#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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4:19 At this altitude, I can run flat out for a half mile before my hands start shaking. And then also you post some questions. Now it is. A cybernetic organism, living tissue over metal endocet. So 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 peeking around corners. So what we are gonna talk about.

4:55 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 ten years. It's at least a sample of it. My guest is Nolan Williams MD. You can find him on Twitter at Nolan Rye R Y 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 gonna 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 and neuropsychiatry.

5:37 Themes of his work include examining spaced learning theory and neurostimulation techniques, development and mechanistic understanding of rapid acting antidepressants, and identifying objective biomarkers that predict neuromodulation responses in treatment resistant neuropsychiatric conditions. That is a long way of saying That he specializes in Looking at I would

6:03 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 neuromodulation 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.

6:46 He received two NarSad Young Investigator Аwards. The Gerald L. Clareman Award. And the National Institute of Mental Health Bio Behavioral Research Award for Innovative New Scientists. Again, you can find him on Twitter or X at Nolan Rye Williams. We'll link to this in the show notes as well. And you can find him online at NolanRWilliams. Dot com. I really enjoyed this conversation. I think it is very important.

7:12 highly tactical, and we also discuss things like Ibigain, which are seemingly unrelated to neuromodulation, and yet Nolan is an expert, very well versed in multiple disciplines. And in multiple toolkits. pharmacological and noninvasive neuromodulatory. 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 without further ado, Nolan Williams.

7:41 M D. Doctor Williams. Good to see you, sir. Yeah, thanks, man. Thanks for having me. And I thought we would start With

7:53 A personal story, not your personal story. But a story of Deirdre Leeman. Yeah. Can you tell us?

8:01 Who this person is. How it fits into your story, but Let's begin with just a description. Of Deirdre.

8:09 Maybe in her fifties, sixties. female in uh Bay Area who has suffered from bipolar disorder much for her life. And Pretty successfully treated for the mania side of things over the years at a psychiatrist.

8:25 Taking care of that part in Marin and Happened to slip into this pretty severe depressive episode a couple of years back, I guess 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

8:41 The year before we were talking it was really early on when we were working on a rapid acting neurostimulation 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 and I got on the phone, I I'll never forget it was like a Wednesday And I I got on the phone her psychiatrist and

9:02 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 needs to go in the inpatient hospital. So essentially gave her some information on how to do that. So I I see her the next morning and and she's in Really bad shape. What does that mean?

9:20 Like how did that show up? When 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, um, sometimes. And so in her case, you know, she couldn't look you in the eyes. look at the ground and she was doing this rocking thing. Which you can see in pretty severe depression, it's kind of these catatonia overlap symptoms, you know, I mean she's like at the And at the very end of the spectrum, one of the highest severity patients we've ever treated. So she was like

9:49 a score of fifty on the moderate out of sixty, like very, very severe, right? And and just rocking and not really talking and And the husbands were counting everything and 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've s they want me to

10:11 True 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. Yeah, yeah, exactly. So keep her not having a suicide attempt basically from now until Monday. Suicidal And I said, You're gonna have to like Take every

10:33 Knife. I don't think they need 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 twenty four hour you know, watch until Monday. And so uh Monday morning rolls around and we uh we bring her in and

10:51 The craziest thing, we had like an a repair on the motor threshold coil, which is the coil you use to kinda get Calibrated on the intensity. And it shorted out the device and blew the uh capacitor bank up on the first stimulator. Blew your flux capacitor. Yeah, yeah, at at like seven AM. 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

11:21 Pretty far away and this thing's weigh like hundred pounds. So I had to send my team over there, run over there and grab it. Bring it over and luckily we were able to kinda get her going and treat her with a second machine. She was in really, really bad shape. That morning and by

11:35 Five o'clock that afternoon she was Basically normal. And the next morning she was like Totally zeroed out and and completely normal. Meaning no suicidality. Meaning no depression, no nothing. I mean she looked like

11:49 Any Person walking the street. Like totally normal. And that was in twenty four hours and We've seen this with bipolar patients quicker. It'll happen really quick for like a bipolar one patient. You can get it done and sometimes in a day.

12:03 Just for clarity, but get it done and don't worry people listening. We're gonna Define terms and get into all this, but you're talking about accelerated TMS. Yeah, we're talking about accelerated TMS. Or rapid acting neurostimulation approach. we're able to get people out of these states and into normal mood. You know, and in short periods of time generally, like two point six 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 twenty four hours.

12:29 I remember it was like Right around July fourth or something, and so we You know, the whole team left. I guess we'll tell you about caffeine later too. So but so my wife and I are like big Phil's coffee fans and so I'll never forget this either. So we go down to the Phil's Coffee uh in Palo Alto after I saw them.

12:47 I'll never forget Clark Lehman, her husband was also into Phil's didn't know I was gonna be there. And I look over and this guy's just kinda staring at me. And I was like Hey, how are you? Good to see you again. I just like just saw the guy like ten minutes ago. And he's like, I still don't understand what happened. And it it makes sense, right? Like

13:05 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

13:23 Clark. And Deirdre really were advocates and have continue to be advocates for this to kinda 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 to feeling like uh it was all solved. And I think she went Maybe a year.

13:41 Completely asymptomatic, ended up needing to get retreated again at some point. But gets like these little touch ups here and there and uh is able to stay Well ongoing and depression. As they tell me depression's not her problem anymore. Mm. And so that's good. She's a great

13:55 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 Huberman. Yeah. Which was a very good conversation. Specifically it was about And I'm not gonna use the right.

14:15 terminology here, so bear with me as a lay person, 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 cingulates. 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 mentioned as context for people.

14:41 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.

14:56 Super. Super potent combination and very un 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 proceduraмі of science.

15:13 As it's been about six months ago now. So One of the Former research track resident postdocs in the psychiatry program at Stanford, Anash Mitra, who's now junior faculty was working with Carl Dyseroth and I

15:27 During that. training phase. And Anish 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.

15:45 The resting state part of it is Basically Tell the person to sit in the scanner and let their mind wander. So that's kinda the resting state or the default mode, however you want to think about it. And functional connectivity What that means is it's the um

15:59 Brain region's 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.

16:13 And blood flow is By time locked, you just mean at the same time. At the same time, correlating. Yeah, exactly. Yeah. And so Blood flow is a surrogate. of electrical activity. It's hard to see Electrical activity kinda Deep in the brain, you

16:27 People see at the surface of the EG. 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'cause you're using that Network.

16:41 Then you need to have cerebral auto regulation 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 Increasing in

16:54 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. Onish got very interested in this idea that The Timing of the blood flow is

17:09 Consistently temporally offset between these nodes. So slightly that people ignored it for a long time, but He was able to through using various math able to show

17:21 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, right? 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. You know, and it's so quick that you see it as

17:39 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. Right, 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 dorsolatal prefrontal cortex, the area that's involved in Control

18:00 precedes slightly. The singulate cortex. And our normal healthy Control population, essentially nearly everybody had that. Directionality.

18:10 In the depressed cohort. Seventy percent of them had it flipped where the Singulate. was temporally in front of the Doris lateral, but not everybody. And if you just had that information

18:23 You wouldn't know what to make of that. Like why why is it some people and not others? But 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

18:37 When we'll talk about you know, what sane is and the and the rapid acting neurostimulation approach in detail, I guess, later, but the the folks that responded to Saint responded to this rapid acting TMS approach were the ones that had the biomarker. And the ones that had no change.

18:54 Did not have the biomarker and look like a normal healthy control. And the signal. on the post scan flipped to look normal. And the folks that responded had the biomarker. And then their brain changed after. And so the

19:09 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 tests all the time in medicine. You ten people come into the primary care doctor's office.

19:23 with blurry vision, um, urinating a lot, drinking a lot. Headache. A lot of those folks probably have diabetes. But not all of them. Some of them have

19:33 You know, migraine headache and knee glasses and you know, 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

19:53 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

20:11 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 lineup. 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

20:27 You know, as a conceptual idea, it's an important Conceptual idea, this general idea of being able to use neuroimaging or whatever it is, EG, whatever it is to Type. different people that are presenting with similar symptoms.

20:42 And be able to Say okay, you're gonna 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.

20:55 in their lives trying to find the answer and we don't really have any tests. Trial and error. Yeah, it's a lot of trial and error. It's like Pharmaceutical. Ready fire aim. Yeah. In a sense. And this raises, I guess, just a meta observation slash question. Perhaps you could just t 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

21:19 In the last year. Let's call it half your pain. A lot of attention to Accelerated TMS. Which is there have been these

21:27 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.

21:43 Theory of psychiatric disorders. So you have a serotonin issue, therefore we're going to treat it in these following ways. You have Such and such an issue, so we're gonna give you S N R I's and then Like you said, it it's a lot of trial and error to figure out what works. And even if something works It may be

22:01 Often only work for a period of time. Mm-hmm. 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 is so fascinating is that it presents an alternative

22:15 Paradigm through which you could look at certain disorders. Right. Like oh, wait a second. Well maybe This person's car when you turn the ignition It's just Tripping things in the wrong order.

22:28 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 uh what would you add to that? You know, there's been I would argue like three eras in psychiatry, you know what

22:46 Psychiatry one point oh, two point oh, three point oh. And you know, the first era was this era in and around Freud and this idea that It was a content. Issue. in a life experience issue which is

22:58 Partially true. It's not that that's not true. It's just not complete. And so then the solution is a content solution, I'll uh initially psychoanalysis all the way through. kind of modern forms of psychotherapy. The limitations of that led us to psychiatry two point oh, right? This idea that we serendipitously found the first antipsychotics and first antidepressants.

23:20 And we were able to de institutionalize Schizophrenia patients. out of inpatient asylum stays with these drugs. Which kind of flew in the face. of this being a content issue.

23:32 What was the first anti psychotic? Thorazine. I was gonna say thorazine. Yeah. Yeah. I don't wanna take you off track, so keep track of where we are. We're at two point oh. How is it serendipitously Discovered. If I remember correctly, I think it was it was like an antibiotic or something like that. And they were trying to develop

23:49 That drug out for something. Completely unrelated and happened to give it to some patients with schizophrenia and they had a dramatic improvement. Yeah. I would love to read a book that is just a collection of case studies like this, right? Yeah. It's like uh Syldenophil, right? Viagra. It's like for angina or whatever. And then the male patients are like, Why aren't there male patients sending their meds back? Oh, wait a second. That's right. Here we here we go. Yeah. Yeah. All right. So thorazine and the serendipitous discovery of Oh wait a fucking second.

