About the Guests: Dr. David Nichols is a retired chemist and father of Dr. Charles Nichols, a researcher studying psychedelics at Louisiana State University.
Episode Summary: Nick and David & Charles Nichols, PhD talk about: the history of psychedelics science from the 1970s to the present; DMT & 5-MeO-DMT; serotonin, inflammation, and psychedelics & anti-inflammatory drugs; psilocybin, ketamine, and other psychoactive drugs; and more.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
David Nichols 4:46
So when I went to graduate school in 1969, my PhD project was on what are called psychotic mimetics which are now called psychedelics. I was lucky I had an NDA fellowship to Studying, I spent, actually finished my PhD and about actually the experimental work about three, three and a half years faster than most people did. Because I had worked in industry for five and a half years before that. So graduate school for me was like a vacation that people wouldn't think that going from undergrad to graduate school like, Oh, my God graduate school. But I had worked five and a half years in industry and gone to night school to finish my BSN night at the same time. So I was burning the candle on both ends, but the graduate school and the research for me was like a vacation. And so in 1970, the Controlled Substances Act was passed that that well, I'm not going to be able to do this anymore, but at least I enjoyed my PhD work. But then I went to Purdue University in 1974. And got an appointment there and was able to continue doing work on these compounds, actually got a grant from the National Institute of Drug Abuse, which I was funded for 28 years and renewed for the final year 29th year, just studying the medicinal chemistry and pharmacology of psychedelics, basically, that was, I have another area but this that's the one that's most memorable for me, and published a lot of papers, wrote book chapters, reviews, all the academic stuff, trained at 40, some graduate students and 20, some postdoctoral fellows and visiting scholars, and started to have to research institute in 1993, because nobody was doing clinical work on psychedelics. And so I got together with some like minded friends, and we started to have to institute raise money from philanthropist was quite difficult because once you have a lot of money, apparently you'd like to hold on to it, you know, give it away very easily. We did raise about $10 million. And the halftracks had funded the seminal studies really, that really got people looking at psychedelics again. We funded Charlie Grover UCLA we funded to Johns Hopkins studies with Roland Griffith, we fund Steve Ross at New York University. And that really, I think those papers were the the impetus for people to realize you actually could do this work again, because prior to that time, no one got in the field because you couldn't get a grant, and still almost impossible to get a grant to study these substances. So though, a couple of grants have been awarded Now recently, but you couldn't get money to fund these for years. And if you're an academic, without a grant, then you'd lose your job after five years if you couldn't get a grant. So I was in the right place at the right time, worked my ass off and was lucky, got a lot of luck, and was able to kind of push this field forward. I made the MDMA for four maps phase one to two studies. The DMT for Rick Strassman study made the psilocybin for the Johns Hopkins studies. So I was encouraging people to work in this field. Pretty much before almost anybody else was in proving that it could be done.
Nick Jikomes 7:50
Yeah, so you've truly been the man behind the curtain. You actually made the MDMA for Rick Doblin map studies and the other ones that you mentioned. Yeah,
David Nichols 7:59
yeah. Nobody else would do it. And Rick Doblin had gotten it this eighth set of maps, and he was an ideal, idealistic young kid. I met him when he was still an undergrad at New College. And he wanted to make MDMA into a drug because he'd been so impressed by its effects. And then he started checking with companies to make it for you need to get preclinical toxicology done, he needed some pure material, and nobody would touch it, because it was, you know, they would touch it, but not for the kind of money he had. And so I did that. And then then it was easy to make the DMT for Rick Strassman. And I got FDA, we got FDA approval to do that. And in this psilocybin I started doing synthetic psilocybin. The first batch was used for Hopkins 2006 studies and normal volunteers. And then I made a great big batch for the clinical studies. So that's, and then I retired from Purdue in 2012. At Purdue, I was eventually Distinguished Professor of medicinal chemistry, molecular pharmacology, and also a named professor of pharmacology. So
Nick Jikomes 9:06
and who's the other guy with us right now? And when did he come on the scene?
David Nichols 9:12
He's the one person that he encouraged not to get
into the field of psychedelics. I tried to discourage him, said he would kill your academic career, but he didn't listen to me.
Charles Nichols 9:22
Now, I came along sometime in the story when he was getting his PhD. At the University of Ottawa, he came along before while he was working at the companies before he went to Iowa, so I remember being a little kid five, six years old, and married student housing. Occasionally, my father would take me into the lab. This is food big chemistry lab, but most of the time it was just being a kid playing around in Iowa. Then when he moved to Purdue grew up in West Lafayette. At Indiana, and my mother was getting her PhD in pharmacology at the time. My father was a medicinal chemist getting in pharmacology. So the a lot of the conversations around the house were very scientifically oriented about drugs and animals. And I would go in and see my mom operate on, on rats doing her study. And my dad was, first I think he had cats as a research animal. And I remember going in and seeing some of the cats and then he switched over to rats after a while. So I kind of grew up in and around the scientific environment in the laboratory. And it was really fascinated by the chemistry and the biology. So I went to Purdue as a chemistry student. And after a couple of years, especially after P Chem, decided that chemistry was not for me. wanted to do something a little bit more interesting. So I switched to biology. And around that time was when the PCR machine was developed and invented, and Purdue had just gotten their first PCR machine and I was fascinated by molecular biology.
Nick Jikomes 11:08
And when is this this is the 1980s Yeah, out miking
Charles Nichols 11:12
This was around 1987. And I joined a lab to do my undergraduate research in bacterial genetics and thought it was just just really fascinating. So any thoughts of pharmacology or drugs or anything like that were were just not an existence I didn't, wasn't interested in in I wanted to be a gene jockeys. My dad felt it at the time. So I ended up going to graduate school at Carnegie Mellon University starting in the fall of 1990. And I didn't really know what I wanted to do, but something having to do with with genetics. And I ended up joining a fruit fly developmental neuro genetics laboratory and studied fruit fly development for my PhD dissertation. But then after several years, working with fruit flies, decided I didn't want to see a fruit fly again. And then I want to do something more mammalian based and through a very crazy circumstances, ended up doing my postdoc in the laboratory of Elaine Sanders Bush, who was, unbeknownst to me, one of the leaders and pioneers in the field of serotonin two receptor research. At the time, I just thought, Oh, my, my father had mentioned her a couple of times that she was a good, good colleague and serotonin. Oh, that's, that's the mammalian brain that could be interesting. And she proposed to me a project, looking at the effects of LSD on gene expression in the brain. Oh, wow, that's perfect. It's kind of combined my love of genetics and my family history of psychedelics. And I had been working there for a year or about a month, and she comes out of her office, waving my CV and she's pointing at it and says, I just was looking at your CV again, and notice that you did your undergrad at Purdue. And then she asked me if I knew Dave Nichols. And I say, oh, that's, that's my father. And from from then on, in and around the lab, she called me Dave. But I got into the field, I think, in this roundabout way, I found my own way to it. So it wasn't a lot of people assume I got into the field because of who my father is. But that really wasn't the case at all. And while at Vanderbilt, I started I got this this strike of inspiration one day that you can use fruit flies for pharmacology experiments, and I asked if we could give some psychedelics to some fruit flies, I got some fruit flies from down the hall. So I had started giving drugs to fruit flies, as well as doing the gene studies in in the rats. So it was time for me to go on the academic trail and find a job. And my father counseled me strongly against it. He said nobody gives a rat's ass about psychedelics, you know, it's kind of destroy your career, you're not going to be able to get grants. So fortunately, I didn't listen to that advice. Being the stubborn son, I guess that I sometimes can be.
Nick Jikomes 14:31
And when was this is this in the 90s? Now,
Charles Nichols 14:33
this was in 9697. When I started in the LNS lab and I started looking for a faculty position around 2003 and got my first and so far only faculty position here at LSU Health Sciences Center in New Orleans in the start of the fall 2004 about a year before Katrina. So I've been here this fall 20 years in in that whole time studying serotonin to receptor pharmacology, cell culture and animal models, looking at gene expression, epigenetic effects, behavioral pharmacology. And somewhere along the way, psychedelics became an accepted potential therapy, which is really exciting.
Nick Jikomes 15:21
So it sounds like, from when you were, you know, your earliest memories, you were a little kid, you were you were in the lab, and mom and dad, were talking about science. So you were sort of always embedded in that kind of environment. Yeah. When did when were you? How old were you, when you first sort of understood, like, what psychedelics were and what what dad was doing with a little bit more specificity?
