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Hello boys and girls, ladies and germs. This is Tim Ferriss and welcome to a very special episode of The Tim Ferriss Show. This is an episode that I think might be an example of peeking around corners. So what we are going to talk about, what we discussed in this episode, I think maybe
a component of the future of mental health treatments in the next, say, five to 10 years. It's at least a sample of it. My guest is Nolan Williams MD. You can find him on Twitter at NolanRiRYWilliams. And Nolan is an associate professor within the Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine and director of the Stanford Brain Stimulation Lab. And we're going to go deep.
Into a lot related to brain stimulation he is a broad background and clinical neuroscience and is triple board certified in general neurology general psychiatry and behavioral neurology in neuropsychiatry. Themes of his work include examining space learning theory and neuro stimulation 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 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 noninvasive 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. He received two NARSAD Young Investigator Awards, the Gerald L. Clareman Award, and the National Institute of Mental Health Biobehavioral Research Award for Innovative New Scientists.
Again, you can find him on Twitter or X at NolanRiWilliams. We'll link to this in the show notes as well. And you can find him online at NolanRWilliams.com. I really enjoyed this conversation. I think it is very important, highly tactical. And we also discuss things like Ibogaine, which are seemingly unrelated to neuromodulation. And yet, Nolan is an expert, very well versed in multiple disciplines.
and in multiple toolkits, pharmacological and non-invasive 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 with our further ado, Nolan Williams, MD.
Dr. Williams, good to see you there. Thanks, man. Thanks for having me. And I thought we would start with a personal story, not your personal story, but a story of Deirdre Lehman. Yeah. Could you tell us who this person is?
how it fits into your story. But let's begin with just a description of Deirdre. So Deirdre is maybe in her 50s, 60s female in Bay Area who has suffered from bipolar disorder much for life and pretty successfully treated for the mania side of things over the years as a psychiatrist.
taking care of that part in Marin and happened to slip into this pretty severe depressive episode. A couple of years back, it's been maybe like four or five years now. And her psychiatrist had actually gone to see a talk that I gave at this mood disorders day, like the year before we were talking, it was really early on when we were working on a rapid acting or a stimulation approach. So the psychiatrist had heard the talk and then her patient kind of fell into this really bad suicidal depression. And so she
reached out to me to treat her and I got on the phone. I'll never forget it was like a Wednesday and I got on the phone with her psychiatrist and she was telling me symptomatically how bad off she was. And I was like, I don't think we can treat her outpatient. She's like way too ill. I think she's going to the inpatient hospital.
So essentially gave her some information on how to do that. So I see her the next morning and she's in really bad shape. What does that mean? 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 sometimes. And so in her case, you know, she couldn't look you in the eyes. You look at the ground and she was doing this rocking thing.
which you can see in pretty severe depression. It's kind of this catatonia overlap symptoms, you know? I mean, she's like at the...
kind of the very end of the spectrum, one of the highest severity patients we've ever treated. So she was like a score of 50 on the modulus of 60, like very, very severe, right? And just rocking and not really talking and, and the husband's recounting 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 said, they want me to,
treat her and i say listen like it's friday we go monday to friday like you have to find a way basically to keep her well from now until monday and that means and by well you mean safe like i think so yeah exactly so keep her not having a suicide attempt basically from now until monday is very suicidal and i said you're gonna have to like.
Take every knife. I don't think any guns, but gun, chemical, like scissors, everything out of the house, the whole, all of it has to go. And you guys have to be on like a 24 hour, you know, watch until Monday. And so Monday morning.
rolls around and we bring her in. And the craziest thing, we had like a repair on the motor threshold coil, which is a coil you use to kind of get calibrated on the intensity. And it shorted out the device, blew the capacitor bank up on the first stimulator, blew your flex capacitor
Yeah, yeah, it like 7 a.m. And I mean, you can't imagine how stressful that was. So we had a second machine, I'll tell you about this later, we were running this, you know, trait hypnotizability modulation study and it was over at the scanner. So it was like pretty far away and this thing's way like 100 pounds. We had to send my team over there, run over there and grab it.
bring it over and luckily we were able to kind of get her going and treat her with a second machine. She was in really, really bad shape that morning and by five o'clock that afternoon she was basically normal and the next morning she was like totally zeroed out and completely normal.
Meaning no suicidality. Meaning no depression, no nothing. I mean, she looked like any person walk in the street, like totally normal, and that was in 24 hours. And we've seen this with bipolar patients quicker. It'll happen really quick for like a bipolar one patient. You can get it done and sometimes in a day.
just for clarity, but get it done. And don't worry, people listening, we're going to define terms and get into all this, but you're talking about accelerated TMS. Yeah, we're talking about accelerated TMS. Our rapid acting or a stimulation approach, we're able to get people out of these states and into normal mood. You know, and in short periods of time, generally, like 2.6 days on average for major depression patients, but it's quicker with bipolar. We've seen, especially with bipolar one patients. So she was totally out of it in 24 hours.
I remember it was like right around July 4th or something. And so we, you know, the whole team left, I guess we'll tell you about caffeine later too. So my wife and I are like big Phil's Coffee fans. And so I'll never forget this either. So we go down to the Phil's Coffee in Palo Alto after I saw them.
I'll never forget at Clark Lehman. Her husband also went to Phil's at no. I was going to be there and I look over and this guy is just kind of staring at me. And I was like, Hey, how are you going to see again? I just like just saw like I like 10 minutes ago. And he's like, I still understand what happened. And it makes sense, right? Like.
To take somebody from the worst you've ever seen them mood wise to like normal in such a short period of time was remarkable for him and you know it ended up being that you know after that period they actually went out and really were helpful with a lot of the philanthropy that led to the trials being funded ultimately the clearance and Clark.
Endure to really were advocates and have continued to be advocates for this to kind of get it out into the world and he was totally based off of that experience of feeling him feeling helpless, you know, and going from that to feeling like it was all solved. And I think she went maybe a year completely symptomatic and ended up needing it retreated again at some point, but gets like these little touch ups here and there and is able to stay.
well on going and depression as they tell me depression's not her problem anymore and so that's good she's a great illustrative case of what this can do and i think with 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 snippet that i pulled from your conversation with andrew juberman yeah which was a very good conversation specifically it was about
And I'm not going to use the right terminology here. So bear with me as a layperson, but the sequencing or abnormal slash pathological sequencing of activation or activity in different parts of the brain. So I don't know if it's the interior singulates.
I think you know what I'm alluding to here. Would you mind just explaining that? Because it was something that I had never been exposed to, and I found it deeply fascinating. And I'll just also mention this context for people who are listening to this, that part of what is deeply interesting to me about a number of the different tools and modalities that you explore in depth is not just the speed of action, but the durability of effect.
Super, super potent combination and very unusual from what I can tell combination of things. All right, so as far as the sequence of activation goes, could you explain what I'm referring to?
We published a paper in the Proceedings of National Academy of Science as it's been about six months ago now. So one of the former research track resident postdocs in the psychiatry program at Stanford, Anish Mitra, who's now junior faculty, was working with Carl Diceroth and I 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. The resting state part of it is basically tell a person to sit in the scanner and let their mind wander. So that's kind of the resting state of the default mode. Everyone think about it. And functional connectivity, what that means is it's the
Brain regions that have blood flow that is time-locked with each other, right? And so essentially these connected brain networks, the blood flow will go up or go down in those areas in a time-locked fashion. And blood flow is really- By time-locked, you just mean at the same time. At the same time. Correlating. Yeah, exactly. And so blood flow is a surrogate of electrical activity. It's hard to see.
electrical activity, kind of deep in the brain. People see it at the surface of the EEG. But with MRI, you use the blood flow as like a surrogate of the electrical activity. And it makes sense. If you're using glucose in a brain region, because you're using that network, then you need to have cerebral auto regulations to the blood.
vessels increase and they dilate more blood goes into that area. So it's just like a response to increased activity. And so you have these increases in blood flow that are supposed to represent electrical activity that are in different separate nodes in the brain, and they come on roughly at the same time. And we've known that for a while. Anishka, very interested in this idea that the timing of the blood flow is consistently temporally offset between these nodes.
So slightly that people ignored it for a long time, but he was able through using various math, able to show that there's a slight offset of the timing such that one brain region slightly comes on before the other. And that's interesting because that infers some level of causality, 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. And it's so quick that you see it as all like this, but really it's more like this. If that makes sense. It's coming on all at the same time. But from this network node, turning this one on, turning that one on or somewhere. Like the lead domino matters. Yeah, that's right. The lead domino, exactly. So in the case of mood, it looks like the dorsolateral prefrontal cortex, the area that's involved in control,
precedes slightly the cingulate cortex and our normal healthy control population, essentially, nearly everybody had that directionality. In the depressed cohort,
70% of them had it flipped, where the singlet was temporarily in front of the door slateral, but not everybody. And if you just had that information, you wouldn't know what to make of that. Like, why is it some people and not others? But what was interesting is when he looked at the folks that had it,
versus the ones that didn't, the ones that had it, were the ones that were responsive to our, we'll talk about what Saint is and the rapid acting or a stimulation approach in detail, I guess, later, but 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 did not have the biomarker and looked like a normal, healthy control.
and the signal on the post scan flipped to look normal in the folks that responded, had the biomarker, and then their brain changed after. And so the post scan looked just like the pre scan on the folks that didn't clinically change in the normality controls.
