• njikomes

Ep #4 Transcript | Bryan Roth: Drugs, Receptors, Zen Meditation & Psychedelics

Updated: Sep 6, 2021

Full episode transcript below. Beware of typos!



Nick Jikomes 0:40

Welcome to the good chemistry podcast. I'm your host, Nick Jikomes. And today I'm speaking with Dr. Brian Roth. Brian is a distinguished professor of pharmacology at the University of North Carolina Chapel Hill School of Medicine, and an elected member of the National Academy of Medicine, and the American Academy of Arts and Sciences. Brian has been running his lab and doing cutting edge research for around 30 years now. And his papers have been cited 10s of 1000s of times, he has been studying the molecular mechanisms of how drugs affect the brain for most of his career. And he's also an avid practitioner of Zen meditation, which he's been doing daily. For many years now. Brian and I discussed a range of topics related to his scientific work, including receptors in the brain and how they work, how psychedelics and other drugs interact with those receptors. We talked about the massive research project that his lab is leading around the study of psychedelics and the development of new drugs to treat psychiatric disease. And Brian also talked about his Zen meditation practice and the types of awareness that that practice can reveal. If you find the content in this episode, interesting or helpful, please do consider liking, sharing, subscribing, downloading all that stuff. I really do appreciate it. And with that, here's my conversation with Dr. Brian Roth.


Professor Brian Roth, thanks for joining me. Greetings. How are you today? I'm good. And where? Where are you? Actually? Where do you? Where's home base for you?


Bryan Roth 2:34

So I'm in at the University of North Carolina, Chapel Hill School of Medicine in the department of pharmacology.


Nick Jikomes 2:43

Interesting, and what would you say your overarching research interest is for your lab.


Bryan Roth 2:50

So, I would say ultimately, we want to understand how psychoactive drugs work at the most fundamental level, and then use that information to design safer and more effective medications, mainly for psychiatric indications. Since my my background is I'm I'm a psychiatrist, among other things.


Nick Jikomes 3:15

Gotcha. So you're actually a psychiatrist, you're an MD and you're also a PhD. Right? Yeah. My PhD in biochemistry. Okay, and do you do any clinical work? Or is it all a lab research focus?


Bryan Roth 3:28

No, I don't. I don't see patients anymore. I did for many, many years, but I haven't for probably 15 years now. Okay, how


Nick Jikomes 3:39

long have you been running your lab?


Bryan Roth 3:43

Since 1991. So that would be almost 30 years, right? Oh, wow. Nine years? Yeah. A few years? A few years? Yeah.


Nick Jikomes 3:54

And you're kind of known as the gpcr. Guy. So I thought maybe we would start with an overview of some basic biology to maybe give people some foundational knowledge that will probably inform the rest of the discussion. So can you just talk a little bit about what what are receptors? Very high level and what do they do for cells? So I think everybody knows what drugs are, right? Yeah, let's assume they


Bryan Roth 4:22

do. Okay, so drugs are typically not always they're typically small, relatively small chemical compounds. For those people that have a scientific background, typically, these are compounds that have molecular weights less than 3000 or I'm sorry, less than 350 Dalton's so these are, these are relatively small compounds. And when you when you take a drug, let's take no system I guess since we're going to talk about psychedelics, let's take LSD as an example. Okay? So when people take LSD, so this is a drug, it's a small compound, to mediate its effects in, in the body, it has to first interact with a protein that's called a receptor. And receptors are proteins that are on that are in cells, the proteins that the cells that we're going to talk about, are cells in the brain that are important for all brain activities. These are called neurons. And receptors are just basically proteins that sit on the surface of the cell, they have openings in them for drugs to come in drugs and neurotransmitters. And when the, when a drug like LSD, or when the natural neurotransmitter, which would be serotonin, gets in, finds its way inside the receptor, there's typically a sort of a pocket in in the protein, it it stabilizes a particular state of the receptor, which is active. And then once this active state has been achieved, then the receptor and the drug complex then turn on a bunch of biochemical reactions inside the cell. And G protein coupled receptors are just one sort of class of receptors that are in the body, their largest class of receptors that are encoded by the human genome, there are about 108, between eight and 900 of them. They're responsible from everything from vision, your sense of smell, your sense of taste, virtually all of your brain functions are mediated in part by interaction with neurotransmitters with G protein coupled receptors, sensations of pain, and pleasure. And so on. So these are, these are really, really important family of proteins in the body.


Nick Jikomes 7:35

So this gpcrs, there are a certain type of receptor, right? And they do lots of stuff. Are they come in many forms? And are they all throughout the brain? Are they in certain cells? Or are they everywhere,


Bryan Roth 7:48

every cell in the body goes, we'll just call them gpcrs. They're technically G protein coupled receptors. But every cell in the body counts them. And every cell in the body expresses, you know, typically 100 or so of them. So they're, they're everywhere. And they're important for every literally, literally every everything that goes on in your body is, is regulated in to some degree or another by gpcr. So they're, they're really, really important. And are these receptors? Are they something that medications that a doctor would prescribe are often interacting with? Yeah, about about 30%, or a third of prescribed medications have their main action by interacting with gpcrs. This includes most psychiatric medications. And then a large percentage of medications of other medic, the other two thirds interact with gpcrs sort of secondarily. So side effects of medications may be may be mediated by sort of chance interaction with gpcr. So the gpcrs may not be the main target for the drug, but the drug interacts with gpcrs. And that, that can be important for serious side effects. Wow. So, so they're really important.


Nick Jikomes 9:36

Yeah. So every single cell in the entire body has some kind of gpcr. Probably many kinds come in many different flavors. So if we stick with the brain, we're talking about neurons, brain cells inside of our heads. There are all kinds of receptors that respond to many different neurotransmitters, things like serotonin and other things. We're probably going to end up talking About serotonin a lot. So what is the psychedelic receptor or the one that's commonly associated with the effects of psychedelics?


Bryan Roth 10:08

Yeah, so that's, that's a receptor near and dear to my heart that I've been studying since 1983. Okay, so probably I've been studying it for more years than many of the people that will be listening to this have been alive. So it's, it's a receptor called the five htt to a, we can just call it the to a receptor. And that's, you know, there's the best evidence is that psychedelic drugs exert their, their psychedelic effects through activating that particular receptor, I think that's fairly well established. And probably, you know, the vast majority of experts would agree that the two way receptor is the target of psychedelic drugs.


Nick Jikomes 11:04

So the classical psychedelics, as I understand it, are pretty much defined by their ability to bind to this receptor. So something like LSD, something like psilocybin, something like that act is to activate it, something like DMT as well. And yet they can have very different effects. Some of them last for many hours. So from last year, just a few minutes, if this is the quote, unquote, psychedelic receptor, what's accounting for the differences in the effects of different psychedelic drugs?


Bryan Roth 11:32

Yeah, so that's, I would say that's something that's really unclear. So let's just take LSD and psilocybin as two examples. So psilocybin is the drug psilocybin is actually inactive. And in your body, so when people take psilocybin it's it's metabolically transformed into a compound called psilocin. So psilocybin itself is inactive. It has to be metabolically transformed to silos. And technically, what happens is there's a phosphate group that's removed, it becomes a free hydroxyl. And then it's then it's able to interact with with really many serotonin receptors. And it turns out that the drugs like LSD, DMT site silos, and I'll call it psilocybin, but just for the science nerds that that may be listening to this when I say psilocybin, just just bear with me and, and, and repeat to yourself silo son.


Nick Jikomes 12:41

Alright, and this is this is the act of compound and magic mushrooms,


Bryan Roth 12:44

this is the act of compound of magic mushrooms, right. So, you know, what we have found over the years is, is these compounds actually interact with dozens of different receptors. And so they have this very complex pharmacology. But when you you know, there are now really well controlled human trials, where humans have been given drugs, the drug, they, they're typically given as a drug called cancer, and which is it's not entirely specific for the five for the two I receptor, but it's reasonably selected for the to a receptor. So when humans are given that, that drug, and it basically blocks the activity of that drug, and then when they're given, you know, a hefty dose of LSD or psilocybin, they don't have a psychedelic experience at all. So that's, that's probably the most compelling evidence we have that the effects are immediate, the psychedelic effects are mediated by by the fight to a receptor. We don't have data like that for a drug like DMT. And I suspect, at some time in the future, somebody will, you know, do a clinical study and determine if the, you know, if the psychedelic effects of DMT also are blocked by a to a antagonists?


