#714: A Glimpse of the Future: Electroceuticals for 70%–90% Remission of Depression, Brain Stimulation for Sports Performance, and De-risking Ibogaine for TBI/PTSD

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Hello boys and girls ladies and germs. This is Tim Ferris and welcome to a very special episode of the Tim Ferris show. This is an episode that I think might be an example of peaking around corners. So what we are going to talk about, what we discuss in this episode, I think may be a component of the future of mental health treatments in the next, say, five to 10 years. It's at least a sample of it. My guest is Nolan Williams MD. You can find him on Twitter at Nolan Rye, RY Williams.

And Nolan is an associate professor within the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine and director of the Stanford Brain Stimulation Lab. And we're going to go deep into a lot related to brain stimulation. He has a broad background in clinical neuroscience and is triple board certified in general neurology, general psychiatry, and behavioral neurology in neuropsychiatry.

Themes of his work include examining spaced learning theory and neuro stimulation techniques, development, and mechanistic understanding of rapid acting antidepressants,

and identifying objective biomarkers that predict neuro modulation responses in treatment resistant neuropsychiatric conditions. That is a long way of saying that he specializes in looking at, I would say, and these are my words, of course, cutting edge treatments and new technologies that can be applied to treatment resistant psychiatric disorders. Let's just say so treatment resistant depression, things that are notoriously difficult to address like OCD, there are many others.

Nolan's work resulted in an FDA clearance for the world's first non-invasive rapid acting neuro modulation approach for treatment resistant depression. And I've tested this myself and we get into this in the conversation. He has published papers in Brain, American Journal of Psychiatry, and proceedings of the National Academy of Sciences. Results from his studies have gained attention in science and the New England Journal of Medicine Journal Watch.

He received two Narc side young investigator awards, the Gerald L. Claremont Award, and the National Institute of Mental Health Biomehavioral Research Award for Innovative New Scientists. Again, you can find him on Twitter or x at NolanRy Williams, we'll link to this in the show notes as well, and you can find him online at NolanRWilliams.com.

I really enjoyed this conversation. I think it is very important, highly tactical, and we also discuss things like IBegin, which are seemingly unrelated to neuro modulation, and yet Nolan is an expert very well versed in multiple disciplines, and in multiple tool kits, pharmacological, and non-invasive neuro modulatory.

And it's this combination, this rare Venn diagram that makes him incredibly interesting to me. So I hope you enjoy this conversation as much as I did, and with our further ado, Nolan Williams MD. Dr. Williams, good to see you, sir. Yeah, thanks for having me. And I thought we would start with a personal story, not your personal story, but a story of Deirdre Lehman. Yeah, could you tell us who this person is, how it fits into your story, but let's begin with just a description of Deirdre.

So Deirdre is maybe in her 50s, 60s female in Bay Area, who has suffered from bipolar disorder much for life, and pretty successfully treated for the mania side of things over the years, had a psychiatrist taking care of that part in Marin, and happened to slip into this pretty severe damage.

In a year depressive episode, a couple of years back, it's been maybe like four or five years now, and her psychiatrist had actually gone to see a talk that I gave at this mood disorders day, like the year before we were talking, it was really early on when we were working on our rapid acting and our stimulation approach. So the psychiatrist had heard the talk, and then her patient kind of fell into this really bad suicidal depression, and so she reached out to me to treat her.

On the phone, I'll never forget it was like a Wednesday, and I got on the phone with her psychiatrist, and she was telling me symptomatically how bad off she was, and I was like, I don't think we can treat her outpatient. She's like way too ill, I think she's going to the patient hospital. So essentially gave her some information on how to do that, so I see her the next morning, and she's in really bad shape. What does that mean? How did that show up?

And people are at the level where they like kind of definitively need to go into the hospital. They're not really totally communicative anymore, and they've got some cognitive issues sometimes. And so in her case, she couldn't look you in the eyes, you look at the ground and she was doing this rocking thing, which you can see in pretty severe depression.

It's kind of this kind of tonia overlap symptoms, you know, I mean, she's like at the very end of the spectrum, one of the highest, very patients we've ever treated. So she was like a score of 50 in a moderate, so 60, like very, very severe, right? And just rocking and not really talking, and the husbands were counting everything. She had bipolar one. So she's hypomanic, I think, or manic, like two weeks before, and then dropped into this very, very severe depression.

So it was her daughter and the husband, they're sitting in the room with me, and I said, they want me to treat her. And I say, listen, like it's Friday, we go Monday to Friday, like you have to find a way basically to keep her well from now until Monday. And that means- And by well you mean safe, like preventing self-hunt. Yeah, yeah, exactly. So keep her not having a suicide attempt, basically, from now until Monday, very suicidal.

And I said, you're going to have to like take every knife, I don't think any guns, but gun, chemical, like scissors, everything out of the house, the whole, all of it has to go. And you guys have to be on like a 24 hour watch until Monday. And so Monday morning rolls around, and we bring her in. And it's the craziest thing. We had like a repair on the motor threshold coil, which is the coil you use to kind of get calibrated on the intensity. And it shorted out the device.

Blue, the capacitor bank up on the first stimulator. Blue your flux capacitor. Yeah, yeah. Like 7am, and I mean, you can't imagine how stressful that was. So we had a second machine, I'll tell you about this later, we were running this, you know, trait hypnotizability modulation study. And it was over at the scanner. So it was like pretty far away. And this thing's way like 100 pounds. I had to send my team over there, run over there and grab it, bring it over.

And luckily we were able to kind of get her going and treat her with a second machine. She was in really, really bad shape that morning and by five o'clock that afternoon, she was basically normal. And the next morning she was like totally zeroed out and completely normal, meaning no suicidality, meaning no depression or nothing. I mean, she looked like any person walk in the street, like totally normal. And that was in 24 hours. And we've seen this with bipolar patients as quicker.

Or it'll happen really quick for like a bipolar one patient, you can get it done in sometimes in a day. Just for clarity, by get it done and don't worry people listening, we're going to define terms and get into all this. But you're talking about accelerated TMS. Yeah, we're talking about accelerated TMS. Our rapid acting or a stimulation approach, we're able to get people out of these states and into normal mood.

And in short periods of time generally, like 2.6 days on average for major depression patients, but it's quicker with bipolar. We've seen, especially with bipolar one patients. So she was totally out of it in 24 hours. I remember it was like right around all I forth or something. And so we, you know, the whole team left, I guess we'll tell you about caffeine later too. So my wife and I are like big fills coffee fans. And so I'll never forget this either.

So we go down to the fills coffee and Apollo Alto. After I saw them, I'll never forget it Clark Lehman. Her husband was also went to fills it. No, I was going to be there. And I look over and this guy is just kind of staring at me. And I was like, hey, how are you? I see again, I just saw like 10 minutes ago. And he's like, I still don't understand what happened. And it makes sense, right?

Like to take somebody from the worst you've ever seen them mood wise to like normal in such a short period of time was remarkable for him. And you know, it ended up being that, you know, after that period, they actually went out and really were helpful with a lot of the philanthropy that led to the trials being funded. And ultimately the clearance and Clark and Dierger really were advocates and have continued to be advocates for this to kind of get it out into the world.

And he, it was totally based off of that experience of feeling him feeling helpless, you know, and going from that to feeling like it was all solved. And I think she went maybe a year completely symptomatic and it ended up needing to retreat it again at some point. It gets like these little touch ups here and there and is able to stay well on going and depression. As they tell me, depression's not her problem anymore. And so that's good. She's a great illustrative case of what this can do.

And I think what the promise of it can be. What I'd love to talk about next is not necessarily direct mechanism of action, but I'd love to hear you just explain a snippet that I pulled from your conversation with Andrew Juberman, which was a very good conversation. Specifically, it was about, and I'm not going to use the right terminology here. So bear with me as a layperson. But the sequencing or abnormal slash pathological sequencing of activation or activity in different parts of the brain.

So I don't know if it's the interior singulates. Yep. I think you know what I'm alluding to here. Would you mind just explaining that? Because it was something that I had never been exposed to and I found it deeply fascinating. And I'll just also mention this context for people who are listening to this that part of what is deeply interesting to me about a number of the different tools and modalities that you explore in depth is not just the speed of action, but the durability of effect.

Super, super potent combination and very unusual from what I can tell, combination of things. All right. So as far as the sequence of activation goes, could you explain what I'm referring to? We published a paper in the Proceedings in National Academy of Science. It's been about six months ago now. So one of the former research track resident postdocs in the psychiatry program at Stanford Honors METRO who's now junior faculty was working with Carl Diceroth and I during that training phase.

And Honors had this interest in a specific way of looking at brain imaging, particularly this type of brain imaging called resting state functional connectivity MRI. And so resting state functional connectivity MRI has been around for a long time. The resting state part of it is basically tell a person sit in the scanner and let their mind wander so that's kind of the resting state of the default mode, how you want to think about it.

And functional connectivity, what that means is it's the brain regions that have blood flow that is time locked with each other, right? And so essentially these connected brain networks, the blood flow will go up or go down in those areas in a time lock fashion. And blood flow is a- I have time lock used to me at the same time. At the same time correlating to you. Yeah, exactly. So blood flow is a surrogate of electrical activity. It's hard to see electrical activity kind of deep in the brain.

People see it at the surface of the EEG, but with MRI, you use the blood flow as like a surrogate of the electrical activity. And it makes sense if you're using glucose in a brain region because you're using that network, then you need to have cerebral auto-regulations so the blood vessels increase and they dilate more blood goes into that area. So it's just like a response to increased activity.

And so you have these increases in blood flow that are supposed to represent electrical activity that are in different separate nodes in the brain and they come on roughly at the same time. And we've known that for a while. Anishka very interested in this idea that the timing of the blood flow is consistently temporarily offset between these nodes.

So slightly that people ignored it for a long time, but he was able through using various math, able to show that there's a slight offset of the timing such that one brain region slightly comes on before the other. And that's interesting because that infers some level of causality. So instead of the whole network coming on at the same time, maybe it's just one area and it's signaling the whole network on. And it's so quick that you see it as all like this, but really it's more like this.

Right. If that makes sense, like it's coming on all at the same time, but from this network node kind of turning this one on, turning that one on or something like the lead domino matters. Yeah, that's that's right. The lead domino exactly.

So in the case of mood, it looks like the door salateral prefrontal cortex, the area that's involved in control precedes slightly the singulate cortex and our normal healthy control population, essentially nearly everybody had that directionality in the depressed cohort. 70% of them had it flipped where the singulate was temporarily in front of the door slater all, but not everybody. And if you just had that information, you wouldn't know what to make of that.

Like why it was some people and not others. But what was interesting is when he looked at the folks that had it versus the ones that didn't, the ones that had it were the ones that were responsive to our, when we'll talk about what SANE is and the rapid acting or stimulation approach in detail later.

But the folks that responded to SANE, responded to this rapid acting, to MS approach were the ones that had the biomarker and the ones that had no change did not have the biomarker look like a normal healthy control. And the signal on the post scan flipped to look normal in the folks that responded had the biomarker and then their brain changed after. And so the post scan looked just like the pre scan on the folks that didn't clinically change and the normal healthy controls.

You know, we see this sort of test all the time in medicine. You know, 10 people come into the primary care doctor's office with blurry vision, urinating a lot, drinking a lot, headache. A lot of those folks probably have diabetes, but not all of them. Some of them have migraine headache and knee glasses and some other things. And it looks like a diabetes presentation, but when you go and do the blood sugar, the blood sugar is normal.

And then you go and in the folks that have elevated blood sugar that look like they have diabetes, you go and you give them a diabetic medicine and then it normalizes. So the blood sugar after looks like the blood sugar of a normal healthy and looks like the blood sugar of somebody that symptomatically presented but didn't have diabetes. And so it was nice to see this and we're replicating this now.

We have money from the National Institutes of Health to do that, but this idea that we're able to have a test that would change and the same thing that signals that there's an abnormality is the thing that changes later. And that's more rare in psychiatry, right? To be able to have all of that line up. So we're pretty excited about that and hope to see it. It does replicate in the larger population of patients. But it's a conceptual idea.

It's an important conceptual idea, this general idea of being able to use under imaging or whatever it is, EEG, whatever it is to type different people that are presenting with similar symptoms and be able to say, okay, you're going to respond to this and not this or vice versa. I think that's part of what we need for psychiatry, right? Because people spend just so much time in their lives trying to find the answer and we don't really have any task. Trial and error.

Yeah, it's a lot of trial and error. It's like pharmaceutical, ready fire aim. Yep. In a sense. And this raises, I guess, just a meta observation slash question. Perhaps you could just discuss this briefly, which is, it seems to me like there have been, and this is part of the impetus for us having this conversation.

Part of the impetus, for me, in the last, let's call it half-year paying, a lot of attention to accelerated TMS, which is there have been these dominant paradigms in certain types of, let's call it, psychiatric treatments for things like depression, treatment, resistant depression. And it seems like a very dominant paradigm for, period of perhaps several decades has been these chemical imbalance theory of psychiatric disorders. So you have a serotonin issue.

Therefore we're going to treat it in these following ways. We have such and such an issue, sure we're going to give you SNRIs. And then, like you said, it's a lot of trial and error to figure out what works. And even if something works, it may often only work for a period of time. So it seems to me, and I want you to absolutely fact check and correct everything that I'm saying.

But that part of the reason that the research you're doing and that others are engaging in so fast things that it presents an alternative paradigm through which you could look at certain disorders. Right? Wait a second. Well, maybe this person's car when you turn the ignition is just tripping things in the wrong order. And if that's causal, we could try to address that. And then maybe that addresses what we might have otherwise perceived as a chemical disorder.