You know, we see this sort of test all the time of medicine. You know, 10 people come into the primary care doctor's office with blurry vision, urinating a lot, drinking a lot, headache. A lot of those folks probably have diabetes, but not all of them. Some of them have, 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 then the folks that have elevated blood sugar that look like they have diabetes, you go and you give them a diabetic medicine and then it normalizes. So the blood sugar after looks like the blood sugar of a normal healthy and looks like the blood sugar of somebody that symptomatically presented but didn't have.
diabetes. And so it was nice to see this and we're replicating this now. We have money from the National Institutes of Health to do that. But this idea that we're able to have a test that would change and the same thing that signals that there's an abnormality is the thing that changes later. And that's more rare and psychiatry, right, to be able to have all of that line up. So we're pretty excited about that and hope to see it. It does replicate in the larger
Population of patients, but it's a, 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.
and be able to say, okay, you're going to respond to this and not this or vice versa. I think that's part of what we need for psychiatry, right? Because people spend just so much time in their lives trying to find the answer. And we don't really have any tasks. Trial and error. Yeah, it's a lot of trial and error. It's like,
pharmaceutical ready fire aim in a sense. And this raises, I guess, just a meta observation slash question. Perhaps you could just discuss this briefly, which is, it seems to me like there have been, and this is part of the impetus for us having this conversation, part of the impetus for me in the last, let's call it, half year paying a lot of attention to accelerated TMS, which is there have been these
dominant paradigms in certain types of, let's call it psychiatric treatments for things like depression, treatment, resistant depression. And it seems like a very dominant paradigm for a period of perhaps several decades has been these chemical imbalance.
theory of psychiatric disorders. You have a serotonin issue, therefore, we're going to treat it in these following ways. You have such and such an issue, sure, we're going to give you SNRIs. And then, like you said, it's a lot of trial and error to figure out what works. And even if something works, it may often only work for a period of time.
So it seems to me and i want you to absolutely fact check and correct everything that i'm saying but that part of the reason that the research you're doing and that others are engaging in so fascinating is that it presents an alternative paradigm through which you could look at certain disorders right like oh wait a second maybe.
This person's car when you turn the ignition is just tripping things in the wrong order. And if that's causal, we could try to address that. And then maybe that addresses what we might have otherwise perceived as a chemical disorder. I have a lot of follow up questions, but is that a helpful way to think about this? Or what would you add to that?
You know, there's been, I would argue like three eras in psychiatry, you know, what friends of mine have called psychiatry 1.0, 2.0, 3.0. 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
Partially true. It's not that that's not true. It's just not complete. And so then the solution is a content solution, a la initially psychoanalysis all the way through kind of modern forms of psychotherapy. The limitations of that led us to psychiatry 2.0, right? This idea that we serendipitously found the first antipsychotics.
first antidepressants, and we were able to de-institutionalize from early schizophrenia patients out of inpatient asylum stays with these drugs, which kind of flew in the face of this being a content issue. What was the first anti-psychotic? Thorazine. I was going to say Thorazine. I don't want to take you off track, so keep track of where we are. We're at 2.0. How was 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 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, soldenafil, right? Viagra, it's like for angina or whatever. And then the male patients are like, why aren't their male patients sending their meds back? Oh, wait a second. That's right. Here we go.
All right, so Thorazine and the serendipitous discovery of... Oh, wait a fucking second. This seems to not necessarily negate, but certainly render incomplete this pre-existing paradigm. Then where does it go from there?
So then I think that to your point, there was this accumulation of assumptions around, well, if we're moving all of these chemicals around in the brain, then it must be that there's a deficiency or an imbalance or whatever. And that led us to recent history where there's quite a bit of prescribing of oral antidepressants and all that stuff. And the third era, this kind of circuit era that I think we're in,
Now, and I'd argue we kind of were entering in 10 years ago, but I think we're pretty squarely at the beginning of now flies in the face of that, right? If I can take a patient as severe as dear Dr. Lehman, get her out of it in a very quick timeframe and looking normal and holding that for a long time, and there was no chemical exchange, right? There's nothing that went into her system, then it gets you into this newer way of thinking about it. It's a circuit problem. The useful thing about this,
Framing one is seemingly consistently true in the sense that we're through all the various modalities seeing these differences, but more importantly, it lets you integrate past ideas into that concept. Drugs act on circuits, therapy acts on circuits, but focal neuromodulation is a really direct way of acting on those same circuits. And so from a patient standpoint, I think it's very empowering.
Because we're not saying to the patient, there's something inherently like missing or too much for you in the sense that you're constrained to having to take these exogenous chemicals to kind of stay well, but rather like there's a circuit.
You know, there's a miswiring sort of misfiring sort of problem. And if we can reroute that information, then you can feel well. And I think there's a level of empowerment that comes to that. One of the things that patients always tell me after they get well with some of our stimulation approaches is that they kind of look at it and say, well, I may get depressed again, but I don't think I'll ever get suicidal.
at that same level again because I know that I've got a way of getting out of it and it's my own volition to choose to do that and it's something I can tolerate and I feel normal. 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 and for a lot of people it's the feeling that nothing can fix this i am broken i'm permanently broken. There is no option other than trying to silence this voice in my head and the only way i can think of doing that is by ending my life.
But once you see, once you experience even more so, something that alleviates that, especially with any type of durability, doesn't need to be forever, but some type of durability and especially if it's rapid acting, right? Then you feel like you have a plan B and that is incredibly empowering. Let me ask you a few questions. The first is,
This type of neuromodulation is that synonymous with the term that I came across. I don't know who coined it. It's a nice term, electrosuticals, or are those different?
Yeah, it's part of that broader term of electrosuticals. Yeah. And so what we had done with what we called SANE or Stanford Accelerated Intelligent Noremodulation Therapy is that we came up with a way of reorganizing conventional TMS, which had been around for some time, reorganizing it in time and in space, right? And so with conventional RTMS that had developed in the mid 80s, first uses a therapeutic within
Clinical trials by my mentor, Mark George, when he was at NIH, the mid-90s, and approved by the FDA in the mid-delight 2000s. It utilized average skull positions to find an average spot to stimulate, which 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? What does TMS stand for?
So transcranial magnetic stimulation, and it was originally developed for what? As a motor probe by Tony Barker in the UK, and the idea is this idea of Faraday's law. So Faraday's law is this idea that you pulse a magnet, you can generate current and electrically conducting substances. So if I take an electric magnet, if I take a TMS machine to the beach and I try to pulse the sand,
Nothing's going to happen because sand is not, as you know, electrically conducting at all. It's an insulator. And so if you put a TMS coil or any electromagnet next to a wire, a copper wire or speaker wire or whatever, you can generate current in that wire.
If you put the coil on the head, it will bypass the skin scalp skull and induce current in the electrically conducting substance in the brain, the kind of brain tissue, right? And so you're able to selectively turn on cortical neurons without really interacting with much of the rest of the head. People do feel something because of the nerves in the scalp.
But 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 kind of send a single pulse, it doesn't really change the brain, but you can probe the brain, right? So I could take that coil from the mid eighties and I could put it over my hand representation, make my thumb move. I could do my wrist representation of my brain. I could make my wrist move. And it's organized in this stereotype way such that essentially the,
The head face areas like closer to the ear and you can march up to the midline of the skulls such that when you get to the midline, you're able to actually move the foot and the leg. If you have a certain kind of coil, you can do that. And so you can actually probe the entire motor system and make all of it move without having any volition to it. Question, what is the value of this probe?
So the value of a probe itself is just as they figuring out the mapping. Yeah, it's like a it's a mapping exercise initially, right? Like where is everything is the same and everybody is it consistent and they wanted to kind of have a way of doing that.
noninvasively, pin rows and others have been doing this invasively as neurosurgeons for 100 years. I guess 50 years at that point. And so they wanted to be able to emulate what the surgeons could do in epilepsy patients. They're doing epilepsy surgery noninvasively. And then what folks realized over the next 10 years is
We can send a signal into the brain that's like Morse code and basically send the signal to change the excitability of the brain and we can measure it if we do it in motor cortex by how much the thumb moves with a set amplitude of the machine. So if I get x movement,
From stimulating hearing, I make the thumb move X amount, and then I send this Morse code signal into the brain to tell it to tone down or to kind of be less excitable. And then I send that same intensity back in, the thumb will move half as much.
And so you've toned down cortical excitability. If instead I get this measurement of x, and then instead of putting in what we call inhibitory or depotentiating stimulation, we put in excitatory potentiating stimulation into the brain. And we do that and then we measure again, it'll be 2x. So we knew by the mid 90s that we could actually move around how excitable the brain was.
In these normal healthy control volunteer murder cortices and so the aha moment for mark in his team. Was this idea that depression at that time on pet scans on spec scans with this kind of hypo activity hypo metabolism meaning lower.
Lower activity, lower metabolism of the prefrontal cortex, where the prefrontal cortex just isn't as active as in as robust as it is in normal, healthy controls. And so he had this idea, well, could we use this excitatory stimulation to drive up activity? And so that was the aha moment in the kind of first version of this.