Charles Nichols 15:44
Well, when he got his job at Purdue, and when I was younger, he I knew he was a chemist. And I knew he was working with cats and rats in the way that he explained things isn't he was working with chemicals that make people dream. So it was like, I thought, Oh, he's figuring out how people dream. And then, of course, this was Hi, Reagan era with just say no, but we never really had any of those discussions around our liberal household. But things sort of, I guess, grew organically, as I grew older, and I think it was probably around when I was a senior in high school, figured out what dad was doing. But there was no Internet back then. So it was really kind of hard to do what what my daughter does, you know, she since she was little, she likes typing into Google. And oh, look, there's lots of pictures his dad and grandpa on the internet.
Nick Jikomes 16:50
Interesting. And so eventually, you start your own lab? And what just give people a brief overview, what is your lab study? And what do you guys work on.
Charles Nichols 17:02
So when I started my lab, it was essentially just all neuroscience, it was studying the receptor pharmacology and drug receptor interactions of five HT to a agonists and psychedelics and how they affect behaviors, and then still continuing on with my rat and five models using them to understand sort of the circuitry and gene expression response to psychedelics. And it was after Hurricane Katrina, about a couple of years, year and a half after that, we got back into the lab that we serendipitously discovered the potent anti inflammatory effects of psychedelics. So, really went ahead full steam with that side of things. And in my laboratory today, I think there's about a third of it is devoted to the anti inflammatory effects of psychedelics and peripheral inflammatory models. A third is devoted to sort of hardcore receptor pharmacology, drug receptor interactions. And a third of it is continuing on with the behavioral genetics side in rodent models and fly models.
Nick Jikomes 18:21
Interesting, David, do you remember those discussions with Charles, when you when he was a little boy, where you told him, You looked at things that made people dream?
David Nichols 18:31
I actually don't have any memory of that. I can remember when he became an academic, I remember telling him don't study LSD. Nobody cares about LSD. Yeah, that's probably but we always had science. I mean, he won in high school, he entered science fair, what to eat to eat every years. And, you know, so he was learning to think like a scientist. And of course, I wasn't in sports and so he didn't do sports. And so really the probably more his hobby was reading and science and, and thinking about the scientific things.
Speaker 1 19:06
In my high school had a really good chemistry program.
Nick Jikomes 19:12
Interesting. So you both been on the podcast before a lot of people listening I think will have some some background in this. So we'll we'll assume some background knowledge for people around psychedelics and some of the basics there. I don't want to you know, tread over ground that we've gone over in previous episodes too much. But obviously, when we're talking about psychedelics, you know, everyone talks about the five HTT to a receptor, and that being the main receptor responsible for the psycho, the site psychedelic effects that they have. There's two interesting branches I want to talk about that you guys know some things about that are interesting. One is sort of non psychedelic effects of some of these compounds that come through the 5g to a receptor, such as 5g to receptors that are found outside the brain and other parts of the body and other tissues. And then the other side that I think is interesting is, you know, other receptor systems that some of these compounds engage with. And so maybe starting with the first one, you know, sort of, I guess the topic is going to be non psychedelic effects that psychedelics can have through the five HTT to a receptor that gets right into some of what you've been working on Charles, to do with like anti inflammatory effects and things like that. So can you give us like a basic sense of what's going on there? How widespread is the five HTT to a receptor outside the brain?
Speaker 1 20:29
Yeah, the five HTT to a receptor is really it's I think it's the most widely expressed serotonin receptor. throughout the body, it's it's been on every tissue that we've looked at so far. From fat cells, skin cells, muscle, endothelial immune cells, T cells, macrophages, it's, it's expressed at not as high levels as in the brain, but because they're G protein coupled receptors, and they're an amplification system, they don't have to be expressed very highly to really have a profound effect on function. So the potency of the effect we discovered, for some of the drugs that we're looking at, are literally orders of magnitude below what the threshold amount would be in some of these animal models that we've looked at. So we think that if the potency is so high, that the the amounts of drugs, some of these drugs that people would need to take could would be essentially micro dosing.
Nick Jikomes 21:33
I see so so you're saying that they can have some of these peripheral effects on inflammation at doses that will not give you a psychedelic effect? Right? Right. And, and what what compounds are we talking about here are these you know, things like LSD, psilocybin, the most famous psychedelics are these other compounds. Um, it's a,
Charles Nichols 21:51
it's a fairly interesting story. Behind that is we first started with DOI, which is a phenethylamine, psychedelic, somewhat related to mescaline in its structure, and we did a lot of work with that. But then we wanted to look to see if other psychedelics had the same effect or for specific for that drug. So we did a comprehensive study where we looked at 25 Different psychedelics across the all the major pharmaco force a few years ago and published on that, and what we found were that some really potent psychedelics like LSD, are not very good anti inflammatories, they have anti inflammatory effects, but they're not as potent, as, as DOI. Right? I see this, this is from that
Nick Jikomes 22:44
study? Yeah, I saw you. I saw you give this talk last year. So I have this, I have this ready to go. But yeah, this is this is a really interesting slide. There's a lot here. Yeah. So to
Speaker 1 22:53
break it down, that dashed line in the middle kind of represents the baseline inflammation level, within our asthma model, that in an animal that we make allergic to an allergen, and has difficulty breathing and has pulmonary inflammation, and sort of the overall measure we're used for that is, is pen H. So the higher the number of pet H, the more inflammation in the lung, the lower the less and so that dotted line is represents the average asthmatic rat, and what the inflammation would be. And so we found several drugs that were completely fully efficacious and blocking inflammation. In this this model. The for example, to Ci to CB four hydroxy. Di P. T. R DOI was the drug that we have used the most, because it's the most selective for the five HTT receptors, but also you can see psilocybin or are the active drug psilocin. Is is in there.
Nick Jikomes 23:59
Yeah, so you have some of these drugs are have really good efficacy. Some of them don't. And sorry, if I missed this, did you say this effect is coming through to a specific Yeah, when
Speaker 1 24:10
we when we test in a to a receptor knockout mouse, we have absolutely no, no effect.
Nick Jikomes 24:17
So So then, so then, I guess the next question here is some of these drugs it's the structure hacking through to a some of them do a really good job at reducing inflammation, or preventing inflammation. But some of them like LSD don't do as good a job some of some of these other ones over here don't do a very good job at all. But they don't they all act through the to a receptor and kind of a similar way. They
Speaker 1 24:39
do they do. So that's one of the projects in my laboratory focusing on receptor pharmacology is to try to figure out why some psychedelics are anti inflammatory and others aren't. And a really good example of this is if you compare, for example, psilocin to DMT you The only difference structurally between those two compounds is that hydroxy at the four position that that LH at the top of that of that ring. And similar for the four hydroxy di PT that's on here, if you take that four hydroxy off di PT, which I don't think it's on this graph here, the IPT also completely loses its anti inflammatory efficacy. And the study that we just published about two weeks ago, we're comparing DOI to a drug called D O T FM, which is also very similar. They're both good strong agonists at the five HTT a receptor, they both produce a behavioral response, very potently. But do TFM has no anti inflammatory efficacy across several models that we've looked at. So there's something about how these different psychedelics are engaging amino acids in the orthosteric binding pocket of the receptor that put it in a particular state that recruits anti inflammatory pathways. That's one of the one of the big things that we're trying to solve in my lab. And
Nick Jikomes 26:07
I guess one of the key things here for people to understand is probably that, just because so if two drugs bind to the same receptor, that does not mean they're going to have the same effect, you can sort of you can essentially turn on the receptor in different ways that have very distinct effects.
Speaker 1 26:20
Right, right. And that's a concept called functional selectivity, that my father was one of the early pioneers of that you could get different responses from a receptor from different drugs.
Nick Jikomes 26:33
David, what are like some of the early earliest examples of that, that were discovered?
David Nichols 26:40
What do you mean functional selectivity? Yeah. Well, the concept really goes back probably to the 90s people. And there were many pharmacologist who didn't believe it, there was the idea that a receptor just turned on and just turned off like a like a light switch. And we had done some we did some early studies showing that the serotonin to a receptor also could lead to changes in other interests, interests, intracellular signaling molecules, depending upon the molecule. So as in addition to being called functional selectivity is also called ligand bias or ligand directed bias, which was a concept that when the ligand binds to the receptor, it produces a conformational state or shape of the receptor, that leads to do a difference in the interior part of the receptor, that then couples to different signaling molecules. So that's been fleshed out over the past 30 years, I guess. And that kind of said, Now, it's pretty widely accepted. So the issue is, nobody completely understands all the elements that determine what a particular what signal will be produced. So major signaling pathways people look at or something called arrestin, signaling, and G protein signaling. But there are other types of signals that are not as well fleshed out. And we think with respect to the anti inflammatories, there's a signal that no one has really found yet that which is one of the things that Chuck's lab is looking forward to figure out what that is, but they must, they must be subtle differences in the shapes of these receptors that allow them to help with differentially to regulators, regulatory molecules within the cell.