I have a lot of follow-up questions. But is that a helpful way to think about this or what would you add to that? You know, there's been, I would argue, like three errors in psychiatry, you know, what friends of mine have called psychiatry 1.0, 2.0, 3.0, and you know, the first error was this error in and around Freud and this idea that it was a content issue and a life experience issue, which is partially true. It's not that it's not true. It's just not complete.

And so then the solution is a content solution, a lot of initially psychoanalysis all the way through kind of modern forms of psychotherapy. The limitations of that let us to psychiatry 2.0, right? This idea that we serendipitously found the first anti-psychotics, first anti-depressants, and we were able to de-institutionalize from really schizophrenia patients out of impatient asylum stays with these drugs, which kind of flew in the face of this being a content issue.

What was the first anti-psychotic? Thorazine. I was going to say Thorazine. Yeah. I don't want to take you off track. So keep track where we are. We're at 2.0. Yeah. How was it serendipitously discovered? If I remember correctly, I think it was like an antibiotic or something like that. And they were trying to develop that drug out for something completely unrelated and happen to give it to some patients. This gets a frenzy on. And they had a dramatic improvement.

Yeah. I would love to read a book that is just collection of case studies like this, right? Yeah. It's like a cell denofil, right? Viagra, it's like for angina or whatever. That's right. And then the male patients, why aren't the male patients sending their meds back? Oh, wait a second. That's right. Here we go. Yeah. All right. So thorazine and the serendipitous discovery of, oh, wait a fucking second.

This seems to not necessarily negate, but certainly render incomplete, this pre-existing paradigm. Yeah. That's right. Then where does it go from there? So then I think that, you know, to your point, there was this accumulation of assumptions around, well, if we're moving all of these chemicals around in the brain, then it must be that there's a deficiency or an imbalance or whatever.

And that led us to recent history where there's quite a bit of prescribing of oral antidepressants and all that stuff. And the third era, this kind of circuit era that I think we're in now, and I'd argue we kind of were entering in 10 years ago, but I think we're pretty squarely at the beginning of now flies in the face of that, right?

If I can take a patient as severe as dear Juleeman, get her out of it in a very quick time frame and looking normal and holding that for a long time, and there was no chemical exchange, right? There's nothing that went into her system, then it gets you into this newer way of thinking about it. It's a circuit problem.

The useful thing about this framing, one, it's seemingly consistently true in the sense that we're through all the various modalities, seeing these differences, but more importantly, let's you integrate past ideas into that concept. Drugs act on circuits, therapy acts on circuits, but focal neuromodulation is a really direct way of acting on those same circuits.

And so from a patient standpoint, I think it's very empowering because we're not saying to the patient, there's something inherently like missing or too much for you in the sense that you're constrained to having to take these exogenous chemicals to stay well, but rather like there's a circuit, there's a misfiring, sort of misfiring, sort of problem, and if we can reroute that information, then you can feel it well. And I think there's a level of empowerment that comes to that.

One of the things that patients always tell me after they get well with some of our stimulation approaches is that they kind of look at it and say, well, I may get depressed again, but I don't think I'll ever get suicidal at that same level again because I know that I've got a way of getting out of it and it's my own volition to choose to do that and it's something I can tolerate and I feel normal.

So I'd like to highlight that last part because not that I'm the world's form of sex root in suicidal ideation, but as someone who came very close to offing himself in college and really just by a series of lucky events ended up not fulfilling that, it's the hopelessness. I mean, for me, and for a lot of people, it's the feeling that nothing can fix this. I am broken. I am permanently broken. There is no option other than trying to silence this

voice in my head. And the only way I can think of doing that is by ending my life. But once you see, once you experience even more so, something that alleviates that, especially with any type of durability, doesn't need to be forever, but some type of durability, and especially if it's rapid acting, right? Then you feel like you have a plan B. And that is incredibly empowering. Let me ask you a few questions. The first is

this type of neuro modulation is that synonymous with the term that I came across. I don't know who coined it. It's a nice term, electro-suiticals, or are those different? Yeah, it's part of that broader term of electro-suiticals. Yeah. And so what we had done with what we called, say, and or Stanford accelerated intelligent neuro modulation therapy, is that we came up with a way of reorganizing conventional TMS, which had been around for some time,

reorganizing it in time and in space. And so with conventional RTMS, it had developed the mid-80s, first uses a therapeutic within clinical trials by my mentor Mark George when he was at NIH, the mid-90s, and proved by the FDA in the mid-to-late 2000s. It utilized average sculpt positions to find an average spot to stimulate, which at the time given the technology that was available, that was the right call, right? Could I pause for one second just to give some additional

context? Yeah. What does TMS stand for? So transcranial magnetic stimulation, and it was originally developed for what? As a motor probe by Tony Barker in the UK, and the idea is this idea of Faraday's law. So Faraday's law is this idea that if you pulse a magnet, you can generate current and electrically conducting substances. So if I take an electromegnaf, I take a TMS machine to the beach and I try to pulse the sand, nothing's going to happen because sand is not, as you know,

electrically conducting at all. It's an insulator. And so if you put a TMS coil or any electromegnaf next to a wire, a copper wire, a speaker wire, or whatever, you can generate current in that wire. If you put the coil on the head, it will bypass the skin scalp skull and induce current in the electrically conducting substance in the brain, the kind of brain tissue, right? And so you're able to selectively turn on cortical neurons without really interacting with much of the

rest of the head. People do feel something because of the nerves in the scalp, but your brain can't feel anything. So that's scalp nerves. And so if you, as they did in the 80s, just kind of

send a single pulse, it doesn't really change the brain, but you can probe the brain, right? So I could take that coil from the mid 80s and I could put it over my hand representation, make my thumb move, I put it over my wrist representation of my brain, I can make my wrist move, and it's organized in this stereotyped way such that essentially the head face areas like closer to the ear and you you can march up to the midline of the skulls and it's such that when you get to the midline,

you're able to actually move the foot and the leg. If you have a certain kind of coil, you can do that. And so you can actually probe the entire motor system and make all of it move without having any volition to it. Question, what is the value of this probe? So the value of a probe itself is just as they thought about the mapping. Yeah, it's like it's a mapping exercise initially, right? Like where is everything? Is it the same? And everybody is it consistent? And they wanted to kind of have

a way of doing that non-invasively. Pinroes and others have been doing this invasively as neurosurgeons for 100 years, I guess 50 years at that point. And so they wanted to be able to emulate what the

surgeons could do in epilepsy patients, they're doing epilepsy surgery non-invasively. And then what folks realized over the next 10 years is we can send a signal into the brain that's like Morse code and basically send the signal to change the excitability of the brain and we can measure it if we do it in motor cortex by how much the thumb moves with a set amplitude out of the machine.

So if I get X movement from stimulating hearing and make the thumb move X amount and then I send this Morse code signal into the brain to tell it to tone down or to kind of be less excitable. And then I send that same intensity back in the thumb will move half as much. And so you've toned down cortical excitability if instead I get this measurement of X and then instead of putting in what we call inhibitory or deep-potentiating stimulation we put in excitatory,

potentiating stimulation into the brain and we do that and then we measure again it'll be two X. So we knew by the mid-90s that we could actually move around how excitable the brain was in these normal healthy control volunteer murder cortices and so the aha moment for Mark and his team was this idea that depression at that time on PET scans on spec scans was this kind of hypo

activity hypometabolism meaning lower. Yeah, lower activity lower metabolism of the prefrontal cortex where the prefrontal cortex just isn't as active as in as robust as it is in normal healthy controls and so he had this idea well could we use this excitatory stimulation to drive up activity

and so that was the aha moment and the kind of first version of this but they were super careful there'd been some seizures in the early days from trying to figure out how all this works and so they wanted to do a stimulation approach that wasn't going to have much of the way of risk and so

they had this once a day very extended protocol and because of the you know the mid-90s it was very hard to get cheap brain scans on patients and so this idea that they were going to have to use kind of average coordinates to target it and so they get average skull measurements and then

they would do kind of a low dose approach once a day and do that out for weeks and then it extended out to months and so the original TMS trials and the original approval was this less efficient version that basically utilized kind of a low efficiency signal into the brain and used kind of

average coordinates to place the coil so average coordinates meaning just by clumsy analogy like we can't take an x-ray of you but we do have a hundred other x-rays that seem to indicate roughly this is where you have your fracture so we're going to aim at those coordinates that's right yeah

that's right and the once a day protocol I've heard the number 36 from somewhere but is it somewhere in generally like the 30 to 40 session range yeah that's exactly right so we're looking at let's just call it for a placeholder 30 to 40 sessions one per day and two perhaps not

necessarily conjure an image but remove an image from the minds of some listeners they may be thinking this is a beautiful mind this is somebody chomping down on a wall at a piece of wood getting electroconvulsive therapy yep yep these are not the same thing yeah it's actually the opposite

so in the goal of electroconvulsive therapy rect which has been around for 100 years is to produce a therapeutic seizure and some people with autobiographical memory troubles it's pretty underutilized as a treatment and psychiatry because of these issues because of particularly one flu over the

cuckoo's nest and in that story and that that movie culturally has actually had an impact on ect and it's one of these things that's kind of for a lot of patients a last ditch resort because of the concerns around the side effects TMS is different you're not trying to induce a seizure in fact you're

not trying to you know have any sort of change in cognition I always tell patients is really boring so you know we have like Netflix running in the background and people have their Netflix movie that they keep watching every day and it's basically just once folks get used to it it's

just part of a routine where they're sitting there and and watching their show or whatever it is and the stimulators turning the brain on and unlike in ect there's no anesthesia there's really no need for anything you can do this in an outpatient setting but the old forms of TMS are

extremely slow you can't use that in a psychiatric emergency and so you know this is something that happens over a couple of months and it's tricky for some people like if you're a working person and you have to do TMS during conventional TMS during business hours and you're you basically

have to tell your boss or sneak out of the office or whatever it is and go do an hour and a half during the middle of the day during like standard kind of bankers hours to be able to do this and it's hard to do that over a couple of months and so and it doesn't address these kind of high

acuity emergencies and so we got very interested in this idea of can we like I said earlier reorganize the stimulation in time and space space being can we personalize it teach persons brain I can talk about that in greater detail and then can we compress these six week courses in this case into a

single day so that's why Deerger was able to get well and in a day is because we gave her a whole six week course in a day you have how many sessions that's 10 triple dose sessions and so it's like 30 30 total equivalent sessions in a day and so the FDA cleared 600 pulses of ITBS once a day five

days a week for six weeks in 2018 and that was for a major depressive disorder that was major depressive disorder we give a triple dose every session so 1800 pulses and so after 10 sessions you've got the equivalent of 30 sessions worth in that first day and you do that for five days and so people

are getting the dose equivalent of seven and a half months worth of TMS in five days and what we found is surprising to us that was this linear is that you know you just pick up remitters as you progress through the days what do you mean by remitters people who completely lose all of their

depressive symptoms to a level that is within the normal range so they're rating at the same level as somebody who's not depressed and you know we can get people there on average at 2.6 days and we're able to do that by personalizing the target and then being able to deliver treatment into that

target you know a lot of treatment over a short period of time and so it's useful about that is somebody can be in a really pretty bad state on Monday morning they can take a week off of vacation they may end up being on the impatient unit or whatever it is but they can go out

get this done and get back to work in a time frame that's actually reasonable and that was really our goal how do we get people acutely out of these high acuity settings and into a state of wellness quick enough that it doesn't make a major impact on their lives just a quick thanks to one of our

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com slash Tim last time drink AG1 dot com slash Tim check it out I've had a number of friends I've certainly heard of many cases where people with certain professions airline pilots firefighters police officers there many more will not report any type of mental health issue

because they'll be suspended in a lot of cases or relieved of duty they will they'll be forced to take time off and in a case like this where you have a compressed protocol there's the possibility of taking PTO or taking a week off and doing this treatment whereas like you said doing it during

bankers hours over months is going to be highly visible right and until the entire system changes which is going to take time if it happens at all this would be an incredibly attractive alternative protocol yeah if it were to work so please continue yeah absolutely yeah now that

and that's the way that we thought about it right is can we take folks who who need to get get well quickly I mean we had people in conventional TMS courses where you know they started they're in really bad shape they lose their job halfway through maybe I get better at the end of it

you know but it took so long yeah you know and so it's one of these things if we can compress that up and get them well in a short period of time and get them out of it you know it gets people back to their lives and it has a low impact on them and I know I'm interrupting a lot but the

threading of this I think is important so we can sort of foreshadow something that is going to be on the minds of a lot of people which is what are the downsides what are the risks so my question is like was it easy to get the sort of ethics board approval to compress all of this new a much

shorter time frame I was able to make a compelling case to the IRB and then eventually to the FDA around safety and so we give 90% of the arresting motor threshold that's depth corrected for atrophy so if somebody it's an older patient they have more prefrontal atrophy then you can

increase the intensity based off of that difference in depth with the motor cortex but essentially what their brain is getting is 90% of the resting motor threshold which is kind of a calibrated number that's based off of these TMS induced motor movements it gives us

a sense of how to dose the stimulation I'll show a bit of my hand here which is I've undergone two separate weeks with different hardware different protocols because I never want to talk about things like this unless I've put myself in the spaceship and been the monkey shot into space

which doesn't mean at this point I am a proselytizer 100% for the treatment but I find it very compelling at least for investigation so to just explain since I recently went through this each morning or certainly on the first morning but on multiple mornings in my case they will test

your motor threshold and that could be a finger or a hand it could be a foot and they'll watch movement really closely and then based on that determine these dose that will be delivered throughout the day during these sessions and in my case it was once an hour for 10 hours a day.