24:20 This seems to Not necessarily negate, but certainly render incomplete this pre existing paradigm. Yeah, that's 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

24:38 then it must be that there's you know, 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 you know, the third era, this kind of circuit era that I think we're we're in

24:55 Now and I'd I'd argue we kinda were entering in ten years ago, but I think we're pretty squarely at the the beginning of now Flies in the face of that, right? If I can take a patient as severe as dear Drilleman 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.

25:16 Right. There's nothing that went Into her system. Then it gets you into this newer way of thinking about the circuit problem. The useful thing about this Framing. One.

25:27 It's Seemingly consistently true in the sense that we're through all the various modalities, seeing these But Yeah, more importantly, it lets you integrate

25:37 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.

25:55 There's something inherently like missing or too much for you. In the sense that Your Constrained to having to take these These exogenous chemicals to kinda stay well.

26:06 But rather like there's a circuit Yeah, there's a m a miswiring sort of misfiring sort of problem. And if we can rerou that information, then you can feel well And I think that there's a level of empowerment that comes of that. One of the things that patients always tell me

26:22 After they get well with Some of our, you know, stimulation approaches is that they You know, they kinda look at it and say, Well I may get depressed again, but I don't think I'll ever get suicidal. uh 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.

26:41 So I'd like to highlight that last part because not that I'm the world's foremost expert in suicidal ideation, but as someone who Came very close to offering 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.

27:05 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

27:15 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? Yep. Yep. then you feel like you have a plan B.

27:32 And that is incredibly empowering. Let me ask you A few questions. The first is This type of neuromodulation is that synonymous with a term that I came across I don't know who coined it. It's a nice term. Electroceuticals.

27:46 Or are those different? Yeah, it's part of that broader term of electroceuticals. Yeah, and so What we had done with uh what we called SAN or Stanford Accelerated Intelligent Neuromodulation Therapy is that we Came up with a way of reorganizing Conventional TMS, which had been around for some time.

28:06 um reorganizing it in time and in space. Right. And so with conventional R T M S Developed in the mid eighties, first used as a therapeutic, but then Clinical trials by my mentor Mark George at uh when he was at NIH in the mid nineties. And uh proved by the FDA in the kind of mid to late two thousands.

28:24 it utilized average sculpt positions to find An average spot to stimulate which You know, at the time, given the technology that was available, that was the right Call, right. Can I pause for one second just to give some additional context? Yeah. What does TMS stand for?

28:40 So transcranial magnetic stimulations. 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

28:55 You pulse a magnet, you can generate current and electrically conducting substances. So if I take an Electromagnet if I take a TMS machine to the beach and I try to pulse the sand. Nothing's gonna happen because Sand is not As you know. Electrically conducting at all. It's an insulator.

29:11 And so if you put A TMS coil or any electromagnet next to A wire, a copper wire, speaker wire, or whatever. You can generate current In that wire.

29:22 If you Put the coil. On the head. It will bypass the skin, scalp, skull. An induced current

29:30 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 the nerves in the scalp.

29:46 But you don't your brain can't feel anything, so that's scalp nerves and so If you as they did in the eighties, just kinda 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 eighties and I could put it over my hand representation to make my thumb move, I can put it over my wrist representation of my brain, I can make my wrist move.

30:07 stereotyped way such that essentially the the head, face areas like closer to the ear and you m you can march up to the midline. of the skulls uh such that when you get to the midline you're able to actually Move the foot.

30:22 in the leg. If you have a certain kind of quail 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

30:36 as they figure out mapping. Yeah, it's like a it's it's a mapping exercise initially, right? Like where is everything? Is it the same and everybody? Is it consistent And they wanted to kinda have a way of doing that. Non invasively. Penrose and others had been. doing this invasively as neurosurgeons for a hundred years. You know, I guess fifty years at that point. And so they wanted to be able to

30:59 emulate what the surgeons could do in epilepsy patients when they're doing epilepsy surgery non invasively. And then what folks realized over the next ten 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 motor cortex. By how much the thumb moves

31:23 with a set amplitude out of the machine. So if I get X movement X amount. And then I send this Morse code signal onto the brain. To tell it to tone down or to kind of be less excitable. And then I send that same intensity back in.

31:40 The thumb will move half as much. Mm-hmm. 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 depotentiating stimulation we put in Excitatory potentiating stimulation.

31:56 Into the brain. And we do that and then we measure again, it'll be two X. Mm-hmm. So we knew by the mid nineties that we could actually move around how excitable the brain was. in these normal healthy control volunteer murder courtesies and so the aha moment for Mark and his team

32:14 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.

32:29 Where the prefrontal cortex just isn't As active as and 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.

32:46 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 gonna have Much in the way of risk, and so they had this Once a day, very extended

33:00 protocol and because of the you know the mid nineties it was very hard to get Cheap brain scans on Patience and so this idea that they were gonna have to use kind of average coordinates to target it.

33:13 Get average. Skull measurements and then they would do kind of a 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

33:26 Less efficient. version that basically Utilise kind of a Low efficiency signal into the brain. And used kind of average coordinates to place the coil. So average coordinates meaning

33:39 Just by clumsy analogy, like We can't take an X ray view, but we do have a hundred other X rays that seem to indicate roughly This is where you have your fractures. So we're gonna aim at those coordinates. That's right. Yeah, that's right. And the once a day protocol I've heard the number thirty six from somewhere, but is it somewhere in generally like the thirty to forty session range? Yeah, that's exactly right. So we're looking at let's just call it

34:02 For a placeholder, thirty to forty sessions, one per day. And to 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 wallet or a piece of wood. Yep. Getting electroconvulsive therapy. Yep, yep. These are not the same thing. Yeah, it's actually the opposite. So in the goal of electric convulsive therapy or ECT, which has been around for a hundred years.

34:27 Is to Produce a therapeutic seizure. And some people with autobiographical memory troubles It's pretty underutilized as a treatment in psychiatry because of these issues, because of particularly one flew over the cuckoo's nest and and that story and that that movie's culturally has actually had an impact on E C T and it's one of these things that's kind of For a lot of patients a last ditch

34:50 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 it's 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

35:14 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 N E C T, there's their 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

35:36 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

35:48 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.

36:12 space being can we personalize it to each person's 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 Deirdre was able to get well in in a day is because we gave her a whole six week course in a day. You gave her how many sessions? So that's ten triple dose sessions. And so it's like thirty Thirty total. equivalent sessions in a day. And so the FDA cleared

36:38 Six hundred pulses of ITBS once a day, five days a week for six weeks in twenty eighteen. And that was for a major depressive disorder. That was major depressive disorder. We give a triple Dose every session, so eighteen hundred pulses and so After ten sessions you've got the equivalent of thirty

36:55 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 it was this

37:09 Linear is that you know, you just pick up Remitters as you progress through the days. People who completely lose all of their depressive symptoms to a level that is within the normal range. Um so they're rating at the same level as somebody who's not depressed.

37:26 And you know, we can get people there on an average of two point six days and we're able to do that. By personalizing the target and then being able to deliver treatment into that, target a you know, a lot of treatment over a short period of time. And so what's useful about that is somebody can be in a really Pretty bad state.

37:44 On Monday morning they can can take a week off of vacation, or they may end up being on the inpatient 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.

37:57 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.

38:10 I Just a quick thanks to one of our sponsors and we'll be right back to the show. This episode is brought to you by AG1, the daily foundational nutritional supplement that supports whole body health. And I do get asked a lot what I would take if I could only take one supplement. And the true answer is invariably AG1. It simply covers a ton of bases. I usually drink it in the mornings and frequently take their travel packs with me. On the road. So what is AG1? AG1 is a science driven formulation of vitamins, probiotics, and whole food source nutrients. In a single scoop, AG1 gives you support for the brain, gut, and immune system. So take ownership of your health and try AG1 today. You will get a free one year supply of vitamin D and five free AG1 travel packs with your first subscription purchase. So learn more, check it out.

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39:16 I've had a number of friends, and I've certainly heard of many cases where People with certain professions, airline pilots, firefighters. Police officers, there are many more. Will not report. any type of mental health issue because they will be suspended in a lot of cases or relieved of duty. Right. They will they'll be forced to take time off.

39:37 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.

39:52 Right. And until the entire system changes, which is gonna take time if it happens at all. This would be an incredibly attractive alternable protocol. If if it were to work. So please continue. Yeah, absolutely. Yeah, no, that and that's the way that we thought about it, right? Is can we

40:07 Take folks who who need to get Yeah, 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 they 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

40:30 Their lives and it has a low impact on it. 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 gonna 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 into 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 ninety percent of their resting motor threshold that's depth corrected for atrophy. So if somebody if it's an older patient, they have more Prefrontal atrophy.

41:06 then you can increase the intensity based off of that difference in depth of the murder cortex. But essentially what their brain is getting is ninety percent of the resting murder 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'd never want to talk about things like this.

41:33 Unless I've Put myself. in the spaceship and been the monkey shot into space. Which doesn't mean at this point I'm a Proselytizer.

41:44 One hundred percent. Yeah. for the treatment, but I find it very Compelling. At least for investigation. So to just explain since I recently went through this.

41:54 Each morning. Or certainly on the first morning, but on multiple mornings in my case, they will test your motor threshold. Right. 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 the sort of dose. that will be delivered throughout the day during these sessions. And in my case it was You know, once an hour for ten hours a day.

42:16 Yeah, so it's just a a way of of getting the intensity and that you need. And so we know that Ninety percent meaning sub motor threshold. There's never been a TMS related seizure. For that.

42:29 Kind of sub motor threshold intensity. Even, you know, giving multiple sessions a day or whatever it is, there's never been a An event like that, it's always been at a higher kind of intensity of the stimulation

42:44 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 You know, 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.

42:58 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. It's sort of the in the magnitude, like the strength of the pulse, not the frequency or the density. Yeah. That's more about the intensity In this case I'm less about the density or the amount. So laying that out.

43:20 It was acceptable and In various parties deemed it to be Non significant risk. And they let us proceed.

43:28 Break through status FDA cleared and all the way through all of the regulatory processes and so it's kind of an on label 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

43:47 Well designed accelerated TMS. It's definitely you know, I'd say More than four or five hundred between trials. You know, we have trials where

43:58 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 A E's we don't have any serious adverse events in the sense we haven't had anybody have a seizure. Yeah. So that's good. What you do see is headache.

44:11 People will have a Headache it's usually from the Not everybody, but you know, a fair percentage of people, and it's mainly related to the coil. Activating scalp nerves. And basically kind of turning the facial musculature on.