Nick Jikomes 14:22

Would your intuition there be that maybe they're partially blocked, but not completely.


Bryan Roth 14:26

So I don't know. We know that in mice for what it's worth. You can block the effects of DMT by blocking the to a receptor. We can block many of many of the behavioral effects you know the the effects that we can measure in a mouse. Many of them are blocked by two a antagonists for you know, all of the psychedelics, but not all. So there are, there are sort of classical mouse behavior. markers of psychedelic drug action that and technically These are things like the head twitch response, nose poking retrograde walking disruption or pre pulse inhibition, they're, you know, a few of these mouse behaviors that are completely blocked when a when mice are given highly highly selective five htt to a antagonists, irrespective of what the psychedelic drug is. So you can it could be LSD, psilocybin, mescaline, DMT, five, methoxy, DMT, 25, cyano, nvao, you know, the N bows?


Nick Jikomes 15:48

What are those, I don't know what the N bows are,


Bryan Roth 15:50

those are designer psychedelics, they're apparently fairly popular in Europe, no, ever, ever made it on the market here on the black market here. So So we have, you know, really, really strong data in in rodents. And for all all psychedelic drugs, and then in humans, we have strong data for two. And we just don't have any data for the rest of them. Now, the other thing that's, that is sort of that distinguishes drugs like LSD, psilocybin and DMT. Those are sort of three drugs that, that in humans, the, you know, if you, if you go to arrowood, or read data from human studies where these drugs have been given the effects, the effects are quite different. And we don't know if that's because of the other receptors that these drugs hit. Or if it's because of something that's called pharmacokinetics. So a drug like LSD, actually takes a long time to interact with the receptor. Once it gets on the receptor, it's on there for a long period of time. Drug like silo, psilocybin is sort of intermediate. And drug like DMT is very rapid, it gets on the receptor very quickly, falls off the receptor fast, and it's removed from the body very quickly. And typically, when people take DMT, they're given very large doses. And one can imagine that the receptors are fully off basically fully occupied nearly instantaneously by DMT. Whereas where that's, that's never going to happen with a drug like LSD, LSD takes a lot actually a long time to get on the receptor. And silos in this sort of intermediate. So it could in part be due to what we call pharmacokinetic things or just could be that drug like DMT, which is sort of a real outlier is, you know, has other pharmacology that's important for its action. And as I said, these drugs interact with dozens of receptors. So it's it, you know, it's conceivable that, that that's something else is going on, it's also possible that they interact with the receptor differently. So but we, we basically need definitive data, we just don't have it. Oh,


Nick Jikomes 18:40

gotcha. So some of these drugs are literally getting on to the receptor very slowly, in the case of LSD, and airy, and it takes a long time. So they might get on some receptors, but not all of them, and then they get on some more later. And then by then, maybe some of its washed out or something or something like DMT it's sort of all hops on all of the receptors that can and then gets right off.


Bryan Roth 19:02

Yeah, and it's removed, but it's removed very quickly from the body as well. So it has it doesn't, it basically is degraded very quickly.


Nick Jikomes 19:13

And is that because it's very similar in structure to a natural neurotransmitter like serotonin.


Bryan Roth 19:19

Yeah. So it's, it's broken down by an enzyme called moto Amy oxidase. And that's everywhere in the body, it's very high in the liver and in the brain. And, and, and basically DMT is, is is gone and, you know, five minutes basically. So, but who knows, you know, that's why science This is why science is fun. Because you can sort of go and go, you know, design these experiments and then see what happens. So it'll be interesting. Somebody will do the actual experiment is sometime in the future and then we'll know.


Nick Jikomes 20:04

So how you probably have quite a large lab, what are the major projects are the major questions with respect to psychedelics that your lab is pursuing right now?


Bryan Roth 20:15

So we have, we have basically two main questions that we're studying the first is so so just to let your listeners know, I actually have the only grant to study LSD.


So there's, there's one person who has an NIH grant to study LSD, and I'm the only one


Nick Jikomes 20:45

in the US or in the world,


Bryan Roth 20:46

in the US. So the NIH, the National Institute of Health only funds, there's, there's literally only one grant to study LSD. And I have it. And I think there's only one other grant to study psychedelics, basically. And that's, that's by Adam Halberstam. And, you know, for for the last several decades, there have been very few labs that have studied psychedelic, so my lab has studied it, you know, for many years, but but mainly on the side because I never had funding to study psychedelic this only in the last three or four years that I was able to finally get a grant. And because of this, we we actually don't know much about how psychedelics mediate their actions in the brain. And so, a good chunk of our work is basically trying to understand, initially at the most fundamental level, how psychedelic drugs mediate their actions. And the idea is that once we can, since since literally nothing is known about them, I mean, literally. And the idea that that I've had is that once we can understand their actions at at the most fundamental level, which is at the atomic and the molecular level, then we can use this as a toehold to basically go out at at more sort of coarse grained levels of understanding. So the single synapse, the neuron, and then the brain. And the inspiration for this, this sort of very reductionistic and sort of molecular approach to psychedelic drug action is inspired. You know, I was inspired when I was a student by, you know, Watson reading about Watson and Crick, where they, you know, basically solved the structure of DNA. And when they, when they saw the structure, then this basically opened up a universe of knowledge. And, you know, basically everything that we know about, about DNA, RNA, you know, molecular biology, springs, initially from the discovery of the structure of DNA. So the maternal vaccine, that and the Pfizer vaccine that everybody is going to go into take, probably soon. was, you know, is, is a nucleic acid based vaccine, it's an mRNA vaccine. And the, basically, you can, you can draw a timeline between the development of that the vaccine and the discovery of the structure of LSD. Okay, is that is that clear at all? That's the idea. If if we can understand initially, at the most fundamental level, how these drugs mediate their actions, then that will ultimately allow us to deconstruct or reconstruct the entire activity of the drugs all the way up to the level of the human.


Nick Jikomes 24:24

Okay, yeah, that makes sense. If you understand the chemistry and the biochemistry at a basic level, you understand exactly how each of these drugs are sitting in receptors, how they're doing that differently in different spots, that sort of unlocks the door to all of the other big questions that one might ask.


Bryan Roth 24:39

Right? Right. So I call this the holy grail of psychedelic drug action. Okay, that's, that's the first that is the, we have to understand that first step. So I would say the last nearly 30 years have been devoted of my work in my lab have been devoted on and off to the to ultimately understanding that first step, we finally understand it. So a good chunk of my lab is, is, is devoted to that. And, and then we're also, we have, we're sort of heavily invested in using that information to create new medications. So we're basically jumping from the most fundamental insights directly into medication development. So the idea is, now we know how psychedelic drugs interact with the receptor code, and we use that information to design drugs that maybe are better than drugs like psilocybin for treating depression, anxiety, you know, and so on. Without perhaps without the psychedelic effects, we'll see. Yeah, we're not I don't know. But we have we're have, we're actually heavily invested in testing, I would say, testing that hypothesis.