Yeah so it's just a way of getting the intensity that you need and so we know that 90% meaning sub motor threshold there's never been a TMS related seizure for that kind of sub motor threshold intensity even giving multiple sessions a day or whatever it is there's never been an event

like that it's always been at a higher kind of intensity of the stimulation in the moment if that makes sense so the amount of magnetic field that's being put out in proximity to the brain and so it's much more it seems to be much more related to that than it does the amount of pulses that

you receive in a day and so I was able to lay that out to the various regulatory bodies and show the evidence that that threshold is really the threshold where risk goes up sort of the the magnitude like the strength of the pulse not the frequency of the density yeah it's more about the intensity

in this case and less about the density or the amount so laying that out it was acceptable in various parties deemed it to be non-significant risk and they let us proceed now this is FDA breakthrough status FDA cleared all the way through all of the regulatory processes and so it's

kind of an unlabel approach these days but you know back then I had to make a lot of those arguments and you know knock on wood we still haven't seen any seizure how many people would you say at this point have gone through well-designed accelerated TMS it's definitely you know I'd say

more than four or five hundred in trials you know we have trials where they're ongoing and I don't know what the clinical outcome of those trials are because I'm blinded to them but I do know that AES we don't have any serious adverse events in the sense we haven't had anybody

have a seizure yet so that's good what you do see is headache people will have a headache it's usually from the not everybody but you know fair percentage of people and it's mainly related to the coil activating scalp nerves and basically kind of turning the facial musculature on and that

actually goes away over time so in the long term you actually see a reduction in migraine headaches you can see a reduction in pain all that sort of thing and people actually have an anti-nose deceptive effect anti excuse me anti-pain effect yeah what was the word you used no susceptible oh

new one yeah yeah yeah yeah yeah yeah and so you can actually have an anti-pain effect and the reason why we think that happens is because you actually anti-pain meaning it could help with chronic pain or something like this at least acute experimental pain there are some chronic pain studies you can see that you release endogenous opioids from stimulation because you can actually use opioid blockers and block the anti-pain effects of TMS so there's this whole kind of pharmacostimulation

thing that people are looking into buddy of mine Joe Taylor who's at Harvard now did these studies when he was an MD PhD and he was able to actually show that there is this release and then you can kind of block it with co-administration of of opiate blocking drugs but yeah that's the idea is

that there is some acute potential headache risk and people can get a little fatigued from this it's like fatigue more like you ran a marathon instead of like depression-related fatigue you know just from kind of being there all week look end of one here but seems you know I spent a lot of time

talking to folks as you know kind of my job my experience was headache for sure I was hesitant to take any type of Tylenol or medication for that just because and this is again as a naive lay person but I was like well you know like if you do take NSAIDs if you're doing say weight training

that can inhibit some of the adaptive response I'm not sure we fully understand what the hell's going on here so I'm I'm just going to deal with the headache it was tolerable I mean you could feel that the fatigue was the fatigue that you might feel if you were cramming for your final exams

every day it was not the fatigue of apathy and and hedonia like the difficulty or impossibility of finding joy and the things you normally find joy with like that type of fatigue is characteristically it was very different it's more like yeah you just crammed for 20 hours to try

to nail your finals because you didn't prepare and you're going to do that every day yeah that's the feeling question for you then we're going to get to the results I want you to discuss the sort of results of of Saint but I think before we do that it's important to maybe describe this

patient population because it is it fair to say that you're seeing it would be an exaggeration maybe say the worst of the worst but you're dealing with patients who've had multiple failed interventions so it seems like that's important to kind of keep in mind if that is true yeah

yeah and so on our randomized control trial people had an average of nine years of the current episode so they were depressed for nine years on average straight before they came into our trial at five plus or minus two med failures and they had a lifetime load of depression of about 25

years so these were folks who've been depressed multiple episodes are very long episodes and they tried a lot of meds to get out of those episodes you know these are not mild cases right these are folks who've kind of been through it for a long time and interestingly that's going back to the

the study that we talked about earlier with the flipping of the signal that flipping the signal was correlated with higher modus scores and so the more moduses the assessment I'm sorry yeah higher depression scores and so the higher your depression rating the higher likelihood you are

to have that signal from the data that we collected and so and that's what we've seen right got it and the switching just to tie it back to what we're talking about is that sort of having the the wrong lead domino or like you have a car where you're trying to start the diesel car without

heating the coil first yeah that's right that's right that's right yeah yeah so it's that directionality and so that's what we've seen folks that are at that kind of more in-stage sort of depression seem to be more responsive to this I think that's because in those cases you're really

correcting this pretty dense brain signaling problem if that PNS work you know replicates and what we've also seen is folks that do really well with door salateral at least or folks who are have a pretty impaired tension and so they actually score up on the concentration item

of the depression scales and so that was something we observed earlier on that if you're if you're saying you can't read a book anymore you can't really follow a you know recipe book to cook your favorite meal or whatever because you just can't attend to it then your likelihood of getting better

from this is higher whereas folks that are more on the kind of obsessive depressive side of things that don't complain as much about cognitive problems and concentration problems but more about they're just ruminating and kind of obsessing on things we've found that inhibiting the right

frontal pole or the frontal cortex so stimulating here and we have OCD trials to do that is pretty effective at shutting that down so it's more of a shutting down than it turning up sort of intervention so some of it's actually like where the illness intersects with the brain anatomy intersects with like the symptomatic presentation to try to derive the best spot to stimulate for those folks and we have some early studies now where we're trying to use brain imaging to actually sort folks

into buckets. Neurali to figure out which target makes sense for their symptomatic presentation based on their personalized FMRI scans. Yeah yeah yeah so I think this would be a good point and we'll mention this again at the end but maybe you could mention any open trials or if people would like to consider enrolling or they know someone who might want to become subject in the studies or anything

you'd like to mention. So we have a number of trials that are ongoing at the Stanford Brain Simulation Lab so it's BSL.Stanford.edu and you can go on the website and then there's like a screening portal and people can go on and fill out their information and essentially

we have trials for anodonic depression we have trials for you know standard severe treatment resistant depression obsessive compulsive disorder borderline personality disorder patients who also have depression bipolar depression and other pilots some addiction work that my collaborators

are working on and so folks have you know that range of symptomatology happy to have folks come through and screen and it's all free which is nice so it's all basically funded through these trials and we're excited to bring people in and see if it makes sense for them to work with us on this and it's a couple of week commitment. What did the results or what have the results looked like with st or slight permutations of that and how do they compare to let's just say more conventional

treatments for these same conditions. So in our original pilot study 90% of people experience remission at the post 90% yeah in the randomized controlled trial it was 79% of people transited through remission at some point in the four week follow up what's interesting is it's

not all at the same time point so if you look at time point by time point it's like in the 50 to 60 percent range the reason for that is because there's this colleagues of my Cornell connoisseurs and others have replicated this finding that there's a sub population of patients that actually

has a slower time to remission and we've seen those two the folks will lose their suicidal ideation and actually peak their antidepressant effect at one month it's usually an older adult and that's what we've seen is is basically it's only in 50 year olds and above we haven't seen that that's

sort of delayed remission that delayed remission yeah but if you're putting together 22 to 80 year olds you're going to have some of these folks but what's interesting is TMS also a probe of the system if you kind of ignore the kind of normal rules of how to define remission and you just ask the

question of who crosses through 79% of our active group crossed through 13% of our control group crossed through and that tells you something I think about the neuroanatomy you know that probably something in the 70% of folks have this door salateral singular problem and then that was a

version of that thinking was seen in our PNS signaling paper too about 70% of those folks had the flip in the signal and so you know my suspicion is is that there's a sub population of people who don't have that who have some other diagnosis it probably looks a lot like depression

but it's probably a different neuroanatomy and we've seen this sort of phenomenon happen in medicine before we used to cluster all the Parkinsonism together so there's lots of reasons that Parkinsonism you know some of those reasons are idiopathic Parkinson's disease in the classic sense the way is idiopathic mean just that it's kind of this spontaneous happening of Parkinson's disease that's the core Parkinson syndrome that we think about Michael J. Fox and others and then you've got other

things that look like it progressive super dukely or palsy Louis body dementia drug related Parkinsonism and so we used to kind of parallel to your like diabetes presentation earlier yeah exactly exactly so we forever lumped all these folks together and it really took the UK brain bank and being able to and that case for Parkinson's link Parkinson's pathology to symptomatic presentation is the UK brain bank and how I've never heard of this yeah so it's like a brain don't I mean there's

lots of brain banks or brain donation entities physical brains or we talk about scans physical brains after death post mortem donations so there's a lot of ways you can donate if you have a neuro psych disease you can donate your brain to science and so a lot of Parkinson's patients don't

know their brains to this brain bank to try to understand what it is and what they found was with like a deep clinical phenotyping before death so then you had this kind of deep phenotyping and then sorry what do you mean by deep phenotyping like a deep kind of understanding of the symptomatology

right so so basically you know does this person's do their trimmer happen on one side or both sides at the same time how do things present how do things present in an observable way that's right exactly in the same way just folks so you have like genotype phenotype right like this would be

similar idea okay yeah so basically what they found was clinically people that have the kind of standard Parkinson's disease typically tend to have a presentation of unilateral onset illness right where one side of the body or the other is much worse from a Parkinsonian standpoint than

the other and it's actually very common for people with Parkinson's to present where fits a leg onset Parkinson's or foot stragging or trimmer just in one hand and that's actually what you would expect from normal Parkinson's if it's like really symmetric it's less likely to be that it's more likely to be something else and they figure that out from essentially the brain biology informing that and being able to link up substantial Niagara problems they found on autopsy with symptoms

and so I think we're at the beginning of an era in psychiatry to be able to do the same sort of thing to take what's lumped together as depression or anxiety or whatnot and to be able to parse it into a lot of different what we call biotypes or into you know people think about as endofenotypes

or whatever these specific kind of flavors of that symptomatology some linked with a very specific brain physiology or brain functional neuronatomy such that you can say that this depression type one needs this treatment depression type two needs this treatment and so on and so forth and so

that's really for my vantage point the future right is being able to to really at an end of one level at a single patient level be able to figure out something about their brain and then help to prescribe what the next step is for them and you know if we can do that we can

also cut time right because we can go straight to the effect treatment for people and cut all the time around diagnosis and there's it's not just time it's risk right and in a lot of these cases absolutely it's risk from potentially the wrong treatment it's also risk from weight

cost potentially also right it's also cost yeah so as you know right like there's a period of time where the diagnosis is uncertain and then there's a period of time where the treatment is uncertain so for bipolar depression the average length of time it takes to diagnose somebody with bipolar

disorder from a depressive episode onset so they come in with depression and the depression's their primary you know presentation seven years till you get some right it's wild right and then that's just to get to that point now you're on the right realm of medications or whatever now you're

talking about in your seven you're having to spend whatever it is like three five seven more years trying to find a solution so you could go from being 25 years old and you know having this be your first depressive episode and you're still trying to figure out what you're going to do about it at 40

and you see these patients I'm just imagining you're like reaching into a dark closet and there's a what you think is a screw head and you're just trying different tools where you're not allowed to touch the screw head that's it versus like let's flip on the light take a photograph yeah

and then go find the appropriate tool for the job just a couple of follow-ups the numbers of your mentioning right the remission rates the people who pass through so to speak yeah how does that compare to like frontline conventional treatments right now you know oral antidepressants in

so there's a study called stardie it's a little it's been an interesting year for stardie in the sense that some people have reanalyzed that data and there's open questions about what the percentages are as far as what percentage of people make it to you know a remitted state

after going through this algorithm but essentially stardie started with a pretty low side effect burden oral antidepressants et alipram and then kind of transited through you know higher risks sort like scenter eyes and what's the trade name for estalipram would you know people would know

it's lexapra lexapra yeah yeah yeah and et alipram selects uh so those drugs you know and then you go to like scenter eyes like a fixer of in the vaccine and then into like the tricyclix them on amino oxycinibutors and so people would go through this algorithm and then they pop out on the

other end after five or six or seven different treatments and then they'd ask the question of after people go through all of this what's their remission rate so that number is kind of been called into question but essentially when you get into like med four which is roughly where

insurance used to start to pay for conventional TMS conventional TMS would beat that pretty well like almost double compared to you know your time at lithium or thyroid hormone things like that when you start getting into that step and conventional TMS would beat that when you get to those

kind of next even more severe steps you start to lose efficacy with conventional TMS so you go from like a remission rate of around 30 percent with conventional TMS down to about 16 percent when you get into the higher treatment resistance levels that's the levels that we ran our trials on

which really that were people normally get about 16 percent remission with conventional TMS that's where we were seeing those numbers could you just repeat those numbers were you seeing what numbers in our open label trial 90 percent in our randomized control trial depending upon how you

look at it it's in like the 50 60 percent at each time point or 79 percent if you're asking did people transit through remission at any more versus 16 percent nothing this wasn't like a head dead it's not a head of a speak but yeah but just just so people have some means of comparison

and in terms of pharmaceutical interventions at that point very low I mean you're talking about sub 10 percent efficacy you know this is around where we're electroconvulsive therapy is thought about right this kind of therapeutic procedure thing we were talking about earlier that's got about

a 48 percent remission rate but it's not fast either and you definitely can't work the day you get it and there's this autobiographical memory things you're talking about a like conventional TMS like a one to two month commitment and then quite a bit of risk for side effects there

you know you get ketamine which produces about a 30 percent spot remission rate with a single infusion and that goes up as you administer more ketamine treatments you know with the IV ketamine forms but as you go from a single infusion to you know what they did in this New England journal