But they were super careful. There'd been some seizures in the early days from trying to figure out how all this works. And so they wanted to do a stimulation approach that wasn't going to have much of the way of risk. And so they had this once a day, very extended protocol. And because of the mid 90s, it was very hard to get.
sheep brain scans on patients and so this idea that they were going to have to use kind of average coordinates to target it so they get average, skull measurements and then they would do kind of a low dose approach once a day and do that out for weeks and then extended out to months and so the original tms trials and the original approval was this. Less efficient version that basically utilize kind of a.
low efficiency signal into the brain and used kind of average coordinates to place the coil. So average coordinates, meaning just by clumsy analogy, like we can't take an x-ray of you, but we do have a hundred other x-rays that seem to indicate roughly. This is where you have your fractures. So we're going to aim at those coordinates. That's right. Yeah, that's right. And the once a day protocol, I've heard the number 36 from somewhere, but is it somewhere in generally like the 30 to 40 session range? Yeah, that's exactly right.
So we're looking at, let's just call it for a placeholder, 30 to 40 sessions, one per day, and two, perhaps not initially conjuring image, but removing image from the minds of some listeners. They may be thinking, this is a beautiful mind. This is somebody chomping down on a wall or a piece of wood, getting electroconvulsive therapy. These are not the same thing.
Yeah, it's actually the opposite. So in the goal of electroconvulsive therapy, ECT, which has been around for 100 years, is to produce a therapeutic seizure. And some people with autobiographical memory troubles. It's pretty underutilized as a treatment in psychiatry because of these issues, because of particularly one flu over the Cuckoo's Nest and that story and that movie culturally has actually had an impact on ECT. And it's one of these things that's kind of, for a lot of patients, a last ditch,
resort because of the concerns around the side effects. TMS is different. You're not trying to induce a seizure. In fact, you're not trying to, you know, have any sort of change in cognition. I always tell patients 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 routine where they're sitting there and, and watching their show or whatever it is in the stimulators turning the brain on and unlike in ECT, there's no anesthesia. There's really no need for anything. You can do this in an outpatient setting, but the old forms of TMS are.
Extremely slow you can't use that in a psychiatric emergency and so you know this is something that happens over a couple of months and it's tricky for some people like if you're a working person and you have to do tms during conventional tms during business hours and you're.
You basically have to tell your boss or sneak out of the office or whatever it is, and go do an hour and a half during the middle of the day during like standard kind of bankers hours to be able to do this. And it's hard to do that over a couple of months. And so it doesn't address these kind of high acuity emergencies. And so we got very interested in this idea of can we.
Like I said earlier, reorganize the stimulation in time and space, space being, can we personalize it 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. And in a day is because we gave her a whole six week course in a day. How many sessions?
So that's 10 triple-dose sessions, and so it's like 30 total equivalent sessions in a day. And so the FDA cleared 600 pulses of ITBS once a day, five days a week for six weeks in 2018. And that was for a major depressive disorder? That was a 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 sessions worth in that first day and you do that for five days and so people are getting. The dose equivalent of seven and a half months worth of tms.
in five days. And what we found is surprising to us that was this linear is that you just pick up remitters as you progress through the days. What do you mean by remitters? People who completely lose all of their depressive symptoms to a level that is within the normal range. So they're rating at the same level as somebody who's not depressed.
And we can get people there on 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 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 on Monday morning. They can take a week off of vacation. 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 timeframe that's actually reasonable. And that was really our goal. How do we get people acutely out of these high acuity settings and into a state of wellness quick enough that it doesn't make a major impact on their lives?
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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. They'll be forced to take time off.
And in a case like this where you have a compressed protocol, there's the possibility of taking PTO or taking a week off and doing this treatment. Whereas, like you said, doing it during banker's hours over a month is going to be highly visible, right? And until the entire system changes, which is going to take time, if it happens at all, this would be an incredibly attractive, alternative protocol. If it were to work, so please continue.
Yeah, absolutely. Yeah, and that's the way that we thought about it, right, is can we take folks who need to get well quickly? I mean, we had people in conventional TMS courses where, you know, they started, they're in really bad shape. They lose their job halfway through. Maybe they get better at the end of it, you know, but it took so long.
Yeah. And so it's one of these things, if we can compress that up and get them well in a short period of time and get them out of it, you know, it gets people back to their lives and it has a low impact on them. I know I'm interrupting a lot, but the threading of this I think is important. So we can sort of foreshadow something that is going to be on the minds of a lot of people, which is what are the downsides? What are the risks? So my question is, like, was it easy to get the sort of ethics board approval to compress all of this into a much shorter timeframe?
I was able to make a compelling case to the IRB and then eventually to the FDA around safety. And so we give 90% of the resting motor threshold that's depth corrected for atrophy. So if somebody, if it's an older patient, they have more prefrontal atrophy, then you can increase the intensity based off of that difference in depth of their motor cortex. But essentially what their brain is getting is 90% of the resting motor threshold, which is
Kind of a calibrated number that's based off of these tms induced motor movements, it gives us a sense of how to dose the stimulation. I'll show a bit of my hand here, which is I've undergone two separate weeks with different hardware, different protocols, because I never want to talk about things like this, unless I've put myself.
in the spaceship and been the monkey shot into space, which doesn't mean at this point I'm a proselytizer 100% for the treatment, but I find it very compelling, at least for investigation. So to just explain, since I recently went through this, each morning,
Or certainly on the first morning, but on multiple mornings, in my case, they will test your motor threshold, right? And that could be a finger or 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 10 hours a day.
Yes, it's just a way of getting the intensity that you need. And so we know that 90% meaning sub motor threshold, there's never been a TMS related seizure for that kind of sub motor threshold intensity, even giving multiple sessions a day or whatever it is. There's never been an event like that. It's always been at a higher kind of
Intensity of the stimulation in the moment, if that makes sense. The amount of magnetic field that's being put out in proximity to the brain. It seems to be much more related to that than it does the amount of pulses that you receive in a day.
And so I was able to lay that out to the various regulatory bodies and show the evidence that that threshold is really the threshold where risk goes up. Sort of the magnitude, like the strength of the pulse, not the frequency of the density. Yeah. It's more about the intensity in this case and less about the density or the amount. So laying that out, it was acceptable in various parties deemed it to be non-significant risk.
And they let us proceed. Now this is FDA breakthrough status, FDA cleared and all the way through all of the regulatory processes. And so it's kind of an on label approach these days, but back then I had to make a lot of those arguments and knock on wood. We still haven't seen any seizure. How many people would you say at this point have gone through well-designed accelerated TMS?
It's definitely, you know, I'd say more than four or 500 between trials. You know, we have trials where they're ongoing and I don't know what the clinical outcome of those trials are because I'm blinded to them, but I do know that AEs, we don't have any serious adverse events in the sense we haven't had anybody have a seizure.
Yeah, so that's good. What you do see is headache. People will have a headache. It's usually from the not everybody, but 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.
And that actually goes away over time. So in the long term, you actually see a reduction in migraine headaches, and you see a reduction in pain, all that sort of thing. And people actually have an anti-nosticeptive effect. Anti-pane effect? Not pain. Yeah. What was the word you used? Nosticeptive. Ooh, new one. All right. Yeah. Yeah. Yeah. And so you can actually have an anti-pane effect. And the reason why we think that happens is because you actually- Anti-pane meaning it could help with chronic pain or something like this.
At least acute experimental pain, there are some chronic pain studies. You can see that you release endogenous opioids from stimulation, because you can actually use opioid blockers and block the anti-pain effects with TMS. There's this whole pharmaco stimulation thing that people are looking into. Buddy of mine, Joe Taylor, who's at Harvard now, did these studies when he was an MD-PhD, and he was able to actually show that
There is this release and then you can kind of block it with no administration of opiate blocking drugs. But yeah, that's the idea is that there is some acute potential headache risk and people can get a little fatigued from this. It's like fatigue more like you ran a marathon instead of like depression related fatigue, you know, just from kind of being there all week.
Look, end of one here, but seems, you know, I spent a lot of time talking to folks as, you know, kind of my job. My experience was headache for sure. I was hesitant to take any type of Tylenol or medication for that just because, and this is, again, as a naive layperson, but I was like, well, you know, like, if you do take NSAIDs, if you're doing, say, weight training that can inhibit some of the adaptive response, I'm not sure we fully understand what the hell's going on here. So I'm just going to 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. It was not the fatigue of apathy and anhedonia, like the difficulty or impossibility of finding joy and the things you'd normally find joy with. Like that type of fatigue is characteristically, it was very different. It's more like, yeah, you just crammed for 20 hours to try to nail your finals because you didn't prepare and you're gonna do that every day. That was a feeling.
Question for you then, we're going to get to the results. I'm going to discuss the results of St. But I think before we do that, it's important to maybe describe this patient population. Is it fair to say that you're seeing it would be an exaggeration, maybe say the worst or the worst, but you're dealing with patients who have had multiple failed interventions. So it seems like that's important to kind of keep in mind if that is true.
Yeah. Yeah. And so 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 at five plus or minus two med failures. And they had a lifetime load of depression of about 25 years. So these were folks who've been depressed with multiple episodes or very long episodes. They tried a lot of meds to get out of those episodes. You know, these are
not mild cases, right? These are folks who've kind of been through it for a long time. And interestingly, that's going back to the study that we talked about earlier with the flipping of the signal, that flipping of the signal was correlated with higher modulus scores. And so the more moduses the assessment, I'm sorry, yeah, higher depression scores. And so the higher your depression rating, the higher likelihood you are to have that signal from the data that we collected. And so, and that's what we've seen, right?