Nick Jikomes 26:06

So the the idea that a lot of people have right now is, for a drug like psilocybin. You know, it's showing promise for treating certain things like depression, say, or end of life anxiety. But of course, you're going to trip on it. So you're going to administer this to a patient or they have administered this to patients under supervision, it's going to take a number of hours for you to have this experience. And that's obviously very time consuming. And it would be nice in theory, if you could design a drug similar to psilocybin or something that had the therapeutic benefits that that clinicians want, but doesn't require a six hour hallucinatory experience. So you're trying to design drugs that do one thing without the other things? How likely do you think that is, some people think that we definitely will be able to dissociate those two things, that I know that other people think that the classical psychedelic effects might actually be an integral part of the therapeutic benefits? Do you have a perspective on how likely it is that we can dissociate those things? I have no opinion. Gotcha. So it could be anything


Bryan Roth 27:10

completely agnostic. Yeah. But we, you know, thanks to the DARPA, which is the Defense Advanced Research Projects Agency. They've given us a hefty, hefty award to basically test that hypothesis. So it's a hypothesis. And, you know, we have some, you know, unpublished data that suggests that, you know, which is, I would say, suggestive, that hypothesis could be true. But, you know, ultimately, it's going to, it's, we're never going to know until we get the right compounds and get them into humans. And we'll know right away, basically, right? Yeah, yeah. And the very first clinical studies will know if the drugs are psychedelic or not. And


Nick Jikomes 28:02

yeah, one advantage to humans, I guess, over mice is you can ask them, they'll tell you right away, yes. Now,


Bryan Roth 28:11

I just want to, so I just want to talk a little bit about about silicides. And, in its, its potential for treating depression and other things. And I don't know if this is what you want me to talk about. But I just want to just want to say a few things to listeners here about this. So as mentioned, I, I spent many, many years as a psychiatrist and actually helped design and execute clinical trials for for many years, when I was at Case Western Reserve Reserve University, and I've, you know, consulted with pharmaceutical companies, and started companies and so on. So I, I have a lot of experience in this space. And when I saw the initial phase two clinical data with psilocybin, I was my mind was completely blown, because the effect size was so huge, and describe the effect for us, what exactly did they find? So they found that after a single dose of psilocybin there was a huge, hugely beneficial effect on depression. And these are these were in in patients that were quote unquote, treatment resistant. These were people with severe depression, for which standard treatments didn't work, initially, they were people with cancer, who are facing end of life issues. And had, you know, anxieties related to this. And remarkably, after basically a single dose Now, now, they actually gave fairly large doses to these to these individuals under very carefully controlled conditions. There was this really dirty Matic dramatically beneficial effect on depression and anxiety which was maintained. And and the longest follow up now is six months. And a significant chunk of the patients are still symptom free after a single dose. So this, this is truly remarkable. So, and I was asked to write a little commentary on, on that on on at least one of those on two of those studies, which I did. So. So it's pretty amazing now. And of course, there are anecdotal reports as well. But based on based on this really dramatic response, the FDA, the US Food and Drug Administration has granted breakthrough status to psilocybin for at least two different indications. So this is, this is pretty amazing. And they're both in what are called phase three clinical trials, these, these are what are called the registration trials. So these are the studies that have to be done with large numbers of patients to demonstrate the drug is safe and effective before it would be approved for use by the FDA. And I anticipate that the you know, my prediction is that it will again show a show big effect. So that's all that's the positive Now, what's the what's the negative? Well, when you drill down into the, into the clinical trial design, which I have done, one of the things that was pretty surprising to me is that when they recruited patients for the study, 90% of them were actually ultimately disqualified from entering the study. And they were disqualified for many, many reasons. One of which was inability to form a therapeutic psychotherapeutic interaction with a therapist. Okay.


Nick Jikomes 32:02

Meaning they attempted to do therapy, and that just wasn't working out.


Bryan Roth 32:06

Well, you know, it's not it's not entirely clear what the criteria were. But, but that's, that's within the that's was in the, in the papers. The other is if there's a history of family history of serious mental illness. So if you have a family history of schizophrenia, so I have a family history of schizophrenia, you're not eligible to take the medication? Because there's a concern that in susceptible individuals psychedelics could induce or exacerbate underlying psychotic conditions?


Nick Jikomes 32:42

And is that is that a fear? Where we just want to be conservative in the in case that is true? Or is there actually clear evidence that you can have a triggering of a psychotic episode from psychedelics, there are no control trials? I see.


Bryan Roth 32:56

So we don't know. The, the other thing was that they excluded individuals that were suicidal. They also excluded individuals that had more than three prior psychedelic experiences, which I thought was interesting. That actually may exclude a lot of potential people that would be enthusiastic about,


Nick Jikomes 33:25

about taking psilocybin. I mean, that one's sort of understandable to me, because you might think, well, if it's people who are enthusiasts, you know, that's just that's another variable, these people might be more likely to report and display effects above and beyond what's actually going on.


Bryan Roth 33:42

At any rate, 90% were excluded.


Nick Jikomes 33:45

So it's a question of generalizability Is that what you're out


Bryan Roth 33:48

and, and if you look at other recently approved, sort of transformative treatments for depression, so there are two of these one is ketamine and the other is brexanolone. So ketamine is approved for treat for for treatment of depression, typically used for people that are suicidal. And, you know, has has sort of a rapid, very rapid antidepressant effect, but it wanes, usually in a couple of weeks. And if you go back to the clinical trial data, about 75% of the patients who were were deemed eligible for the study, I say, which is more, I would say more typical,


Nick Jikomes 34:34

you would exclude a quarter rather than 9%


Bryan Roth 34:38

rather than 90%. And that's the case for the two big trials of psilocybin. So this is, this is not just one trial and brick, the brexanolone is sort of an interesting competitor as well. And what does that What does it


say?


It's it's technically what's called a steroids. So it's uh, you know, it's in the same chemical classes cholesterol or you know, anabolic steroids or estrogen, testosterone. And it was approved for treat for postpartum depression. So this is depression that women have after they give birth, which is can be very serious. And it's given as an infusion, over 60 hours. Okay, so pretty, pretty noxious treatment, a continuous infusion for 60 hours, but it has this remarkable effect in some way similar to psilocybin. but less than 50% of the patients in those trials were excluded. Okay, so that's a little concerning to me. That's, that's the downside. And, it, it makes me, so the concern I have is that large numbers, so that so, you know, as I said, I expect psilocybin, you know, we'll have a, we'll have a, how this robust effect and the phase three clinical trials. You know, if I was a betting man, I'd be willing to bet on that. On that outcome, but it may come with a lot of strings attached in terms of patient eligibility. And so may not be, you know, ultimately, you know, will not be suitable for the general population. So I, I hope we can, we can improve on that in some way. And that's, that's a big, sort of a big reason that, that we're spending so much time and effort and in sort of formally testing this hypothesis that we can, that we can separate those two effects. If we can't, then hopefully, we can come up with something that has has a little bit better safety profile than LSD, there are some, some problems, some safety problems with those drugs, which I could go into, but basically preclude sort of micro dosing and things like this.


For Yeah,


Nick Jikomes 37:33

I do want to get into that, because I have heard that for some of these, but I want to ask first, if you've been studying psychedelics to some extent, for decades, but it's only really in the past few years, that's become this new sexy area. Right, doing it for a long time. Where did this interest come from? Was it always there?


Bryan Roth 37:53

Yeah, you know, ever since I was a teen, a teenager. So I grew up in Montana. And, you know, sort of the tail end of the 60s, I was a little kid basically. And, you know, I knew about people who had taken LSD and actually had bad experiences. One, one person I knew ended up in a in a psych hospital for months. And, and as I sit in, as I said, I there's this family history of schizophrenia. And when I was when I, you know, literally, when I was 13, or 14, I started reading up about these, these things, you know, in Montana, you don't have much to do. Not a lot going on there. But we did have a public library. And it and, you know, I was taking high school chemistry. And so I realized these are drugs, these are drugs, this is a drug that's causing this effect. So drugs like LSD, you know, clear to me as a, as, you know, a 14 year old is, is affecting how people view reality. And on the other hand, there are these, these other drugs that people take who have who are psychotic. And when they take them, they're not so psychotic. And I just found this really interesting, what the hell is going on here? And so I was I was just, you know, just interested in that. And it wasn't until I was in college. There was a, a visiting. Basically, this professor from Oregon, came through. One, one week to By this, I was going to the small college in Montana. And I think he was probably coming to Montana to, to do to go fishing or hunting or something like that. But as an excuse he, he gave a lecture to the biologists. And he was a neuroscientist. And he showed this diagram of synaptic transmission. And he said, and he talked about receptors. And that was the first time I'd ever heard the term receptor in my life. And when was this? This was this would have been in 1973, or 74, maybe 75. Somewhere in that maybe 1975.