44:25 And that actually goes away over time. So in the long term You can actually see a reduction in in migraine headaches and you see a reduction in Pain, all that sort of thing, and people actually have an anti nosus deceptive effect. Anti, excuse me? Anti pain effect. Yeah. What was the word you used? No susceptive. Ooh, a new one. 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? Uh at least a cute

44:54 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 pharmaco stimulation thing that people are looking into. Uh a buddy of mine, Joe Taylor, who's at Harvard now.

45:14 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 kinda 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.

45:30 From this it's like fatigue. More like you ran a marathon instead of like depression related fatigue, you know, just from kinda being there all week. Look, N of one here, but seems you know, I spent a lot of time talking to folks as you know, kinda 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 N SEDs 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 I'm

46:02 I'm just gonna deal with the headache. It was tolerable. I mean, you could feel it. The fatigue was the fatigue that you might feel if you were cramming for your final exams. Every day. Yep. It was not the fatigue of Apathy and anhedonia, like the difficulty or impossibility of finding joy in the things you would normally find joy with, like that type of fatigue is characteristically it was very different. It's more like yeah, you just

46:26 Crammed for twenty hours. to try to nail your finals'cause you didn't prepare and you're gonna do that every day. Yeah. That was the feeling. Question for you then. We're gonna get to the results. I want 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. Is it is it fair to say that you're seeing It'd be an exaggeration, maybe we say the worst of the worst, but you're dealing with patients who've had multiple failed interventions.

46:52 So it seems like that's important to kinda Keep in mind if that is true. Yeah. Yeah, and so in 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. had five plus or minus two med failures and they had a A lifetime load of depression of about 25 years. So these were folks who've been depressed with multiple episodes or very long episodes. They tried a lot of meds.

47:19 To get out of those episodes. Yeah, 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 uh talked about earlier with the flipping of the signal That flipping of the signal was correlated with higher moderate scores and so the more

47:38 Moders is the assessment. I'm sorry, yeah, um 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?

47:52 Got it. And the switching just to tie it back to what we were 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. Yeah. Yeah. So it's that directionality. And so um That's what we've seen folks that are at that kind of more in stage.

48:12 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 P and A S work.

48:25 you know, replicates and what we've also seen is Folks that do really well with dorsolateral at least are folks who are Have a pretty impaired tension. And so they actually score up on the concentration item. of the depression scales and so

48:40 That was um 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 up yeah, 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

48:59 Have 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 found that um inhibiting the the right frontal pole orbital frontal cortex, so stimulating here and we have uh O C D trials to do that. is pretty effective at at shutting that down. So it's more of a shutting

49:20 Down then it's Turning up. sort of intervention. So Some of it's actually like Where

49:28 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 neurally. To figure out which target makes sense for their symptomatic presentation. Based on their personalized FMRI scans. Yeah. Yeah. Yeah.

49:52 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

50:02 Would like to consider. enrolling or they know someone who might want to become subject in a study. Is there anything you'd like to mention? So we have a number of trials that are ongoing at at the Stanford Brain Stimulation 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 out their information and essentially We have trials for anodonic depression, we have trials for standard severe Treatment resistant depression, obsessive compulsive disorder, borderline personality disorder.

50:33 Patients who also have depression, bipolar Depression, another 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.

50:49 Which is nice. So it's all basically Funded through these trials. And We're excited to bring people in and and see if it makes sense. For them to work with us on this and um it's a couple of week commitment. What did the results or what have the results looked like with Saint?

51:05 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, ninety percent of people experienced remission at the post. Ninety percent. Ninety percent, yeah. In the

51:22 Randomized control trial. It was seventy nine percent 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 fifty to sixty percent range. The reason for that is because there's this

51:39 Colleagues of mine at Cornell, Connor Liston and others have have replicated this finding that There's a sub population of patients that actually has a slower Time to remission. And we've seen this too, though. Folks will lose their suicidal ideation actually.

51:54 peak their antidepressant effect at one month. It's usually in older adults. And that's what we've seen is is basically it's only in fifty year olds and above. We haven't seen that now. That sort of delayed remission. That delayed remission, yeah. But if you're Putting together twenty

52:09 Eighty year olds you're gonna have some of these folks. But what's interesting is TMS also probe of the system. you kind of ignore the kind of normal rules of how to define remission and you just ask the question of Who crosses through?

52:22 Seventy nine percent of our active group crossed through, thirteen percent of our control group crossed through. And that tells you something, I think, about the neuroanatomy, you know, that Probably something in the seventy percent. Uh folks have this dorsolateral. Singular problem. And then that was

52:38 A version of that thinking was seen in our P and A S signaling paper too. About seventy percent of those folks had the flip and 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.

52:56 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 c classic sense the way just that it's kinda the

53:18 spontaneous happening of of Parkinson's disease that's the Sure. Parkinson syndrome that we think about Michael J. Fox and and others. And then you've got other things that look like it. Progressive supernuclear palsy. Louis Body Dementia, drug related Parkinsonism.

53:36 And so we used to kinda lump 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 in that case for Parkinson's link Parkinson's pathology to symptomatic presence. Yeah, so it's like a brain don I mean there's lots of brain banks or brain donation. Entities. Physical brains or are we talking about scans? Physical brains after death, post mortem donations. So there's a lot of ways you can donate if you have a neuropsych disease, you can donate your brain. To science and and so a lot of Parkinson's patients donated their brains to this.

54:14 Brain bank to try to understand what it is and what they found was with like a deep Fanical. Phenotyping before Death. So then

54:23 You had this kinda deep phenotyping and then kind of understanding of the symptomology, right? So So basically, you know, does this person's Do there trim or happen on One side or both sides at the same time.

54:40 How do things present? How do things present in an observable way. That's right. In the same way just folks, so you have like genotype, phenotype, right? Like so this would be similar idea. Okay. Yeah. So basically what they found was Clinically people that have The kind of standard Perkinson's disease. typically tend to have a presentation of unilateral onset illness. Right, where one side of the body or the other

55:03 is much worse from a Parkinsonian standpoint than the other. And it's actually very common for people with Parkinson's To present were If it's a leg onset Parkinson's or foot's dragging or Trimmer just in one hand. And that's actually what you would expect from normal Parkinson's if it's like really symmetric.

55:21 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. Being able to link up substantia Nigra problems they found on autopsy. With symptoms.

55:35 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 indo you know, people think about as Indophenotypes or whatever these

55:52 specific kind of flavors. Of that. Symptomatology, some linked with a very specific brain physiology or brain functional neuroanatomy such that

56:04 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 a at an in of one level, at a a single patient level.

56:23 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 of treatment for people.

56:37 And cut all the time around diagnosis. I mean there's it's not just time, it's risk, right? Absolutely. It's risk from Potentially the wrong treatment's also risk from weight. Cost potentially also. So as you know, right, like there's a period of time Where the diagnosis is uncertain.

56:55 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.

57:06 Disorder from a depressive episode onset, so they come in with depression. And the Pressions they're Primary, you know, presentation. Seven years. So you get them.

57:17 Right. It's wild. Right. And then That's just to get to that point. Now you're in the right realm of medications or whatever, now you're talking about In year seven, you're having to spend Whatever it is, like

57:30 Three, five, seven more years. Trying to find a solution. So you could go from being Twenty Five years old. And

57:39 You know, having this be your first depressive episode. and you're still trying to figure out what you're gonna do about it. At forty and 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 screwhead. And you're just trying different tools where you're not allowed to touch the screwhead. That's it. Versus like, let's flip on the light, take a photograph.

58:00 Then go find the appropriate tool for the job. Just a couple of follow ups. The numbers that you're mentioning, right? The remission rates, the people who Who passed through, so to speak. Yeah. How does that compare to like frontline conventional treatments? Right now.

58:16 So there's a study called Sturdy, it's a little It's been an interesting year for Star D 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.

58:30 to you know a remitted state after going through this algorithm, but essentially star D Started with a pretty low Side effect burden, oral antidepressants, Citalopram, and then kind of transited through, you know, higher risk sort like SNRIs and What's the trade name for Citalopram? What do you know people would know? Uh Lexapro. Lexipro. Yeah. Yeah, and Citalram selects a So those drugs, you know, and then you go to like asinerized, like a effectserve and lafaxine, and then into like the tricyclic and the monoamina oxidase inhibitors and so people

59:01 would go through this algorithm and then they'd 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's kind of been called into question, but essentially When you get into like

59:16 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, you're talking about lithium or thyroid hormone, things like that, when you start getting into that step. And conventional TMS would beat that.

59:35 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 thirty percent with conventional TMS down to about sixteen percent. when you get into the higher treatment resistance levels That's the levels that we ran our trials on. Which really that

59:54 We're People normally get about sixteen percent remission with conventional TMS. That's where we were seeing those numbers. Can you just repeat those numbers? Were you saying what numbers? In our open label trial ninety percent in our

1:00:06 Randomized control trial. Depending upon how you look at it, it's in like the fifty, sixty percent at each time point or Seventy nine percent if you're asking, did people transit through remission at any point? Versus sixteen percent. And this wasn't like a head to head. It's not a head to head. Just just so people have some means of comparison. And in terms of pharmaceuticals at that point? Very low. I mean you're talking about sub ten percent efficacy.

1:00:31 You know. This is around where where electriconvulsive therapy is thought about, right? This kind of therapeutic seizure thing we were talking about earlier. That's got about a forty eight 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.

1:00:49 Things you're talking about. Like conventional TMS, like a one to two month. Commitment and then quite a bit of risk for side effects there. You know, you've got ketamine, which produces about a thirty percent

1:01:01 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 that was published a couple months ago, like

1:01:19 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.

1:01:30 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, sulcive, and other psychedelic drugs that I think you've thought about and talked about on this show. before that are are also coming. Over the next couple of years.

1:01:46 Few follow up. Comments and questions. So you mentioned a number of things. Borderline personality disorder, bipolar as as two examples. Part of the reason that I'm so interested in neuromodulation right now. Accelerated 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

1:02:13 Psychotherapy trial. Our Eligible. Four. 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

1:02:28 physiologically, psilocybin shouldn't technically pose. A risk. But if they have A lot of panic. Rapid heart rate, et cetera. There might be complications, right? Elderly patients, et cetera. So

1:02:39 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.

