he pretty much had an open free reign to make whatever he wanted [1:03:07] and then he would test the compounds [1:03:09] and I encouraged him to publish his testing method [1:03:14] which he did, it was published in 1986

[1:03:16] and told if he came up with a new molecule, [1:03:21] he would choose a dose that was one-tenth to one-fiftieth [1:03:24] of the dose that he thought might have any effect [1:03:26] based on what the parent structure was. [1:03:29] And then he would start at that dose [1:03:30] and he would start taking a higher dose and a higher dose. [1:03:33] He would take it up to a point where he felt like [1:03:35] either it was toxic or wasn’t doing anything [1:03:38] or was doing something bad to him.

[1:03:40] So we corresponded a lot. [1:03:42] I had like three folders of correspondence with him. [1:03:44] And I was going to originally put into a book called Conversations with Sasha, but there was so much of it. [1:03:50] I just gave all the letters to the archives at Purdue University.

[1:03:54] There’s a psychedelic archive at Purdue University. [1:03:57] People want to look that up. [1:03:58] There’s a lot of literature there, people’s books, a lot of stuff they’ve collected. [1:04:03] But my correspondence with Sasha is all in the archives at Purdue University right now.

[1:04:09] But we started off on the telephone. [1:04:11] And then after email became available, we started sending emails back and forth. [1:04:17] And I really liked him. [1:04:21] He was one of a kind. [1:04:25] I went once when I visited him.

[1:04:26] He went to, there was a club there. [1:04:31] My memories fail me on the name of the club. [1:04:33] A Bohemian Club. [1:04:35] And the Bohemian Club was mostly rich folks who got together and put on skits and dinners and dances. [1:04:42] And he took me there and he said, he told me, he says, the only reason I’m here is because I’m a unique character.

[1:04:51] If I was sort of ordinary, there’s no way I would get into the Bohemian Club. [1:04:54] And he played a viola. [1:04:56] And I went one night when he was playing, they had a band there. [1:05:01] and they would have camps in the summer.

[1:05:05] They would have camps for people that had special interests. [1:05:09] So he went to the camp that was called Tuners, T-U-N-E-R-S, Tuners, [1:05:13] and they were all people that played musical instruments, [1:05:15] and they’d get together and they would just improvise and play music. [1:05:19] Anyway, they had a band they played, [1:05:21] and he and I would have a lot of philosophical discussions [1:05:24] about the nature of what these drugs were [1:05:27] and, of course, government repression.

[1:05:29] And Sasha would take these, and then after his first wife passed away, then he married Ann. [1:05:35] And then after he would find a new molecule, Ann was very interested in taking psychedelics. [1:05:41] And so he would find a dose that he thought that she could tolerate, and he would give it to her, and then she would write her impressions of it.

[1:05:50] And he wrote his first book, PiHKAL, which is the acronym for Phenethylamines I Have Known and Loved, P-I-H-K-A-L. [1:05:59] He wrote a second book called TiHKAL, tryptamines I have known and loved, T-I-H-K-A-L. [1:06:05] And the TiHKAL, the first half of it is sort of autobiographical.

[1:06:09] He tells his story and then Ann tells her story. [1:06:12] And then the second half of the book are all these recipes for the chemicals that he made. [1:06:19] Some of them are chemicals that I sent him because I couldn’t do testing at Purdue University as a faculty member.

[1:06:25] But I would have some intuition that it was an interesting molecule. [1:06:29] and would send a sample to him. We collaborated on a paper together. I met him when he came to [1:06:37] Iowa City, and he gave a talk to the psychiatry department. He had a friend there who had been

[1:06:45] in Berkeley and invited him out to give a talk. And so I wanted to meet him and didn’t really [1:06:52] get much of a chance. But then Professor Charles Barfnick, who was my mentor at Iowa, [1:06:59] said, well, Sasha Shulgin is going to come.

[1:07:02] He’s going to go to the airport in Cedar Rapids in the morning, [1:07:05] and I’m going to come and get you, and you can ride to the airport with him. [1:07:08] So I was waiting upstairs with bated breath, and I thought they had forgotten me, [1:07:14] and Barfnick comes running up the steps and says, come on, Shogan’s in the car. [1:07:18] So I ran down, and it wasn’t a very long drive from Iowa City to Cedar Rapids, [1:07:23] 20 minutes or so, I think.