paper those published a couple months ago like you know six treatments over a couple of weeks it starts to accumulate more time and so we're able to from my standpoint we're able to get the most bang for your buck the quickest and with the least kind of interruption and I think people's ability to do stuff during that time but there you know there are other things ketamine cell side and other psychedelic drugs that I think you've thought about and talked about in this

show before that are also coming over the next couple years. A few follow up comments and questions so you mentioned a number of things borderline personality disorder bipolar as two examples part of the reason that I'm so interested in neuromodulation right now accelerate TMS in particular

although I'm also interested in other things that I know less about like focused ultrasound and so on which we might get into if we have time is that many of the conditions that would be screened out there would be exclusionary criteria in say a psychedelic assisted psychotherapy trial are

eligible for this type of treatment which is incredibly interesting there are people also who might have something that is more common extreme hypertension some type of like ocular issue where physiologically psilocybin shouldn't technically pose a risk but if they have a lot of panic

rapid heart rate etc there might be complications right elderly patients etc so part of the reason this entire realm of treatment possibilities with neuromodulation is interesting is because these tools could be available to people who would not be good candidates for some of these other

things that you're mentioning what I'd love to ask you about because this has been one of the questions that's just stuck in my head is the topic of delayed remission so having these patients I can't remember the number I was looking at some of the charts maybe three or four people at

a end of 16 I can't recall that's right okay there we go who had this remission at like week four yeah or something like that how do you explain this and why is it older patients or does it seem to be older patients and how do you relate it to a few things right so in the case of say SSRIs

some folks also have this like a lot of people like delayed onset of benefits right yeah and then you have ketamine this is going to be a bit of a sloppy question but I'm sure you can clean it up for me then you have ketamine which is very rapid acting and I have heard I do not

have the credibility or the the means of parsing all of this like okay well ketamine acts directly on NMDA receptors seems like maybe SSRIs do that but in a very indirect way and that explains the delayed benefits in some patients don't know if that's true or not don't know if I'm

even wording that correctly how do you kind of tie this to or not the delayed remission because I'm just like how does that even work right I'm like okay if you put a drug in someone's head and it triggers a cascade or maybe it triggers some type of exceptional neuroplasticity that then

shows the fruits of that at weeks whatever two three four okay but I just cannot figure out I haven't been able to figure out like a plausible mechanism for the accelerated TMS and that delayed remission how do you think about that like even if it's speculation yeah it's and it

would be yeah it would be speculation but I think you know so we've only seen an older adults you know we know the brain plasticity and older adults goes down as a generality and there's a lot some metrics about why folks think that and you're you know you're as you talked about earlier

really it's it's claiming for a test you're actually sending a memory signal into the brain so the stimulation pattern you're sending into the brain is kind of Moris code is really a turn-on stay on remember to stay on memory signal that's going into the brain and you're just basically

taking the hippocampus the part of the brain that's involved in memory and like that signaling that comes out of there and you're playing that back through prefrontal cortex in a way to try to tell the prefrontal cortex to turn on and remember to stay on and I think part of what's

going on is because that older brain is a little less likely to have flexibility plasticity it takes some time for the signal to kind of fully lay its tracks into the brain we don't have any sort of biology to kind of back that up yet but what we're doing right now and we haven't analyzed this

data yet is we're actually scanning people every single day and we're scanning people multiple times out to the month and I find it funny you mean FM or FMRI scanning yeah yeah so we're actually getting like 10 scans spread out over it's a lot of coffin time it's a lot yeah yeah

we know people have been very cool about this and so with that we think that we're going to be able to potentially spell some of this out right like why are these delayed remitters happening but my suspicion is is that it's probably a plasticity related issue interestingly you know

ketamine and TMS may have more in common with each other than one would initially think right like you know a lot of the TMS effects are probably in part glutamate related is ketamine and then as we talked about earlier there's an dodging us opioid release from TMS we've done some work with opioid

related mechanisms and ketamine and so it's probably a confluence of not one neurotransmitter system but like an orchestra of neurotransmitter systems that are being affected across these interventions and you know it's my suspicion that that's probably what needs to happen in order

for these treatments to be effective and our old views on you know this kind of chemical imbalance sort of 1990s view of like one neurotransmitter one neurotransmitter receptor sort of problem of the brain is way too simplistic and that it's probably a lot more complicated as one would

imagine a lot more complicated than that outside of accelerated TMS if you're looking out say over the next five years for rapid acting potentially durable antidepressant effects what other tools or molecules or treatments are most interesting to you we have a paper coming out soon

in nature medicine on looking at at IBM as a potential treatment for in this case for military traumatic brain injury but a lot of these folks had depression generalizing xia disorder and PTSD and so it was a interesting that was another interesting story so as approached back in 2018

by a professor senior professor at Stanford who was tapped by some folks to kind of find somebody who'd be willing to partner with a non-profit called vets at the time who were sending and I think you've you've interacted with amber marcus capone a little bit yeah I interviewed Rick Perry and

Rick Doblin two years ago at their veteran state fundraiser yeah I was there I remember it was an interesting one here you know we partnered up with them and I had to again go to the Stanford IRB and ask them for another edgy and you know you have to give the Stanford IRB credit

can you just fill out IRB oh sorry institutional review board it's the entity that reviews all all research protocols at institutions and so this is the kind of governing body that's in place that's been around for about a hundred years that essentially is a non conflicted uninvolved group

of senior professors that look at your proposed research and then determine if it's ethical and safe and answering the questions that you think you're going to answer and so just like going to them to talk through doing accelerated TMS in St. we were able to talk to them about doing a study where

people would come to Stanford knowing in the IRB knowingly agrees to them then going down to Mexico to take an illegal in the US root bark extract that's been utilized for millennia in the country of Gabon and related areas and in central west africa and as you can imagine this was not

a quick turnaround nor should it have been for the IRB in the sense that I had to convince them this was science worth doing at that time though is it fair to say you're the TMS guy or was it like in the air that you also had an interest in exploring something like an iBoga and iBagin?

people knew that I was very open-minded to things them a pragmatist right I mean for me like patients the most important thing that I have this view of psychiatry that it's going to look like inpatient cardiology in 20 years we're going to use drugs we're going to use devices we're going

to be able to figure out what the best things is for that patient to your point you know some of these things are good for different problems and so I think that was known that I was open to that we'd we'd just been running this ketamine mechanism trial and so I was tapped to look at this and

a couple of other people too and I found out later they had gone to like a lot of people and apparently I was like the only person that was willing to do this trial like I felt kind of special back then and then like later realized that like a wait a second I was on the the bachelor at and I didn't

realize it so essentially yeah and then the bachelor at was a tricky one and so we ended up reluctantly agreeing to this and admittedly like I almost pulled out a couple of times because iBagin has this street knowledge and academic knowledge that it has a death risk right it has a

one roughly one in three hundred risk of death from Torsaud's to point this fatally rhythmic that can happen with certain cardiac acting drugs and it works through this what they call HRG potassium channel other things do this or like FDA cleared cancer drugs and they rhythmia

drugs that'll do it too so it's not in context it's like something that happens with lots of different drugs that we use but I think it was a somewhat of a stigma and a bias around particularly an addiction drug and so folks had been trying to get this through the FDA and I aged and whatnot

in the nineties Howard Lotzoff and others and it was a very complicated drug and I had known about it since residency I'd read about it I thought that you know it's like wow this is like the most promising anti addiction drug on the planet but I'd thought it was completely unstudyable and I

kind of like kept doing my other stuff and then at that point how did you come across iBagin where did you find it in 2012 2010 I think this has been like early debra mash stuff for no no I come across this book breaking up in the head by Daniel pinch back yeah and he and I was a big I think

he wrote for the New Yorker or something and I was stuck I was like going kite surfing in South America and I was stuck in the sand Salvador airport and there's like five English speaking books or something and I picked this book up in the airport like that was in the sand cell in the airport

yeah yeah okay and so I got a hold of this book and read it waiting on my flight which was like eight hours delayed to get to prove and so essentially he just like lays the whole thing out it's very interesting he talks about his own personal experience of it and I read a lot about it there was

some work that folks like Ken Alper and others had published on the kind of case report level outcomes but then also cardiac problems and then I figured it was kind of unstudyable and then in 2018 I was approached him was asked to do this trial and so we went to the IRB spending a

year back and forth and like right when they were about to they approved it COVID hit so we were actually supposed to start right when COVID happened and it paused the whole thing and then it took a while to get it back online but it was actually the quickest recruiting study I've ever run

we got 30 people down on like eight months now is that because of the sort of category of like potential death of despair I mean is it because of the patient population were you dealing with addicts so the patient population was and that was the unique part about this it was veterans

with traumatic brain injury some of which were alcohol use disorder so you know what we used to call alcoholism more than a third like I think 13 or 14 people out of the 30 but everybody had TBI a lot of them most of them had depression most of them had PTSD and so you know we're running

this trial I was put like my best neuropsychology postdoc on it in a couple other superstars when it was running in the background and I was like you know we'll get this into pretty good journal or whatever thinking we'd see some people get better some not whatever and I remember I was I was asked

to give a talk about it at a very prestigious university and ask the postdocs we just wrapped up the immediate post and ask the postdocs to put the data together and we have data to present for them and they showed me like the clinical outcomes and I was like completely blown away it was

way better than I think we anticipated very consistent improvements and like basically everybody some people would lose it you know before the month but most people held it and they're holding it out to a year now and I was floored I actually pulled them to delete all the code and

start the analysis over because they had to have done something wrong in the math she's always finding the postdoc always they kind of say yes and look at you he's ruined my weekend and so so we we did it again and it was the same exact findings so they I was wrong they're right they

had done it right the first time yeah and essentially really really striking and the time this will come out in a nature medicine will have published this somewhat prestigious yeah so much you know top five biomedical journals in the world and they that's like being nominated for best picture

of the Academy Awards I mean scientifically speaking right it's up there it's up there it's a nice deal and it's it was very surprising that for me that they were going to be open to publishing an open label paper which you know historically you're you're going to publish in that kind of a

journal like a randomized trial so just for clarity sake for folks listening so open label means no placebo control and also to just rewind for a second I want to mention to people that for accelerated TMS how do you know it's not placebo effect you mentioned the control group but that's a sham treatment right like you're basically people feel like they're getting a treatment but they're not actually getting the proper treatment yeah in that case you want to ask a blind guess and that's

actually been a big so I was going to get into here a big problem with with a lot of the psychedelic trials and why there's a lot of criticism for a lot of the psychedelic trials is that they kind of know that the blind guess is going to be highly skewed so it was one trial where they did

psilocybin frial call used to sort of there was like 99% correct blind guess rating so the p-value is highly significant in our saints studies to my like great surprise our blind guess was chance could you explain what would you mean by blind guess these are the experimenters trying to guess

who is in which this is the patients trying to guess what they got I see yeah so mr. Smith you you know you just wrapped up your treatment which treatment you get active or sham what's your confidence got it in what you got and so what we found which is really interesting for saint was

that I didn't know what people got but I talked to some of these people and I heard some of this so it was really interesting you know patients who've gotten totally better and they'd say things like yeah you know I just got lucky with placebo this time they ended up getting active and then the

folks that didn't get any better that they got sham would say things like you know I'm not even good enough to respond to like the active treatments so they so so it's confusing enough for them where they were making the wrong guess 50% of the time which is what you what you're looking for is about

50% error rate as a coin toss sidebar on that and this is kind of staccato the way that I'm trying all this conversation but having gone through two weeks different hardware different practitioners etc and having had a lot of conversations with technicians and so and it also seems like for some people it takes a while for their narrative to catch up with like the hardware upgrade right in the sense that they they say well maybe I got lucky or maybe I don't really feel that much and yet

their assessments are improving and or their significant others see dramatic changes right and that's true that's not specifically a TMS effect or a saint effect or sell rate TMS effect that's true I think for a lot of treatments you see that I mean I've even I've had calls and since our date has

been out on I began where I've had people call me and say hey Mr. or Mrs. so and so they like like look amazing and they're not they don't think they're they're any better you know and so I think you can see it across the board psychedelics you know neuromod there's a certain problem called

a lexathymia and about 25% of people of treatment resistant depression lexathymia yeah and so A meaning without lex meaning the ability to describe thymia mood and so they can't really uh describe their mood right and so they have an inability to accurately rate their mood and

the way you know that is Alexa thymia I'm gonna use that at a fancy cocktail party so tonight how you doing sorry got a lexlexa thymia and the way oh sorry you may better know that is difficulty to describe mode yeah that's it that's it sorry I'll I'll try to back off of a medical

medical joke no I like it I'm learning all sorts of words yeah it's an interesting term and it's an interesting phenomenon and you see this in psychiatric conditions like if you ask them very specific questions like well when's the last time you've been sad or thought about anything negative

oh it's like been a week or two are you depressed yes well why do you know that I don't know you know they just don't know it's also like a self-reporting problem too I think in some cases right it's like if you have someone like how many calories do you eat yesterday like most people

will be off by like 30 to like 60% or something yeah that's right and I think what the remedy for that is that you have a clinician radar and the clinician radar asks these really really pointed very detailed questions and then the patients able to answer and then it's like a formula to

calculate what that mood rating is in that case and sometimes it's just off from what their perception is they're kind of metapreception of the whole thing but when you get down to the brass tax their answer right and so we've we've seen that and that's been true across these

problems and there's ways of constructing trials to deal with that but yeah we've seen that with psychedelics as well so we went after military TBI and these were all special operations yeah they were basically all Army Rangers Navy seal former Army Rangers or former Navy seals and

there's been a big cohort of these folks that have gone down I mean some people in Congress have gone down and done this and it's spoken about it publicly I mean it's this national defense authorization act the NDA I think is just you know went through the Senate and the House