1:03:02 Some of the charts. Maybe it was three or four people out of s and of sixteen. I can't recall. That's right. Okay, there we go. Who had this remission at like week four. 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

1:03:24 A lot of people like delayed onset of Benefits. And then you have ketamine. This is gonna 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 I have heard I do not have the credibility or the the means of

1:03:40 parsing all this and like okay, well catamine X Directly On NMDA receptors. Seems like maybe SSRIs do that, but in a very indirect way. And that explains the delayed

1:03:53 Benefits in some patients. How do you kind of tie this to or not the delayed remission. Cause 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

1:04:15 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 How do you think about that? Like even if it's speculation. Yeah, it's and it would be sp yeah, it would be speculation. But I think you know, so we've only seen in older adults, you know, and we know that the brain plasticity in older adults goes down as a generality and there are lots of metrics about why folks think that. And you're you know, you're

1:04:42 As you talked about earlier, it really it's it's cramming for a test. You're actually sending a memory signal into the brain so that the stimulation pattern that you're sending into the brain this kind of Morris code is really a turn on, stay on, remember to stay on memory signal. That's going into the brain and um 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

1:05:05 playing that back through the prefrontal cortex in a way to try to Tell the prefrontal cortex to turn on. Part of what's going on is Because that

1:05:16 Older brain is a little Леклі то Flexibility, plasticity. It takes some time for the signal to kind of Fully lay its tracks.

1:05:25 Into the brain. We don't have Any sort of biology to kinda 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. Mm. And we're scanning people multiple times out to the month. So now each funded way. Scanning you mean F MRI. F MRI scanning, yeah, yeah. So we're actually getting like ten scans spread out over

1:05:48 It's a lot of coffin time. Yeah. Yeah. Yeah. We know people are been very cool about this. Uh and so with that, we think that we're gonna be able to Potentially spell some of this out, right? Like why are these delayed remitters happening? But it might Suspicion is that it's probably a plasticity. related issue. Interestingly, you know, ketamine and 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.

1:06:19 And then as we talked about earlier, there's an endogenous opioid release. Mm-hmm. From uh TMS. Um we've done some work with opioid. related mechanisms and ketamine, and so there's probably a confluence of not one or a transmitter system, but like um an orchestra. of neurotransmitter systems that are being affected across these

1:06:40 Interventions and Yeah, 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 nineteen nineties view of like one Neurotransmitter, one neurotransmitter receptor sort of problem in the brain is way too simplistic.

1:07:01 And then it's probably a lot more complic 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

1:07:19 Molecules. Treatments are most interesting to you. We have a paper coming out soon in Nature Medicine on looking at at IBN. As a potential Treatment for

1:07:31 In this case for military traumatic brain injury, but a lot of these folks had depression. Generalized anxiety disorder and PTSD. And so it was a Interesting that was another interesting story. So I was approached back in twenty eighteen By a professor

1:07:46 A senior professor at Stamford who was tapped by some folks to kinda find somebody who'd be willing to partner with a a non profit called Vets at the time. Who were sending and I think you've you've interacted with with Amber Marcus Capone uh a little bit. Yeah, I interviewed Rick Perry and Rick Doblin two years ago at their Veterans Day fundraiser. Yeah, I was there. I remember that was an interesting one. You know, we partnered up with them and I I had to again go to the Stanford I and ask them for another. Edgy and it you know, you have to give the Stanford I credit.

1:08:17 Install out IRB. Oh sorry, Institutional Review Board. It's the entity that reviews all all research protocols at at 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 Propose research and then determine if it's ethical and safe and answering the questions that you think you're gonna answer. And so

1:08:43 Just like going to them to talk through doing accelerated TMS and 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 a an illegal in the US root bark extract that's been utilized for millennia in the country of Gabon and related

1:09:06 Are in central West Africa. And as you can imagine, this was not a quick turnaround. Uh 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 Ibigain? People knew that I was

1:09:30 Very open minded to things. I'm a pragmatist, right? I mean, for me, like patient's the most important thing, the I have this view of psychiatry that it's gonna look like inpatient cardiology in twenty years where we're gonna use drugs, we're gonna use Devices we're gonna Be able to figure out what the best things is for that patient. To your point, you know, some of these things are good.

1:09:50 for different problems. And so I think that was known that I was open to that. We'd We've just been running this ketamine mechanism trial. And so I was tapped to look at this and a couple 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 kinda special back then and then like later realized that like Oh wait a second, I was on the the Bachelorette and I didn't realize. Yeah, I was on the bachelorette and I didn't realize it. So essentially Yeah the and the in the and the bachelorette was uh tricky one. Um you know and and so we uh

1:10:28 We ended up reluctantly agreeing to this. And and admittedly, like I almost pulled out a couple of times because I begin 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 Torsad's de point this fatal arrhythmia that can happen with certain cardiac acting drugs and it works through this

1:10:51 What they call HRG potassium channel. Other things do this or like FDA cleared cancer drugs and arrhythmia 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 there was a

1:11:06 Somewhat of a stigma to bias around Particularly an addiction drug. And so Folks had been trying to get this through the FDA and NIH and whatnot in the nineties. Hard Lotsov and others, and it was a very complicated

1:11:20 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 thought it was completely unstudyable and I kinda like

1:11:35 Happened Doing my other stuff and then At that point, how did you come across Ivy Game? Where did you find it? In twenty twelve, twenty ten, I think. But this been like early Deborah Match stuff or No no, I come across this book

1:11:48 Breaking Open the Head by Daniel Pinchek. Yeah. And he you know, he's a big ne I think he wrote for the New Yorker or something and uh And I was stuck. I was like going kite surfing in South America and I was Stuck in the San Salvador Airport. Five. English speaking books or something and I

1:12:07 picked this book up in the airport like stuff. That was in the San Salvador airport. Yeah. Wow. Yeah. Okay. And so I got a hold of this book. And Reddit waiting on my flight, which was like eight hours delayed to get to Peru. 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.

1:12:33 on the kind of case report level outcomes But then also the cardiac problems. So then I figured it was kind of unstudyable. And then In twenty eighteen, I was approached and was asked to do this trial. And so we

1:12:47 Went to the IRB, spent 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 uh

1:12:58 Paused the whole thing and then uh It took a while to get it back online, but it was actually the quickest recruiting study I've ever run. We got thirty people done in like eight months. Now is that because of the sort of category of like potential death of despair. I mean, is is it because of the patient population? Were you dealing addicts? So the patient population was And that was the unique part about this. It was

1:13:21 Veterans. With traumatic brain injury, some of which were alcohol use disorders, so you know, we we used to call alcoholism More than a third, like th thirteen or fourteen people. Out of the thirty. But everybody had TBI, a lot of them most of them had depression, most of them had PTSD.

1:13:38 And so, you know, we're running this trial. I was put like my best neuropsychology postdoc on it and a couple other Superstars when it was running in the background and I 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 uh I remember I was I was asked

1:13:58 to give a talk about it at a very prestigious university And ask the postdocs, we just wrapped up the immediate post and asked 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

1:14:15 way better than I think we anticipated very consistent improvements in like basically everybody some people would lose it. You know, before the month, but most people held it and and they're holding it out to a year now. And I was Florida. I actually Tell them to delete all the code and start the analysis over'cause they had to have done something wrong in the math. Which is always fun. The postdoc always uh they kinda say yes and look at you. You just ruined my weekend. Um so

1:14:41 So we uh we we did it again and it was the same exact findings. So they I was wrong they were right. They had done it right the first time. Yeah, and essentially really, really striking and by the time this will come out, you know, Nature Medicine will have Publish this. Somewhat prestigious. Yeah, somewhat, you know, top five biomedical journals in the world and they say being nominated for Best Picture at the Academy Awards. I mean, scientifically speaking, right?

1:15:06 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 gonna be open to publishing an open label Paper which, you know, historically you're you're gonna Publish. In that kind of a journal, like a randomized trial. So just for clarity's sake for folks listening, so open label means no placebo control. And also

1:15:25 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 wanna ask a blind guess, and that's actually been a big uh so I was gonna 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 kinda know that the blind guess is gonna be highly skewed. So there's one trial where they did psilocybin for alcohol use disorder. I think it was like ninety nine percent correct blind guess. Rating, um so the P value is highly significant.

1:16:03 In our same studies, to my like Great surprise our blind guess was chance. Mm. Could you explain what bl what do you mean by blind guess? These are the experimenters trying to guess who is in which

1:16:15 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 did you get? Active or sham? What's your confidence? Got it. And 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'd gotten Totally better, and they'd say things like, Yeah, you know, I just got lucky with placebo this time and they ended up getting active and then

1:16:41 The folks that didn't get any better or that that 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 was confusing enough for them where they were making the wrong Guess fifty percent of the time, which is what you What you're looking for is about fifty percent error rate and uh it's a coin toss. Sidebar on that, I know this is

1:17:01 Kind of. Sticato the way that I'm trying to hold this conversation, but Having gone through two weeks different hardware, different Practitioners, et cetera. And having had a lot of conversations with technicians and so on, it also seems like for some people it takes a while for their narrative to catch up with like

1:17:17 The hardware upgrade. Right in the sense that they They say, Well maybe I got lucky Or maybe I I don't really feel that much. And yet their assessments are improving and or There's significant others.

1:17:29 See dramatic changes, right? And that's true. That's not specifically a TMS effect or extend effect or accelerated TMS effect. That's true, I think, for a lot of treatments. You see that I mean I've even I've had calls in Since our data's been out on IBam where I've had people call me and say, Hey, Mr

1:17:46 Or Mrs. So and so. They look 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 Alexithymia in about twenty five percent of people with treatment resistant depression. Lexithymia. Yeah, and so A meaning without Lex meaning the ability to describe thymia mood and so they can't really

1:18:10 Yeah. Describe their mood, right? So they have a An inability to Accurately rate their mood and the way you know that is Alexithymia. Mm-hmm. I'm gonna use that at a fancy cocktail party, so

1:18:21 Tim, how you doing? Sorry. Got a lex of time, yeah. Oh sorry, you may better know that as difficulty to describe mode. Yeah, that's fair. Yeah. So I'll I'll try to back off on the medical medical journey. 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?

1:18:47 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 ask someone like how many calories did you eat yesterday, but like most people will be off by like thirty to

1:19:03 Like sixty percent or something, right? Yeah, that's right. And I I think what The remedy for that. Is that you have a clinician rater? The clinician rater asks these. Really, really pointed

1:19:14 Very detailed questions. And then the patient's 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 they're Perception is

1:19:27 They're kind of meta perception of the whole thing. But when you get down to the Brass tacks 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 Uh military TBI.