[1:07:24] So I got to talk with him for 20 minutes. [1:07:26] That was my first meeting of him. [1:07:28] and I called him Alexander. He said, no, call me Sasha. Everybody calls me Sasha.

[1:07:33] And I said, have you, have you made any molecules that have a sulfur atom on the ring? [1:07:38] And it turns out I had made from my PhD work, I’d made a comment called DOB, which was a very [1:07:43] potent psychedelic. And I said, I had made that. He said, oh yeah, I haven’t published it, but I’ve

[1:07:47] made that too. So we both kind of made DOB at the same time. But then I asked him if he had many, [1:07:52] many molecules with sulfur atom. And he said, no, no, I tried once and then just got a black tar [1:07:58] And so I didn’t do it any further.

[1:08:00] So after I got to Purdue, I found a way to make starry material for a drug that would have a sulfur in the pair position. [1:08:08] And so I corresponded with him and I said, hey, I found a way to make a sulfur molecule. [1:08:14] How about we collaborate on this, we make it and, you know, I’ll do the first part, you do the second part, we’ll publish it.

[1:08:21] We published that in Journal of Pharmaceutical Sciences. [1:08:23] That was my first paper published with Sasha. [1:08:25] the compound, he actually [1:08:28] it was called [1:08:30] para dot [1:08:31] P-A-R-A-D-O-T [1:08:34] and when he first [1:08:36] took it in his trials [1:08:38] he had a mystical [1:08:40] experience and so he was very [1:08:41] cautious about that [1:08:44] he didn’t tell me, he had tested

[1:08:46] he said well I can’t talk about it [1:08:48] something happened I can’t talk about it [1:08:50] I didn’t know what was going on [1:08:52] and then he took a second dose and it didn’t have [1:08:54] the same effect. It was one of those cases where he was just in the right place at the right time, [1:08:58] and this drug triggered a mystical experience. But that’s in the book. It’s in Peridot. So then

[1:09:04] that was a sulfur, methyl sulfur in the four position of an amphetamine, a dimethoxamphetamine. [1:09:14] So then he had a, there was a guy, it was just a good name, Neocastagnoli, [1:09:20] who had hired a postdoctoral fellow that had come from Purdue. [1:09:24] He’d been at Purdue when I was there, but I didn’t know him.

[1:09:27] And so he was trying to find projects for him. [1:09:32] And so Sasha called me and said, well, Neil’s got this new postdoc, [1:09:37] Peyton Jacob, and he said he’s trying to find a project, [1:09:39] and we made the sulfur compound. [1:09:42] Are you going to make any more sulfur compounds?

[1:09:44] I said, no, that was the only one I was interested in. [1:09:46] He said, okay, well, good. [1:09:47] So then Peyton went ahead and made some more sulfur derivatives, put a sulfur in the three position and put a sulfur in the five position and extended out.

[1:09:56] I guess Sasha and Peyton made 20 or 25 analogs of psychedelic amphetamines that had sulfur atoms attached to one place or another. [1:10:05] So, yeah, but that was that was very productive. [1:10:09] And then when I made some molecules that I couldn’t test at Purdue, I’d send samples of everything to him.

[1:10:14] So he had samples of them. [1:10:15] So some of the stuff in there, I’d made some LSD at Purdue, and he couldn’t make LSD, he didn’t have a license to make it. [1:10:25] And I made some, and I’d actually sent it to him. [1:10:28] He wrote it up in there as if he had made it.

[1:10:31] So there was some cover there for some stuff that I had done for him and vice versa. [1:10:39] That’s fascinating. [1:10:40] I mean, so David, I’ve got seven questions for you and they’re personal questions. [1:10:45] So, you know, take your time answering them.

[1:10:47] But what have you changed your mind about in the last 50 years or so? [1:10:59] What’s up, guys? [1:11:00] Xavier Katana here. [1:11:02] And you have been listening to an episode of the Human Experience Podcast. [1:11:05] and this was just a teaser episode of a little bit of what we offer at thehumanexperience.com

[1:11:14] slash membership when you sign up. So if you made it to this part of the episode, [1:11:21] thank you so much for listening. You can hear the rest of it, like I said, at thehumanexp.com [1:11:28] slash membership sign up it helps us stay in the loop of creating these conversations for you guys [1:11:37] to hear so i hope you guys enjoyed this one one we will check you next week thank you so much for [1:11:46] listening as always xavier katana out [1:11:58] Thank you.