Got it. And this switching just to tie it back to what we were talking about is that sort of having the wrong lead domino or like you have a car where you're trying to start the diesel car without heating the coil first. Yeah, that's right. That's right. Yeah. So it's that directionality. And so that's what we've seen folks that are at that kind of more in stage.
Sort of depression seemed 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 PNAS work replicates. And what we've also seen is.
folks that do really well with dorsolateral, at least, are folks who have a pretty impaired tension. And so they actually score up on the concentration item of the depression scales. And so that was something we observed earlier on that if you're saying you can't read a book anymore, you can't really follow a recipe book to cook your favorite meal or whatever, because you just can't attend to it, then your likelihood of getting better from this is higher.
Whereas folks that are more on the kind of obsessive depressive side of things that don't complain as much about cognitive problems and concentration problems, but more about they're just ruminating and kind of obsessing on things. We found that inhibiting the right frontal pole or the frontal cortex. So stimulating here and we have OCD trials to do that.
is pretty effective at shutting that down so it's more of a shutting down than it turning up sort of intervention so. Some of it's actually like where the illness intersects with the brain anatomy intersects with like the symptomatic presentation to try to drive the best spot to stimulate for those folks and we have some.
Early studies now, we're trying to use brain imaging to actually sort folks into buckets, nearly to figure out which target makes sense for their symptomatic presentation. Based on their personalized fMRI scans. Yeah. Yeah. Yeah. So I think this would be a good point. And we'll mention this again at the end, but maybe you could mention any open trials or if people would like to consider enrolling or they know someone who might want to become subject in studies or anything you'd like to mention.
So we have a number of trials that are ongoing at the Stanford Brain Simulation Lab, so it's bsl.stanford.edu. And you can go on the website, and then there's a screening portal, and people can go on and fill out their information. And essentially, we have trials for anodonic depression, and we have trials for standard severe treatment resistant depression, obsessive compulsive disorder, borderline personality disorder,
patients who also have depression bipolar depression and other pilots some addiction work that my collaborators are working on and so folks have. That range of symptomatology happy to have folks come through and screen and it's all free which is nice so it's all basically funded through these trials and we're excited to bring people in and see if it makes sense for them to work with us on this and it's a couple of week commitment.
What did the results or what have the results looked like with Saint or slight permutations of that and how do they compare to let's just say more conventional treatments for these same conditions.
So in our original pilot study, 90% of people experienced remission at the post, 90%, 90%. In the randomized control trial, it was 79% of people transited through remission at some point in the four-week follow-up. What's interesting is it's not all at the same time point. So if you look at time point by time point, it's like in the 50% to 60% range,
The reason for that is because there's this colleagues of my Cornell, Connor, listen, and others have replicated this finding that there's a subpopulation of patients that actually has a slower time to remission. And we've seen this too. Folks will lose their suicidal ideation and actually peak their antidepressant effect at one month. It's usually an older adults. And that's what we've seen is basically it's only in 50 year olds and above. We haven't seen that. That's sort of delayed remission. That delayed remission, yeah.
But if you're putting together 22 to 80-year-olds, you're gonna have some of these folks. But what's interesting is TMS also probe of the system, if you kind of ignore the kind of normal rules of how to define remission, and you just ask the question of who crosses through, 79% of our active group crossed through, 13% of our control group crossed through. And that tells you something, I think, about the neuroanatomy, you know, that
Probably something in the seventy percent of folks have this dorsal lateral singular problem and then that was a version of that thinking was seen in our p&s signaling paper to about seventy percent of those folks had the flip in the signal. And so you know my suspicion is that there's a sub population of people who don't have that who have. Some other.
Diagnosis, it probably looks a lot like depression, but it's probably a different neuroanatomy, and we've seen this sort of phenomenon happen in medicine before we used to cluster all the. Parkinsonism together, so there's lots of reasons that Parkinsonism.
You know, some of those reasons are idiopathic Parkinson's disease and the classic sense, the way is idiopathic. I mean, just that it's kind of this spontaneous happening of Parkinson's disease that's the core Parkinson's syndrome that we think about Michael J. Fox and others. And then you've got other things that look like it, progressive super nuclear palsy, Lewy body dementia, drug related Parkinsonism. And so we used to kind of parallel to your like diabetes presentation earlier.
Yeah, exactly, exactly. So we forever lumped all these folks together and it really took the UK brain bank and being able to, in that case, for Parkinson's link, Parkinson's pathology to symptomatic presentation. What is the UK brain bank? And now I've never heard of this. Yeah. So it's like a brain, I mean, there's lots of brain banks or brain donation entities, physical brains, or are we talking about scans?
Physical brains after death postmortem donations so there's a lot of ways you can donate if you have a neuro psych disease you can donate your brain to science and so a lot of Parkinson's patients don't know their brains to this brain bank to try to understand what it is and what they found was with like a deep clinical.
phenotyping before death so then you had this kind of deep phenotyping and then sorry what do you mean by deep phenotyping like a deep kind of understanding of the symptomatology right so so basically you know does this person's their trimmer happen on one side or both sides at the same time.
how do things present? How do things present in an observable way? That's right. Exactly. In the same way, just folks, so you have like genotype phenotype, right? Like this would be similar idea. Okay. Yeah. So basically what they found was clinically people that have the kind of standard Parkinson's disease typically tend to have a presentation of unilateral onset illness, right? Where one side of the body or the other is much worse from a Parkinsonian standpoint than the other. And it's actually very common for people with Parkinson's
to present where 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. It's less likely to be that it's more likely to be something else and they figured that out from essentially the brain biology informing that of being able to link up.
Substantia nigra problems they found on autopsy with symptoms and so i think we're at the beginning of an era in psychiatry to be able to do the same sort of thing to take what's lumped together as depression or anxiety or what not and to be able to parse it into a lot of different. What we call biotypes are into you know people think about as into phenotypes or whatever these.
Specific flavors of that symptomatology some linked with this very specific brain physiology brain functional neuroanatomy such that you can say that this depression type one needs this treatment depression type two.
needs this treatment and so on and so forth. And so that's really, from my vantage point, the future is being able to really at an end of one level, at a single patient level, be able to figure out something about their brain and then help to prescribe what the next step is for them.
And, you know, if we can do that, we can also cut time, right? Because we can go straight to the effect of treatment for people and cut all the time around diagnosis. I mean, it's not just time, it's risk, right? I mean, in a lot of these cases, absolutely. It's risk from potential to the wrong treatment. It's also risk from weight. It's cost, potentially, also, right? It's also cost, yeah. So as you know, right, like there's a period of time.
where the diagnosis is uncertain. And then there's a period of time where the treatment is uncertain. So for bipolar depression, the average length of time it takes to diagnose somebody with bipolar disorder from a depressive episode onset. So they come in with depression and depression is their primary, you know, presentation seven years till you get them. Right. It's wild. Right. And then.
That's just to get to that point. Now you're on the right realm of medications or whatever. Now you're talking about in year seven, you're having to spend whatever it is like three, five, seven more years trying to find a solution. So you could go from being 25 years old and having this be your first depressive episode and you're still trying to figure out what you're going to do about it.
at 40 and you see these patients. I'm just imagining you're like reaching into a dark closet and there's a, what you think is a screw head and you're just trying different tools where you're not allowed to touch the screw head versus like, let's flip on the light, take a photograph and 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 pass through, so to speak, how does that compare to like frontline conventional treatments right now?
Orland had a presence in so is a study called star d it's a little interesting year for star d in the sense that people reanalyze that data and there's open questions about what the percentages are as far as what percentage of people make it to you know a remitted state after going through this algorithm but essentially star d started with a pretty low.
Side effect burden oral antidepressants to teleprom and then kind of transited through, you know, higher risk sort like SNR eyes and what's the trade name for us teleprom? What do you know, people who know, Lexapro? Lexapro? Yeah. Yeah. Yeah. And cetalopram selects a, so those drugs, you know, and then you go to like, S-enerize, like effects serve in the vaccine and then into like the tricyclics and monomene oxase inhibitors. And so people
would go through this algorithm, and then they pop out on the other end after five or six or seven different treatments, and then they'd ask the question of after people go through all of this. What's their remission rate? So that number has kind of been called into question, but essentially when you get into like.
Med 4, which is roughly where insurance used to start to pay for conventional TMS, conventional TMS would beat that pretty well, like almost double compared to, you know, your time at lithium or thyroid hormone, things like that when you start getting into that step.
and conventional TMS would beat that. When you get to those kind of next, even more severe steps, you start to lose efficacy with conventional TMS. So you go from like a remission rate of around 30% with conventional TMS down to about 16% when you get into the higher treatment resistance levels. That's the levels that we ran our trials on, which really that where people normally get about 16% remission with conventional TMS. That's where we were seeing those numbers.
Can you just repeat those numbers where you're seeing what numbers in our open label trial 90% in our randomized control trial, depending upon how you look at it, it's in like the 50, 60% at each time point or 79% of you're asking, did people transit through remission at any versus 16% versus this wasn't like a head dead thing, but just just so people have some means of comparison. And in terms of pharmaceutical interventions at that point,
very low. I mean, you're talking about sub 10% efficacy. You know, this is around where we're electroconvulsive therapy is thought about, right? This kind of therapeutic seizure thing we were talking about earlier. That's got about a 48% remission rate, but it's not fast either. And you definitely can't work the day you get it. And there's this autobiographical memory things you're talking about a like conventional TMS like a one to two month.