Nick Jikomes 40:43

Okay, mid 70s, you're learning about receptors for the first time,


Bryan Roth 40:47

the very first time I'd ever heard the term receptor, and just said, Wow, that's what I need. That's why you should find out about


Nick Jikomes 41:01

an epiphany.


Bryan Roth 41:03

Yeah, it wasn't quite an epiphany. But I was like, What are receptors? This is really cool. And, you know, there was no research and I was very interesting, you know, I had this interest in drugs that make basically drugs that make people crazy, and drugs that make them say, Okay, I got this, I this interest in this and I, you know, since I, since I was 14, I, I decided I was going to become basically become a psychiatrist. I didn't I didn't know how that would ever, ever occur. But that's what that's what I was going to do. And so I got into medical school, and there was a guy there that studied receptors in and I asked if I can get in his lab, and he said, Yes. And so I got in, you know, I started basically volunteering in his lab, and then you know, got a PhD on opiate receptors, basically, even though my interest was, you know, basically psychedelics and anti psychotic drugs. That was my interest. Those two things. He didn't study them, so I studied opiate receptors. And then, when I finished my PhD, I went to the National Institute of Mental Health do a postdoc and that's when I studied started studying you know, what I study now basically, the psychedelic receptor, it's also also the receptor for one of the receptors for eight what are called atypical anti psychotic drugs. And you know, I must say that, that when I first started studying this receptor, I didn't start studying it because it was the receptor for LSD or anti psychotic drugs. It was, it was because nobody in the lab was working on it. And the guy was working for was a really famous neuro pharmacologist, and he just said, Brian, you should study this receptor.


Nick Jikomes 43:10

And was that the Kappa opioid receptor?


Bryan Roth 43:12

No, that was the five htt to a receptor. Okay. So yeah, so I got my PhD on opiate receptors. And when I when I finished my PhD, I vowed never to study opiate receptors ever again in my life. I was that because I Well, at the time the field was it was filled, it was filled with all these really interesting characters. Most of them are dead sadly dead now. But you would go to the scientific meetings and everybody would be yelling and arguing with each other. And I just decided I didn't want to be in a field with these crazy people who didn't get along with each other. So when I went to and I to the NIMH here was the serotonin receptor, nobody knew anything about the five htt to a receptor and, and the guy he was working for said, Brian, you should study this. So I did and then then lo and behold, it turns out to be the receptor for LSD.


Nick Jikomes 44:26

So why did why did he think you should study it if that wasn't even known yet?


Bryan Roth 44:32

So I don't know if this is going to be interesting at all, but it it was for it was for a crazy reason. Okay. So it turns out that serotonin doesn't bind to the, to this to the to a receptor very well. It has it technically has what's called low affinity. And there were some unusual things about the way the receptor was regulated, which I won't go into for this audience. It's sort of technical. But this guy was working with his name is Mineo Costa, he's, he sadly is dead now. But at the time, he was literally the most famous neural pharmacologist in the world, he was a member of the National Academy of Sciences. The lab had 50 postdocs in it a while, it had two floors at the NIMH, and, you know, was was an amazing, an amazing place to work. So, he actually thought that there was another neurotransmitter or perhaps a neural peptide that bound the bound to the five htt to a receptor. Not serotonin. Okay. And so he said, Brian, I want you to find a peptide that binds to this receptor. Okay. And he was a really smart guy. So this is around the time that encapsulations were discovered, you know, the endogenous ligands for the opiate receptor, endorphins, di northend for the Kappa receptor. And so on. So it wasn't, it wasn't, you know, that wild of an idea to suspect that there, you know, this could be another receptor for something else in the brain that we don't put, we don't know. And so I spent a about a year or year and a half in the cold room trying to isolate the peptide for this receptor. And I went to him and I told him, it's serotonin. I'm sorry.


It's a seratonin receptor. They almost kicked me out of the lab. He was very angry.


Nick Jikomes 46:57

But so anyways, you you kind of happened to run into this receptor, and then it turns out to be the quote unquote, psychedelic receptor. Yeah. And and I guess the rest is history. Yeah. So I just stuck with it. Wow.


Bryan Roth 47:13

Wow. And so always no insight, no particular insight on my part.


Nick Jikomes 47:21

And so you had you had this interest in psychotics and anti psychotics, you had this interest in receptors and psychedelics, you had this family history and schizophrenia, did you stay away from ever experimenting yourself with psychedelics for that reason?


Bryan Roth 47:36

Yeah, you know, it's, if you have a family history of schizophrenia, it's not. I don't think anybody would, would recommend that you take psychedelics.


Nick Jikomes 47:46

Interesting. So what do you make of today, you know, the last whatever, four or five, six years, you now have this Renaissance or boom, in research on psychedelics, you also have a lot of money going into the private sector for startups is


Bryan Roth 48:03

about huge amount of money going into the private sector. Yes.


Nick Jikomes 48:06

What do you what do you make of this whole phenomenon? Or is it mostly exciting? Are you is there are there any cautionary notes you have for people? Are things already getting overblown at all? What's your what's your general sense of, of the research that's going on?


Bryan Roth 48:21

There isn't. So there there is. You know, I'd say the clinical trial research from the, the UK group and the, in the Hopkins group and the volin Fighter Group. So those are sort of the three the Switzerland group. They're doing, you know, pretty good, pretty excellent. Human human research.


Nick Jikomes 48:49

So at Hopkins, that's the people that many listeners may have heard about in the news in the US that are working until seibon. And in the UK, is that compass pathways? No, it's


Bryan Roth 48:59

catcard Harris and Okay, and not these. Yeah. And then in in Switzerland is friendsville inviter. Of course, brands, brands volin. Vitor, like me has been studying, you know, psychedelics for decades. For decades, he was the only person doing human studies with with psychedelics. So, there are, you know, there are there is this handful of clinical groups that are doing, you know, really, really excellent, excellent clinical studies, finally, you know, control controlled clinical trial trials. Finally, in terms of basic science, there isn't a lot of really good basic science still. So, as I said, I you know, I literally have the only grant to study psychedelics from a basic perspective and then there is a this group, Adam Halberstadt and Mark Guyer. So Mark Mark Guyer. I don't know if he's semi retired or if his lab is not entirely active, it may still be, but he, you know, he sort of has studied psychoactive drugs, including psycho and psychedelics for decades, as well. They they sort of do behavioral pharmacology, excellent behavioral pharmacology. And that's about it. I mean, there are some other other people Charles nickels does some research sort of on a smaller scale, but it's there isn't there isn't a lot of basic research that that's being done. There are a number of I guess David Olson does some as well. Not not directly with psychedelics, but sort of psychedelic inspired research.


Nick Jikomes 51:05

That was the recent paper about Ibogaine. Right.


Bryan Roth 51:08

Ibogaine, an Ibogaine derivative? Yeah. They're, you know, and, but there are many, many companies, mainly looking at, you know, seems to be mainly silicided. And some of them are, have licensed, I think some of they would also has a company, Charles Nichols, as a company, they may have some new chemical matter. But there isn't, you know, there isn't much known about these compounds, these newer, these newer compounds. So we, you know, we have this paradoxical thing that venture capitalists and, you know, rich people, sort of rich hippies are pumping lots of money into this into psychedelic space. But there's not a firm foundation of science that underlies a lot of what's going on. There's a lot of enthusiasm. But, you know, it's, it's, it's, it's fascinating to me. You know, we don't really know much about how these drugs exert their actions. And I don't know if I was an investor, I would want. Want to know a little bit more about that.


Nick Jikomes 52:33

What, what do you make of the research, so you sort of study things at the basic level, the very small level, so receptors and chemicals and molecules. And then there's people like the group in the UK and elsewhere that are doing fMRI brain imaging studies, there's some eg work out there looking at the global brain states and patterns of brain activity when people ingest psilocybin. Do you follow that literature closely? And what do you think? What are the basic takeaways that we know about so far, about how psychedelics are affecting global patterns of brain activity?