Nick Jikomes 28:20
I see so so you could have one receptor like 5g to a, it could actually be hooked up to different protein and information pathways in the cell and which one is hooked up to or which drug binds to the outside can determine like which one of those gets turned on. It's not just one effect, like a light switch, like you said, right?
David Nichols 28:39
So when when the drug actually binds to the exterior portion of the receptor, the receptor is actually seven alpha helices packed together in a bundle. And so when it binds, there's a complementarity between the ligand and the receptor, the residues in the receptor. And so it'll orient the receptor in a certain way, with a different Well, LSD, for example, is a large tetracycline molecules for rigid rings that are hooked together, and it sits down there, you can imagine it's pretty clunky, that forces a receptor to adapt itself to the LSC molecule, because the LSD molecule is so rigid, but if you put a smaller molecule like mescaline in there, where there's a lot of flexibility, now the receptor has the ability to adapt to different shapes and still accommodate the ligand. And so the shapes those different shapes and nations of the receptor, determine what's able to bind on the interior within the cell of the receptor.
Nick Jikomes 29:36
So, so, you know, when we looked at that graph, Charles, you know, it was basically a graph showing us that different types of 5g to a receptor drugs, they have different levels in of efficacy with respect to this inflammation effects, some of them could lead to much lower inflammation, some of them not at all, some of them somewhere in the middle. What about serotonin itself? This relationship between serotonin and inflammation at this receptor will set
Speaker 1 30:04
serotonin primarily is pro inflammatory. So when there are sites of inflammation in asthma and arthritis, diseases like that there are high levels of serotonin and that serotonin helps to cause immature T cells to mature causes a recruitment of other inflammatory cells like eosinophils to the lung, through five HT to a receptors. So it could be that the reason that five HT to a receptors are expressed so widely throughout the body is that that's one of the main mechanisms that serotonin uses to indicate inflammation to activate the immune
Nick Jikomes 30:44
system. And so you, you know, you've been studying these drugs in an asthma model. So you're looking at lung tissue. And I mean, that's a very interesting area, there's more to talk about there is is 5g to a bit involved in inflammation within the brain itself.
Speaker 1 31:03
There is evidence that it is there is a significant percentage of patients that have major depressive disorder that have neuro inflammation, you can detect elevated levels of inflammatory biomarkers in the serum and in the cells.
Nick Jikomes 31:23
Well, that's a, you know, I'm thinking of an industry. Interesting question here. Now, if you have major depression, and you're saying that there can be this correlation with neuro inflammation, you just told us that serotonin generally is pro inflammatory. But the first line medication people typically get for depression is an SSRI, which would elevate serotonin levels. So are SSRIs actually promoting inflammation?
Speaker 1 31:49
No, actually the opposite. There's been a body of work looking at how activation of serotonin transporters can produce an anti inflammatory effect through specific mechanisms. So that's been studied for, I would say the last 1515 years or so. So that's that's, that's an established pathway. Like if you have activation of the serotonin transporters, you you have a effect primarily on il one beta and suppression of that. So that's, that's a different parallel pathway. I think what what we're looking at is something that the drugs are binding to the five HT to a with such potency, that it's really an active anti inflammatory process. It's overriding anything that serotonin itself could be doing.
Nick Jikomes 32:43
And so is it. I imagine it's, you think it's plausible that some of these drugs or perhaps new drugs that that you or others are designing, they could be potent anti inflammatories that either don't have psychoactive effects, because they're so potent? You can use a very, very low dose? Or perhaps because some of these don't actually cross the blood brain? blood brain barrier.
Speaker 1 33:08
Right, right. So it could simply be if it doesn't cross the blood brain barrier, then you wouldn't have to worry if it was non psychedelic or not, but you'd still get exposure to the to a receptors in the periphery
Nick Jikomes 33:21
and how similar so a lot of these drugs are very similar structurally to serotonin. That's, that's why they interact with the serotonin receptors. One of them that's very, very similar is that I want to talk about a little bit is DMT. So David, can you just tell us tell everyone a little bit about serotonin DMT how similar are they structurally.
David Nichols 33:44
So they they're built around a two ring system called an endo, it's a six membered ring fused to a five membered ring with a nitrogen atom. And like most drugs that interact with mono main systems, there's an aromatic system, two carbons away from the basic nitrogen. So there's an end goal of this buyside be kindled two carbons away from a basic nitrogen atom. Now with die in Dimethyltryptamine, basically, all you have to add to that template is to one carbon methyl groups to the nitrogen, so it's an N and dimethyl. And trip to me tryptamine is an endo with the two carbon sidechain in the mean. So an N and dimethyl seratonin is also got the indle core and has the two carbon Sidechain. But instead of having methyl groups, it just says an NH two, so it's a primary amino group. And in addition, it has a hydroxy group attached to the five position. So DMT doesn't have any oxygen attached over in the Indo ring and it's a tertiary amine, which makes it more lipophilic and more easily to penetrate the central nervous system. So chemically, they have the similar core, but serotonin is a primary means DMT is a tertiary amine, and serotonin. It also has this aromatic hydroxyl sticking off in the five position.
Nick Jikomes 35:05
And so you said you were the one who synthesized the DMT for Rick Strassman studies where he was giving human patients IV DMT. Right. How did how did that relationship start?
David Nichols 35:19
I was actually invited to a meeting at the Esalen Institute in Big Sur, California. I was one of only two academics that were there, Rick Strawson was probably the other one. And then we had all the grand who boss of the psychedelic genre, they're Stan Grof, and Ralph Metzner and DNA unit, you can go down the list, they were all there. And the goal of the meeting was to sort of formulate a strategy to prevent MDMA from becoming scheduled. We had two meetings, one in the fall and one in the spring, when was the sorry, it was in the fall of 8484. Okay, in the spring of 85, but in fall of 84, and Rick Strassman, because we were both academics, we kind of hung around together, I was aware of a paper that he'd written a course called adverse effects of psychedelics. It was a review paper that came out, I think, in 84, where he said that the incidence of adverse effects with psychedelics was actually very, very low indicating the safety of psychedelics in general. And so we were talking and it was funny because we're walking along. And, of course, esslyn is kind of a new age place. And we're walking along. And and Rick and I were making a joke about how many healers there were, because these places all had shamanic healers and Medic meditative healers and sound healers and people do in every kind of technique for producing some kind of healing, whatever. And recommend to me, there's more healers here than you can shake a fucking stick at. And we both laughed. But anyway, what we talked about was no one was doing any clinical work with psychedelics. I said, Well, Rick, I said, I'm a chemist, but you're a psychiatrist. You're at a psychiatrist and psychiatry department and university, New Mexico, you could study these clinically if you wanted to. The problem was, there was no money to do it. But he thought, well, he'd always been interested in DMT as an endogenous molecule. And I had studied at some in earlier years. And so he said, Do you think I could? I said, Well, sure you could. So we met, we had a couple of meetings with Daniel Friedman. Danny Freeman was one of the early LSD researchers when he was at Chicago, and he was the acting head of active chair at the acting head of psychiatry at I believe, UCLA. And we met with him and he counseled Rick, he said, you know, do a study, I'll find some some I'll try to find some people that would support you. And there actually was the Scottish Rite foundation, I think some supplied some funds. And he said, but don't try to do any therapy or anything like that. That's too controversial. Just look at markers, look at blood pressure and heart rate and measure blood plasma markers, and prolactin and things like that. And so there was a fellow there who was the chairman of the psychiatry department. I think his name was uhland. Booth, if I remember correctly, and he had moved there, because his wife couldn't tolerate the weather. She had a lot of allergies. And so he moved to New Mexico where the air was kind of more pristine to get away from where he was. So he had a big reputation. So he worked with Rick to help design the study. And then Rick came to me and he said, you know, what, if I get all this stuff done, and everything's approved, and I've got a source of funding out, but then I can't get the DMT. I had made the so I made the MDMA for Doblin in 1985. And so, by the time Rick came back to me, and said, you know, so we met at 485. He came back a year or two later, and he said, Well, I can't get anybody to make the DMT. Could you make it and since I had made the the MDMA for Dobbin, and the MDMA synthesis was the first time I've worked with FDA, people on FDA regulators, they'd sort of give me some counsel, this is what you need to do. These are the things you need to watch out for. You need to have a record of all the reagents used and the lot numbers and yada, yada, yada and all that. So Rick said, Could you make the DMT because nobody would do it. And it was a controlled substance. I think it was controlled. It was a controlled substance by then. And so I said, Well, I made the MDMA. And so sure, I could do it as a simple synthesis. So I worked again with the FDA people and made it for him. And then he did a study with the DMT.