Commitment and then quite a bit of risk for side effects there. You get ketamine, which produces about a 30% spot remission rate with a single infusion, and that goes up as you administer more ketamine treatments with the IV ketamine forms. But as you go from a single infusion to what they did in this New England Journal paper that was published a couple of months ago,
You know, six treatments over a couple of weeks, it starts to accumulate more time. And so we're able to, from my standpoint, we're able to get the most bang for your buck, the quickest and with the least kind of interruption. And I think people's ability to do stuff during that time. But there, you know, there are other things, ketamine, psilocybin, other psychedelic drugs that I think you've thought about and talked about on this show before that are also coming over the next couple of years.
few follow-up comments and questions. So you mentioned a number of things, borderline personality disorder, bipolar as two examples. Part of the reason that I'm so interested in neuromodulation right now, accelerate TMS in particular, although I'm also interested in other things that I know less about, like focused ultrasound and so on, which we might get into if we have time, is that many of the conditions that would be screened out
There would be exclusionary criteria in say a psychedelic assisted psychotherapy trial are eligible for this type of treatment, which is incredibly interesting. There are people also who might have something that is more common, extreme hypertension, some type of like ocular issue.
where physiologically, the psilocybin shouldn't technically pose a risk, but if they have a lot of panic, rapid heart rate, etc., there might be complications, elderly patients, etc., so part of the reason this entire realm of treatment possibilities with neuromodulation is interesting is because
these tools could be available to people who would not be good candidates for some of these other things that you're mentioning. What I'd love to ask you about, because this has been one of the questions that has just stuck in my head, is the topic of delayed remission. So having these patients, I can't remember the number I was looking at some of the charts, maybe it was three or four people at a end of 16, I can't recall. Okay, there we go. Who had this remission in 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, a lot of people, like, delayed onset of benefits, right? 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 have heard I do not have the credibility or the means of
parsing all this and like, okay, well, ketamine X directly on NMDA receptors seems like maybe SSRIs do that, but in a very indirect way. And that explains the delayed benefits in some patients. Don't know if that's true or not. Don't know if I'm even wording that correctly.
How do you kind of tie this to or not the delayed remission? Because I'm just like, how does that even work? Right? I'm like, okay, if you put a drug in someone's head and it triggers a cascade or maybe it triggers some type of exceptional neuroplasticity that then shows the fruits of that at weeks, whatever, two, three, four, okay.
I just cannot figure out, I haven't been able to figure out a plausible mechanism for the accelerated TMS and that delayed remission. How do you think about that? Even if it's speculation? Yeah, it would be speculation. We've only seen an older adults. We know the brain plasticity in older adults goes down as a generality and there are lots of metrics about why folks think that.
As you talked about earlier, really, it's cramming for a test. You're actually sending a memory signal into the brain so that the stimulation pattern you're sending into the brain is kind of worse. Code is really a turn on, stay on, remember to stay on memory signal that's going into the brain. And you're just basically taking the hippocampus, the part of the brain that's involved in memory and like that.
Signaling that comes out of there and you're playing that back to the prefrontal cortex in a way to try to tell the prefrontal cortex to turn on. Remember to stay on and I think part of what's going on is because that. Older brain is a little less likely to have flexibility plasticity it takes some time for the signal to kind of fully lay its tracks into the brain we don't have.
Any sort of biology to kind of back that up yet, but what we're doing right now, and we haven't analyzed this data yet is we're actually scanning people every single day, and we're scanning people multiple times out to the month, and I just find a lot of scanning. You mean FMRI scanning? Yeah, yeah. So we're actually getting like 10 scans spread out over.
It's a lot of coffin time. It's a lot. Yeah, yeah, yeah. People have been very cool about this. And so with that, we think that we're going to be able to potentially spell some of this out, right? Like, why are these delayed remitters happening? But my suspicion is, is that it's probably a plasticity related issue. Interestingly, you know, ketamine and TMS may have more in common with each other than one would initially think, right?
You know, a lot of the TMS effects are probably in part glutamate related is ketamine. And then as we talked about earlier, there's endogenous opioid release from TMS. We've done some work with opioid related mechanisms in ketamine, and so it's probably a confluence.
of not one neurotransmitter system, but like an orchestra of neurotransmitter systems that are being affected across these interventions. And it's my suspicion that that's probably what needs to happen in order for these treatments to be effective and our old views on
You know, this kind of chemical imbalance sort of 1990s view of like one neurotransmitter, one neurotransmitter receptor sort of problem in the brain is way too simplistic and that it's probably a lot more complicated as one would imagine a lot more complicated than that. Outside of accelerated TMS.
If you're looking out, say, over the next five years for rapid acting, potentially durable anti-depressant effects, what other tools or molecules or treatments are most interesting to you.
We have a paper coming out soon, Nature Medicine, on looking at IBM as a potential treatment for, 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 an interesting, that was another interesting story. So I was approached back in 2018 by a professor
Senior professor at Stanford who was tapped by some folks to kind of find somebody who'd be willing to partner with a non-profit called Vets at the time, who are sending, and I think you've interacted with Amber Marcus Capone a little bit. Yeah, I interviewed Rick Perry and Rick Doblin two years ago at their Veterans Day fundraiser.
Yeah, I was there. I was an interesting one here. We partnered up with them, and I had to, again, go to the Stanford IRB and ask them for another edgy. You have to give the Stanford IRB credit. Can you just spell out IRB? Oh, sorry. Institutional review board. It's the entity that reviews all research protocols at institutions. And so this is the governing body that's in place that's been around for about 100 years that essentially is
non-conflicted, uninvolved group of senior professors that look at your proposed research and then determine if it's ethical and safe and answering the questions that you think you're going to answer. And so, just like going to them to talk through doing accelerated TMS and saying we were able to talk to them about doing a study where people would come to Stanford knowing in the IRB knowingly,
agrees to them then going down to Mexico to take an illegal in the U.S. root bark extract that's been utilized for millennia in the country of Gabon and related areas in central West Africa. And as you can imagine, this was not a quick turnaround. Nor should it have been for the IRB in the sense that
I had to convince them this was science worth doing. At that time, though, is it fair to say you're the TMS guy, or was it like in the air that you also had an interest in exploring something like an Ibogor and Ibogaine?
People knew that I was very open-minded to things that I'm a pragmatist. For me, the patient's the most important thing. I have this view of psychiatry that it's going to look like inpatient cardiology in 20 years. We're going to use drugs when you use devices. We're going to be able to figure out what the best thing is for that patient. To your point, some of these things are good.
for different problems. And so I think that was known that I was open to that. We'd 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'd gone to like a lot of people. And apparently I was like the only person that was willing to do this trial. Like, I felt kind of special back then. And then like later realized that like,
a wait a second i was on the the bachelorette and i didn't realize it's so essentially yet and then in the bachelorette was a tricky one on the end so we uh... we ended up reluctantly agreeing to this and admittedly like i almost pulled out a couple of times because
I began 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 torsades to point this fatal arrhythmia that can happen with certain cardiac acting drugs and it works through this.
what they call HRG potassium channel. Other things do this or like FDA cleared cancer drugs and 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 it was somewhat of a stigma and a bias around particularly an addiction drug.
And so folks had been trying to get this through the FDA and NIH and whatnot in the 90s, Howard Lotsoff and others. And it was a very complicated drug. And I'd 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 unstudiable. And I kind of like kept doing my other stuff. And then at that point, how did you come across Ibogaine? Where did you find it?
in 2012, 2010, I think. Would this have been like early Deborah Mash stuff or? No, no, I come across this book, Breaking Up in the Head by Daniel Pinchback. Yeah. And he, you know, he was a big, I think he wrote for The New Yorker or something. And I was stuck, I was like going kite surfing in South America. And I was stuck in the San Salvador airport. And there's like five English speaking books or something.
picked this book up in the airport, like, stuck. That was in the sand cell in the airport? Yeah, yeah, yeah. Okay. And so I got ahold of this book and read it 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 was very interesting. He talks about his own personal experience of it. And I read a lot about it. There was some work that folks like Ken Alper and others had published.
on the case report level outcomes, but then also cardiac problems. And then I figured it was kind of un-studiable. And then in 2018, I was approached and was asked to do this trial. And so we went to the IRB, spent a year back and forth and like right when they were about, they approved it, COVID hit. So we were actually supposed to start right when COVID
happened and it paused the whole thing and then It took a while to get it back online, but it was actually the quickest recruiting study I've ever run we got 30 people done in like eight months now is that because of the Sort of category of like potential death of despair. I mean is it because of the patient population were you dealing with addicts? So the patient population was and that was the unique part about this it was veterans and
with traumatic brain injury, some of which were alcohol use disorder. So, you know, we used to call alcoholism more than a third, like 13 or 14 people out of the 30. But everybody had TBI. A lot of them, most of them had depression, most of them had PTSD. And so, you know, we're running this trial. I was put like my best neuropsychology post doc on it and a couple other superstars when it was running in the background. And I was like, you know, we'll get this into
Pretty good journal or whatever thinking we see some people get better some not whatever and i remember i was i was asked to give a talk about it a very prestigious university and ask the postdocs we just wrapped up the immediate post and ask the postdocs to put the data together and we have data present for them.