Bryan Roth 53:10

So I think it's mainly phenomenological data right now. I don't I don't read their you know, I must admit, I don't read their papers that closely, because I just don't, it's just too fuzzy of a level for me. We are, you know, I have a big lab. And so we are actually looking at things at a more integrative level. And so for the DARPA grant, we actually have a huge behavioral effort, mouse behavioral effort. And we have collaborations with basically the the best neuroscientists in the world to look at neuronal firing and things like this. So for the DARPA grant. I've been able to bring together a team which in their in their respective areas, I think is is literally world class. So we have we have one of the world's experts on what's called cryo electron microscopy. This guy Jago skinny Otis at Stanford. The group that's that's basically the world Leading the Leading group in the world in sort of computational discovery of drugs, which is the shortcut in Irwin group at UCSF, the basically the, the world's greatest person in terms of understanding the dynamics of receptor activation. This is Ron Gerard Stanford. The Duke behavioral core is is running Duke University. Behavioral core is running all of the all of the behavioral studies at a level that really no one else in the world can do. And then we have a huge medicinal chemistry effort. So we have five full time chemists. And we're, you know, we also have basically one of the leading people who does proteomics, this guy, Nevin Krogan, his lab at UCSF is trying to understand sort of the proteomic networks, we're doing transcriptomics networks. So it's sort of an it's a Manhattan style effort, that it's like a Manhattan Project for understanding psychedelic drugs.


Nick Jikomes 55:51

So, so you've got multiple teams, and you guys are looking at psychedelics at multiple levels, meaning you're zooming in very close to look at very zoomed in pictures of things have synapses,


Bryan Roth 56:03

the atomic level, yep, the molecular level, the cellular level, the neuronal level, and the behavioral level. So, yeah, we have a huge effort in making, you know, engineered mice to, for, for various things. And then we were basically combining this with drug discovery. So the goal is basically to deliver new medications. So it's unprecedented, basically. It's, it's, the grant is $27 million. So this is, this is like, for, for this sort of effort, this is, this is a huge amount of money. And, and on top of that, I have you know, this, this merit grant from nationalist drug abuse, basically, I understand at the molecular level, what's what's going on with these drugs. So, we, we have this, we're very fortunate to have this really, you know, outstanding team of, of scientists, that can bring sort of World Class brains to really accomplish a complex problem, which, which is unprecedented, I would say, and in the history of study of psychedelics, so, our hope is at the end of end of the four to six year period, that there are, you know, will not only have new medications, but will actually have some knowledge about how these drugs exert their actions in the brain


Nick Jikomes 57:51

for interesting what Finally, basically, so we can probably expect to see a body of work here, multiple papers, yes, this papers, which compounds are you? Are you focused just on LSD? Are you doing multiple different studies on different compounds?


Bryan Roth 58:07

So it's a big project. So we're, we're in the process now. So there, there are 30 investigators working on this. So 30 scientists, just on this project, and then with with my other funding, there are probably another four or five, so maybe 35 people working on this project. And so, in terms of the basic biology of psychedelics, we're actually looking at hundreds of known psychedelic drugs. And we're in the process of putting together basically paper that will serve as, as the database for our understanding of psychedelics. So every psychedelic drug that is known to be psychedelic, we're looking at right now. And at many different levels, so the receptor pharmacology, the signaling, transcriptomics, proteomics.


Nick Jikomes 59:17

So you're building a database, essentially, for researchers, where every known psychedelic will have a complete or at least a very thorough database of which receptors, they bind to what they do at those receptors, how genes are turned on or turned off because of that. And all of that will be available for researchers to tap into.


Bryan Roth 59:39

Yep. It'll be free online. For anyone, for anyone. That's, that's awesome. Yep. And we're also so that's just a small part of this project that's like this, this much of that project. Okay. The big part of the project is actually to come up with what's called New Chemical matter. So what we want to do is we want to come up with completely new structures of compounds, that will activate the receptor in specific ways. And so we know that the signaling of these receptors is extraordinarily complex. And we're basically just we're designing and discovering completely new chemical entities that look like nothing that has ever been seen on the planet Earth, to activate these receptors in distinct ways,


Nick Jikomes 1:00:39

so literally drugs that don't exist on earth, and in normal biology, and therefore drugs that have the potential to activate receptors and have effects that we've never seen before,


Bryan Roth 1:00:52

right, great. And of those, we're basically doing chemical optimization to make them have better what are called drug like properties or medication like properties. And we're optimizing them, ultimately, to be candidates for testing in humans.


Nick Jikomes 1:01:16

And what, what, so when you optimize something for a candidate to be tested in humans? What exactly does that mean, you're minimizing the risk of side effects and things like that?


Bryan Roth 1:01:25

Oh, it's a huge, it's a huge amount of work. So it's, you have to sit there, what are called drug like properties. So these are things like, Can you take the drug by them as a pill form? And will it give to the brain? Okay. So that's one. So that process is very complicated. There are many things that regulate that process. And all of those things need to be optimized and, and characterized. And then you want to, you want to make sure that it doesn't have, you know, the potential for serious side effects, you want to make sure it's specific for the receptor. And you don't want to, you know, you wouldn't want it to disappear within a minute of entering the bloodstream. Right. And you probably wouldn't want it to hang around for days. So you want to optimize that as well. So they're, they're just many, many things that, that need to be need to be taken care of. A lot of these can now be predicted with computational tools, but ultimately have to be, you know, tested and quantified. So there's, there's a huge science involved in this. But that's, that's one of the things. So, to give you a sense. So we're about six months, six or seven months into the project. And already, we've evaluated around 500 novel compounds that have been created just for this project. Oh, wow. Yeah. We've already, we've already put two of them in mice. Wow.


Nick Jikomes 1:03:16

So it's gonna be this, I mean, enormous body of work with this really rich database that anyone can tap into. And, like, not only drugs that we know about, but essentially alien drugs that that are made from scratch. Right? Yeah. This is cool. Yeah. Yeah. So your tax dollars? Literally, yeah. Um, so what is what? How does like someone like DARPA decide that this is this is where they want to fund research? Can you give us some insight into how research funding actually works and where they decide to put things you would have to talk to them,


Bryan Roth 1:03:55

but basically, they put out what's called an RFP receptor request for proposals. And what they wanted was the title of the thing was biased agonists as rapidly acting neuropsychiatric agents. Sort of a mouthful. Focus farm, I think was the name of it. But the idea was basically what I outlined to you. Can you come up with a non psychedelic psychedelic? So is it possible to create a drug which is effective like psilocybin, but is not psychedelic? So the idea is, can you come up with a drug that you take one dose and you're, you're cured?


Nick Jikomes 1:04:40

Yeah, that would be nice. Wouldn't that be great?


Bryan Roth 1:04:43

So DARPA likes I don't know how they come up with these ideas, but DARPA likes to my understanding, I can't speak for DARPA, but but from what I understand and talking with other people is they like to pick impossible projects


and So it's a moon. It's like the moonshot for Google Shopping. They know that, you know, many of them will fail. But if, you know, the upside is, is huge, high risk, high reward reward. So the idea is, you know, it'd be great if we could, you know, come up with something where, if you're depressed to take a pill, and the next day, you're not depressed. Wouldn't that be wonderful? Right? That would, that would transform humanity. So that's the task they gave us. And they gave us a certain time schedule. What was the time schedule? Yeah. What's their expectation here? Four years, four years? So they, so they give you $27 million. But there are strings attached? Oh, yes. And so what what would they expect you to have to show for yourself, after four years is a certain number of papers? Is it a certain kind of result? They want to come they want to compounds basically ready to go? What happens? Just out of curiosity, what happens if you don't come up with too?


Well, so there are milestones that we have to meet along the way? And if we don't meet our milestones?