1:19:45 And these were all special operations. Mm-hmm. Yeah, they're 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 have spoken about it publicly. I mean it's this um National Defense Authorization Act, the NDAA I think is

1:20:06 Just um you know, went through s the Senate and and the House um both approved it and yesterday and it's going to Biden and so you know, to earmark money for Trybe again. Or trials, you know, which is pretty cool. So the military community and some of the government is pretty aware that

1:20:22 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 puts 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

1:20:44 The kind of veteran psychedelic angle is is an important one, you know, for like a lot of ethical Moral reasons and you know, and a lot of 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 researcher on these therapeutic tools.

1:21:07 Yeah, it's super cool to work with those guys. And this was a monotherapy in the sense that it was just Ivy and 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 M U D M 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 amo outside of this kind of month follow up.

1:21:30 Period. But the data that we're publishing in Nature Medicine is just the Ibegain effect. It was tricky,'cause that to kinda divorce those two together'cause that's what's been going on, as you know, in Mexico quite a bit.

1:21:43 So all the accused out to the one month. Effects are all Direct Ivy Gane effects. And it's you know, super cool. And the thing that that I found really interesting About this drug.

1:21:54 Is it it? Produces What I think is probably the 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

1:22:14 Epoch in time. Some people would call life review, right? Life review or slideshow, yeah, exactly. And so You know, it's interesting, everybody's kinda got a different version of what the slideshow ends up playing out to be like for them, and so Some people say I Found myself in this room and it was like my TV from childhood and all of a sudden it was playing all these things or I found myself in a hall of mirrors and it was playing all these things so like the

1:22:35 Context can be very different, and the mind seems to shape that, but the Actual replay seems to be pretty stereotyped. Stereotype meaning like it's a pattern that repeats. Or is it 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.

1:22:58 This kind of replay part. That happens. And you know, from what I Have heard There's kind of a cathartic.

1:23:06 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 in the reasons for the other. Which to me is like the hardest thing to explain.

1:23:27 You say it one more time. When people have this slideshow or life review, they seem to have it It's a third party 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 kinda like that. Like Scrooge goes back and sees himself as a kid. He sees himself as like when he broke up with his significant you know, all that stuff.

1:23:52 It's almost like that, like you're having a similar sort of thing where you're I've used 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 and I'll 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're you're able to hold this neutral place

1:24:18 And you're able to have this sense of where you were and why you did what you did. And you have the sense of the other. And you're able to I don't know, into it I don't know what that is. You somehow

1:24:30 Stored it at the time. And you weren't able to fully 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?

1:24:48 On both sides and then dissolve the Problem. And people say they'll they kinda would work through all of this and you know, there's one veteran, 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?

1:25:05 And so this idea that at the core of it For a lot of this ends up being A childhood trauma thing that's kinda 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 just a pattern of trauma.

1:25:25 And the ability to kind of Resolve it. by understanding it this kind of you know more Meta empathic viewpoint. And so

1:25:35 That's right, I think the tools really gonna be important is this ability to have what seems to be a pretty profound or atrophic effect. Yeah, we were able to see disability improvements from traumatic brain injury. But also this pretty pronounced Kind of

1:25:49 Pathardic. re evaluation, reconsolidation of Past life problematic memories. Alright, as I want to do, let me hop in with uh just a few comments that we can bounce around if we want and then a whole bunch of questions. So the the first comment is with the special Operations

1:26:09 That's who are friends of mine. What I've observed maybe similar to what you're describing, that is Part of what has 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.

1:26:31 high overlap, like incredibly high overlap. Of course, there are many other factors that contribute to them being like the one person out of ten thousand 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 W

1:26:49 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 IBegain different from some of these other psychedelics? And uh I want to say One maybe place to explore would be glial cells. Am I making this up? Gleal derive Neurotrophic Factor, there we go.

1:27:18 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 f the five H T two A receptors, right? So they're five H T two A agonists, they produce These kind of classic psychedelic

1:27:38 Experiences from Largely from that Receptor, you can selectively knock out five H T two 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.

1:27:53 So it produces a dream like state. Some people call it an atypical psychedelic, you know, we've elected to kinda use a senior gen term'cause I think it more accurately reflects what's going on in the trip. And in the way of kind of perceiving what it is.

1:28:07 It does have some five H T two A action, but that's Probably the minority of the effect. It affects a broad range of other receptor systems so like salvia For instance, as a kappa agonist, right? Um you know, and so there's kappa mu effects, there's NMDA

1:28:26 effects with IBegain, there's cert effects, so Ceraturnan effects. And then there's this upregation of B D N F brain derived neurotrophic factor and G D N Fleal derived neurotrophic factor. And so And both of those are, you know, profound or trophic factors for Plasticity in the brain. The problem is is this has been

1:28:45 Psychedelics were thought of as relatively obscure fifteen, twenty years ago to study. Obviously that's changed now, but I began extremely obscure, right? So there were handful of studies They 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.

1:29:04 What I can tell you is that it was a paper published, you know, I think fifteen or twenty years ago where they took mice and they got them to self administer alcohol, so that's kind of like a way of like an addiction model or whatever, and alcohol self administration or sucrose self administration, sugar self administration. It's like a way of Kind of getting you can put cocaine in the water and get milding addiction. Yeah, exactly. And so if you give a mouse IBN, you can get them to stop self administering Alcohol. It's interesting we saw that in humans that stopped drinking as well in our our study.

1:29:34 Or you can In this case you can 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 seeking part of the brain. And it emulated the same effects as the Ibegaine, right? So this G D and F effect in the dopamine system at least. And

1:29:53 G D and F is 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 when I'm talking about the Cyber Game Stuff. One of the big pharma companies.

1:30:09 A hundred billion dollars. Instead. Don't just resynthesize IBogaine, but make a drug that works like Ibogaine or I I think even some of the classic psychedelics. But really specifically I began I think they'd have a hard time doing it. Because we don't have the neuroscience to understand what's going on there.

1:30:25 And I think it's because It's not a one receptor. It's not super clean in that way. It's like promiscuous. People use that term dirty drug. I I think it's it has the wrong connotation, but Yeah, yeah. I I mean like L S D is pretty kinda

1:30:40 Promiscuo on there. Yeah, I think prom promiscuous I like to think about sophisticated I like to think about it like a symphony. There we go. Right? Like you're interacting with these neurotransmitter systems in proportions in such a way that it produces this effect. My suspicion is

1:30:57 That it's Probably more sophisticated than we wanna A tribute and I mean maybe not you, but like the scientific community wants a tribute to nature being able to pull off, you know? But it's this idea that maybe somehow

1:31:10 We have this drug that just happens to work the way it works because it's able to interact with these systems and Pretty important ratios are 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 gonna be hard to reproduce. I mean obviously Sasha Shog and others were able to Take uh emulate similar sort of five H T two A effects, but

1:31:33 I don't even think he was able to produce an I begin 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

1:31:47 really how to study it, it's gonna take a new wave of neuroscience tools to be able to capture all the effects, you know, in real time. Of uh Symphony of follow up questions. Okay. And also I'll give you you can choose. This is this is 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

1:32:14 In this particular case, someone's sister was a Heroin addict. Who is now homeless acting as a prostitute, like l living under an overpass.

1:32:26 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 the there's a question of is this risky? And the follow up is compared to what? And in in this particular conversation it was well, she could die tomorrow. Yeah, from an OD or this and the other thing. So so I'm I'm just kind of setting the table with that. But improving the safety profile is 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.

1:33:01 Caffeine, I guess, or coffee. Right. Okay. Unexpected, presumably. Yeah. And so my question there, which I sort of seeded I've'cause I mentioned I would want to talk about this, it's like Any overlap in terms of mechanism or how does this compared to something like semi glutide, right, like an Azempic.

1:33:17 Or some of the the newer gen, I think it's Monjaro, maybe getting that wrong. And then the last one and I've been wanting to ask somebody about this. You mentioned five H T two A. It seems like some psychedelics exert effects also on five H T two B 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 uh some type of cardiac complication as well, like some type of like vent like ventricular hypertrophy valves.

1:33:46 Valves. Exactly. So the question there is do you think Is that Microdosing, for instance. Which has become all the rage. Could that potentially have Long term.

1:33:58 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 uh specifically has a section about this issue of cardiac valve or problems, particularly from these more classic psychedelics. The problem with iBogaine is different, right? The problem with Ivygaine is that it interacts with her potassium channel. There are a number of groups.

1:34:24 Folks at Columbia, folks at U C 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 her. Is that you do you mean like noribogaine or something like that, or is it more of a noribigaine, the the primary metabolite of Ibogaine that goes after two D six is a normal part of The I began process has a similar cardiac risk profile. Oh, does um profile. So it's drugs that are

1:34:53 I think they called him like Tabernau or something, but uh A boga logs or something, I think is what what was Point it uh Davis, but Essentially these are drugs where they like try to

1:35:04 Engineer off. that interaction which may or may not have an effect on its brain Oh facts. And so I wanna answer the question I'm trying to ask, and the question I'm trying to ask is does I begin

1:35:19 Help. With certain, you know, human illness. By modifying the molecule, it's not Ibigain anymore, it's something else, and then you're asking the question is does something else helping? the view is maybe maybe it's close enough to IBM to do something similar And I've taken like a different stance on this where I basically

1:35:36 Taken the frame of How do you Preserve the molecule. And really lean in on the cardiac risk.

1:35:44 How do you put an airbag in the car instead of redesigning the whole car? You know, a an airborne shuttle or s I don't know, whatever. So it's putting an airbag in with a you know, with a high likelihood of of saving the person and so we received

1:36:02 Torsades 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 in really interesting about this

1:36:14 arrhythmia torsades that everybody's worried about is that the treatment for it per the American Herd Association guidelines is to give IV magnesium. Which is incredibly safe. I've given many times for various things and ER. And you can just give it to people and you'll eventually urinate it out or whatever. And so you can

1:36:34 Give it. Get people through this risk period, they may be slightly hypermagnesemic or a little high on their magnesium in their blood, and it'll go out and everything's all good. And you know, there have been about a thousand operators that have gone down to Mexico so far, and to my knowledge, and we looked into this pretty significantly, there hasn't been a single Case of Troussades. Conversely, like

1:36:55 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

1:37:11 The thing that can cause that problem. then it's much more likely that you could knock out the risk or significantly reduce the risk. It's also about doing it in a monitored bed setting so Ticasin, T I K O S Y N is a drug that is approved for atrial fibrillation and it's an antiarrhythmic.