And they showed me like the clinical outcomes and I was like completely blown away. It was way better than I think we anticipated very consistent improvements and like basically everybody some people lose it. You know, before the month, but most people held it and they're holding it out to a year now.
And I was floored. I actually told them to delete all the code and start the analysis over because they had to have done something wrong in the math. She's always fun, the postdoc always. They kind of say yes and look at you. Just ruined my weekend. So we did it again and it was the same exact findings. So I was wrong. They're right. They had done it right the first time.
Yeah, and essentially really, really striking and the time this will come out, you know, nature, medicine will have published this somewhat prestigious. Yeah, somewhat, you know, top five biomedical journals in the world. And they, it's like being nominated for best picture of the Academy Awards. I mean, scientifically speaking, right? It's up there. It's up there. It's a nice deal. And it was very surprising that for me that they were going to be open to publishing an open label.
paper, which historically you're going to publish in that kind of a journal like a randomized trial. So just for clarity sake, for folks listening, so open label means no placebo control. And also to just rewind for a second, I want to mention to people that for accelerated TMS, how do you know it's not placebo effect? You mentioned the control group, but that's a sham treatment, right? Like you're basically people feel like they're getting a treatment, but they're not actually getting the proper treatment.
Yeah, in that case, you want to ask a blind guess. And that's actually been a big, so I was going to get into here a big problem with with a lot of the psychedelic trials and why there's a lot of criticism for a lot of the psychedelic trials is that they kind of know that the blind guess is going to be highly skewed. So there's one trial where they did psilocybin for alcohol use disorder. It was like 99% correct blind guess rating. So the P value is highly significant. In our same studies, to my like great surprise, our blind guess was chance.
Could you explain what you mean by blind guess? These are the experimenters trying to guess who is in which
This is the patients trying to guess what they got. I see. Yeah, so Mr. Smith, you 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 a 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, patients who'd gotten totally better, and they'd say things like, yeah, I just got lucky with placebo this time, and they ended up getting active, and then,
The folks that didn't get any better that they got sham would say things like, you know, I'm not even good enough to respond to like the act of treatment. So they so so is confusing enough for them where they were making the wrong guess 50% of the time, which is what you what you're looking for is about 50% error rate as a coin toss.
Sidebar on that, and this is kind of staccato the way that I'm trying all this conversation, but having gone through two weeks, different hardware, different practitioners, 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 the hardware upgrade.
In this sense that they say, well, maybe I got lucky, or maybe I don't really feel that much, and yet their assessments are improving and or they're significant others see dramatic changes.
And that's true. That's not specifically a TMS effect or a staining effect or celery TMS effect. That's true. I think for a lot of treatments, you see that. I mean, I've had calls and since our data has been out on Ibogame, where I've had people call me and say, hey, Mr. or Mrs. So-and-so, they look amazing and they're not. They don't think they're any better. And so I think you can see it across the board, psychedelics, neuromod.
There's a certain problem called alexithymia and about 25% of people are treatment resistant depression. Lexithymia. And so A, meaning without Lex, meaning the ability to describe thymia and mood. And so they can't really describe their mood, right? And so they have an inability to accurately rate their mood. And the way you know that is. Alexithymia. I'm going to use that at a fancy cocktail party, sir. Tim, how you doing? Sorry. Got alexithymia.
In the back, oh sorry, you may better know that as difficulty to describe mood. Sorry, I'll try to back up for the medical, medical journey. No, I like it. I'm learning all sorts of words. It's an interesting term, and it's an interesting phenomenon. When you see this in psychiatric conditions, like if you ask them very specific questions, like, well, when's the last time you've been sad or thought about anything negative? Oh, it's like when 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 do you eat yesterday, like most people will be off by like 30 to like 60% or something, right?
Yeah, that's right. And I think what the remedy for that is that you have a clinician raider, and the clinician raider asks these really, really pointed, 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 they're kind of meta perception of the whole thing. But when you get down to the brass tax, they're answering, right? And so we've seen that and that's been true across these problems and there's ways of constructing trials to deal with that. But yeah, we've seen that with psychedelics as well. So we went after military TBI and these were all special operations.
Yeah, they were basically all army rangers, Navy SEALs, former Army Rangers, 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 spoken about it publicly. I mean, it's this National Defense Authorization Act. The NDAA, I think, has just, you know, went through the Senate and the House, both approved it yesterday, and it's going to Biden. And so,
you know, to earmark money for for Ibogaine for trials, you know, which is pretty cool. So the military community and some of the government is pretty aware that this is a possibility. There's been a lot of advocacy that Amber and Marcus have been involved in. And my hope is that coming out of a journal like Nature Medicine that really kind of validates what we were seeing and put some context to what we observed and what we found in our study.
will help to spur more funding and more focus. And I think the kind of veteran psychedelic angle is an important one, you know, for like a lot of ethical moral reasons and, you know, and a lot of also have like a political immunity bracelet, right? So it's a very important subpopulation. And it's very fortunate that it aligns with sort of driving forward the research around these therapeutic tools.
Yeah, it's super cool to work with those guys. And this was a monotherapy in the sense that it was just IBM. I know that at least in many places in Mexico, they sometimes combine it. Well, they don't combine it, but they sequence it with 5MEO DMT at the tail end. Was this Ibogaine alone?
Yeah, so as I began alone, and then we had folks come back later to do the 5MEO outside of this kind of month follow-up period, but the data that we're publishing in Nature Medicine is just the Ibogaine effect. It was tricky because that
Kind of divorced those two together because that's what's been going on as you know in Mexico quite a bit. So all the acute out to the one month effects are all direct I began effects and it's you know super cool and the thing that that I found really interesting about this drug is that it produces.
What I think is probably the most stereotyped trip, if you want to call it, or 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 apocked in time.
Some people would go live review live review or slideshow yeah exactly and so you know it's interesting everybody's kind of different version with 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 my tv from childhood all of a sudden was playing all these things where i found myself in hall of mirrors and was playing all these things of like the context can be very different in the mind seems to shape that but the actual replay seems to be pretty stereotyped.
Stereotype meaning, like, it's a pattern that repeats, or it's just like a common characteristic. It's a common characteristic. And it's closed eye only. It's not open eyes. It's not for a lot of people that I began to experience. It's kind of really around this part, this kind of replay part that happens. And, you know, from what I have heard, there's kind of a
reevaluation 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 of the reasons for the other which to me is like the hardest thing to explain. You say it one more time.
When people have this slideshow or life review, they seem to have it as a third-party person in the experience. You know, like...
What is this Christmas Carol Scrooge or whatever when they go back and they go back in life and you see like you become the observer of your own past experience, right? It sounded 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. It's almost like that. Like you're having a similar sort of thing where you're of use the analogy of Tom Cruise, 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 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 able to hold this neutral place, and you're able to have this sense of where you were and why you did what you did, and you have this sense of the other, and you're able to, I don't know, intuit,
I don't know what that is. You somehow stored it at the time and you weren't able to fully access it and you're able to access it, whatever that is, being able to forgive or to forget or to understand this person's position as well as your own. And then seemingly like unlock the lock on both sides and then dissolve the problem. And people say they'll, they kind of would work through all of this. And you know, there's one
Veteran, you know, I would say why went through all this military stuff in the back of the room. It was my early childhood trauma, you know, and so this idea that at the core of it for a lot of this ends up being a childhood trauma thing that's kind of buried below all of it and really being able to actually both access that in a way that you can understand. Understand that in many cases, the traumatizer was themselves traumatized and that it's a pattern of trauma.
and the ability to kind of resolve it by understanding at this kind of, you know, more meta and pathic viewpoint. And so that's why I think the tools really going to be important is this ability to have what seems to be a pretty profound or a trophic effect. And we were able to see disability improvements from traumatic brain injury, but also this pretty pronounced kind of cathartic re-evaluation, re-consolidation of past life problematic memories.
All right. As I want to do, let me hop in with just a few comments that we can bounce around if we want, and then a whole bunch of questions. So the first comment is, with the special operations vets who are friends of mine, what I've observed, maybe similar to what you're describing, that is,
Part of what is contributed to them being extremely high performers in these high stress environments is their ability to tightly compartmentalize, which they developed when they were traumatized as kids. Super high overlap, like incredibly high overlap. Of course, there are many other factors that contribute to them being like the one person out of 10,000 who doesn't get washed out of training, being that unbreakable in a sense. But with those friends, and look, it's tiny,
sample size. But of those friends, I wouldn't say any of them would claim to have PTSD or moral injury, like a feeling of having done the wrong thing. But the TBI, and this is where I want to lead into a question, which is not to negate the fact that a lot of people could have, of course, meet the diagnoses for complex PTSD and so on. With the TBI, what makes Ibogaine different from some of these other psychedelics? And I want to say one maybe place to explore would be glial cells, am I making this up?
Glailder, I'm not a trophic factor, yeah. Glailder, I'm not a trophic factor, there we go. What makes it different? In terms of mechanisms of action, therapeutic effect, compared to some molecules people might be more familiar with, psilocybin or otherwise.
The classic psychedelics like psilocybin, as you know, primarily affect the 5-HT2A receptors, right? So there are 5-HT2A agonists. They produce these kind of classic psychedelic experiences from largely from that receptor. You can selectively knock out 5-HT2A receptors, and you can knock out the psychedelic effect. So we've largely thought about kind of this class of psychedelics in that way. Ibogaine's a new neurogen.