Nick Jikomes 1:06:12

I see. So it's it's faced funding? Yes. Yeah. So it's,


Bryan Roth 1:06:19

it's


it's, there's a very high level of supervision and oversight. So we need very frequently with the program managers and, you know, give updates and all this stuff. It's It's nothing for people that have NIH grants, it's nothing like it the level of oversight and, and expectation is, is extremely high. It's, it's more like if you're in a biotech company, it's it's that sort of pressure. You know, you have a certain timeline, you have things that need to get done, if you don't get those things done. Or if it looks like your project is not going to work. They want to find out as soon as possible so they can cut the funding. I think. So it's, you know, it's a pretty tight. It's a pretty tight schedule. It's, it's a very difficult project. But we have an awesome team, and we're making great progress. So I think we'll get I think we'll get to the finish line. But, you know, we'll see.


Nick Jikomes 1:07:28

Yeah, that's amazing. I mean, that's, it sounds like a heroic effort. It's a distributed team. And I mean, I'm really excited to see what comes out of that. I mean, I love the fact that you guys are gonna have this database, I used to work in academia, I now work in the private sector. So I, you know, I can no longer just put all of all of the data I have access to out into the world. And so I appreciate just hearing the things like that are gonna go Yeah, yeah. Yeah. The other thing that I wanted to talk to you about, because I've heard this about you, in fact, the first time I heard about you was, I've never met you for the listeners. So I've never talked to Brian before, but I was in the same room as you one time. And it was, I don't know, six or seven years ago, when I was a graduate student. At Harvard, you gave a talk. And then there's a you know, there's often a student lunch after a talk. So scientists will come in to give a talk present the research and the structure of LSD at that talk right. Now, this was about this was about dreads, I think, or dreads. Okay, okay. Yeah, this is actually my introduction to you to Brian Roth was when I started graduate school, I started using these things called dreads, okay, which are tools, they're, they're gpcrs receptors, like we were talking about, they've been modified, right? And you can use a bag of tricks in in the lab to put these receptors into animals. And it allows you to then activate those receptors, say and manipulate the animal's behavior to see how certain neural circuits are working. So I was using dreads to make animals hungry. I was working on GRP neurons, right? Oh, yeah, yeah, yeah. Yeah. So you can Yeah, so you can put these things into animals, make them do something, in this case, eat. And so I learned about brian ross, I went to see brian ross speak. You talked about dreads, and then in the student lunch afterwards, there's a sort of a q&a with the graduate students. You mentioned that you were Zen Meditation practitioner, right. If memory serves me, correct. I think you said that you meditated for something like four hours every morning. Yeah, yeah. So walk us through that. How is that your schedule? Is it four hours every day and at least four hours a day? Is that continuous all at once?


Bryan Roth 1:09:42

Let me just before I get into that, let me just say that one thing you may not know about dread technology is that I invented it to deconstruct psychedelic drug action.


Nick Jikomes 1:09:56

I did not know that. Yeah.


Bryan Roth 1:09:59

So was the reason I invented it, basically. And the idea was we would make, you know, a GQ what we now call the GQ dread. We put it in layer five pyramidal neurons turn it on in and recapitulate the actions of LSD. So that was that was the idea, basically.


Nick Jikomes 1:10:18

Okay, so I think what, so what you just said was you were trying to create a receptor, such that you could put it into particular neurons in the brain, turn it on without a drug, right and make the animal essentially behave as if it had taken LSD. Right? Yeah, wow. But it turned out to be this great tool that allows neuroscientists to selectively turn on or turn off neurons in order to figure out how the brain is actually doing what it does.


Bryan Roth 1:10:43

Yeah, yeah. And, you know, 1000s of labs around the world use it. It's, it's, it's, it's quite amazing. Sadly, my lab doesn't use the technology.


Um, but anyways, yeah, yeah. With that segue, we can we can talk about from dreads to meditation, from dreads to meditation, right? So I remember hearing that this is several years ago, and I was like, Did he just say four hours a day? So it Yeah. Is that all at once? Or is it broken up? So I usually get up around three or four in the morning. And I will, I have actually a little meditation room that I set up here and at home. And of course, everybody is asleep, my wife is asleep. My dogs are asleep. And I meditate until, you know, around eight o'clock, basically. Wow. And then I may meditate in the afternoon or at night. But, you know, that's, that's my typical day. And how long do you sleep each night? usually got to sleep between eight and nine. So I get plenty of sleep. It doesn't. So it doesn't affect your sleep drive,


as well. So I get like, I don't know, six hours of sleep a night? Probably.


Nick Jikomes 1:12:12

So that's probably the low end of the normal spectrum. Yeah,


Bryan Roth 1:12:15

yeah. Yeah, I get by with a little less sleep probably than the normal person, the quote unquote, normal person. typical person. Yeah.


Nick Jikomes 1:12:22

Yeah. And what, what style? Is there a particular type of meditation you're doing? Yeah, I practice in. And what is that, as opposed to mindfulness meditation, or some other form of meditate. Um,


Bryan Roth 1:12:37

so the particular so they're basically three, I guess, you could say, three types of Zen, three types of Zen meditation. And all this, others discuss all three, and then I'll tell you what I do. So sort of the one standard way of Zen Meditation is, is what's called following the breath or counting the breath. Basically, when you breathe in, you count one. When you breathe out, you count you know, you're not doing this when you're talking, but basically, in your mind, you're breathing in one, and then 234, all the way up to 10, basically. And when you get to 10, you start over again. So that's called counting the breath. And that that typically is refined to following the breath. So you follow the breath going in, and then you follow the breath going out, or you could just work could be, you only count the exhalations. So those are variations so that basically, sort of basic basic breath practice. So that's, that's a very common type of meditation. It's called breath practice. And typically, when people start out with Zen practicing zen, they start out with breath practice. And you can stay with breath practice your entire life. So breath, the breath, you know, following the breath is is a complete practice of meditation. Once once one gain some I would say facility or is acquainted with breath practice for a time. So that practically you wouldn't if you were counting your breath, you wouldn't lose the count for 15 minutes or so. So the instruction with breath practice is if you forget what number you're on, you start you go back to one, basically. So if you're able to do this for 15 minutes or 30 minutes without sort of, mainly without losing the count, then If you wish you can go to another practice. And there are basically two other practices in Zen. The first is what's called Cohen practice kayo ABN. And the other practice is what's called, they have these Japanese term shikantaza. And co on practice is so, so let me back up. So breath practice, you can, you can sort of do on your own. You could, you could do it on your own without, you know, without a teacher, it's, it's helpful to have a guide, but, you know, I've just now taught you the basics of breath practice, you could go home and practice, practice, basic Zen Meditation with that practice, core and practice or she can taza you definitely it definitely is coupled to have a teacher so call on practice is, is typically only started during a during a Zen retreat of at least, typically of seven days. So you, you wouldn't ordinarily take up call in practice, if you weren't, if you didn't have I won't say if you're not dedicated sufficiently, but if you don't have the time to spend a week meditating where you're and, and in a Zen center, this would be you get up at 4am. And you go to sleep, you know, lights or, you know, you can go to sleep around 10pm. And during that time period from 4am to 10pm. you're meditating most of that time. Okay. In a meditation hall with other with other Zen practitioners. So, so common practice, is, is focusing your attention on a question. And a typical, quite, you know, a typical question. I think a lot of people have heard of that of this one, what is the sound of a single hand? Or what is the sound of one hand clapping, but, but really, it's what is the sound of one hand would be a con, that's a con.


Another con would be, show me the face before your parents were born, show me your face before your parents were born. That might be another con. Okay. But typically, the first con that people work on is is a con called mu mu. Or some people will say the con is is the word No, no. And it's a very short con, where a student comes to a Zen master. And he says, he asked the question does does even a dog have Buddha nature? And the Zen teacher says no, or moo, moo in Japanese. And that's the colon. And then you focus on that word,


mu.