1:37:30 That can be pro rhythmic in the same way as I begin. It actually has more risk. than I be in the the rates of torsades are higher with Ticusin it's approved. And it's totally say if you just do it in a monitored cardiac bed. And so I think that We have to my suspicion if we're gonna do a study in the US with

1:37:48 I mean, we're just gonna need to do it in a moderate 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 gonna have to Think about well.

1:38:06 Not just Can This place and wherever Mexico, wherever it is, provide. you know, a good pure form of ibian, but what's the kind of the wraparound risk reduction there? And I think that's what people have to think about.

1:38:18 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. I think the reason why the veterans that we studied We're so interested in going is because as you point out, there's

1:38:32 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 friend 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 I did the trial ultimately My view was there's no way

1:38:53 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 how many Things that these folks have done, how much time they've spent in the VA hospital and all that good stuff, and so

1:39:17 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 ya 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

1:39:34 kind of brain acting drug I've been involved in in looking at. Okay, let's talk about the Alcohol and the caffeine. Yeah. So

1:39:43 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 two diabetics, like semi glutide and

1:40:02 Ozempic 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 food and stuff. I mean, it's wild to see how the like the societal Ripple effects. Walmart apparently has uh yeah and I have friends. Sold less food. Yeah, and I have friends who have been obese effectively their entire lives, never had an exercise, and 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 how these things work, but I certainly don't, so I'm I'm not yet there.

1:40:41 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 C and S kind of psych addiction side of things, people are still in the like

1:40:59 Is this doing something? Yeah, it looks like it's doing something there, but not any deeper than that. I think we'll learn about that on the kind of Ozimbic drug side of things, and then IBM's been Relatively underexplored from a basic science standpoint, but my suspicion is is that It is probably similar enough in maybe some of the same mechanisms are being Inacted because what you're finding is a similar phenomenon across both

1:41:23 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.

1:41:38 And As you can expect from the Term it's expecting something, right? So you you're primed to think Th this thing's gonna help for this reason. I'm always really

1:41:51 clued in when you have really obscure off target. Non expectancy phenomenon happening? So in the c in our Evergame trial, as you mentioned a minute ago, basically everybody quit drinking coffee. For a period of time and like none of them

1:42:07 really went into it. As most of us don't, our coffee habit is maybe a concern. Yeah, it 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

1:42:25 Focused on dealing with being overweight or focused on, you know, their alcohol use problem or their 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

1:42:48 Change that's happening and what People will tell you phenomenologically about this is It puts A pause in between stimulus and response. In a phenomenal and I can't like prove this per this is just what everybody seems to come back and say. It puts

1:43:06 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 kinda gets into this question of Free will and all the stuff that people think about.

1:43:18 Where there's a moment where instead of making the habitual action, the person finds himself in a purely Unbiased choice phenomenon. And what People have opiate use disorder would say in those scenarios

1:43:34 When they would relapse after I began is they'd say You know what? I just I had something about it. I didn't crave it. I no I just wanted to do it or something, w r wanted to remember or whatever, but it wasn't this Habitual action, right?

1:43:48 And they go back and they do I begin again after they'd gone back into the addiction and then they they had all the negative consequences and they say, You know what? They got back to that choice again and they're like It's not worth it anymore. I'm gonna go this way. But they were able to pause and make those decisions. And it sounds like from talking to the various veterans that have gone through our

1:44:08 Study is that They'd 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

1:44:28 Establish new patterns. The drug eventually Is gonna wear off. You know, as all drugs eventually do, and you probably do lay down a level of habituating again, but if you

1:44:39 Could during the period of time when you're Brain seems to be pretty Plastic. you know, shift and lay down new patterns that when The drug wears off.

1:44:48 Assumably you kinda lock into that. New set of patterns. And I think that's what's really Interesting and probably a little bit different than the Ozimbic in the sense that The Ozimbic seem to kinda take away From what folks will say a lot of the like seeking or rewarding aspects of things like food or whatever is just cravings. Yeah, cravings. Whereas this seems to introduce

1:45:11 a level choice. What would be very interesting in So you're 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'em an Ibagaine. sort of drug and then you think about how do you use something like an Ozimbic to kinda follow on with that, right? We're able to kinda gate some of it. And it's way out there and probably not anything anybody's gonna do any time soon.

1:45:34 But it's an interesting idea, right? If these are Essentially habit affecting drugs that we haven't had tools to really use before, which I think's pretty cool. Yeah, and folks who want to dive deeper into this sort of reopening of Let's call it critical windows. I mean I'm borrowing that terminology from uh Professor Gouldan, but Pretty fun stuff to dig into as well, if you want to

1:45:57 Sort of scientifically. at least for the time being, reinforce 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 Here we have. All right. Let's hop to a few other questions. One is coming back to Ivy Gains specifically. The two things that have been Of greatest interest to me with respect to IBN R T B I?

1:46:24 Right. So if someone has No addiction. No PTSD. The only issue they have is Some form of T BI. Do you think there is a role for Ibagan? So we can place hold that. There's part two to this question, which is

1:46:38 I've heard reports and I haven't gone into the literature on this site. I don't know. Maybe this has been explained somewhere, but I've certainly heard reports of opiate addicts who have seem to indicate that I began or I boga. after treatment during which they do not seem to experience

1:46:57 Much in terms of withdrawal symptoms. And I wanna 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

1:47:11 The seeming diminishing or disappearance of for a period of time physical withdrawal symptoms. It's a little tough with the cohort that we studied because they were You know, it was military T BI. While I understand that

1:47:26 The PTSD diagnosis is pretty ubiquitous in the system. It's Probably true in a fair amount of folks, especially folks who've been exposed to a lot of Combat related trauma in earlier life trauma. And in our group it seemed to be there in in most of the participants, it was depression and anxiety. And so we haven't studied a pure TBI group. And so the confound is

1:47:48 Without Studying a pure TBI group that somehow had Maybe it was a competitor in martial arts uh you know, or something like something like that where they like intended to Potentially get hit in the head. Probably intended to hit other people. In go into the ring knowing that you're probably gonna get hit. Motor vehicle accidents, there's really high rates of PTSD in those because

1:48:20 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 like football players right. I mean, a lot of reported depression. Who knows? It could be a lot of other factors involved, but highly correlated, yeah. Yeah, and those guys, you know, they're gonna hit their head in the game probably at some point. And so that population where it's more of a pure T BI population, you know, you could

1:48:47 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 at the 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 in and I'm like, No one.

1:49:05 Just give me your wild ass guess, like mechanistically, what's going on here. It's the symphony, right? Which is Sounds kinda like maybe even hooky or like a little like less direct, but I I just think that there's something about interacting somehow with multiple different neurons at the same time. It must produce this. I mean the maybe the G D and F B D and F alone could do this. I'm not saying it can't, but I

1:49:30 suspect that it's a more complex process. And the problem is we don't have great tools to evaluate that, but sometimes s nature is uh trumps our human scientific abilities. And I think that that IBM certainly is there in twenty twenty three. 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 in scurvy, but it took us another hundred years.

1:49:55 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 gonna figure out this works before we have any idea on how it works. Your second question, which is I'm gonna answer it the same way. But it's very unique to IBM. You can take somebody who's going through fluorid opioid withdrawals and you can have them Not only Have a cessation or stopping of

1:50:21 Of a desire to go take more heroin or 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

1:50:35 diarrhea, like headache, sweating, all the stuff that people will go through when they're going into opiate withdrawals. And this seems to really kinda like Knock that out. It's likely again that Because it's interacting with the opioid receptors, it's interacting with the glutamate system, but

1:50:52 It is To my knowledge. None of the other psychedelics can do that. Ketamine can't really do that. So this is a pretty unique thing to IBegain that it can pull this off. And why I think it's such an important drug to understand. I mean, I would argue that

1:51:07 Because of how broad I be in Seems to work across now Most of the major psychiatric diagnoses uh with the absence of something like schizophrenia, but anxiety, depression, PTSD, there's traumatic brain injury, you know, multiple different addiction. types, it's gonna behoove scientific community to really kind of break down

1:51:27 why it does what it does over the next 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 IBoga in and I bug? I I believe there's something happening in Kentucky.

1:51:44 Yeah, so I've been down to Kentucky to testify in front of the opiate abatement commission of Kentucky. It was myself along with Sreeni Rao. Ty Debermash, who's uh C of Demorex was at the University of Miami for a while in Canal Peruz. Who was it MYU? And is it kind of an academic practice psychiatrist and

1:52:05 There's a guy by the name of Brian Hubbard, which is he's a very interesting guy. He's a 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.

1:52:28 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 opius disorder fall into the realm of What we think about as replacement therapy, you're replacing a higher risk opiate for with a lower risk opium. So that's the boxon and

1:52:49 Which contains buprenorphine and um methadone. Or opiate blocking drugs like naltrixone. 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 Saboxin and so there's

1:53:17 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 use disorder patients. And the numbers I'm not gonna get into'cause 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.

1:53:41 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 kinda similar to To some of these Wagobi sa kind of drugs, you can drive down some of the pleasure

1:54:00 Around. This is more theoretical at this point, but you 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

1:54:15 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 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.

1:54:37 And this is As we described earlier, such a high risk phenomenon. That a one in three hundred risk is not um Is that one in three hundred or one in one hundred? One and one at a risk of a heads. It can be a trivial just blood on the tip of the electrode. Which is asymptomatic. About a third of those people are gonna be

1:54:56 You know, in a more complication. Yeah, have a real complication. So And then you get about a one in three hundred risk of a torsad's risk with Ibegaine. Right. And so next door in in Kentucky. Similar odds. Yeah. 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 IB gain risk is probably a little less actually than the DBS risk if you just kinda look at everything.

1:55:21 When 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 the few people that does all this stuff, so I can kinda and you juxtapose. off in separate worlds. So anyway. Thanks, man. Yeah. So I went down there and there were a million questions about the cardiac risk and about whether or not this should be done. And in particularly 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 Sabax and

1:55:56 Naltrexone and methadone. Don't work. And we we need to Spend some money on trying to help those people. Also, working is quote unquote working has different outcomes, right? If you're talking about like substitution therapies as well, right? Yeah, no, I think you're totally right. I think it is living on opiates

1:56:13 If you're you're having to do this your whole life, I mean it's tricky. You lose your prescription in a flight to wherever and then now you're in a really bad place. And so this idea of Instead of replacement Substitution or whatever. Interruption.