So it produces a dream-like state. Some people call it an atypical psychedelic. We've elected to use this in your age in terms, because I think it more accurately reflects what's going on in the trip and in the way of kind of perceiving what it is. It does have some 5-HT2A action, but that's probably the minority of the effect. It affects a broad range of other receptor systems. So like Salvia,
For instance, there's a CAPA agonist rate, and so there's CAPA-mu effects. There's NMDA effects. With Ibogaine, there's certain effects, so serotonin effects. And then there's this upregulation of BDNF, brain-derived neurotrophic factor, and GDNF, glial-derived neurotrophic factor. And so, in both of those are profound neurotrophic factors for
plasticity in the brain. The problem is, is this has been psychedelics were thought of as relatively obscure 15, 20 years ago to study. Obviously, that's changed now, but I began extremely obscure, right? So there were a handful of studies that were performed in publishing good journals over time, but it's very limited in the data that we have so far. So it's hard to like give you some sort of definitive answer. What I can tell you is that it was a paper published, you know, I think 15 or 20 years ago where they
Took mice and they got them to self-administered alcohol, so that's kind of like a way of like an addiction model or whatever, an 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 mice to addiction. Yeah, exactly. And so if you give a mouse, Ibian, you can get them to stop self-administering alcohol. It's interesting we saw that in humans to stop drinking as well in our study. Or you can, in this case, you could actually
drill a small hole in the mouse's brain, you can inject GD&F 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 Ibogaine, right? So this GD&F effect in the dopamine system at least, and GD&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 this Ibogaine stuff, like, if we gave one of the big pharma companies $100 billion and said, don't just resynthesize Ibogaine, but make a drug that works like Ibogaine. 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. 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 think it has the wrong connotation. But yeah, yeah, I mean, like LSD is pretty kind of promiscuous on there.
Yes, I think from the promiscuous, I like the thing about like a symphony. There we go, right? Like you're interacting with these neurotransmitter systems and proportions in such a way that it produces this effect. My suspicion is,
That it's probably more sophisticated than we want to attribute to, I mean, maybe not you, but like the scientific community wants to attribute to nature being able to pull off, you know, but it's this idea that maybe somehow we have this drug that just happens to work the way it works because it's able to interact with these systems and
Pretty important ratios are pretty important kind of simultaneous effects and that's really what's driving it and that's the part i'm saying it's going to be hard to reproduce i mean obviously such a shotgun others were able to take an emulates similar sort of five ht2 effects but.
I don't even think he was able to produce an eye began like multi receptor sort of symphony like this there hasn't really been another drug like it in this way and so trying to think about what that is and how to really had a study it is going to take a new wave of neuroscience tools to be able to capture all the effects you know in real time.
I have a symphony of follow-up questions. Also, I'll give you, you can choose. This is dealer's choice. You're the dealer. We could go with, and we will get to all these, but improving the safety profile of IBM, which I should also say, I've had people reach out to me, which is always can be very uncomfortable for me, but a friend of a very close friend. In this particular case, someone's sister was a heroin addict.
who is now homeless, acting as a prostitute, like living under an overpass. And the reason I bring up that level of detail is that for a lot of interventions, in this case, I began at that point, the cardiac risk, or some of the risks were known. And there's a question of, is this risky? And the follow-up is compared to what? And in this particular conversation as well, she could die tomorrow.
Yeah, from an OD, or this is the other thing. So I'm just kind of setting the table with that, but improving the safety profile is one question. Another, because you mentioned the cessation of, or the minimizing of the AUD, right? So like people stopping drinking. We were also talking before recording people stopping drinking caffeine, I guess, or coffee, right? Yeah, we saw that. Okay.
unexpected, presumably. And so my question there, which I sort of ceded, because I mentioned I would want to talk about this. It's like any overlap in terms of mechanism, or how does this compare to something like semagluetide, or like an ozempic, or some of the neurogen, I think it's Mongero, maybe getting that wrong. And then the last one, and I've been wanting to ask somebody about this, you mentioned 5HT2A. It seems like some psychedelics exert effects also on 5HT2B receptors, and
If I'm not mistaken, there's some data to suggest that that can continue stimulation, like agonism of that B, can lead to some type of cardiac complication as well, like some type of like, like, the curricular hypertrophy. Valves, exactly. So the question there is, do you think that microdosing, for instance, which has become all the rage, could that potentially have long-term negative cardiac effects?
The FDA guidance document for psychedelics that they released actually like on the last day of the psychedelic science meeting, which is really interesting, is specifically has a section about this issue of cardiac valve, real or problems, particularly from these more classic psychedelics. The problem with Ibogaine is different, right? The problem with Ibogaine is that it interacts with her potassium channel. There are a number of groups, folks, Columbia, folks at UC Davis, who have
Look 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. Set you do you mean like nor I began or something like that or is normal. Nor I be in the primary metabolite of I began that goes after two d six is a normal part of the I began process has a similar cardiac risk does profile so it's drugs that are.
I think they called him like tabernathologs or something, but I bogologs or something. I think it's what was coined at Davis. But essentially, these are drugs where they like try to engineer off that interaction, which may or may not have an effect on its brain effects. And so I want to answer the question I'm trying to ask. And the question I'm trying to ask is, does Ibogaine
help with certain human illness. By modifying the molecule, it's not Ibogaine anymore. It's something else. And then you're asking the question is, is something else help the view is maybe it's close enough to Ibogaine to do something similar. And I've taken like a different stance on this where I've basically taken the frame of, how do you preserve the molecule and really lean in on the cardiac risk?
How do you put an airbag in the car instead of redesigning the whole car? Instead of making it a, you know, an airborne shuttle or something, 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 talk about this in the article, but essentially all the patients that were treated received torsades like IV magnesium at the start, right? What type of magnesium?
So it's like magnesium sulfates. So it's basically just like IV bag magnesium. And so what's really interesting about this arrhythmia torsades that everybody's worried about is that the treatment for it for the American Heart Association guidelines is to give IV magnesium, which is incredibly safe. And I've given many times for various things in the ER and you can just give it to people and you'll eventually urinate it out or whatever. And so you can
Give it, get people through this risk period. They may be slightly hypermagnesiumic or a little high on their magnesium in their blood and they'll go out and everything's all good.
And you know, there have been about a thousand operators 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 torsades. Conversely, like the New Zealand study that was published a couple of years ago, they had a death out of 10 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 thing that can cause that problem? Then it's much more likely that you can knock out the risk or significantly reduce the risk. It's also about doing it in a monitored bed setting. So, T-K-S-N-T-I-K-O-S-Y-N is a drug that is approved for atrial fibrillation, and it's an antiarhythmic
that can be pro-arithmic in the same way as Ibogaine. It actually has more risk than Ibogaine. The rates of torsades are higher with tikensin, it's approved. It's totally safe. You just do it in a monitored cardiac bed. My suspicion is if we're going to do a study in the US with Ibogaine, we're just going to need to do it in a monitored cardiac bed with cardiologists involved.
And I think if you do that, you're good, right? I think the trick is between now and when, in theory, one could see an approval eventually from the FDA for this, you're gonna have to
Think about, well, not just can this place in wherever Mexico, wherever it is, provide, you know, a good pure form of IBM, but what's kind of the wraparound risk reduction there? And I think that's what people have to think about as 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. And the reason why the veterans that we studied were so interested in going is because as you point out, there's a lot of risks from not doing things, too.
There's also a lot of social proof in that community now. Oh yeah. Right? And like a friend will go down with their friends to like sit in the same room and it's a tight group, right? It's a super tight group and it's pretty cool, right? And I think it's...
The reason why I did the trial ultimately, my view was there's no way that all of these very high performing special operators are all going down to Mexico and taking this thing, which is not recreational at all, and spending a week down there dealing with this, and then they're not really getting benefit. They're getting some pure placebo effect. It just seemed unlikely to me given how treatment resistant and how many things that these folks had done, how much time they'd spent in the VA hospital and all that good stuff.
That's why we did it, and what we found was enough of a consistent finding and this reversal of disability such that, well, I can't tell you this works because I don't have that level of evidence on it, that the signal that this could work is really high. It's the highest of any kind of brain-acting drug I've been involved in looking at.
Okay, let's talk about the alcohol and the caffeine. Yeah. So, mechanism of action, I mean, you sort of mentioned the GDNF in the animal models, like the direct kind of injection. How do you think about this and does it in any way tie into what we're seeing with some of these
Drugs that are, I guess, designed for type two diabetics, like semi-glutide and those epic like drugs, but they're having such an effect on various types of cravings that large box retailers are having to revise sort of in a panic their sales projections and inventory planning around like snack foods and stuff. I mean, it's wild to see like the societal ripple effects.
Walmart, apparently, has sold less food. Yeah, and I have friends who have been obese. Effectively, their entire lives never had an exercise habit, 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 not yet there. But how do you think about this? Are there any overlaps with these? Are they completely different mechanisms, just presenting similarly?
There's no evidence that there's a direct overlap in mechanism just because the kind of CNS kind of psych addiction side of things people are still in the like.