And so that's co on practice. And, you know, it sounds weird, right? kind of strange. Focusing on this word Mo, what is this word mu? What is this mean? Oh. So it's very helpful to have a teacher to at least at least understand what what the practice is. And so,


so, is there an answer to that or is it meant to be unresolvable. So there is a resolution of the colon. And in con practice, the goal if you could, if you could say is a goal is to see things as they are, at least initially, with a sudden insight, what's called kensho. And in in common parlance, this would be having an enlightenment experience. Okay? So the goal, the goal of common practice is to have that experience. They, we would say, in Zen to have the same experience that the mythical Buddha had, at least to a small degree, some tiny degree, to see things as they are to see into the nature of reality, suddenly. And then the goal of subsequent call on work would be to clarify that vision, clarify that understanding so that, that that understanding is permeate your life basically. So that you are the understanding. And, and that's why it's, you know, very helpful to have a teacher we would, it's nearly impossible. It's not, it's not entirely impossible, but it's nearly impossible to do it without to, to, to do that, to have that sort of practice without a teacher. For most people, teacher is is is essential. So you, I take it that you did have a teacher, at least at one point,


I have a teacher Yeah. So I've been I've been practicing Zen for 30 years with the same teacher. And then the third type of Zen practice is what's called shikantaza. Which is, is probably the most, it's, in some ways, it's the most difficult of all practices, or the easiest of all practices. And she can taza is you could say, I'll just use some sort of jargon here. It's


being


in what would be non dual awareness. Are you are you acquainted with the idea of non dual awareness?


Nick Jikomes 1:22:17

I am, but can you can you describe that?


Bryan Roth 1:22:20

So that would be where there's no sense of a separation? This, this is sort of what people describe it as a peak psychedelic experience, right?


Nick Jikomes 1:22:31

Yeah.


Bryan Roth 1:22:32

Non dual. I in the universe are one. Right? So it can show so it can show is that that experience? I in the universe or one? above the heavens and below the heavens? I am the Honored One. I walked the universe alone. I am the universe. Okay. That's kensho. That's also the peak psychedelic experience, from what I understand at least one from what I can read. So she can taza is, is that sitting?


Nick Jikomes 1:23:15

And so? So I take it that you have experienced that state? And if so, is that something that has happened multiple times briefly? Or are you able to sit with that type of non dual awareness for extended periods of time?


Bryan Roth 1:23:31

So we don't, we don't talk about what our own experiences is, then. There's this little but I can speak about it. In the third person. I think I think that would be fair, there is this. There's this funny cartoon I just saw that I sent to a longtime friend of mine, which is sort of a takeoff of Fight Club. So you know, the movie Fight Club. So it says it's, you know, what's it Brad Pitt? And who is the other guy in Fight Club? Edward Norton, Edward Norton, you know, are looking at each other. And one of them says the first word word. The first rule of Satori club is we don't talk about Satori.


So, so, you know she can taza is is basically a moment to moment practice. So it would be you know, it would be every moment every moment of awareness is is re Remembering or re is recognizing the non dual nature of reality. So that would be the practice of she can tell us is instant by instant awareness of the non dual nature of reality, if that makes any sense at all?


Nick Jikomes 1:25:23

Well, I, I think it does, but I think it might not to most people, so why don't we? So in the context of say, like neuroscience speak, right? Would it be fair to say something like this, that your Zen practice or certain altered states that you can enter into, through meditation or from other?


Bryan Roth 1:25:44

So let me just let me just back up here. So. So in zen, one of the one of the marvelous things about Zen is that these are not altered states. So this is the natural state of the mind. This is sorted. So Zen is part of Buddhism, I don't want to get too philosophical here. But in, in most schools of Buddhism, this is what's referred to as the natural condition.


Nick Jikomes 1:26:23

So what's that mean? It's not,


Bryan Roth 1:26:24

it's not an altered state at all, the mind is there.


Nick Jikomes 1:26:27

It's something prior to all of the differentiated forms of awareness that one may have had through conditioning throughout life.


Bryan Roth 1:26:39

It's, you It's so we would say it's actually always there. But it's not recognized. It's there, it's there all the time. It's just that


Nick Jikomes 1:26:57

would you describe it as maybe perhaps the form the form of experience into which all of the particulars are, are put


Bryan Roth 1:27:07

it's, it's more like the mind is just distracted from recognizing things as they are more like that. It's more like just distraction. And the, the various techniques of meditation are basically ways to remove the noise, this noise in the mind, this distraction. So that you can see things as they are. So it's not, it's not. It's not in any way an altered state. In that way, it's it's different from the psychedelic experience. So people that have a psychedelic experience, they would, you know, have this experience of oneness. And it would remain sort of a pleasant memory, right? I had this experience of oneness, it was great. Where did it go? Right? I remember it was wonderful. Where Where is that now? So in zen, it's sort of moment to moment recognition


of


just just a recognition of this is this is the way things are facing. Now, how can you say this a neuro biological terms? So one way I like to think about it is what's called the default, you know, about the default mode. Okay? Yes.


Nick Jikomes 1:28:38

Let's let's describe that for people that what is what is that?


Bryan Roth 1:28:43

So it's, it's, it's basically the way the brain works, I won't say to my I'll distinguish the mind from the brain this way, that is the way the brain works. So the brain basically has things that turn around, sort of, under their own, seemingly under their own without any external force. And a lot of this is experienced as chatter in the mind. So when you're sitting down, you know, listening to music or something, you're not only listening to music, there are thoughts basically going through your head, right. This is the default. To rate extent, this is the default network. It just, it's turning all the time.


Part of the practice of what part what, what meditative practices do is they and one of the reasons the default network continues is that our attention is shifted to it. Okay. So if we didn't, if we, if we didn't reflexively shift our attention to the thoughts run out of steam, they run out of steam, they don't disappear entirely. But you then recognize this sort of silence between the thoughts. That's sort of one way of looking at it. And the silence is the natural state of the mind, is the silence. Just luminous, what you call luminous what one could call luminous awareness. Now that's not kensho or Satori or enlightenment, but that to recognize that silence is is an initial first step. So so that's what happens, basically. So that's why I say it's a natural, it's just it's just things. It's the, it's the way the mind is, naturally. But we just don't see it. Because we're distracted with basically the way that the way that things work, our mind works. It's continually generating this chatter in our heads, which we pay attention to,


Nick Jikomes 1:31:30

and what. So on the one hand, this makes sense. But I could see how someone would would hear this and think, well, if this is the natural state, and if meditation is good for you, if it's something you should do, because it's somehow better to recognize these things that you've just explained to us. Why on earth, would there be a default mode that has evolved in the brain that is chattering to begin with?


Bryan Roth 1:31:58

So I don't know. But it seems to be the way things are. So I don't I don't profess to know anything about the way the way that bind is, is constructed. Other than to say there must be some evolutionary advantage to having a default network. I don't know what that is.


Nick Jikomes 1:32:26

So how did you get in? How long have you been practicing? Again, how long you've been doing this?


Bryan Roth 1:32:31

So I actually started meditating when I was probably 16 or so.


Nick Jikomes 1:32:38

And what was the original impetus for you? Was it just curiosity?


Bryan Roth 1:32:42

Oh, no. So sort of 100 off. This is a funny story. But so my dad heard about Transcendental Meditation as a way to keep your kids off drugs. And as I said, it was sort of the tail end of the 60s. And there was this young woman who had spent time with Maharishi Mahesh Yogi who was the head of transcendental meditation, and was a transcendental meditation teacher and this, and she had come back from wherever she had trained with him, India or whatever. And had had set up shop as a meditation teacher. And she had, she had a special deal for families. And so my dad had all of us take the transcendental meditation course. And so I started meditating. Back when I was 16, or 17, did transcendental meditation and it was it was actually very helpful for me.


Nick Jikomes 1:33:58

And what is TM? How does that work?


Bryan Roth 1:34:01

So it's, it's, it's what's called a mantra practice. Where you instead of focusing on the breath, or co on you focus on a sound, basically. So one, one mark, this is not sort of a tm mantra, but one mantra might be the word oma. Focus on the word home. So they basically give you a word that you focus your attention on. And the practices is basically like every meditative practice, you focus on the word. And then when your your mind wanders away from the word you basically bring your attention back to the word and the mind steadily gets quieter and quieter. And, you know, it's interesting when I when I took tm, they said the goal of tm was cosmic consciousness. They didn't Explain what cosmic consciousness was, or even why that might be something you would want to. But it was, it was very helpful for me. Decreased my anxiety, I think I got along better with people and helped me focus. So I practice tm for a number of years. And when I got to medical school for various reasons, quit, quit practicing tm. And then when I was finishing up my psychiatry training at Stanford, I took up sand. And I've been basically doing it ever since.