both approved it yesterday and it's going to Biden and so you know to earmark money for for I began for trials you know which is pretty cool so the military community and some of the government is pretty aware that this is a possibility there's been a lot of advocacy that Amber

and Marcus have been involved in and my hope is that coming out of a journal like nature medicine that really kind of validates what we were seeing and put some context to what we observed and what we found in our study will help to spur more funding and more focus and I think the the kind of

veterans psychedelic angle is is an important one you know for like a lot of ethical more reasons and you know and a lot of also like a political immunity bracelet right so it's it's a very that one important sub population and it's very fortunate that it aligns with sort of driving

forward the research around these therapeutic tools yeah it's super cool to work with those guys and this was a monotherapy in the sense that it was just IBM I know that at least in many places in Mexico they sometimes combine it well they don't combine it but they sequence it with

five Miodium T at the tail end was this I began alone yeah so it was I began alone and then we had folks come back later to do the five Mio outside of this kind of month follow up period but the data that we're publishing and nature medicine is just the I began effect it was tricky because that

kind of divorced those two together because that's what's been going on as you know in Mexico quite a bit so all of that acute out to the one month effects are all direct I began effects and it's you know super cool and the thing that that I found really interesting about this drug

is that it produces what I think is probably most stereotyped trip if you want to call it or you know the psychological phenomenon that happens alongside the drug effects and so people will describe this earlier life autobiographical replaying of emotionally salient memories that are apocalyptic

in time some people would got life review life review or slideshow yeah exactly and so you know it's interesting everybody's kind of got a different version with the slideshow it's that playing out to be like for them and so some people say I found myself in this room and it was

what my TV from childhood and all of a sudden it was playing all these things where I found myself in a hall of mirrors and it was playing all these things of like the context can be very different in the mind seems to shape that but the actual replay seems to be pretty stereotyped

stereotype meaning like it's a pattern that repeats it or it's just like a common characteristic it's a common characteristic and it's closed eye only it's not open eyes it's not for a lot of people that I began experience it's kind of really around this part this kind of replay part

that happens and you know from what I have heard there's kind of a cathartic re-evaluation of these memories and interestingly an ability to not only have insights into your own reasons which may have been good or bad for feeling or behaving or doing whatever it was but also reasons for

they have some insight and the reasons for the other which to me is like the hardest thing to explain you say one more time you when people have this slide show or life review they seem to have it as a third party person in the experience you know like what is this Christmas Carol Scrooge or

whatever when they go back and they go back in life and you see like you become the observer of your own past experience right it's kind of like that like Scrooge goes back and sees himself as a kid sees himself as like when he broke up with his significant you know all that stuff it's almost like

that like you're having a similar sort of thing where you're of use the analogy of Tom Cruise and the minority report where you're able to go back and see these events and what's so fascinating and why I've why I've said now I continue to say I think this is the most sophisticated drug on the

planet is that I think that there's nothing else that can seem to do this right where you have these experiences where you you're able to hold this neutral place and you're able to have this sense of where you were and why you did what you did and you have this sense of the other and

you're able to I don't know into it I don't know what that is you somehow stored it at the time and you weren't able to fully access it and you're able to access it whatever that is being able to forgive or to forget or to understand this person's position as well as your own and then

seemingly like unlock the lock on both sides and then dissolve the problem and people say they'll they kind of would work through all of this and you know there's one better and you know would say well I went through all this military stuff and at the back of the room it was my early childhood

trauma you know and so this idea that at the core of it for a lot of this ends up being a childhood trauma thing that's kind of buried below all of it and really being able to actually both access that in a way that you can understand understand that in many cases the traumatizer was themselves

traumatized and that it's a pattern of trauma and the ability to kind of resolve it by understanding at this kind of you know more meta empathic viewpoint and so that's right I think the tools really going to be important is this ability to have what seems to be a pretty profound or a trophic effect you know we were able to see disability improvements from traumatic brain injury but also this pretty pronounced kind of cathartic re-evaluation, re-consolidation of past life

problematic memories. All right as I want to do let me happen with just a few comments that we can bounce around if we want and then a whole bunch of questions so that the first comment is with the special operations vets who are friends of mine what I've

observed maybe similar to what you're describing that is part of what is contributed to them being extremely high performers in these high stress environments is their ability to tightly compartmentalize which they developed when they were traumatized as kids super high overlap like

incredibly high overlap of course there are many other factors that contribute to them being like the one person out of 10,000 who doesn't get washed out of training right being that unbreakable in a sense but I with those friends and look it's tiny sample size but of those friends like I

wouldn't say any of them would claim to have PTSD or moral injury like a feeling of having done the wrong thing but the TBI and this is where I want to lead into a question which is not to negate the fact that a lot of people could have of course meet the diagnoses for complex PTSD and so on with the TBI what makes I begin different from some of these other psychedelics and I want to say one maybe place to explore would be glial cells am I making this up?

Glial derived neurotrophic factor yeah glial derived neurotrophic factor there we go what makes it different in terms of mechanisms of action therapeutic effect compared to some molecules people might be more familiar with psilocybin or otherwise the classic psychedelics like psilocybin as you

know primarily affect the five HTT A receptors right so they're five HTT A agonist they produce these kind of classic psychedelic experiences from largely from that receptor you can selectively knock out five HTT A receptors you can knock out the psychedelic effect so we've largely thought

about kind of this class of psychedelics in that way I began to know neurogen so it produces a dream like state some people call it an atypical psychedelic you know we've elected to kind of use this in the origin term because I think it more accurately reflects what's going on in the trip

and in the way of kind of perceiving what it is it does have some five HTT A action but that's probably the minority of the effect it affects a broad range of other receptor systems like salvia for instance as a capa agonistrate you know and so there's capa mu effects there's an MDA

effects with iBegin there's certain effects so certain effects and then there's this upregulation of beating up brain drive neurotropic factor and gDNAF gleeldrive neurotropic factor and so and both of those are you know profound neurotropic factors for elasticity and the brain the problem is

this has been psychedelics were thought of as relatively obscure 15 20 years ago to study obviously that's changed now but iBegin's extremely obscure right so there were a handful of studies that were performed in publishing good journals over time but it's very limited in the data that we

have so far so it's hard to like give you some sort of definitive answer what I can tell you is that there was a paper published you know I think 15 or 20 years ago where they took mice and they got them to self-administer alcohol so that's kind of like a wave like an addiction model or whatever alcohol self-administration or sucrose self-administration sugar self-administration it's like a wave kind of getting you can put cocaine in the water and get you get my addiction

yeah exactly and so if you give a mouse iBegin you can get them to stop self-administering alcohol it's interesting we saw that humans have stopped drinking as well in our study or you can in this case you could actually drill a small hole in the mouse's brain you can inject GDNF directly into

the ventral tegmental area the area that produces dopamine for the kind of more of the pleasure of seeing part of the brain and it emulated the same effects as the iBegin right so this GDNF effect in the dopamine system at least and GDNF has thought to regulate dopamine neurons and so

you know I think that that's probably at least a pretty strong part of it and what makes it so unique but I always tell people like where I'm talking about this iBegin stuff like if we gave one of the big pharma companies a hundred billion dollars and said don't just recenthize iBegin but

make a drug that works like iBegin or I think even some of the classics psychedelics but really specifically iBegin I think they'd have a hard time doing it because we don't have the neuroscience to understand what's going on there and I think it's because it's not a one receptor

it's not super clean in that way right it's like promiscuous people use that term dirty drug I I think it has the wrong connotation but yeah yeah I mean like LSD is pretty for kind of the promiscuous on the room yeah so I think for me promiscuous I like to think about like

sophisticated I like to think about like a symphony there we go right like you're interacting with these neurotransmitter systems and proportions in such a way that it produces this effect my suspicion is that it's probably more sophisticated than we want to attribute and I mean maybe not you but

like the scientific community wants to attribute to nature being able to pull off you know but it's this idea that maybe somehow we have this drug that just happens to work the way it works because it's able to interact with these systems in pretty important ratios or pretty important kind of

simultaneous effects and that's really what's driving it and and that's the part I'm saying it's going to be hard to reproduce I mean obviously Sasha Shoggin others were able to take emulates similar sort of 5-HT2A effects but I don't even think he was able to produce an eye-begined like

multi receptor sort of symphony like this there hasn't really been another drug like it in this way and so trying to think about what that is and how to really how to study it it's going to take a new wave of neuroscience tools to be able to capture all the effects you know in real time of

symphony of follow-up questions okay and as I'll so I'll give you you can choose this is the dealer's choice you're the dealer so we could go with and we will get to all these but improving the safety profile of IBM which I should also say like I've had people reach out to me

which is always can be very uncomfortable for me but like friend of a very close friend and in this particular case someone's sister was a heron addict who is now homeless acting as a prostitute like living under an overpass and the reason I bring up that level of detail is that

for a lot of interventions in this case I began at that point the cardiac risk or some of the risks were known and there's a question of is this risky and the follow-up is compared to what and in this particular conversation as well she could die tomorrow yeah from an OD or this is

the other thing so so I'm just kind of saying the table with that but improving the safety profile right is one question another because you mentioned the cessation of or the minimizing of the AUD right so like people stopping drinking yep we were also talking before recording people

stopping drinking caffeine I guess or coffee yeah right okay unexpected presumably yeah and so my question there which I sort of seated I've said I mentioned I would want to talk about this it's like any overlap in terms of mechanism around how does this compare to something like semi-glute

hydrolytic and ozemic or some of the the neurogeno I think it's mongeraume getting that wrong and then the last one and I've been wanting to ask somebody about this you mentioned 5HT2A it seems like some psychedelics exert effects also on 5HT2B receptors and if I'm not mistaken there's some

data to suggest that that can continue to stimulation like agonism of that B can lead to some type of cardiac complication as well like some type of like vent like a particular hyperchip valves valves exactly so the question there is do you think that micro dosing for instance which has

become all the rage could that potentially have long-term negative cardiac effects the FDA guidance document for psychedelics that they released actually like on the last day of the psychedelic science meeting which is really interesting is specifically has a section about this issue of

cardiac valve real or problems particularly from these more classic psychedelics the problem with I began is different right the problem I began is that it interacts with her potassium channel there are a number of groups folks Columbia folks at UC Davis who have looked at this and their

solution is to modify the molecule and to affect it in such a way that it no longer interacts with herg is that you do mean like nor I began or something like that or is it normal nor I began the primary metabolite of I began that goes after 2d6 is a normal part of the I began process

has a similar cardiac risk profile so it's drugs that are I think they call them like tabernethalogs or something but I boga logs or something I think is what what was coined it Davis but essentially these are drugs where they like try to engineer off that interaction which

may or may not have an effect on its brain effects and so I want to answer the question I'm trying to ask and the question I'm trying to ask is does I begin help with certain you know human illness by modifying the molecule it's not I began anymore it's something else and then you're asking

the question is is something else help the viewers maybe it's close enough to I began to do something similar and I've taken like a different stance on this where I've basically taken the frame of how do you preserve the molecule and really lean in on the cardiac risk how do you put an

airbag in the car instead of redesigning the whole car instead of making it up you know an airborne shuttle or whatever so it's putting an airbag in with a you know with a high likelihood of saving the person and so we talk about this in the article but essentially all the patients

that were treated received twerzads like IV magnesium at the start right what type of magnesium so it's like magnesium sulfate so it's basically just like IV bag magnesium and so what's really interesting about this arrhythmia twerzads that everybody's worried about is that the treatment for

it for the American Heart Association guidelines is to give IV magnesium which is incredibly safe and I've given many times for various things and the ER and you can just give it to people and you'll eventually urinate it out or whatever and so you can give it get people through this risk period

they may be slightly hyper-magneticemic or a little high on their magnesium and their blood and it'll go out and everything's all good and you know there've been about a thousand operators have gone down to Mexico so far and to my knowledge and we looked into those pretty significantly there hasn't

been a single case of twerzads conversely like the New Zealand study that was published a couple years ago they had a death out of ten people and so we're not doing head to head I can't tell you for sure what the deal is there but my suspicion is is that if you give what is the treatment for the

problem you're worried about before you give the the thing that can cause that problem then it's much more likely that you can knock out the risk or significantly reduce the risk it's also about doing it in a monitored bed setting so TIKESEN TIKO SYN is a drug that is approved

for atrial fibrillation and it's an anti-rhythmic that can be pro-rhythmic in the same way as I began and actually has more risk than I began the rates of twerzads are higher with TIKESEN it's approved and it's totally safe you just do it in a monitored cardiac bed and so I think that

we have to my suspicion is if we're going to do a study in the US with IBM we're just going to need to do it in a monitored cardiac bed with cardiologists involved and I think if you do that you're good right I think the trick is between now and when you know in theory one could see an approval

eventually from the FDA for this you're going to have to think about will not just can this place in wherever Mexico wherever it is provide you know a good pure form of IBM but what's kind of the wrap around risk reduction there and I think that's what people have to think about is they kind of

think about you know that taking on that level of risk it's not trivial risk though it's a real risk the reason why the veterans that we studied were so interested in going is because as you point out there's a lot of risks from not doing things too there's also a lot of social proof in that

community now oh yeah right and like a friend will go down with their friends to like sit in the same room and it's a tight group right it's a super tight group and it's pretty cool right and I think it's the reason why did the trial ultimately my view was there's no way that all these special

these very high performing special operators are all going down to Mexico and taking this thing which is not recreational at all and spending a week down there dealing with this and then they're not really getting benefit they're getting some pure placebo effect it just seemed unlikely to

me given how treatment resistant and how many things that these folks have done how much time it's been in the VA hospital and all that good stuff and so you know that's why we did it and what we found was enough of a consistent finding and this reversal of of disability such that the well I

can't tell you this works because I don't have like that level of evidence on it that the signal that this could work is really high it's the highest of any kind of brain acting drug I've been involved in looking at okay let's talk about the alcohol and the caffeine yeah so mechanism of action

I mean you sort of mentioned the GDNF in the animal models like the direct kind of injection how do you think about this and does it in any way tie into what we're seeing with some of these drugs that are I guess designed for type 2 diabetics like semi-glutide and

the ozemic like drugs but they're having such an effect on various types of cravings that large box retailers are having to revise sort of in a panic their sales projections and inventory planning around like snack foods and stuff I mean it's wild to see like the societal ripple effects.