Nick Jikomes 39:43
So you know, you know 8485 Obviously, people like you knew what DMT was. The MT was known to specialists, at least at this time, but I don't think it was very widely like beyond that. It was probably pretty unheard of. So did Rick already know about DMT and And why was it that he used DMT? Why wasn't he keen on doing psilocybin or some other some other drug,
David Nichols 40:06
he had developed the hypothesis that endogenous DMT, that DMT was produced endogenously, he still has promoted that idea that is produced endogenously and might be related to the symptoms of schizophrenia. And so the Scottish Rite Foundation, who I believe provides some of his funding, they were set up to fund research in schizophrenia. So that was his initial idea was, if it produces schizophrenia, maybe if we just give it intravenously, and there have been some earlier papers showing that was psychoactive. So he had said, Well, you know, let's give it and see what it looks like, what are the symptoms? Does it look like schizophrenia, whatever. So I think that was the motivation for working with with DMT. The idea he had that it was an endogenous psychology.
Nick Jikomes 40:57
And so when When did he actually do those studies? And what are the Cliff Notes in terms of what he found and what he measured?
David Nichols 41:04
Well, he published a couple of papers in archives of General Psychiatry, I believe, in early 9394, something like that. And in addition to seeing modest increases in blood pressure and heart rate, the people at the higher doses, has saw these aliens, and you may have heard about all this. And so he wrote a book called DMT, the spirit molecule where these people had discussed, you know, when they took these high doses of DMT, they were transported to an alien landscape. And they saw these alien beings and creatures dmtl. It's whatever. And Terence McKenna had talked about those. Terence McKenna, of course, was an early smoker of DMT. And it talked a lot about the DMT elves and the DMT entities, etc. But Strassman, as far as I know, was really interested more in the possibility that DMT could be produced in people with schizophrenia and mental illness, and that that was producing the symptoms.
Nick Jikomes 42:04
And so this idea, I mean, it's a very intriguing idea, it would imply that, you know, there's, there's some level of endogenous DMT production in the brain, either all the time, or it gets released at specific and under specific circumstances or in, you know, under certain pathological conditions. Is there much evidence for this? What do we actually know today about, you know, any evidence that there's detectable DMT in the brain at levels that would make it relevant for some of these things.
David Nichols 42:35
They're already tackable levels of DMT in the brain, if you use HPLC LC mass spec, we've been detected. I actually wrote a review article, I was invited to speak at breakin convention conference in, in London some years ago. And they wanted me to talk about DMT as an endogenous molecule. I said, Why don't believe it really is he said, that's why we want you to come. And so I gave a talk about it and present all the evidence to say, there's not enough there, there's not enough there. He got a biochemist and a couple of other people to provide data to suggest that, you know, if they strangled rats, for example, the levels of DMT in the rat brains went up. So he said, Well, maybe when people are dying, maybe the Near Death Experiences DMT. But when you strangle rats, everything goes up. They have a tremendous flood of all kinds of transmitters in the brain because their brains dying, and you know, it's the trauma and stress releasing it. Um, they they're still they're still a group of people that talk about DMT as an endogenous molecule that's produced in significant amounts. But I really don't, I don't subscribe to the idea that that happens. There are many other things that I've pointed out things. If someone's under stress, things like endorphins are produced, and endorphins are more potent than DMT and can reduce weird psychiatric effects and mental effects. So I actually don't believe there's any evidence for it, but Han and Steve, when there's a, there's a biochar? Yeah. Steve Barker, and he's in Louisiana. And, and then there's another biochemist, I think, in Michigan, and they provided data where they've claimed that, you know, there's enough produced and it could be concentrated Nick cosy said, Well, you could be concentrated in the vesicles. And could cause you know, the release and but it's, it's really, in my opinion, it's a house of cards. It's it's really, it's a cute hypothesis. You think when somebody's dying, and they have a near death experience and have these patients and it could be a flood of DMT. But I just don't I just don't buy into that at all. I don't think the evidence is very strong. There are just a few people that really are pushing this point of view. That's execute theory. People like it
Nick Jikomes 45:00
Why. So, you know, we kind of touched on earlier, Charles through some of your work on inflammation, you pointed out that silos and and DMT, even though they're very similar chemically, they're very different effects in your inflammation model. Obviously, one of the other things that characterizes DMT that people always talk about is just the potency and the vividness of the subjective effects, together with the fact that it's so short lasting, even, you know, it's, you know, it's very close to sight losen in terms of chemical structure, but you know, it lasts for a few minutes, as opposed to several hours long mushroom trip that you can get with magic mushrooms. What is it? You know, do we know or understand why the subjective effects are so potent? And and the, and the drug doesn't last that long in terms of the structure and how it's interacting with receptors and things like that? Yeah,
Speaker 1 45:48
I think a lot of that is just the pharmacology and the route of administration. That DMT itself is not orally active, like unlike psilocybin, psilocybin is winter ion that has that phosphate that stabilizes it. So it can be taken orally. And when you take psilocybin orally, I think the length of time is really the absorption into into the circulatory system from the gut. Because if you I found, I think some early imaging papers were done with intravenous psilocybin, and that was about a 20 minute trip with some of those. I think they were doing that in the David nuts lab for some of those early imaging studies. So it's not necessarily that the one drug lasts more than the other. It's really the route of administration. If you smoke it, or inhale it, it's going to go directly into your circulatory system, and then it will be metabolized through monoline monoamine oxidase largely. But, Simon it's it's oral,
Nick Jikomes 46:53
it's you know, and that would that would that would make sense of why I Alaska which is just orally active DMT lasts much longer than inhaled DMT. Exactly.
Speaker 1 47:02
Yeah. Yeah, the big grass, several hours,
David Nichols 47:07
the beta carbolines in ayahuasca prevent monoamine oxidase from breaking the sidechain down. In fact, I've argued that Ayahuasca is basically just an orally active psilocybin type molecule, this the effects are very similar.
Nick Jikomes 47:21
Interesting, another, you know, sort of another interesting comparison is you've got, you know, DM, DMT, and DMT, which most people just refer to as plain DMT, then then you've got five methoxy DMT. So very similar chemically, very intense experiences that people report with these two drugs. Usually, they're inhaled. So they're both short acting, but the content of the experience is very different. So what is what do we know about the differences between DMT and five Meo DMT that account for their differences? There's
David Nichols 47:52
a couple of pharmacological things right off the bat. The psychedelic effects presumably, are mediated by activation by the CTA receptors, but five methoxy DMT in animal models, and also in vitro, has really powerful effects and stimulating the serotonin one a receptor. And one A receptors are also expressed on the axons of a of the cortical pyramidal cells, so they actually have a different effect. And we don't really understand that, but probably the five methoxy DMT. The fact that it's so different, is related to the fact that it's such a powerful 5g One A agonists DMP doesn't have that much five HC one agonist activity, but five methoxy DMT is a really potent five HT one agonist as well. And
Nick Jikomes 48:38
is that is that is that something that distinguishes five Meo DMT from most other psychedelics do most of them not interact with this receptor or do so much more weakly,
David Nichols 48:49
much more weakly, the phenethylamines, like mescaline don't really activated at all, it's mostly the tryptamines. And there again, five effects the DMT is almost unique. Some people call it the god molecule because you completely lose consciousness. And whereas with DMT, it's more entertaining and visual five effects DMT really shuts off people's consciousness. And nobody, you know, we just were too early and then studied these to really understand what it is. But if you look at a cortical pyramidal cell, the fibers T to a receptors are on apical dendrites and they activate the cells so they fire more easily they increase the gain fibers to one A receptors, among other places, they're located on the axons, and they hyperpolarize. So they almost can direct the effect on the pyramidal cells that you see when you activate the two A receptors. But the one A is also located in other places in the brain. So we really don't understand. I mean, you know, the brain is much more complex than we can possibly comprehend. And although we know a lot more than we used to, I think it just they're subtle nuances, and also the idea that you have some differences in signaling a DMT act debates the receptor, and you probably generate a certain set of signals, arrested in G proteins by methoxy. DMT activates the same receptors, but probably also direct targets different types of intracellular signaling molecules. So it's pretty cool. I think it's more complex.