1:56:26 Which is what I be in is gonna do and I think at some level what DBS is gonna do too, right? It's gonna 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

1:56:44 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

1:56:53 Is this view that One, uh the the current treatments are fine or whatever, and then two The How could it be That this

1:57:02 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 hubristic part of the human psyche, which is that

1:57:16 I need to start the fire, I need to hammer the wheel, I need to you know And I think at some level The sort of not invented here kinda thing. Yeah. Yeah, right. And and I think the idea that somehow Somehow this just exists. It it goes around the psyche. In a way that doesn't really work and we saw this with Scurvy too, right? I I've spent a lot of time like studying Scurvy because I I I'm very interested in this human phenomenon.

1:57:40 There were people called anti fruiters. I'm not kidding you. It's a real term. Wow. And they were in the Royal Societies in the seventeen fifties, and so we knew from fourteen ninety eight. 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

1:58:00 At some point. Scurvy got worse and all that, and people said there's there's 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.

1:58:16 Yeah, so James Lynde ran the first clinical trial in the history of humans. On Scurvy and citrus fruit. Where gave all these like various weird concoctions like

1:58:26 Poisons and they were trying to give people cyanide, they were trying to give people alcohol mixed with acid. This is what they thought. Yeah. And so he gave people he randomized people on a ship with scurvy to these various things in 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, and I think this is this meta phenomenon of People need to feel like they made it.

1:58:50 In that culture within that context. This is the latest and greatest thing. It needs to be kind of like very Proximal in time. Needs to be new, you know, it's gotta be the new thing to be the solution. And I think that's part of what's going on.

1:59:04 In Kentucky from my view of it,'cause if you look at West Virginia And you just look at like the actual information. Of what's going on. You probably be more likely to cause and I I don't think that people should, but

1:59:17 question the brain surgery thing, if you really get down to it. over the IBAM thing just on the risk portfolio and having to have a implant a device for the rest of your life. But nobody sent uh there's 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 da da.

1:59:36 And that's totally cool. from their perspective. And I think that we've gotta as a culture and as a scientific community really Change the way that we think about evaluating tests and particularly therapies. And look at the inherent Scientific complexity.

1:59:52 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.

2:00:05 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 I think both of those things are are a yes, you know, we should be. It's the best candidate that we know about. And uh the risks are are mitigatable and similar to to DBS. So many facets to this, like insurance reimbursement, scaling, therapist availability, or I should say more medical availability for like the duration of stay that would be required with I began versus like there's so many facets to all of this. In terms of

2:00:36 Say getting to patient ten thousand, right? For whether it's this DBS. implants, surgery, or Ivy Gane, right? There's so many levels of nuance. But at the basic science level and the further research, who am I to say? But it seems like the Cost and severity and prevalence of the problem is such that

2:00:54 The answer is of course yes. Of course it's yes. I do want to ask you about synthesis. Specifically really a divine because I'm Always fascinated by rate limiting steps and also unintended consequences of

2:01:09 using different compounds that occur in nature. But before we get there, I want to very selfishly throw in a wild card question. around IRBs and funding studies and getting ethical approvals because I would love to see more studies on extended fasts in 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 in humans. Any suggestions? I think everything's studyable if the risk benefit ratio is

2:01:43 On the right side of things. At least at Stanford I think that's the evaluation is Extended Fass. In

2:01:50 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.

2:02:04 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 gonna 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 R B is

2:02:21 We're gonna randomize people to no motorcycle helmet or motorcycle helmet and have them do laps around the university, you know? We pretty much know the answer to that question and and the benefit of knowing in a randomized control 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 gonna be some effect on

2:02:54 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 uh the 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 something like that, up until maybe the forties and fifties, 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

2:03:33 a ketogenic diet for certain psychiatric conditions. Because you see Some incredible results and Chris has been on the podcast. With Say ketogenic diet.

2:03:44 as applied to conditions like schizophrenia, for instance. Uh I mean remarkable transformations where people get off of half a dozen or dozen medications and like you I am Interested in Practical.

2:03:59 solutions and especially things that are uncrowded from the perspective of scientific support, which for a while has been psychedelics. But certainly accelerated TMS. I'm 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

2:04:25 at hand now to human fasting. That may not be the argument that I would use, but certainly there is 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 Sh also has a great book on MDMA. And MD Macist psychotherapy, the history and implications that recently came out. And she traveled to I think it was Gabun, although I think there is also you you I think you can also find Iboga in Cameroon, if I'm not mistaken. And she went on the ground to look at all the implications of global demand for

2:05:02 I began and I boga. 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 two users of psychedelics like a plea for a more ethical menu of options, something like that, to just point out Some of the Diminishing natural supplies for

2:05:21 Say Peyote. Almost certainly gonna go extinct. Use something else. Use San Pedro cactus. Look at the growth cycles. Just don't touch it. Unless you're part of a culture that has this 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 Ibigain can be had in, I guess, a a number of different ways. Maybe you could speak to like the known options and then looking forward what some of the most interesting options are for

2:05:48 Whether it's like extraction or s or synthesis. There's kind of the straight. extract out of the Iboga tree as 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 it drives the prices up in the buiti. the people that take Iboga and Iboga and um Gabon and and surrounding countries.

2:06:12 no longer can access it because of the the high cost, which is the last thing that you want to have happen, 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

2:06:28 Another tree, then Ghana and other places in Africa. That has uh voican gene. Afrikaana Street and Has voacan, which is uh A very similar but not identical

2:06:41 Alkaloid to Ibigaine. It's actually not even a controlled substance, so Vocanine is Not on the controlled substances list. And it's not as much of an issue'cause there's not really a current medicinal usage of voican or u 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 commercial use. Yeah, yeah, and it's pretty ubiquitous too. I mean I've I've heard that It's not just in Africa, it's in some of Central and South America. And so you can um you can extract the voicangian and then you can do this simple

2:07:15 Chemical Step. to get it to Ibergane. You know, to sort of Do a synthesis pathway. A Vibegain from De Novo it's like twenty

2:07:24 six plus steps or something like that. This is like the last step before it's Ibe in from Vovakanji and 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 a chemical out of the plant. So the other way to think about it is'cause you do a full chemical synthesis and people have looked at that and tried to do it. It's very hard though because

2:07:48 Ibigain has two chiral centers, so it has the potential for four stereonantromers. And that chemistry is complicated. And so full synthesis It's a tricky process. My suspicion is that Whether it be Biosynthesis or

2:08:03 straight full synthesis, but there's gotta be a way to make this that avoids trees eventually. I think it's better for the environment. It's gonna be more scalable It's gonna be something that standard pharma's gonna wanna see happen, um to really be able to use it. But there's still some time to get from A to B as far as that goes. So I think it's not a done deal. It's not completely figured out yet. So bridging from that, I mean, this is actually a completely separate question, but also raises some sustainability

2:08:31 Ethical questions. Five M E O DMT, so five methoxy. DMT. So first of all, I would really implore people, I'll link to this in the show notes as well. Read the blog post that I put together. So if the five MO DMT it's present in quite a few different plants, different nuts.

2:08:46 Most people who have heard it in the zeitgeist to know it within the context of Bufal Varius, there are other scientific names for this Toad the snoring 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 has beat the drum about this to his credit.

2:09:10 People are not gonna like this, but there is no documented indigenous use of the Snoring Desert Toad. Ken Nelson, look it up in the eighties, produced a pamphlet after testing God knows 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 ten to twenty minutes, ten to fifteen minutes. So from a business model perspective, I understand the appeal, much like I understand the appeal of The newly branded psychoplastagens, right? Yeah.

2:09:47 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 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 its 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

2:10:18 Yeah. is from a therapeutic outcomes perspective versus being a business differentiator. Does that make sense? Like this is something we kinda like. You know, we put a nice set of icing on top of the cake and that includes this

2:10:32 What can often be a sublime experience, not always for people, and can be destabilizing for some folks in the form of five M E O DMT. 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 Ibegaine to figure out what the Ibegaine effects were in isolation and

2:10:52 As I described earlier. Yeah, we had Extremely remarkable effects in the absence of doing the five MEO. I think what? People say about this the five MEO is that it just takes the edge

2:11:03 At minimum it just seems to take the edge off. The gray day, which is a day that happens for Not everybody that Take cyber game, but a fair percentage of people such that there's a name for it. Where people

2:11:16 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 meaning depressive symptoms. Okay, yeah, what makes it hard, anxiety. Yeah. Anhedonia low low motivation Sadness. I think

2:11:36 Probably what's going on is there was like a serious kind of flooding of your C and S with a whole host of effects from this drug and then and then the brain's then kind of reacting to that and then it seems to kinda rebound out on its own without the five MEO, but it sounds like from what I've heard

2:11:55 Five MEO 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?

2:12:08 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 MEO after a five MEO and we can actually answer that question, does it have an effect in the long term? It's hard because there's like a floor effect of just like the profound improvements that we saw. Just from IBN, so you'd have to My

2:12:28 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 MEO just'cause you know, everybody's flooring out just with IBA. When 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, yeah. So I mean essentially we're seeing people drop down within that normal range. On the assessments. 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 which are in the normal range.

2:13:10 And so you'd have to zero people out with a five MEO, 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 were a couple of people that relapsed at 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

2:13:30 It would be a hard study to deal with. And I think from like a Purist. I wanna see this go through the FDA and kinda do the F DA things and see if we can get You know, the first drug kind of through the process. I don't wanna say it's a distraction from a US kind of scientific regulatory

2:13:48 strategy standpoint, but it's definitely something that would add complexity. So I think at the level of clinics that are 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.

2:14:11 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 harm I mean five MO DMT, I have some experience with it. I understand the appeal. It's like Sachetananda, et cetera. 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 I have friends who are very experienced psychonauts. We're talking like a hundred plus reps with things like ayahuasca who have been pretty much even keel with

2:14:49 their various experiments and been knocked pretty sideways for non trivial periods of time. Five five MA or DMT. Maybe that's Just the sample set that I'm dealing with, but Yeah, and I totally agree with you. You know, medicine is a

2:15:04 Discipline and a profession of risk mitigation and risk benefit ratios and everything. And anybody that would proclaim themselves to be physician scientists 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

2:15:27 Square all that. I think to your point It would totally make sense if the person was in such a bad place in the grade A that you were worried About them. I think there's a justification there if you really Is it seems that they do have some

2:15:41 General experience that this was helpful to kinda getting folks out. The reality is is that we're really Not gonna know much of anything and a lot of this is gonna be in the realm of anecdote until we do Do the trials in the US and really

2:15:57 Thoroughly document. everything that happens with this draw, with I began with Five Bio, which as 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 Well

2:16:13 MDMA may be a substance that Certainly not everybody could Use but like I 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

2:16:27 constrained to a smaller population where the risk benefit is 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 gotta 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 one point oh Two point oh.