Walmart apparently has yeah yeah and I have friends who have been obese effectively their entire lives never had an exercise habit now they're doing pull-ups for the first time which is again not an endorsement because I don't understand and maybe nobody really quite understands exactly

these things work but I certainly don't so I'm not yet there but how do you think about this are there any overlaps with these are they completely different mechanisms just presenting similarly there's no evidence that there's a direct overlap in mechanism just because the kind of

CNS kind of psych addiction side of things people are still in the like is this doing something yet looks like it's doing something there but not any deeper than that I think we'll learn about that on the kind of ozemic drug side of things and then I began to spend relatively under explored

basic science standpoint but my suspicion is is that it is probably similar enough and maybe some of the same mechanisms are being enacted because what you're finding is a similar phenomenon across both instances we thought these were diabetes drugs and then there was a significant weight

loss observed and then we thought these were weight loss drugs and then everybody's quitting all their other habits and placebo works by a phenomenon called expectancy and as you can expect from the term it's expecting something right so you're primed to think that this thing's going to help

for this reason I'm always really glued in when you have really obscure off target non-expectancy phenomenon happening so in the in our again trial as you mentioned a minute ago basically everybody quit drinking coffee for a period of time and like none of them really went into it as most of us

don't our coffee habit is maybe a concern you know looks like coffee like protective against like Parkinson's and some other things you know so it's kind of a mixed bag about that but it's generally the thing we're the least worried about trying to deal with right is a generality people

are much more focused on dealing with being overweight or focused on you know their alcohol use problem or they're in this case PTSD and depression and TBI and all these other things that folks were worried about and so when we started seeing like consistent reports of people stopping their

caffeine intake it was really a signal for me I was like you know what that's really interesting I mean there's probably a bigger systemic change that's happening and what people will tell you phenomenologically about this is it puts a pause in between stimulus and response

and a phenomenal and I can't like prove this this is just what everybody seems to come back and say it puts a period of time between when you normally have a trigger to do something and go do it and it was a habitual action and really kind of gets into this question of

prewill and all this stuff that people think about where there's a moment where instead of making the habitual action the person finds himself an purely unbiased choice phenomenon and what people have obi used to sort or would say in those scenarios when they would relapse after

I began is they'd say you know what I just I had something about it and crave it and I just wanted to do it or something wanted to remember or whatever but it wasn't this habitual action right and they go back and they do I began again after they'd gone back into the addiction and then they

they had all the negative consequences and they'd say you know what they got back to that choice again and they're like it's not worth it anymore I'm going to go this way but they're able to pause and make those decisions and it sounds like from talking to the various veterans that have gone through

our study is that they approach things like coffee and they'd be like you know I'd do this but do I need to do it which is really striking actually it's not something that people typically tend to do right you get into all these habitual actions and your your life is just made up of a lot of

habitual actions and they they were able to reevaluate all those habitual actions and then establish new patterns the drug eventually is going to wear off you know as all drugs eventually do and you probably do lay down a level of habituating again but if you could during the period of time

when your brain seems to be pretty plastic you know shift and lay down new patterns that when the drug wears off, assumeably you kind of lock into that new set of patterns and I think that's what's really interesting and probably a little bit different than the ozimbix in the sense that

the ozimbix seem to kind of take away from what folks will say a lot of the like seeking or rewarding aspects of things like food or whatever it's just cravings yeah cravings whereas this seems to introduce a level of choice what would be very interesting you know so you know kind of

alluded to this earlier is you know you take somebody who has a pretty significant addiction like this and you give them and I began sort of drug and then you think about how do you use something like an ozimbic to kind of follow on with that right we're able to kind of gait some of it and it's way out there and probably not anything anybody's going to do anytime soon but it's an interesting idea right of these are essentially habit affecting drugs that we haven't had tools to really use before

which I think is pretty cool yeah and folks who want to dive deeper into this sort of reopening of let's call it critical windows I mean that I'm borrowing the terminology from professor Gould Dolan but pretty fun stuff to dig into as well if you want to sort of scientifically

at least for the time being reinforced what a lot of experienced facilitators have been saying for a long time which is like the post period matters a lot if you're gonna have knee surgery make sure you do your your rehab all right let's hop to a few other questions one is coming back

to I began specifically the two things that have been of greatest interest to me with respect to I began our tbi right so if someone has no addiction no PTSD the only issue they have is some form of tbi do you think there is a role for I began so you can place hold that there's part two to

this question which is I've heard reports and I haven't gone into literature on this side I don't know maybe this has been explained somewhere but I've certainly heard reports of opiatex who have seemed to indicate that I began or I bogeh opens a window after treatment during which they do

not seem to experience much in terms of withdrawal symptoms and I want to know what the hell is going on there if that seems to be observed right so those are the two questions somebody who just has tbi do you think there might be a role for an I began or something like it compared to other options

and then the seeming diminishing or disappearance of for period of time physical withdrawal symptoms it's a little tough with the cohort that we studied because they were you know as military tbi while I understand that the PTSD diagnosis is pretty ubiquitous in the system it's

probably true to fair amount of folks especially folks who've been exposed to a lot of combat related trauma in earlier life trauma in in our group it seemed to be there and most the participants it was depression and anxiety and so we haven't studied a pure tbi group and so the confound is

without studying a pure tbi group that somehow had maybe it was a competitor in martial arts what do you know or something like multiple concussions yeah something like that where they like you probably intended to hit other people for sure but intended intended to go into the ring

knowing that you're probably going to get hit because the problem right is in a lot of these cases motor vehicle accidents there's really high rates of PTSD in those because there's not an expectation you're about to get hit in the head but there's probably a population you could study

that's pure traumatic brain injury where I'd have like football players right I mean yeah we've football a lot of reported depression who knows it could be a lot of other factors involved but yeah football players another great example highly correlated yeah yeah and those guys know they're

going to hit their head in the game probably at some point and so that population where it's more of a pure tbi population you know you could ask that same question that we asked in this more you know mixed population which is does tbi disability improve we saw a dramatic improvement in tbi disability one month mark less actually right after it really took a while for it to work if you had to guess right we're two drinks and I'm like no just give me your wild ass guess like mechanistically

what's going on here it's the symphony right which is sounds kind of like maybe even hokie or like a little like less direct but I just think that there's something about interacting somehow with multiple different neurotransmitter systems at the same time that must produce

this I mean the maybe the gd and fbd and f alone could do this I'm not saying it can't but I suspect that it's a more complex process and the problem is we don't have great tools to evaluate that but sometimes nature is trumps are human scientific abilities and I think that that i began certainly

is there in 2023 it's like the story of scurvy right like we associated eventually after like a bunch of weird stuff we eventually associated eating oranges with improvement and scurvy but it took us another hundred years to synthesize vitamin C yeah you know and so that's I think what's

so hard about this scientifically and to get the kind of scientific community fully on board with these ideas is that we're likely going to figure out this works before we have any idea on how it works your second question which is I'm going to answer it the same way but it's very unique to iB

and you can take somebody who's going through florid opioid withdrawals and you can have them not only have a cessation stopping of of a desire to go take more heroin or prescription opiates or whatever it is but you can have them basically blunt or completely attenuate the physical withdrawal

symptoms of withdrawing from opiates which is diarrhea like headache sweating all the stuff that people will go through when they're going into opiate withdrawals and this seems to really kind of like knock that out it's likely again that because it's interacting with the opioid receptor as it's

interacting with the glutamate system but it is to my knowledge none of the other psychedelics can do that kind of mean can't really do that so this is a pretty unique thing to iBegin that it can pull this off and why i think it's such an important drug to understand i mean i would argue

that because of how broad iBegin seems to work across now most of the major psychiatric diagnoses with the absence of something like schizophrenia but anxiety depression PTSD this traumatic granetry you know multiple different addiction types it's going to behoove scientific community

to really kind of break down why it does what it does over the next couple of decades i think and try to really kind of back engineer what it is but yeah we have no idea outside of the lab and more in the wild what are some of the more interesting things happening related to iBegin

and iBoga i believe there's something happening Kentucky yes i've been down to Kentucky to testify in front of the opiate abatement commission of Kentucky it was myself along with shreni rau tae devermash whose CEO of dimmer x was at the University of Miami for a while in canelpros

who was it in my unit is it kind of an academic prior practice psychiatrist and there's a guy by him at brian hybrid which is he's a very interesting guy is an attorney by training who has worked in a bunch of different domains within Kentucky state government and whatnot and he

for one reason or another has become completely convinced that the money that ended up being some of the lawsuit money for some of the opiate over prescription that happened particularly in Kentucky and West Virginia but all over the country should be utilized for novel therapeutics and

not just for more of the same sort of treatments that we have available the conventional treatments that are available for opiate used to sort of fall into the realm of what we think about is replacement therapy you're replacing a higher risk opiate with a lower risk opiate so that's

suboxone and which contains buprenorphine and methadone or opiate blocking drugs like neltrixan there's a fairly high fail rate on those drugs part of it is psychosocial you know we put people in the right environment you could probably drive up the rates of that there's also a prescription

issue you used to have to have like a special FDA license to prescribe it i used to have this thing and then recently that was knocked out so everybody with a medical license can prescribe suboxone and so there's kind of a group of drugs that can do some work on this but there's

certainly folks that we would think about as treatment resistant opiate used to sort of patients and the numbers i'm not going to get into because there's you know they're debated or whatever but whatever those numbers are it's a good chunk of folks and they don't really have much to offer

and so people have thought about lots of different options for them and one of the options is brain surgery so in West Virginia a group of neurosurgeons are actually doing full on there's a surgical form of neuromodulation called deep brain stimulation where you can actually put an implanted

device into the reward system and also kind of similar to to some of these wigovies that kind of drugs you can drive down some of the pleasure around and this is more theoretical at this point of opiates as well as there's some data out of you know a couple of different studies with even

like weight loss for stimulating in the reward circuitry what's interesting is that there's a one in one hundred risk of a head bleed from that treatment and about a third of them it ends up being a pretty significant head bleed right yeah and so what's really interesting is you have no

one in West Virginia organizing all these hearings about it's just happening they're letting people do the science and all that stuff and i don't disagree with doing that by the way i think it's a useful thing to explore and it may be a solution for this and this is as we described earlier such a

high risk phenomenon that a one in three hundred risk is not is that one in three hundred one in one in one hundred one in one hundred risk of a head bleed it can be a trivial just blood on the tip of the electrode which is asymptomatic about a third of those people are going to be you know

in a more significant yeah have a real complications so and then you get about one in three hundred risk of a torsades risk with iBegin right and so next door in in Kentucky similar odds yeah you got a similar odd concern you know both of which can be kind of dealt with in the hospital

i'd argue that the iBegin risk is probably a little less actually than the dbs risk if you just kind of look at everything and they're having these significant hearings there's a lot of opinions about this and a lot of shocker right and i'm you know i'm one of a few people that does all this stuff

so i can kind of and you juxtapose part of the reason why i have this conversation because you like you bridge a bunch of interesting often separate worlds anyway thanks been yeah so i went down there and there are a million questions about the cardiac risk and about whether or not

this should be done and in particular they should state funds be funding this and there are various opinions about that my opinion and the reason why i was willing to go down there and support the effort is there are a sub population of people in which suboxone now trick sound and methadone

don't work and we we need to spend some money on trying to help those people also working is you know quote-a-quote working has different outcomes right and if you're talking about like substitution therapies as well right yeah now i think you're totally right i think it is living

on opiates if you're you're having to do this your whole life i mean it's tricky lose your prescription and a flight to wherever in the niauer in a really bad place and so this idea of instead of replacement substitution or whatever interruption which is what i be in is going to do and i think

at some level what dbs is going to do too right it's going to interrupt that system that circuit that's driving the seeking behavior and be able to kind of reorganize the brain such the person approaches the problem in a different way is a promise that i think everybody wants to see i

think that the interesting part about this whole phenomenon down there is you know from the folks that are opposed to this is this view that one that the current treatments are fine or whatever and then two that how could it be that this extract from a root in an african country somehow be

something that can do what modern humans in pharma can't do and it goes back to what i think is a pretty hebristic part of the human psyche which is that i need to start the fire i need to hammer the wheel i need to you know and i think at some level this would have not invented here kind of thing

yeah yeah right and and i think the idea that somehow somehow this just exists it goes around the psyche in a way that doesn't really work and we saw this with scurvy too right i've spent a lot of time like studying scurvy because i i'm very interested in this human phenomenon

there were people called anti fruters i'm not kidding you it's a real term wow and they were in the royal societies in the 1750s and so we knew from 1498 that folks that were going around the horn of africa and going to Asia that way they'd plant like citrus trees all the way there so we

were doing this and at some point scurvy got worse and all that and people said there's those like literally no way that these fruits could be the solution for this humans have to solve this and actually the fruits are probably what's making it worse yeah yeah so james lind ran the

first clinical trial in the history of humans on scurvy and citrus fruit regained all these like various weird concoctions like poisons and they were trying to get people cyanide they were trying to get people alcohol mixed with acid this is what they tell me yeah and so he gave people he randomized