Nick Jikomes 50:16
I see. But but, you know, to a first approximation, if we know that 5g to a receptors are often concentrated in the apical dendrites of certain neurons in certain parts of the brain. And you said 5g, who want a is often concentrated on the axons and has hyperpolarizing effects. And we would expect drugs that hit the one A and to a receptor to have a very different pattern of activity that they elicit from one that primarily hits to a but not one. I.
Speaker 1 50:43
Yeah, I mean, yeah, yeah, it's like for for tryptamines, like, like, like DMT and psilocybin, it's about a one to one ratio, and how it's interacting with the two eight and the one A, but for five Meo DMT, there's about 100 fold selectivity for one A over two a, so it's a week agonist to to a in the One A, so it's almost a selective one agonist with some to activity.
David Nichols 51:10
If you do animal experiments with five effects of DMT, and one of the some of the psychedelic, almost any other psychedelic, the animals respond to activation, that's why we see to a receptor. But if you go into, say, rats, and you get five methoxy, DMT, the primary salient cue that they pick up on is activation of serotonin on a receptor. So it's really a difference in pharmacology, they're
Nick Jikomes 51:32
interesting. So one of the so that's a very different, that's an interesting difference in pharmacology. One of the other things that is very interesting about five Meo DMT to me, other than the experience itself, is, and I've heard other people report this, but I'm not sure to what extent it's been formally studied. But but I've had two separate experiences with five Meo DMT in my life, and I will never forget the first one, because I was told with confidence ahead of time, by the, by the person overseeing this, that five Meo DMT was very likely to result in what he called reactivations. And he said that this would be some kind of experience similar to the drug experience, long after the drug had worn out the next day, the day after, and so forth, where you would basically trip to some extent, again, probably at night while you were sleeping. And this could happen for days or even weeks after, after the drug administration. And at the time, you know, I just sort of silently listened to this. And I thought to myself, you know, I've never heard of anyone actually having an acid flashback or anything like that. I've never heard of this. I didn't, I didn't buy it. But I'll be damned if just that didn't happen. I would say for about two weeks, every night, I would wake up in the early morning hours and have, you know, probably an experience, it was roughly 50 to 80% of what the actual drug experience was. Is that something that's been reported widely for five Meo DMT and hasn't been studied at all?
David Nichols 53:05
It's not something I've heard of you may be a very suggestible personality. It's, it's, it's,
Speaker 1 53:13
I think it's been written about tonight, it's not uncommon from, from what I understand, and so we had a recent publication that was a hypothesis piece that was largely driven by Peter Hendricks graduate student, Haley Durand, on a hypothesis that the five Meo DMT experience and a therapeutic effect may be due to partial seizures and the temporal lobe of the brain because of the overlap of the symptomology between complex partial seizures and by Vimeo experience with those reactivations that are pretty much unique to find them you very, very similar to sort of recurrent kindled seizures after a major seizure event.
Nick Jikomes 54:05
Interesting. Okay, so this has been reported, but no one's really done careful studies of this. No.
David Nichols 54:10
And I've known people that have been abused by MyTaxi CNT, including myself and and that hasn't happened.
Nick Jikomes 54:15
Interesting yet happened to me the first time but not the second time at all. Interesting, okay, so I'm also just interested more generally in so five Meo DMT is an example of a psychedelic that has strong interactions with other receptors beyond the five HTT to a receptor. Are there any other major psychedelics, psilocybin, LSD, and any of the big ones that people are studying most intensively right now that have that have interactions with other receptor systems that we think are going to be important for their effects or for potential therapeutic outcomes?
Speaker 1 54:54
So, primarily the phenethylamines like mescaline, like DOI UNM, DOB to CB they primarily affect just five HT two receptors, although there's some interesting data from another lab that is pointed towards an additional receptor, but that's unclear what that could be the tryptamines like Siloso, in di PT, four hydroxy, di PT, they all will activate, bind to and activate almost all serotonin receptors, where you have LSD is will bind to and produce activity and almost all serotonin receptors and other monoaminergic receptors like dopamine adrenergic. So the studying a drug like LSD makes it sometimes really difficult to interpret what those results are. There is some evidence that other receptors like the five HD one a are feeding into some of the behavioral effects and rodent models. In humans, I'm not sure if it's really been demonstrated that other receptors are feeding into the effects of either LSD or psilocybin or mescaline, like compounds, I don't think that work has been done.
Nick Jikomes 56:16
So, I guess building on the site, you know, going back to this idea of functional selectivity. So you can have two drugs that each interact with the same receptor, but they do so in different ways. And so the yield, they can yield different, potentially very different effects. In the context of what's going on currently in in psychedelic medicine, there is this big push to try and find psychedelics that have therapeutic efficacy for psychiatric diseases, you know, similar to what we've seen with MDMA for PTSD, psilocybin for depression, and so forth. But you know, a lot of people are asking the question, can we re engineer some of these drugs so that they retain this therapeutic benefit? But we don't have to babysit someone for a five hour psychedelic trip? Can we engineer out the psychedelic component, but retain the therapeutic component? What do you guys think about the how plausible it is that we will achieve that? And are there are there any good examples or anything like that, in terms of functional selectivity? Are some of these drugs you know, able to activate, say, a five HTT to a receptor in a way that doesn't yield psychoactive effects, but does retain some of those therapeutic effects?
Speaker 1 57:30
I think they were for at least for anti inflammatories, developing a non psychedelic to a agonist to engage stet still yet to be found pathway. I think that's, that's very feasible and something that we can do. I know if it gets to the psychotherapy. That's, that's a little bit different on whether or not you could have a non psychedelic psychedelic, that would be an effective antidepressant. I know my dad has some opinions on that.
David Nichols 58:01
Yeah, I mean, it's not it's not there's not a simple answer to that. If all it does is activate the serotonin to a receptor, it's probably going to be a psychedelic, it's going to have to activate some other ancillary receptor that cancels out the five E's to affect it, maybe you'll get the thing that's. And when people ask me, oh, is that really important thing? Because there are people think we need to engineer the psychedelic effects out? And what my answer has been, well, you know, for somebody who has major depressive disorder, given them a pill that addresses the depression, that's like an SSRI. There's nothing wrong with that. But if you talk to people who have been in hospice, and have had psychedelics, or people who are dependent on different drugs, you say, Well, did you would you like to have that taken out? And the people say, no, no, that was one of the most important experiences of my life. So I've seen interviews with people who had been given psilocybin assisted therapy who were at end of life. And they're very powerful experiences where they, they, they get a different view on their life. They want to reconnect with the siblings and friends that they become a strange with. And they just get a whole different perspective on the nature of death and dying and they lose their fear of death. I don't think you can do that with a pill. And I think similarly, when you talk about alcohol use disorder or are not necessarily spoken with alcohol use disorder. When people have been treated with psilocybin assisted therapy for that. They go back and they revisit, like, when did I start drinking? Why did I start drinking? What was my motivation for drinking, and they do a lot of real introspection, get insights into what caused them to start drinking and why they keep drinking and then if they're successful, they stop. And I don't think you can do that with a pill. There's too much cognitive introspection that occurs for like an obsessive compulsive disorder is probably the same way maybe eating disorders sold turns out to be the same way. I think for just major depressive disorder, if you can come up with something that works better than an SSRI and and somehow involves activation of the to a receptor, that's great. But I'm I'm very agnostic in terms of whether you could make something that really would be classified as a psychedelic wouldn't produce any effects. And if you think about it, the serotonin to a receptor is localized on apical dendrites of these cortical pyramidal cells, cortical parameter cells in the cortex. Those are the major computational units in the brain. That's where everything comes together all your subcortical information, your vision, your vision, your imagination, all kinds of things, they converge on those cortical pyramidal cells. If you ever see a picture of one, they have all kinds of inhibitory and excitatory inputs and outputs. That's the major computational unit. And so activation of serotonin to a receptors depolarizes those membranes so they become more easily fired, and increase the gain of those cells. How can you do that to the major computational unit in your brain without having some kind of a central effect, it'd be like taking a computer and somehow overclocking the CPU and expecting it to work the same way as it did before. So I think it's kind of naive to think that it would have just the same effect as a psychedelic, but what would produce that kind of intoxication. Now you might get something activates it to a receptor, which leads to therapeutic improvement, but maybe it maybe it hits some other receptors, and so receptors, that will attenuate whatever the psychedelic effect is, but you'll still get the behavioral effects. So it's a reasonable way to go. But as far as taking the experience away from people who are in hospice and palliative care, or people who have substance use disorders, I think it'd be talking to those people almost to a person, they'll say, No, this is really valuable. It wouldn't have worked for me, I've really got a lot out of you know, I've seen these people talk about, you know, the first woman that was in Charlie grubs study. It was a Hispanic woman. And she tried to get her husband in his study, because he drank a lot. And she, but he wouldn't go and so she was talking to Michael Bogut Schultz, who is the Principal Investigator. And she said, Yeah, my husband will come. He said, Well, do you drink? She said, Yeah, so let's see. He gave her the test. And she she qualified for inclusion into his test. So she was I saw her on camera talking about what happened. She said she realized when she took the psilocybin, and there's no therapy while you're taking the psilocybin, it's all beforehand. And afterwards, she had an airship eyeshades and earphones, she said, I realized what I was doing is I go to work, I come home, I was tired, I'd sit down, my kids who want attention, I'd push them away, and I pour myself a drink. And I would just drink and just ignore the kids. And she realized I was cheating my children, that my presence as their mother, and that she stopped drinking. It was a profound insight she had, she says, Now I come home, I have the kids, I bring him around, I hug him off. We talked about what they did in the daytime and everything. And I don't think you can do that with a pill that just isn't going to happen with with a pill it was it was a cognitive effect of this that really made her realize how much better her life and her parenting could be.