Nick Jikomes 1:35:40

And how did that get started? You mentioned having a teacher and needing a teacher, how does one actually go about finding someone to help with that? Well, so I went to the Yellow Pages. And now we should explain the Yellow Pages,


Bryan Roth 1:35:58

go to the network, go to the net, and go to Google Maps and type in meditation teacher and you know, most of you are you'll find some. But I was in Cleveland at the time. And I'd sort of taught began teaching myself Zen. But I realized I, you know, it'd probably be a good idea to learn about it in a more formal way. And I had, I had this book, sort of a famous Zen book called The three pillars of Zen. And at the back, it said, For further information, contact the Rochester Zen center. So Rochester was, you know, probably 200 miles away from Cleveland. So I called him up on the phone. And I said, I want to learn about Zen. They said, Okay, why don't you come to an introductory workshop, and you we can teach you about Zen. So I went basically, it cost was, I think it'll cost $75 for two, it was a two day workshop, you got free meals and free, free room and board basically for 75 bucks. So it was was a good deal. That was, that was actually a good sign. They didn't charge me $1,000 for two days, 75 bucks. And, you know, I met the teacher and you know, then started started practicing basically.


Nick Jikomes 1:37:23

And so, you said that the stated goal for tm was cosmic consciousness. You talked earlier about this form of non dual awareness. Right? is it accurate? To say that what you're describing there is a form of conscious awareness in which your brains construction of a self of a model of itself is somehow gone, but awareness is retained?


Bryan Roth 1:37:54

I wouldn't say that. So, I think what, what's commonly described in the literature is that one sees through the illusion of a separate self. So if you read accounts of people who have, you know, quote, unquote, who have been more deeply enlightened, they would say that the illusion, so they recognize the illusion of the separate self, basically, that's what they would say, delusion is still there. Right. And at the same time, the awareness of the non dual nature of reality is there simultaneously is what probably what they would say.


Nick Jikomes 1:38:54

Gotcha. So those are two different things. This recognition of the apps the illusion of self and this non dual awareness, those are separate but related. It's the same thing. It's the same thing.


Bryan Roth 1:39:07

Yeah. Yeah, they would, they would say it occurs simultaneously. I say, Oh, so they would say, they would say. So there's this sort of classic Zen saying before enlightenment, mountains were mountains and rivers and rivers. When enlightened mountains are no longer mountains, rivers are no longer rivers. And after enlightenment, mountains are mountains and rivers are rivers. That's what they would say. If that makes I don't know if that makes any sense at all.


Nick Jikomes 1:39:53

I suspect it will be puzzling to a lot of people.


Bryan Roth 1:39:59

So So what is it? What is that things are exactly the same, nothing changes. Just the How can I say? Just the mistaken belief in separation is gone?


Nick Jikomes 1:40:46

And how would you know having having sort of gone? If


Bryan Roth 1:40:50

that makes any sense at all, it's probably just gobbledygook.


Nick Jikomes 1:40:54

So I think I think for a lot of people where you start to get hung up is they've this sort of mistaken perception as you described it, they've never experienced that. Right? So it's like a negative. It's like trying to imagine a negative when you've never, you've never actually experienced the absence of this thing that's always been there.


Bryan Roth 1:41:13

Yeah, yeah. Although I would say you do all the time. And maybe just don't notice it. So you know, when you see a beautiful sunset, or


Nick Jikomes 1:41:27

anytime that you're quote, unquote, lost in the moment, are you engaged? Yeah. Yeah. You're not thinking I'm sitting here. I'm doing this. You're, you know, you're making the jump shot in the championship game, you're fully engaged in the right.


Bryan Roth 1:41:41

Or you're eating a marvelous Nacho?


Nick Jikomes 1:41:46

Yeah, yeah. The point being that you can, you can achieve the same state that you might more readily associate with the, you know, the high octane peak experience, you can also have that exact same type of framing for the mundane, everyday experience of eating a Nacho. Right? Do you ever do you ever miss a day? Do you ever you know, you're in the middle of the week, you've got a big DARPA meeting coming up? Do you ever miss your meditation session? No,


Bryan Roth 1:42:18

I don't. With a couple of exceptions, there have been have been times when, you know, like, I've been on a plane for 24 hours. Literally, so I'll, I'll I'll meditate in the seat, basically, of the plane. But no, I don't think there have been any days where I have completely missed meditation entirely. In 30 years, maybe once or twice, basically, because I was awake all night, and, you know, couldn't could informally meditate the next day. Wow. It's, you know, I just naturally wake up at, you know, three or four sometimes earlier, sadly, and, and, you know, I have nothing other to do nothing better to do. So I meditate basically. Rather than, you know, other I guess other things I could do with that time. And I. So, yeah, I don't I would say, if nothing else, my practice has been regular. You know, I can't say that it's been, you know, particularly productive, but at least I put in the hours. If nothing else, I'm not particularly good as a meditator. But I, I do practice.


Nick Jikomes 1:43:53

What is that? Well, what is what exactly does that mean to not be good at it?


Bryan Roth 1:43:58

I'm just, I'm just being funny. I mean, anytime selling meditation, anytime the attention wanders, you know, which will? I guess unless you were the Buddha himself, or, you know, some greatly enlightened being, some mythical light being your attention is always is eventually going to wander. And it's always, you know, wrecking basically the, the act of meditation is really the simplest that part of it is, oh, my mind wandered. Let's, you know, just make that movement. Is that just that recognition? And that, you know, that's a moment to moment. That's always something, something you're practicing because nature of the mind is to sort of wander off.


Nick Jikomes 1:44:49

Interesting. Do you follow the literature at all on meditation, like the neuroscience of meditation?


Bryan Roth 1:44:56

I do not interesting. Yeah. No, absolutely. People have asked me that before, I'd have no curiosity about it at all. Interesting, interesting seems to work for me.


Nick Jikomes 1:45:13

Interesting. Well, as we wind down, Brian, maybe I'll just ask you one or two more questions. What do you what are you most excited about the next one to three years in terms of questions that you think might get answered by the work in your lab? So I,


Bryan Roth 1:45:37

the thing, the thing, so I, you know, for better or worse, I don't think that way. You know, I've always had this this deep interest in psychedelic drug action. But what gets me most excited in the lab is basically the latest data, which is unexpected. Cyber big lab, and you know, people are working hard and, and almost every lab meeting somebody has something, which I get excited about that I, you know, Wow, that's cool. And, you know, I


Nick Jikomes 1:46:22

always looking forward to the next surprise.


Bryan Roth 1:46:24

Yeah, yeah. Yeah, I mean, we've had some pretty intriguing thing, you know, I, sadly, I can't talk about it, because it's not, we haven't written it up yet. But just some, I have this amazing group of postdocs and students and professional people in the lab. And every week, there's just something that's just really amazing that it's like, wow, I never would have guessed that. So I'm just I'm just, you know, I don't wait for it. I don't, I don't really think about it. But that's what gets me excited is like new data.


Nick Jikomes 1:47:15

Well, Brian, thank you for taking the time. I really appreciate it. We just talked for almost two hours. Okay, I got another meeting here. And we covered a lot. So thanks, again, Brian Roth from University of North Carolina. Any any final comments you want to share?


Bryan Roth 1:47:29

No. I always like to thank the funding agencies, the NIH and DARPA, your tax dollars at work. You know, I'd like to thank everybody for that. It, you know, it really is we can't do it without government support. It's, it's so essential. And, you know, there are many things about our society which, you know, sadly, we, we that are problematic, but one of the one of the really wonderful things about the society as it is today, is that they support basic science and you know, without that, we wouldn't wouldn't have things like the vaccine for COVID-19. And, and hopefully, we'll have better medications here before too long. So I just just like to thank everybody for that. And thank you for your time as well. So thanks, Brent. Okay, bye.



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