people on a ship with scurvy to these various things and citrus fruit and what happened was the citrus fruit receiving people at the end of the week were taking care of everybody else but it took another hundred years i think this is this meta phenomenon of people need to feel like

they made it in that culture within that context this is the latest and greatest thing it needs to be kind of like very proximal in time it needs to be new you know it's got to be the new thing to be the solution and i think that's part of what's going on in Kentucky for my view of it because if

you look at west virginia and you just look at like the actual information of what's going on you'd probably be more likely to cause and i don't think that people should but question the brain surgery thing if you really get down to it over the i-begin thing just on the risk portfolio and

having to have a implant device for us you're like but nobody said it was like nothing there and it's because we're making this western society is making this really innovative new treatment that requires a brain surgery and that's totally cool from their perspective and i think that we've

got as a culture and as a scientific community really changed the way that we think about evaluating tests and particularly therapies and look at the inherent scientific complexity and not the temporal proximity and the fact that we made it or whatever you know those sorts of things that

that i think drive people to have these misconceptions and so so yeah so Kentucky's really interesting it's really an argument about whether or not some of this money should be earmarked and whether or not it should be studied and i think both of those things are or yes you know we

should be it's the best candidate that we know about and the risks are mitigatable and similar to to dbs so many facets to this like insurance reimbursements scaling therapist availability or i should say more medical availability for like the duration of stay that would be required with

i-begin versus like there's so many facets to all of this in terms of say getting to patient 10,000 right for whether it's this dbs implant surgery or i-begin right there's so many levels of nuance but at the basic science level and the further research who might i say but it seems like the

cost and severity and prevalence of the problem is such that the answer is of course yes yeah of course it's yes i do want to ask you about synthesis specifically really a dive again because i'm always fascinated by rate limiting steps and also unintended consequences of

using different compounds that occur in nature before we get there i want to very selfishly throw in a wildcard question around irb's and funding studies and getting ethical approvals because i would love to see more studies on extended fasts and humans but to my knowledge those

basically got taken off of the table if i wanted to try to make the case and fund some science related to extended fasts and humans any suggestions i think everything's studyable of the risk benefit ratio is on the right side of things at least it's damford i think that's the evaluation is extended fasts in normal healthy controls but i think if you can make an argument for some sort of medical psychiatric whatever it is condition that you think that the benefit of doing that significantly

outweighs the risk i think i can make that case then i think you can do it yeah and so it's really is just that right it's this ethical and i think it's i agree with it right it's this ethical justification that we're going to be able to do more good by trying to do something like this than to do harm i mean if people a study that would never go through any irb is we're going to randomize people to no motorcycle helmet or motorcycle helmet and have them do laps around the university you

know like we pretty much know the answer to that question and the benefit of knowing and a randomized controlled trial way the benefit of the answer to that question you know does not outweigh the risk at the individual patient or participant level of participating in a trial like that so that trial

would never get done right and so i think that's the way that we that we have to kind of look at it so if you've got a reason your reason is you think that there's going to be some effect on coronary artery disease or something like that i think there are a couple of different

approaches i could take just in case there's anyone listening who who wants to do this uh and there are extended people study fasting in animals all the time but it's said that for whatever set of reasons at some point it seems to have been taken off the table for human subjects i mean

there was research done i want to say like that up until maybe the 40s and 50s but then it kind of vanished and i'm very interested in if i had to make the case i would probably make some type of case around what chris palmer at harvard and other people have called metabolic psychiatry so to look at

this almost like the accelerated tms equivalent of a ketogenic diet for certain psychiatric conditions because you see some incredible results and chris has been on the podcast with say ketogenic diet as applied to conditions like schizophrenia for instance i mean remarkable

transformations where people get off of half a dozen or a dozen medications and like you i am interested in practical solutions and especially things that are uncrowded from the perspective of scientific support which for a while has been psychedelics but certainly accelerated

tms and agnostic when it comes to the tools and i think i'd probably make the metabolic psychiatry argument but the fact of the matter is i also feel like it's been so long since we applied modern tools and tracking of biomarkers and so on everything that we have at hand now too human

fasting that may not be the argument that i would use but certainly there's that okay so synthesis there's a great piece that came out in national geographic not too long ago by journalist named Rachel newer i think i'm getting the last name right and you w e r she also has a great book on

mdma an mdma assist psychotherapy the history and implications that recently came out and she traveled to i think it was good button although i think there is also you i think you can also find iboga in camera room from not mistaken and she went on the ground to look at all the implications

of global demand for i've again and iboga and it's very very nuanced but it seems clear and i wrote a piece a long time ago on my blog which was a letter to users of psychedelics i can plea for a more ethical menu of option something like that to just point out some of the diminishing

natural supplies for say peyote almost certainly going to go extinct use something else use simpadric act is look at the growth cycles just don't touch it unless you're part of a culture that has us as an integral part of tradition and healing as would be the case for say people who are

in the native american church and so on but i began can be had and i guess a number of different ways maybe you could speak to like the known options and then looking forward with some of the most interesting options are for whether it's like extraction or synthesis it was kind of the straight

extract out of the iboga trees you're pointing out and that's that one's probably a pretty big ethical issue because what's happening and i think that national geographic article really reflect this is that there's such a global demand that drives a price is up in the weaty the people's that

take i began iboga and um gaban in in surrounding countries no longer can access it because of the the high cost which is the last thing that you want to have happened right that's the thing that you're that everybody i think should be trying to avoid first and so what else can you do so another

way to do this is that there's a another tree and then gana another places in africa that has vokong gene is vokonga african is treated and has vokong gene which is a very similar but not identical alkaloid to i began it's actually not even a controlled substance so vokong gene is

not on the controlled substances list and it's not as much of an issue because there's not really a current medicinal usage of vokong gene or utilization of that within those cultures that have these trees it's also more commercially cultivated if i'm not mistaken right for maybe fragrances or

something i can't recall the commercially use yeah and it's pretty ubiquitous too i mean i've heard that it's not just in africa that's in some of central and south america and so you can you can extract the vokong gene and then you can do this simple chemical step to get it to i

began you know just so just do a synthesis pathway of i began from denovo it's like 26 plus steps or something like that but this is like the last step before it's i began from vokong gene and so it's really pretty straightforward to do that but you're still talking about a botanical you're

still talking about essentially growing a plant to derive a chemical out of the plant so the other way to think about it is could you do a full chemical synthesis and people have looked at that and tried to do it it's very hard though because i began has two carols centers so it has the

potential for four stereonantrimers and that chemistry is complicated and so full synthesis as a tricky process my suspicion is that whether it be biosynthesis or straight full synthesis but there's got to be a way to make this that avoids trees eventually i think it's better for the

environment it's going to be more scalable it's going to be something that standard pharma is going to want to see happen to really be able to use it but there's still some time to get for me to be as far as that goes so i think it's not a done deal it's not really figured out yet

it's abridging from that i mean this is actually a completely separate question but also raises some sustainability ethical questions five mio dmt so five mthoxy dmt so first of all i really implore people i'll link to this in the show notes as well read the blog post that i put together so

the five mio dmt it's present in quite a few different plants different nuts most people who have heard it in the zeitgeist note within the context of boofal various their other scientific names for this toad this northern desert toad and that has turned into a huge mess in terms of

like cartel harvesting and over harvesting from these poor toads it can be synthesized there are ways to synthesize it hamilton morris to beat the drum about this to his credit people are not going to like this but there is no documented indigenous use of the snorren desert toad

ken nelson you look it up in the eighties produced a pamphlet after testing godness how many things brilliant amateur biochemist but nonetheless it is very very it is interesting and appealing on a whole number of levels a lot of people are trying to commercialize it because at least in

earth time it is a short experience right so it's going to tend to 20 minutes 10 to 15 minutes so from a business model perspective i understand the appeal much like i understand the appeal of the newly branded psychoplastogens right psychedelics with the content slash mind altering aspects

as removed as possible we might come back to that but my question related to this is not so much on the production side because people can read about that separately and i think it's important for people to read about it's more of practical use following i began administration

i believe i've heard people describe it's use on what some people call the gray day following administration could you speak to this because i'm trying to discern for myself how important or critical it is from a therapeutic outcomes perspective versus being a business differentiator

does that make sense like this is something we kind of you know we put a nice set of icing on top of the cake and that includes this what can often be a sublime experience not always for people can be destabilizing for some folks in the form of five of the odmt so what's your

take on this so we specifically made sure that folks weren't getting a second kind of confounding drug on top of the i began to figure out what the i began effects were in isolation and as i described earlier you know we had extremely remarkable effects in the absence of doing the

five of me oh i think what people say about this the five of me oh is that it just takes the edge at minimum it just seems to take the edge off the gray day which is a day that happens for not everybody that takes i began but a very percentage of people such that there's a name for it

where people for some reason end up having kind of a bad day in and around day two three where they they really have a hard time and then it goes away the next day hard time being depressive symptoms for some people it's hard okay yeah what makes it hard and exciting yeah yeah in hedonial low

low motivation sadness i think probably what's going on as there was like a serious kind of flooding of your cns with a whole host of effects from the strong and then and then the brains then kind of reacting to that and then it seems to rebound out on its own without the five of me oh but it

sounds like from what i've heard five of me oh kind of bridges people out of that so they don't have to really have to experience that feeling now the question would be does it do something else beyond that that's useful we have no idea what we i suppose what we could have done or maybe what

we could do in a subsequent study is to just randomize people to getting no five in me oh after five in me oh and we can actually answer that question does it have an effect on the long term it's hard because there's like a floor effect of just like the profound improvements that we saw

just for my being so you'd have to my guess is that the statistics would tell you that you have to do a pretty large sample to be able to see something if it's there with five in me oh just because you know everybody's flooring out just with i began you say flooring out you're just does

that mean that the amplitude of the effect is so great that you would need to in terms of like seeing a large percentage improvement over the i began you'd need to see something great or what do you mean by flooring out yeah yeah so I mean essentially we're seeing people drop down

within that normal rank on the assessment on the assessment so you'd need to see and you know people are going into the range of like a score of five six something like that on various scales the PTSD scales the depression scales during the normal range and so you'd have to zero people out

with a five in me oh essentially or the other thing that it may do which nobody knows probably is whether or not it makes some of these folks who were and you'll see in the paper there are a couple of people that relapse the month mark maybe it helps the durability on some people it could

do those things so I'm not saying that it doesn't have a benefit it's just it would be a hard study to deal with and I think from like a purest I want to see this go through the FDA and kind of do the FDA things and see if we can get you know the first drug kind of through the process

and I want to say it's a distraction from a US kind of scientific regulatory strategy standpoint but it's definitely something that would add complexity so I think at the level of clinics you're doing this in Mexico and they have free range to use these substances I

don't think it's on the face of it like a terrible thing to do I think it makes sense why they're doing it do you really think that I just I guess just to push on that a little bit I'm like okay so people have a hard day but it's known that this is a phenomenon so they could prep people for the

possibility that they would experience this hard day if they're not somehow edging into dangerous territory where they're likely to self-harming I mean five in me oh DMT I have some experience with it I understand the appeal this like such ananda etc but it's not risk-free well you're strapping

yourself to a rocket yeah I mean that is a big big gun right yeah yeah which is not to malign anyone who is using this in a clinical setting but it's not risk-free I mean I have friends who are very experienced psycho knots we're talking like a hundred plus wraps with things like ayahuasca

who have been pretty much even keel with their various experiments and been knocked pretty sideways for non-trivial periods of time by five in me oh DMT maybe that's just the sample set that I'm dealing with but yeah and I totally agree you know medicine is a discipline and a profession of

risk mitigation and risk-benefit ratios and everything and anybody that would proclaim themselves to be a physician scientist that doesn't believe that isn't seeing it as it is everything that I do is some sort of risk mitigation exercise where I'm looking at this thing has these risks but this person has these inherent risks and how do you square all that I think to your point it would totally make sense if the person was in such a bad place in the great day that you

were worried about them I think there's a justification there if you really is it seems that they do have some general experience that this was helpful to kind of getting folks out the reality is is that we're really not going to know much of anything and a lot of this is going to be in the realm of

anecdote until we do do the trials in the US and really thoroughly document everything that happens with this draw with I began with five of me which is you know people are trying to put through trials and commercialize that and so I think there's a moment where we'll be able to kind of rectify

all of this and figure it out I agree with you too that I think that where MDMA maybe a substance that certainly not everybody could use but like a decently broad population based drug that a fair amount of the population that had PTSD could go after I think that these substances are more

constrained to a smaller population where the risk benefit is right for them and so absolutely it's a tricky moment I think we know just enough to be dangerous in some places and we got to get through this just enough to be dangerous moment to the like we know how to not be dangerous moment

as a culture and do that with kind of the scientific process so much earlier you were laying out psychiatry 1.0 2.0 3.0 I'd love for you to feel free to speculate right it's going to be speculation but putting aside like the I know it's hard to do like shepherding stuff in its simplest form

cleanest form through the FDA etc but like what might psychiatry 4.0 like that's right in the sense that for instance something that's on my mind and I'll keep it short is as I understand it very at a very primitive level the way that some of the accelerated TMS protocols work from a

hardware perspective is you're kind of hitting nodes at the exterior of the hub and kind of triangulating in a way to hit what you're trying to hit but perhaps you could use for instance my conversation with Nora Volkov of Nida just talking about focused ultrasound so maybe you use

that to hit the deeper structures directly hit the nucleus of commons or whatever it might be and then relate to that if we're talking about like Freud and so on focusing on content and then you've got this sort of neurotransmitter focus so it's a serotonin issue and then now you have the