Nick Jikomes 1:03:18
What do you think? You know, people talk about now that the psychedelic renaissance that we're in this new golden age. Do you think there's any risk that or what do you think the biggest risks are that that something interrupts this resurgence in research with these substances?
David Nichols 1:03:40
I think there's enough momentum now that it'd be very tough to stop that. Even if there was some new recreational drug that started flooding the streets. They would focus on that I think the psilocybin has been demonstrated to be effective for depression and anxiety and substance use disorders. MDMA has been shown to be effective. We expect MDMA to be approved probably this year later, for treatment with PTSD. The therapeutic effects of these have now come to the fore. And I think any congressman who tried to who tried to shut down research and access to this, I think he would get a lot of pushback. And many of the states in North Carolina where I live, they had a bill that they put forward to the state legislature to appropriate four or $5 million to set up a couple of trial programs with psilocybin and MDMA and have an oversight board. I mean, so the states themselves and state legislatures are recognized and this may be a therapy that we need.
Nick Jikomes 1:04:41
Are you still working at Brian Roth's slab David?
David Nichols 1:04:44
Yeah, I do. Although I had a heart attack in 2019, and then COVID hit and then I had a brain bleed I felt was take an anticoagulant and I had an subdural hematoma. And so basically after the heart attack, and in February of 29, team, my basically didn't go in the lab anymore fact. In fact, I'm supposed to go in the morning tomorrow to help clean out some of my chemicals. I still dial into his group meetings. And if I can have some input, I will and just kind of see what's going on. But no, my work in the lab is basically stopped. I mostly consult salting, for some companies that have been working with psychedelics, that sometimes chemistry, I
Nick Jikomes 1:05:26
haven't had a chance to look into it. But I saw recently that they had some pretty major results, they announced using alpha fold, do you were you able to see any of that research or follow along with that?
Speaker 1 1:05:39
Yeah, that was really, really interesting. Using using the computational program, to fold the receptor and do docking, they could prospectively identify a number of compounds with activity to five HTT to a receptor. But when they went back, historically, none of those compounds would fit. So I think by using a computational model with this receptor, and with other receptors, I think it's going to really open up some new doors and identifying additional chemo types. For the two a and other receptors, it's really fascinating.
David Nichols 1:06:14
That Alpha food program is really powerful. It's really powerful.
Nick Jikomes 1:06:20
And so, Charles, what kind of questions are you guys working on in the lab to either build on the anti inflammatory results that that I saw you present at the conference, that chart that we looked at? Or that that haven't been published yet? What's what's going on sort of on the cutting edge for you? Oh,
Speaker 1 1:06:36
so we we have been working in collaboration with a colleague, Dr. Ken mix at Loyola University here in New Orleans on identifying additional potential diseases that could benefit from psychedelics. So, we've been looking at a model of rheumatoid arthritis. And seeing some really interesting results there will be presenting that at the our I ESRP. meeting here in New Orleans in a couple of weeks. But that is, we see differential effects of different psychedelics that add multiple outcome measures in this mouse model of rheumatoid arthritis, again, underscoring that one psychedelic is not another psychedelic, in fact, psilocybin in we've been testing chronic, low sub behavioral doses of three different psychedelics, and psilocybin is the worst performing in almost all of the outcome measures, where as the phenethylamine ones are better, which is different than what we see in the asthma model, where the psilocybin or psilocin is just as good as DOI is. So this is, this is some, I think, pretty exciting proof of principle for this really the first demonstration of chronic low dosing in a model that treats active symptoms.
Nick Jikomes 1:08:04
Yeah, I guess this speaks to to the concept of micro dosing, so at least if your inflammatory results are using super small doses, and the fundamental biology here, Charles, like you mentioned earlier, is that these GPCRs act as really good amplifiers, basically. So they often you can get strong biological effects with very little activation some of these receptors. So why is microdosing in general to psychedelics in your views? Do we know or is it likely to be doing something even in the brain and in terms of psychoactive effects at sub sub psychedelic doses?
Speaker 1 1:08:39
I think based on our our data across several different animal models of inflammatory diseases, the amount of drugs necessary to produce a sustained therapeutic effect would be considered a micro dose, whether micro dosing is effective for what people are micro dosing for, like cognitive effects, memory, I don't think that it's really the data's not out there that shows that it's having really any positive cognitive effects. But it could be that say somebody has some neuro inflammation that's affecting depression, that anti inflammatory effects, these very low doses could be could be playing a role, so I don't discount micro dosing. Completely, I think that at least at the potency that we're seeing for the inflammation that those were probably therapeutic levels for some of these drugs, but for cognitive enhancement and memory. I'm not so keen on that. And in fact, LSD, which is one of the more commonly drug use drugs used for micro dosing is one of the poorest anti inflammatories that we found you really have to be at those behavioral levels to see any anti inflammatory effects.
David Nichols 1:09:55
Clinical studies have not shown any effectiveness for micro dosing because they're normal people, and the thing that that Chuck is talking about is an inflammation, it takes less of the drug. And one of the things that we speculated about is that when the tissue is inflamed, the serotonin to a receptors are upregulated and invoke a different signaling pathway so that low doses can address the inflammation. But as far as people microdosing to feel good and feel happy, and whatever, I think it's mostly placebo effect. Most people don't appreciate how powerful the placebo effect really is.
Nick Jikomes 1:10:36
And David, if we go back to like the the early days, you know, you were talking about your time at Esalen and all the people who were there, like when you think back to those days compared to like where we're at now? Like, are you surprised? Are you surprised that we've gotten to where we are right now, when you think back of what you've lived through?
David Nichols 1:10:56
Oh, yeah, yeah, I'm very much surprised. You know, when I proposed to hefter Institute back in, not late in the early 90s. And Shogun, and Sasha were friends of mine and said, Dave, the government will never let you do research on psychedelics, which is why just because when people take them, they see that, you know, the games that the government is playing the data. So I just don't believe that. I think it's just a question of qualified people haven't been in the field, and there hasn't been money to fund it. And you know, and so I got a lot of pushback from people in the beginning. And when we start hefter Institute, I saw a woman a few years ago who her husband, she and her husband were one of the early donors to Hector, they gave 10,000 hours. He was a real estate developer, I think, in San Diego. And I saw her at a reception a few years ago. And I says, Do you remember way back when and you guys gave me $10,000? And she said, Oh, yeah. Oh, yeah. I said, Do you remember what your husband said? And she looked at me, you're funny. He's, he said, nobody can ever know where this money came from. And she started laughing. She's it's not something. It's changed so much. I mean, I was, you know, I, you know, I never thought this would happen. Not Not, not in my lifetime. Some woman asked me some years ago, she says, What do you see as the future for all this? And I said, Well, someday, probably long after I'm dead, you'll be having a midlife crisis. And you'll go in and you'll see your doctor and he'll send you down to a shaman slash psychiatrist at the corner, who will give you a session with us with a psychedelic and give you a new perspective on your life. And she says, Oh, my God, do you think you'll be dead by then? I said, probably. But if the vector is pointing in the right direction, that'll be okay. But you know, I never imagined it just it just took off. It's just, there's so much interest. And I started the I started saving. I save reprints. I send chocolate aiic A rape and I said to him, I started saving reprints on my computer, and I can't keep up anymore. I have 4000 reprints on psychedelics in my computer now. And there's a dozen I haven't even logged in yet.