2:16:53 Three point oh? I'd love for you to Feel free to speculate, right? It's gonna be speculation. But putting aside like the I know it's hard to do, but like Shepherding stuff.

2:17:03 In its simplest form, cleanest form through the FDA, et cetera. What might psychiatry four point oh look like? 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 accelerate TMS Protocols work.

2:17:23 from a harbor 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, in my conversation with Nora Volkov of Nida She's talking about Focused ultrasound. So maybe you use that to

2:17:41 hit the deeper structures directly. You hit the nucleus occumbens or whatever it might be. And then related 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, oh it's a this 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

2:18:05 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 and gals, but a lot of these operators and men who go through the IBGA experience, I mean they will and maybe there's a visibility bias'cause 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 would attribute the therapeutic effects to much of the content, right? This reconciliation and so on. So what might Psychiatry four point oh

2:18:30 Look like that. We have a paper. Coming out soon where we're actually trying to use neurostimulation to change Trait hypnotizability to make people more suggestible transiently. Mm-hmm. And it and it's probably an ability to

2:18:44 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.

2:18:56 Example. 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.

2:19:10 I think for O C D And he was had a normal musical taste. He listened to whatever other 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, alright. Yeah, yeah. So totally sold all of his other um albums and Listen to Johnny Cash and the batteries for these the brain stimulators will wear out after time and you need a new one.

2:19:37 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 battery's dead and then they'll have a reemergence of symptoms. And so this gentleman did. So I think it was his O C D and his O C D got worse again. And he fell out of favor with Johnny Cash and threw away all of his Johnny Cash albums and start listening to whatever he was listening to to before. Went in, got a battery change, the battery was put back in. And he's like, for fuck's sake, I gotta go back to the shop and buy my Johnny Cas. And that's what he did. Yeah. And so just like we don't really understand how Evergame works, we really don't understand what happened. It was a very

2:20:12 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

2:20:33 For some people they're gonna see rose colored glasses where they saw blue before or whatever. It's like I can give you s a different set of glasses to watch the movie, but I can't change the movie directly. My suspicion is is that we're Gonna edge into a world where Maybe we can change the movie. And that's where it starts to get Both very interesting and very

2:20:53 Ethically complicated. And that story about Johnny Cash, that doctor Had no intention of doing that'cause 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 that was playing in the hospital when he woke up and his brain

2:21:13 the reward system just kinda like attached to it or whatever. But it's one of these things where We're gonna get to a place of sophistication, I think we're gonna be able to do that. And what happens in medicine as I I see it is we're always redefining what's illness. It used to be that high blood pressure was like one fifty over a hundred or something, and then it was one forty over ninety, and then it's one thirty over eighty, and now it's one twenty five over like seventy five or whatever it is.

2:21:38 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.

2:21:52 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 semivolition 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

2:22:07 sooner in that process and we have emerging tools that can Help you with this sort of content. Targeting manipulation sort of thing. then I think you're gonna be talking about much more specific sort of interventions.

2:22:22 That's like very sci fi though. You know, it's not something that I think there's even a like a hint of. I wouldn't even know how to tell you. How to do that now or like one shot on goal is just to move around this brain trait. We do have a study with Rog Eron where we're actually Packaging ketamine into nanoparticles? Mm-hmm. Infusing them into the through an IV into the bloodstream and then using ultrasound to kinda open the nanoparticle ketamine and drop ketamine just in the cingulate in the area that we were talking about earlier.

2:22:52 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 a clinical improvement.

2:23:14 What's necessary and sufficient to produce the trip. And I think that's gonna be way more important than modifying the molecules. Because it's like a Confound. We're not really answering the question of This tripless IBGane work. This is not IBogaine, you know, it's just some other thing, right? But

2:23:30 What what we really want to know is does triplus IBN work'cause we just put it in the Amygdala are just into the Singulate or something like that. In isolation isn't sufficient to produce the trip, but it's sufficient to produce a therapeutic effect.

2:23:45 If we can pull that off, we're gonna start next year on that. That's gonna be super cool because it's gonna give us the ability to have more of these questions. You could even think about it, like if you had a long acting anesthetic, right, where you Had somebody with pretty pronounced Psychosis, schizophrenia symptoms. Coming in.

2:24:02 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 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 an aesthetic where you're putting somebody into a

2:24:23 Medical coma or something. You're just shutting down this one area. Which you could potentially do through neuromodulation and not pharmaceutical, right? You can People have tried to do that. With deep brain stimulation you can actually do a jamming signal in certain areas and shut it down too.

2:24:40 And that may be the long term solution, right? That you're using drugs like focal drugs to test it. It's a commitment. It's not something you can do in an emergency. Yeah. Right. But you could in theory do this in the ER. You could take somebody that was acutely psychotic. You could put an aesthetic that could kind of shut down that system for transiently for a couple of days. And you could kinda get them more on board with

2:25:01 thinking about what the long term solution is when the fear system isn't in place as 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

2:25:15 It's fun. In si right, so to speak. Right. I mean you look at Snow Crash by Neil Stevenson and There are many many examples. But Do you think you could change handedness?

2:25:30 Hand dominance? That one would be hard. I think it's possible to do that. Uh. Childhood. And we do do this in stroke, right? We do this constraint.

2:25:39 therapy sort of stuff where you actually constrain the 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, or the minimal Movement of their arm. And then they have an intact side that's totally fine, right? You actually Constrain the intact side.

2:25:58 And force the person to use the affected side. to drink water or to write or whatever and when what you're trying to do is to kinda 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

2:26:16 Corpus calosotomies 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 you 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

2:26:42 It's mostly that the brain gets fixed. Mm-hmm. You know, the interesting thing about this idea of critical periods and maybe what I be in 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 neuro rehab it better. Mm-hmm and that's gonna be I think one of the questions that'll come out of the data that we're gonna present is

2:27:03 How far can this go? When we saw like People go from mild to moderate. T BI disability to none on average, which is awesome and like never heard of, but If you keep pushing on that.

2:27:14 How far could you go with something like that? And that's gonna 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 I like to be

2:27:29 relatively disrupting and I like to be in spaces where nobody else is working. Mm-hmm. I start to not like it when everybody's doing it. Yeah. So I'm like always now like where am I going? I'm always looking for the 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 a positive signal that I need to do it kinda thing. And so I think this area of Certainly this area of using

2:27:56 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

2:28:12 case reports may be too strong, or 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 it's 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 flowers sparkle just a little bit more. I mean you notice details you would otherwise not noticed. And

2:28:44 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 Rodgers 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

2:29:09 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 poll done at one point. It's 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 it could be all made up, who knows. But I remember

2:29:40 The report supposedly Indicating that the yes answer was very, very high percentage of respondents, right? So If they're looking at something that has a lower risk profile. And is basically

2:29:52 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 One or two and then

2:30:10 By day three they've like zeroed out and then like Thursday, like day four or 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 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 he was like

2:30:30 Completely present in the present moment and able to just be there. And present and 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 kinda like totally present mindful Moment, I've had a ton of folks come back and tell me this, so if they

2:30:52 remit really early and we keep treating and we treat them through And it looks now that Yeah, we've had folks come through For this and folks come through for psychedelic. Treatments. It looks like

2:31:04 Day three four five. 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.

2:31:15 And it's very similar. For 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?'Cause you really are truly in this moment not thinking about the present or the future. Yeah, I've had a lot of folks actually offer

2:31:32 And at some point we need to do this, but offer various Philanthropic gifts. For me to run trials on athlete performance. I knew it. I knew it. Of course.

2:31:43 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 host finance guy triathlete friends. It is basically that. Yeah. And uh We cycle every morning and and randomize us to shammer active stimulation before we get on the bikes. And he's like The reason why this is good is'cause we make the same exact times and everybody knows their times and da da and can you

2:32:09 Change this. There's a little bit of evidence for this. It was a paper that was published 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 it with two four one three five two four like that. It's like a complex And a multi step. Finger task.

2:32:33 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 who had Sham. That's non trivial. Seems non trivial. Yeah. So it's interesting, right? Like there's some really early like Preliminary data to suggest that You could potentially improve performance with Nuristem. The thing about it is, is that if you could have something something that, you know, people have been thinking about TMS as a treatment for insomnia.

2:32:59 Others for acute anxiety, if you could come up with something that could But the breaks on a couple of different symptomatologies. You can 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

2:33:16 process for dealing with things. I think Trying to treat depression in isolation or something like that, you're You're never gonna 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, this hypnotizability stuff drive people up to be able to

2:33:34 receive information better, or study better, or 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. I think it's very interesting. It's it's also very sci fi though. I mean we're not anywhere close to knowing we can do that yet. Yeah, not even close yet.

2:33:57 But Fun food for thought, at the very least. Nolan, one more time, where can people find your lab? Online. So it's B S L Dot Stanford dot EDU. This is the Stanford Brain Simulation Lab.

2:34:11 Right. 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?

2:34:21 Before we wind to a close. Any comments, public complaints? Well, it's it's been super fun. I mean, I think you're um 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 neuroscip side and the psychedelic side. Yeah. Yeah. And so appreciate the kind of the knowledge coming in.

2:34:45 and your interests and you know, I appreciate the ability to 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

2:35:17 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

2:35:38 It was just like control Z. undo and back to the person they used to be and it's been durable with I wanna say Let's call them single day boosters maybe once a quarter or once every six months. And I think it's now been durable I wanna 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 bachelorette. I've I suspect that'll happen again.

2:36:04 And thanks for taking the time for the conversation, man. Look forward to watching 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 tim.blog slash podcast. Till next time, be a little bit kinder. than is necessary to others and 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 before the weekend?

2:36:35 Between one and a half and two million people subscribe to my free newsletter, my super short newsletter called Five Bullet Friday. Easy to sign up, easy to cancel. It is basically a half page that I send out. every Friday to share the coolest things I've found or discovered or have started exploring over that week. It's kinda like my diary of cool things. It often includes articles I'm reading, books I'm reading, albums perhaps, gadgets, gizmas, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcast guests, and these strange esoteric things end up in my field, and then I test them and then I share them with you. So if that sounds fun, again, it's very short. a little tiny bite of goodness before you head off for the weekend, something to think about. If you'd like to try it out, just go to Tim.blog slash Friday. Type that into your browser, Tim.blog slash. Friday, drop in your email and you'll get the very next one.

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