electraceutical kind of structural nuance and experimentation but it seems like these things aren't necessarily wrong they're just at least if we're looking at the content of the molecules incomplete but if you talk to a lot of these guys who go through say the engals but a lot of

these operators and men who go through the iBegin experience I mean they will and maybe there's a visibility bias because they can't see what the hell's going on in their head but from a chemical perspective but they can remember the content but like a lot of people attribute the therapeutic

effects to much of the content right this reconciliation and so on so what might psychiatry 4.0 look like we have a paper coming out soon we're actually trying to use an underestimulation to change trait hypnotizability to make people more suggestible transiently

and it's probably an ability to zero in on specific content and manipulate that content through circuit based intervention you know and that's like a pure speculation but I'll give you an anecdotal kind of case report example and so there was a patient who got similar sort of deep brain stimulation

approach that I was describing earlier that they're looking at in West Virginia for prediction and that individual received deep brain stimulation I think in Europe I think for OCD and he was had a normal musical taste he listened to whatever all the range of standard artists and then he got

his deep brain stimulation and he became obsessed with Johnny Cash like totally sold all of his didn't see that coming all right yeah so totally sold all of his other albums and listen to Johnny Cash and the batteries for these deep brain stimulators will wear out after time and you need a new one

and it's decently common that if the person's doing pretty well then they will forget to come in and then all of a sudden their batteries dead and then they'll have a reemergence of symptoms and so this gentleman did so I think it was his OCD and his OCD got worse again and he fell out of favor

with Johnny Cash and threw away all of his Johnny Cash albums and started listening to whatever he was listening to before when in got a battery changed the battery was put back in and he's like for fuck's sake I got to go back to the shop and buy my Johnny Cash and that's what he did yeah and so just like we don't really understand how I've been game works we really don't understand what happened there right it was a very illustrative case and I love talking about that case because it gets into

this area that I think people are really worried about right now about specific content manipulation I don't think we can do that you know we don't have the tools to do that we have these like broad tools that basically change the lens of the world that you look through like I can change your brain

in such a way that you're like for some people they're going to see rose color glasses where they saw blue before or whatever it's like I can give you a different set of glasses to watch the movie but I can't change the movie directly yeah I can't change the movie directly my suspicion is is that

we're going to edge into a world where maybe we can change the movie and that's where it starts to get both very interesting and very ethically complicated and that story about Johnny Cash that doctor had no intention of doing that because nobody knows how to do that and maybe they played

Johnny Cash in the OR maybe not they didn't report that in the case report but there's no clear sense of why that happened either is this the first song I was playing in the hospital when you woke up in his brain the reward system just kind of like attached to it or whatever but it's one of

these things where we're going to get to a place of sophistication I think we're going to be able to do that and what happens in medicine is I see it as we are always redefining what's illness it used to be that high blood pressure was like 150 over 100 or something and it was 140 over 90

and it's 130 over 80 and now it's 125 over like 75 or whatever it is it's not that the illness has changed it's our definition of illness changed and so you know my suspicion is is that as we have enough tools to be able to knock out these major mental illnesses which are effectively like

in states right at the end of the day we let the system go all the way to like this kind of completely semi-functional in state where people have semi-evolution and they're kind of stuck in these mindsets and these behaviors if we can figure out what that is and we have ways of intervening

sooner in that process and we have emerging tools that can help you with this sort of content targeting manipulation sort of thing that I think you're going to be talking about much more specific sort of interventions that's like very sci-fi though you know it's not something that I

think there's even a hint of I wouldn't even know how to tell you how to do that now are like one shot on goal is just to move around this brain trait we do have a study with ROG era where we're actually packaging ketamine into nanoparticles infusing them into through an IV into the bloodstream

and then using ultrasound to kind of open the nanoparticle ketamine and drop ketamine just in the single it in the area that we were talking about earlier in this case in pain patients because it's easy to measure pain scales and pain reactivity but what I think will be really interesting with that

is if you could take that same technology and start to drop various psychedelics into specific brain regions and you can do a behavior mapping exercise what's necessary and sufficient to produce the clinical improvement what's necessary and sufficient to produce the trip and I think that's

going to be way more important in modifying the molecules because it's like a confound we're not really answering the question of does triplets I began work is that I began you know it's just some other thing right but what we really want to know is does triplets I began work because we just

put it in the amygdala or just into the singular or something like that and that an isolation isn't sufficient to produce the trip but it's sufficient to produce the therapeutic effect if we can pull that off we're going to start next year on that that's going to be super cool because it's going to

give us the ability to have more of these questions and you could even think about it like if you had a long acting anesthetic right where you had somebody with pretty pronounced psychosis gets a frittia symptoms coming in and you're able to shut down their amygdala for a couple of days

with an anesthetic just in the amygdala and nowhere else they're totally awake they're still with you but they're fear response or into the singular they're kind of salience of the environment response goes down because you're able to kind of temporarily shut it off but you're not having to give

like a whole body whole brain anesthetic where you're putting somebody into a medical coma or something you're just shutting down this one area which you could potentially do through neuro modulation and not pharmaceutical right you can so people have tried to do that with deep brain

stimulation you can actually do a jamming signal in certain areas and shut it down to and then maybe the long term solution right using drugs like vocal drugs to test it it's a commitment it's not something you do an emergency yeah right but you could theory do this in the or you could take

somebody it was acutely psychotic you could put an anesthetic that could kind of shut down that system for transiently for a couple of days and you could kind of get them more on board with thinking about what the long term solution is when the fear system is in place is much all total

speculation it's it's not something I have any direct data to support but it's definitely interesting let's push into a little bit more sci-fi because it's it's fun and also a lot of things that start in sci-fi end up in in sci right so it's true right I mean you look at snow crash by Neil

Stevenson and there are many may examples but do you think you could change handedness hand dominance that would be hard I think it's possible to do that at childhood and we do do this in stroke right we do this constraint therapy sort of stuff for you actually constrain if you have a big

stroke where you have on one side of the brain you have a pretty devastating stroke where people can't move their arm and all that good stuff they have minimal movement of their arm and then they have an intact side that's totally fine right you actually constrain the intact side

and force the person to use the affected side to drink water or to write or whatever and what you're trying to do is to kind of reorganize the neural system in such a way where there's more cross-functional like attribution of that side and so we have some evidence there's ways to do that

there's kids who need corpus calisotomies and various different like pretty significant like say epilepsy surgeries when they're really really young like one-years-old two-years-old three-years-old whatever and when you look at those cases it can lose like a pretty substantial part of their

brain from whatever surgery they needed to deal with their problem or if they had a trauma or whatever and they can reorganize the system to be able to reallocate resources to be able to do bilateral sort of functions and so it's mostly that the brain gets fixed you know the interesting

thing about this idea of critical periods and maybe what I began is doing and whether or not you can make a more plastic brain is this idea that if you could bring the brain to a more juvenile state then you could probably neurorehabit better and that's going to be I think one of the questions

that'll come out of the data that we're going to present is how far can this go I mean we saw like people go from mild to moderate TBI disability to non-on-average which is awesome and like never heard of but if you keep pushing on that how far could you go is something like that and that's

going to be a question that I don't have an answer for but at least there's like a signal there to look that's kind of part of what I like about the general work that I try to do is I like to be relatively disrupting and I like to be in spaces where nobody else is working I start to

not like it when everybody's doing it yeah I'm like always now like where am I going I'm always looking for the thing or nobody's really in that space studying it I always like it when people think it's if people think it's like really weird it's like a positive signal that I need to do it

kind of thing and so I think this area of certainly this area of using psychedelic drugs to try to treat neuro deficits is not something that a whole lot of people are really like looking into right now so it's pretty curious and hopefully we can ask some of those questions

one aspect of the accelerated TMS in terms of case reports maybe too strong word anecdotal reports that I found interesting is it seems like some folks report increased visual acuity or like color contrast and I found that very interesting for a few reasons number one is that

is very commonly reported say if you're on lower doses or higher doses but let's just say low to moderate doses of certain psychedelics right it's sort of like the dial on your HD visual perception is set forward a few clicks right the flower is sparkled just a little bit more

I mean you notice details you would otherwise not notice and the reason I'm bringing this up I mean that raises a lot of questions but I'm bringing that up specifically because there are athletes who have talked about the performance enhancing benefits of some types

of psychedelic use and I think Aaron Rogers would be one example of this although I don't want to say it's sort of in session use it's I think more longer term implications however there are people certainly I know athletes who have used these things to enhance their perceptual

faculties which then leads me to wonder and almost assume that neuromodulation will be used as a very hard to detect means of performance enhancement in sports it's hard for me to see how that would not be the case with people who are willing to I think there was some type of pull done at

one point is like would you be willing to take a drug that would guarantee you to get a gold medal but it would reduce your lifespan by like five or ten years and the answer for this thing that I'm I could be all made up who knows but I remember the report supposedly indicating that the

yes answer was very very high percentage of respondents right so if they're looking at something it has a lower risk profile and is basically going to be impossible for like the world anti-doping association to track yep why wouldn't they try it absolutely I'll tell you we've had a number

of patients who've gone through and they remitted really early so they lost all their symptoms really early in the week so like they wanted to and then by day three they've like zeroed out and then like Thursday like day four five they're coming in and they're saying you know what

you know I remember this one guy who's like I was driving by the beach and I saw the sun setting or whatever it was and I wanted to stop and for whatever reason just like sit on the beach and I don't normally do that and then he described how it was like completely present in the present

moment and able to just be there and present was like watching the water for an hour and he said I've never been able to do that before but I used to do these mindfulness courses that I couldn't understand and it fell a lot like that and I went and found my book and it sounded like I was having

this kind of like totally present mindful moment I've had a ton of folks come back and tell me this so if they remit really early and we keep treating and we treat them through it looks now that you know we've had folks come through for this and folks come through for psychedelic treatments

it looks like day three four five out of a psilocybin experiment where you've got the person's no longer having any trip you know but they're just calm and peaceful and kind of pretty relaxed and present and it's very similar to that and so I think that you're probably getting a similar

or the same state there and I would assume a state where a lot of good performance can happen from right because you really are truly in this moment not thinking about the present of the future you know I've had a lot of folks actually offer and at some point we need to do this but offer

a various philanthropic gifts for me to run trials on athlete performance I knew it I knew it of course so I had yeah one of our donors said to me I will give you the money if you will take me and all my group of friends or my post-finance guy triathlete friends basically that yeah and we cycle

every morning and randomize us to sham or active stimulation before we get on the bikes and he's like the reason why this is good is because we make the same exact times and everybody knows their times and can you change this there's a little bit of evidence for this it was a paper that was

published a couple of years ago where they took people and taught them to do like complex motor tasks like hand tasks where it's like tap digit one three five one three five one three five and then interspersed with two four one three five two four like that it's like a complex kind of

multi-step finger task and if you prime the motor learning area before you do that you can cut the speed of acquisition in half compared to the people that had sham that's non-trivial right seems non-trivial yeah and so it's interesting right like there's some really early like

preliminary data to suggest that you could potentially improve performance with nurse them the thing about it is is that if you could have something something that you know people have been thinking about TMS is a treatment for insomnia others for acute anxiety if you could come up with

something that could put the brakes on a couple of different symptomatologies and you could make maybe it's a TMS device maybe it's another technology you can make it something you could bring home then you'd have the ability to have this kind of full service sort of process for dealing with

things I think trying to treat depression and isolation or something like that you're you're never going to be able to scale one treatment alone but if we get to a place where we can use this for a lot of different functions and actually you know the sympathizability stuff drive people

up to be able to receive information better study better whatever do motor tasks better and then turn it off and flip it on to like sleep mode you know and you had a level of more control over your brain than just your own volition it's your volition plus your volition to do these things

and I think it's very interesting it's it's also very sci-fi I mean we're not anywhere close to knowing we can do that yet yeah not anywhere close yet but fun food for thought at the very least Nolan one more time where can people find your lab online so it's bsl.stanford.edu it's a

Stanford brain stimulation lab great and any other websites you'd like to point people to no I think I think that one's that's the place to go that's home base anything else you'd like to say before we wind to a close any comments public complaints

it's been super fun I mean I think you're you've definitely gotten yourself quite up to to speed and kind of right in the the center of a lot of the pulse of this both on the meristym side in the like the pulse yeah yeah yeah yeah yeah and so appreciate the kind of

the knowledge coming in and your interests and you know I appreciate the ability to have a conversation around these topics so thank you for saying that I really have enjoyed delving into this field you've been incredibly helpful as a resource and a sanity check since I get all

excited about things and sometimes can can fly off the rails but it's been so much fun to engage with this burgeoning hopefully soon to be dramatically expanded the field of experimentation especially given the remission rates and the durability I mean I've seen and the reason I first began exploring this was I saw a friend's family completely transformed and the before and after was just one of the most unbelievable transformations I've ever seen in my life and it happened quickly

I think it was about day three many many failed interventions really critical situation lots of self-harm and it was just like control Z undo and back to the person they used to be and it's been durable with I want to say let's call them single day boosters maybe once quarter or once every six months and I think it's now been durable I want to say probably a year and a half which is just phenomenal so I appreciate the work you do I appreciate you being the last man standing on the scientific

bachelor at I suspect that'll happen again and thanks for taking the time for the conversation man look forward to watch what you do in the future and for everybody listening we will link to everything we discussed in the show notes including Nolan's lab at Timed Uplog slash podcast until next time

be a little bit kinder than is necessary to others end to yourself and thanks for tuning in hey guys this is Tim again just one more thing before you take off and that is five bullet Friday would you enjoy getting a short email from me every Friday that provides a little fun

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