Nick Jikomes 1:13:00
I talked to I talked to Dennis McKenna, a few months ago on the podcast, when you were at Esalen in the 80s. And around that time period, did you ever meet Terence McKenna?
David Nichols 1:13:12
I met him once. And I was actually at someone's house. Prior to taking off we were going to go to S and Terrence came in and he was early. I was early. I was staying with someone. So I was there. He came and sat down. And I looked at him I said, you know Terence? The thing that's puzzling to me is, you know, he had the theory that the mushrooms were sort of an alien intelligence that came down and I think the thing that's that's really strange to me is that these alien mushroom intelligences have come down and made their own shit. Because he broke out laughing. He broke out laughing. And then in the big room, and in esslyn, he rolled a bunch of joints and there were four of us or five of us sitting in a circle. And he was there at the head. He was rolling his joints up and God knows what he put in. I think he'd grown powdered some hashish and put into so he was passing around and people were just taking a token. I was sitting on his left one, I guess I guess I was next to him on that note, we went around the other side. I took one toke and what are he was smoking was really dynamite. And so he passed it around a second time. And it came to me and I said I'm going to pass he looked at me really funny. And then it passed around again and everybody and said that's enough. That's enough. He says, Well, I had a bunch of babies. And you know the way parents talked and he had rolled four joints he proceeded to smoke the other three and you know nobody I mean his his ability to smoke dope was legendary.
Nick Jikomes 1:14:56
So what do you guys think is have you followed at all the. So there's, there's current, there's a lot of interesting work being done right now and a little bit of controversy and debate over how exactly this piece of the puzzle works. And that's the relationship between classic psychedelics and some of the other drugs that are adjacent to them, and neuroplasticity. So a lot of people talk about to a receptor agonist being able to promote hyper plasticity, then you've got sort of Gould, Dolan, and and people over there talking about meta plasticity, and they're not really promoting hyper plasticity, they're changing how easily plasticity can be induced by things like experience. Have you guys been following, like that area of the field at all? And what do you make about the idea that psychedelics are promoting hyper plasticity in the brain?
Speaker 1 1:15:49
Yeah, I, we, we found that over 10 years ago in our lab, with LSD in the rat, brain and fly brains, and so there is a lot of plasticity that is induced, I think, was Brian Roth all the way back to 1009. Has Has that paper. So it's been known for a long time that psychedelics do induce plasticity, but so do a lot of other things like methamphetamine and cocaine. So one of the things that we've been looking at in my lab is the potential functional plasticity rather than structural plasticity. And that's among unpublished data that we have that 100 days in a rat model, after we, after we give a single injection of psilocybin, we see these profound changes in the in the functional plasticity of the medial prefrontal cortex, we see a a Hypo polarization of the mean resting potential, we see significantly increased firing rates, so the the neurons in the mpfc, and our models are firing more, they're more easily fired. And this is three some months after a single dose. So we went in with this with the hypothesis. Well, it let's investigate, if it is structural plasticity, we would expect to see genes for synapses to be increased PST, 95 SP to a synapse. And and when we looked in several areas of the hippocampus and the medial prefrontal cortex, we just didn't see any evidence of that. So my current theory is that there is this increase in structural plasticity that other groups and we have seen. It's induced by ketamine induced by psilocybin. But the difference is, we think that it croons back to a baseline level after a few weeks. Whereas in the case of ketamine, the behavior reverts back to the depressive like behavior. But for psilocybin and other psychedelics, there's an epigenetic change, which is occurring to upregulate potete are certain ion channels to make them more conductive. So you're pruning back to the same number of synapses, but the ones that are left are more efficient. So what we're doing now is we are looking at different channel subunits at these time points, looking for epigenetic factors, to see if maybe there is this sort of window of hyper plasticity that then prunes back down to more functional plasticity.
Nick Jikomes 1:18:25
And to help people understand what you're talking about here. Can you just define explicitly what's the difference between structural and functional plasticity.
Speaker 1 1:18:32
So structural would be like the number of dendritic spines a lot of people have been giving LSD to neurons in a dish, or other psychedelics and just counting how many connections are between the axon and the dendrite, and there's a certain density. So what we've seen is that there's a nice robust of 15 to 20% increase in the actual physical number of connections between neurons and specific circuits, both in a petri dish and in the real living brain. Those effects, there have been a couple people who have looked sort of long term and a couple of different models. But the persistence of those, if you think about it, it takes a lot of energy to maintain 20% more connections in your brain, and you want to go back to homeostasis. So it makes a little bit more sense to me that you might want to make those new connections in this critical window of plasticity, but then prune things back in the case of psychedelics, to where now you've strengthened the relevant the relevant connections with ion channels that are more conductance. So you're you're making those those connections that are they're more efficient. Yeah. And so you're you're you're maintaining the As antidepressant like state over the long term, whereas for something like ketamine, it doesn't maybe that doesn't happen. I
Nick Jikomes 1:20:08
see. Yeah, I mean, roughly speaking, it kind of sounds like Gould Dolan's idea, which is that some of these psychedelics are inducing states of meta plasticity. And it's akin to reopening, you know, the critical periods that that happen, normally naturally across development, where you've got these windows where things are heightened, and you actually make more synapses than you need. But then there's this sort of pruning process to get rid of the extraneous ones.
Speaker 1 1:20:30
Right at a rough level, I think we are in an agreement at that, that I think there's this sort of maybe two to four week period where there are more synapses. And we have shown some of our early work that we published, I think, four years ago, that the environment that we put a rat in the first week after we gilts give it psilocybin really profoundly shapes. What that antidepressant anxiolytic effect is five weeks later, that if we take a rat, we give it psilocybin, and we expose it to a stressor within that first week that we believe it develops better coping skills. So when we tested in an elevated plus maze, for example, for anti anxiety effects, there's a profound anxiolytic effect of a psychedelic when it's stressed, and then rescued from that stress, it just learns to think better. It learns better coping skills, and if it just rests and doesn't try to escape, then it will get rescued. Whereas if we don't give it that stressor over the first week, if we wait to the second week of the third week, we don't have any anxiolytic effect that we can detect from from that psychedelic five weeks. So there is something about the immediate week or so afterwards that tunes the brain to allow it to somehow I think, mature to a more healthy state.
Nick Jikomes 1:21:58
And what were you saying there about differences between psilocybin and ketamine?
Speaker 1 1:22:02
So ketamine, when we do them in a side by side comparison, both are believed to induce the plasticity through convergent mechanism through mTOR, and BDNF. But the effects of ketamine in humans and an animal models were off after about two weeks. And we have seen that other people have seen it in human therapy, you have to go back for repeat repeat treatments for ketamine, they don't last for four years, as in the case of some studies with psilocybin have shown. So there's a fundamental difference in something beyond just this convergent glutamatergic mechanism inducing BDNF and plasticity where psychedelics have the capacity to maintain whatever that therapeutic effect is. Whereas for ketamine, you're back to a baseline depressed state within a week or two. And so that's some of what we're trying to do in the lab. Now, let's look at these longer later time points and identify what those changes are.
Nick Jikomes 1:23:02
I see that Yeah, I've heard I've heard that before. That ketamine is antidepressant like effects are not as robust and don't last as long as as things like psilocybin. So is that a pretty reproducible finding?
Speaker 1 1:23:17
Right, yes, several laboratories have have shown that ketamine wears off
Nick Jikomes 1:23:22
here, isn't it? Like I've seen I live in Seattle, but I've seen these in a number of cities, but I see these ketamine clinics all over the place. Now. What I mean, are you guys seeing that too? Is there any? Do you have any concern about how common those types of clinics are becoming?
Speaker 1 1:23:40
It is, it is concerning because it's really off label use for a lot of ketamine. It's just somebody who has a strip mall clinic come in, give them their injections. And I think one of the one of the reasons for that was that there was really kind of no medical billing code and insurance reimbursement. But the I think they just, they had a medical billing code a few months ago that was released. And insurance is now starting to reimburse more, and that's gonna, I think, have more qualified physicians who have been through that training to us. The only FDA approved use of of ketamine now is spravato which is the the nasal spray for for depression. Everything else is really experimental or off labor, and it's really unregulated.
Nick Jikomes 1:24:37
What do you guys think are some of the what are some of the most exciting things that you think we're going to learn answers to about psychedelics, their mechanism, mechanism of action, especially in terms of how they work in the brain? What do you think we're going to learn in the next you know, one to three years that we don't know today?
Speaker 1 1:24:59
I hope to figure out how they're anti inflammatory. I've been working on that for almost 15 years.
David Nichols 1:25:07
Yeah, the, the insights we're going to get, I mean, in India, not just in depression, but in substance use disorders and anxiety. And both these, they're going to be powerful tools as we understand how they can be used to be powerful therapeutics, but they're going to give insight whenever you get a new, like chlorpromazine, when it was first introduced in 1952. Nobody knew how it work. And then later on, they find out oh, what blocks dopamine D two receptors. So that led to this whole, you know, the whole field of you know, rip, you know, knock off anti psychotics, I think once we understand what's actually going on to leave the depression, or whatever it is, it's going to give us insight into new cures New Directions for cures. Just a better understanding of the brain, which we have a really primitive understanding of the brain as it is, even though we think we know a lot, it's, it's really a huge, huge, you know, bio computer that we don't understand very well. And so these are going to be tools, that the stuff they're doing, looking at functional connectivity, and the stuff that Robin card, Harris was doing an Imperial College while looking at brain dynamics. These are things nobody was really looking at very much before. So we're going to get a lot of insight into how the brain works and how it, how it fails and how you can restore it. So it's it's hard to say any specific thing, but just a general increase in our awareness and knowledge about how the brain works and new therapies and other therapies. Psychedelics can lead to these therapeutic improvements. I think that's just it's a whole big field.
Nick Jikomes 1:26:44
And then, you know, I think you mentioned earlier briefly that, I think this year, we're expecting to hear from the FDA about, you know, about the MDMA assisted psychotherapy that Rick Doblin has done through maps, is that sort of the next big milestone in terms of the next big thing that might happen that really pushes us to the next level with some of these therapies? And are there any other Is there anything even close to the MDMA assisted psychotherapy in terms of in terms of becoming an FDA recognized therapy?
David Nichols 1:27:17
I think psilocybin for treatment resistant depression will probably follow in 2025. Compass has done big clinical trials, they've got Breakthrough Therapy approval from the FDA. The you know, the problem with all of these is scalability and cost of MDMA for PTSD. It's usually two to three sessions. And even if they're six hour sessions, and if you've got people there, the cost of the room, the cost of the sitter's the medication is not even it's not significant in the cost. Same thing for psilocybin, you know, psilocybin session, produced at scale probably would cost you $100 For the psilocybin or maybe even $50 for the psilocybin, but having two competent professionals there to clinical rental for the day. I mean, Steve Ross told me when they were doing their first studies with psilocybin in cancer patients, I said, What do you think the cost has been per patient? And he said, Yeah, we've estimates 25,000 hours a patient. Insurance companies are not going to be going for 25,000 hours of patient unless you can demonstrate like this person has been, it's costing us 10,000 hours a year for drugs, but we give them psilocybin therapy, they're cured, and we don't have to do it forever. So it's, there's going to have to be some some some kind of figuring to see how these things can be scaled and be economical, and have her insurance reimbursement because normal people can't afford to go in and get somebody 10,000 or 15,000 hours and say, you know, I'm so depressed and nothing's working. So I think the scalability is a big cue, but I think psilocybin is not far behind. The MDMA trials started before psilocybin trials started. And certain compasses done big trials, phase three trials. So I think that's going to be next on the next on the watch list. And of course, once you get approval for psilocybin for depression, or treat resistant depression, you saw and it's also got a Vega, they're also moving toward that, once you get approval for one, doctors can use it off label. So with all these smaller studies, once it's demonstrated to be safe, like for alcohol use disorders, smoking use disorder, end of life, OCD agents, if all these met turnout, they'll be able to train people will be able to use them once there's a demonstrated therapeutic signal. So we see that for depression, and end of life existential distress. So I think once psilocybin is approved, you'll see a lot of these other indications. And so maybe somebody who's in hospice, you don't have to pay for the clinical ruin. You just have to have a set are there during the day when they do the trip. So it might be feasible for those kinds of things pretty quickly. I don't I don't see PT MDMA as being useful for very much. I know people have looked at MDMA for end of life distress and MDA for alcoholism. But I haven't seen any signals that is really going to work for that. But for PTSD seems to work. Great. So scalability, that's the thing everybody's looking at how do we get insurance company reimbursement? Yeah.
Nick Jikomes 1:30:33
So I don't want to take too much more you guys time. You know, I'll just ask you a couple of final questions here. But, you know, Charles, like, what do you look looking forward to for the rest of your career and flight? You know, can you give us the broad strokes of like, what's it been like to go from the kid going into dad's lab to becoming a psychedelic scientist yourself. And then just like, sort of getting to this point, where were each of you are at,
Speaker 1 1:30:58
it's, it's been really surreal for me. When I started my lab up, one, two years ago, there were maybe half a dozen people in the world who studied psychedelics. And as he said, I used to do literature searches, and I'd pull up maybe two or three, every couple of weeks would pop up with serotonin to a or something, and now I get 40 to 60 a week, from people, I just can't keep up with it anymore. So it's, it's been tremendous to see it grow so much as it has in the interests and in the legitimacy of the field that I don't have to really, I don't get strange looks when I tell people I study psychedelics anymore. When I can tell people I'm out of the closet, I study psychedelics. But what I'm what I'm really looking forward to is now on both fronts with the anti inflammatory and antidepressant, you know, just what are the mechanisms out solving those? Because they're completely new, completely novel? How are they anti inflammatory? How are they antidepressant and gaining gaining really exciting biological insight that can someday be translated to clinical use and therapies to help people and just better the world? That's, that's what I'm looking forward to a better world.
Nick Jikomes 1:32:30
Yeah, and David, I think most parents when they tell their children not to get involved in drugs, and they find out that they've defied, defied them, they get very upset. But I wonder if you've had a different experience?
David Nichols 1:32:44
Yeah, well, no, I'm sure I've sent my father because he never knew what I was doing for my PhD. You know, really, it was more the wisdom I'd had, I'd realized so many people had been interested in this field, and it not succeeded, because there wasn't any grant money. Yeah. And for Chuck to be in this field, you know, he raised 71 of his early grants, it was a study that mechanism I think of LSD and ISIS, nobody gives a shit about the mechanism of LSD. I said, if you want to use LSD as a tool to study something else, then you could probably do that. But I said, you know, it's going to be the kiss of death for as far as getting funding. So he again, was very lucky. And just as an example of the St. Inflammatory stuff, after Katrina wiped out his lab in New Orleans, he contacted me because a lot of those samples that he had showed for anti inflammatory activity were samples that he got from me, because I had cabbage, a bunch of them when I retired. And he said, Is there anything that's scheduled that's not scheduled one that's up IBC, two agonist. And there was only one it was DOI was already why. And I've worked out a patented method for making RNs DOI when I was a graduate student, and I had a bottle of it, I sent it to him. So the whole anti inflammatory stuff if he'd said, if he'd said, Dad, you know, are there any psychedelics that are not controlled substances? Because he was waiting on his license? And if I said, No, there aren't any. I mean, his career might have taken a different tack altogether. So there's been a lot of luck involved. And I'm pleasantly surprised he has been able to keep this field going. I joked to people that we were starting to nickel serotonin dynasty. But, you know, really, and really, it was quite propitious that he got his background in genetics. And I was a chemist and I, and then I did a postdoc in pharmacology, so I knew a lot of chemistry and I could make things and I could put them in animals and behave and observe them. But his going into a field that allowed him to have a genetics, has an expertise has really facilitate his ability to do things now because that's exactly what's required to understand what's going on, going in and being able to, you know, do a genomic analysis and proteomic analysis and all of these things that are techniques that genetics, people know that he knows, has given him a unique capacity that I don't have So, you know, in a sense, I'm almost jealous of his success, if you will, because I wish I could do some of the things that he can do. But, you know, he's doing them at least. And, you know, when I retired in 2012, and moved down here, I build a woodshop down in my basement, my house, I was going to make Native American wooden, Native American flutes, because I play this as a hobby. It's this in Ghana, mostly with dust and everything, because when all this started cooking up, people started wanting me to give zoom lectures and go and give talks on psychedelics as if he wanted somebody to give a talk on psychedelics, there was only like one or two people in the United States that you could get to do it. And I was one of them. And so I was always glad to do it. So yeah, it's, it's, it's amazing. And the fact that I counseled him not to do it, and he didn't take my advice was a really good thing. I think he was always kind of stubborn.
Nick Jikomes 1:35:52
I think that's a great place to end it. And I know it's a little bit later for you guys. So thanks again for taking the time. I really appreciate it. This was this was a fun format to with both of you on at the same time. So I appreciate you guys throwing that out there. David and Charles Nichols. Thank you guys.
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