Is this doing something yet looks like it's doing something there, but not any deeper than that. I think we'll learn about that on the kind of a zimbec drug side of things. And then IBM's been relatively underexplored, basic science standpoint. But my suspicion is, is that it is probably similar enough and maybe some of the same mechanisms are being enacted because what you're finding is a similar phenomenon across both.
instances. We thought these were diabetes drugs, and then there was a significant weight loss observed. And then we thought these were weight loss drugs, and then everybody's quitting all their other habits. And placebo works by a phenomenon called expectancy. And as you can expect from the term, it's expecting something, right? So you're primed to think that this thing is going to help for this reason.
I'm always really clued in when you have really obscure off-target, non-expectancy phenomenon happening.
So in the Caribbean trials, you mentioned a minute ago, basically everybody quit drinking coffee for a period of time. And like none of them really went into it. As most of us don't, our coffee habit is maybe a concern. You know, 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
focused on dealing with being overweight or focused on their alcohol use problem, or in this case PTSD and depression and TBI and all these other things that folks were worried about. And so when we started seeing consistent reports of people stopping their caffeine intake, it was really a signal for me. I was like, you know what? That's really interesting. I mean, there's probably a bigger systemic change that's happening. And what people will tell you phenomenologically about this is
it puts a pause in between stimulus and response. And a phenomenal, and I can't like prove this, but this is just what everybody seems to come back and say, it puts a period of time between when you normally have a trigger to do something and go do it. And it was habitual action and really kind of gets into this question of, we will and all this stuff that people think about where there's a moment where instead of
making the habitual action the person finds himself in a purely unbiased choice phenomenon in what people have ob use disorder would say in those scenarios.
when they would relapse after I began is they'd say, you know what? I just had something about it. I didn't crave it. I just wanted to do it or something. I wanted to remember or whatever, but it wasn't this habitual action, right? And they go back and they do I began again after they'd gone back into the addiction and then they had all the negative consequences and they'd say, you know what? They got back to that choice again and they're like, it's not worth it anymore. I'm 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 study is that they'd approach things like coffee and they'd be like, you know, I 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 life is just made up of a lot of habitual actions and they were able to reevaluate all those habitual actions and then establish new patterns.
The drug eventually is going to wear off, you know, as all drugs eventually do. And you probably do lay down a level of habituating again. But if you could during the period of time when your brain seems to be pretty plastic, you know, shift and lay down new patterns that when the drug wears off, assumably you kind of lock into that new set of patterns. And I think that's what's really interesting and probably a little bit different than the ozimbics in the sense that the ozimbics seem to kind of take away
From what folks will say, a lot of the seeking or rewarding aspects of things like food or whatever, it's just like cravings. Cravings, whereas this seems to introduce a level of choice. What would be very interesting, so you alluded to this earlier, is you take somebody who has a pretty significant addiction like this and you give them an Ibogaine sort of drug and you think about how do you use something like an ozmbic to kind of follow on with that, right?
We're able to kind of gate some of it and it's way out there and probably not anything anybody's going to do anytime soon. But it's an interesting idea right of these are essentially habit affecting drugs that we haven't had tools to really use before which I think is pretty cool. Yeah and folks who want to dive deeper into this sort of reopening of.
Let's call it critical windows. I mean barring the terminology from Professor Ghoul Dolan, but pretty fun stuff to dig into as well if you want to. 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
year we have. All right, let's hop to a few other questions. One is coming back to IBM specifically. The two things that have been of greatest interest to me with respect to IBM are TBI, right? So if someone has no addiction, no PTSD, the only issue they have is some form of TBI. Do you think there is a role for IBM? So you can place hold that. There's part two to this question, which is,
I've heard reports and i haven't gone into the literature on the side i don't know this is a explain somewhere but i've certainly heard reports of opiate addicts who have seemed indicate that. I began or i boga opens a window after treatment during which they do not seem to experience much in terms of withdrawal symptoms.
And I want to know what the hell is going on there if that seems to be observed, right? So those are the two questions. Somebody who just has TBI. Do you think there might be a role for an Ibogaine or something like it compared to other options and then 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 TBI. While
I understand that the PTSD diagnosis is pretty ubiquitous in the system. It's probably true to fair amount of folks, especially folks who've been exposed to a lot of
combat related trauma in earlier life trauma. And in our group, it seemed to be there in most of the participants. So was depression and anxiety. And so we haven't studied a pure TBI group. And so the confound is without studying a pure TBI group that somehow had maybe it was a competitor in martial arts, you know, or something like multiple concussions or whatever.
Yeah, something like that where they, like, intended to potentially get hit in the head. Probably intended to hit other people well for sure. But intended to go into the ring knowing that you were probably going to get hit. Because the problem, right, is in a lot of these cases.
motor vehicle accidents. There's really high rates of PTSD in those because there's not an expectation you're about to get hit in the head, but there's probably a population you could study that's pure traumatic brain injury where I have like football players, right? I mean, a lot of reported depression.
Who knows? There could be a lot of other factors involved. Yeah, football players, another great example, highly correlated. Yeah, and those guys know they're going to hit their head in the game probably at some point. And so that population where it's more of a pure TBI population, you could ask that same question that we asked in this more mixed population, which is, does TBI disability improve? We saw a dramatic improvement in TBI disability at 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, just give me your wild ass guess, like mechanistically, what's going on here? It's the symphony, right, which is sounds kind of like maybe even hokey or like a little like less direct, but I just think that there's something about
interacting somehow with multiple different neurotransmitter systems at the same time that must produce this. I mean, maybe the GDNF, BDNF alone could do this. I'm not saying it can't, but I suspect that it's a more complex process. And the problem is we don't have great tools to evaluate that, but sometimes nature is, uh, trumps are human scientific abilities. And I think that, that I began certainly is there in 2023.
It's like the story of scurvy right like we associated Eventually after like a bunch of weird stuff. We eventually associated eating oranges with improvement in scurvy But it took us another hundred years to synthesize vitamin C. Yeah, you know and so that's I think what's so hard about this scientifically and to get the kind of scientific community fully on board with these ideas is that We're likely 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 and
It's very unique to Ibian. You can take somebody who's going through florid opioid withdrawals and you can have them not only have a cessation or stopping of a desire to go take more heroin or prescription opiates or whatever it is, but you can have them basically blunt or completely attenuate the physical withdrawal symptoms of withdrawing from opiates, which is
diarrhea, like headache, sweating, all the stuff that people will go through when they're going into opiate withdrawals. And this seems to really kind of like knock that out. It's likely again that because it's interacting with the opioid receptors, it's interacting with the glutamate system, but it is to my knowledge, none of the other psychedelics can do that. I mean, can't really do that. So this is a pretty unique.
thing to Ibogaine that can pull this off and why I think it's such an important drug to understand. I mean, I would argue that because of how broad Ibogaine seems to work across now, most of the major psychiatric diagnoses with the absence of something like schizophrenia, but anxiety, depression, PTSD, this traumatic brain injury, multiple different addiction types, it's going to behoove scientific community to really kind of break down
why it does what it does over the next couple decades, I think, and try to really kind of back engineer what it is. But yeah, we have no idea. Outside of the lab and more in the wild, what are some of the more interesting things happening related to I began in Iboga? I believe there's something happening in Kentucky.
Yes, I've been down to Kentucky to testify in front of the Opiate Abatement Commission of Kentucky. It was myself along with Shrinney Rao, Ty, Deborah Mash, who's the CEO of Demorex, who's at the University of Miami for a while in Kenal Peruse. Who was it, MIU? And is it kind of an academic pro-practice psychiatrist? And there's a guy by the name of Brian Hubbard, which he's a very interesting guy. He's an attorney by training.
who has worked in a bunch of different domains within Kentucky state government and whatnot. And he, for one reason or another, has become completely convinced that the money that ended up being some of the lawsuit money for some of the opiate over prescription that happened, particularly in Kentucky and West Virginia, but all over the country, should be utilized for novel therapeutics and not just for more of the same sort of treatments that we have available.
The conventional treatments that are available for opiate use disorder fall into the realm of what we think about as replacement therapy, you're replacing a higher risk opiate with a lower risk opiate, so that's suboxone, which contains buprenorphine and methadone, or opiate blocking drugs like naltrexone. There's a fairly high fail rate on those drugs. Part of it is psychosocial. We put people in the right environment. You could probably drive up
The rates of that, there's also a prescription issue. You used to have to have like a special FDA license to prescribe it. I used to have this thing. And then recently that was knocked out. So everybody with a medical license can prescribe suboxone. And so there's kind of a group of drugs that can do some work on this. But there's certainly folks that we would think about as treatment resistant opiate use disorder patients. And the numbers I'm not going to get into because there's, you know, they're debated or whatever.
whatever those numbers are. It's a good chunk of folks, and they don't really have much to offer. And so people have thought about lots of different options for them. And one of the options is brain surgery. So in West Virginia, a group of neurosurgeons are actually doing full-on, there's a surgical form of neuromodulation called deep brain stimulation, where you can actually put an implanted device into the reward system, and also kind of similar to
To some of these wagovis, that kind of drugs, you can drive down some of the pleasure around, and this is more theoretical at this point, but opiates as well as there's some data out of a couple of different studies with even weight loss for stimulating in the reward circuitry. What's interesting is that there's a one in 100
risk of a head bleed from that treatment in about a third of them. It ends up being a pretty significant head bleed, right? Yeah. And so what's really interesting is you have no one in West Virginia organizing all these hearings about it. It's just happening. They're letting people do the science and all that stuff. And I don't disagree with doing that, by the way. I think it's a useful thing to explore and it may be a solution for this. And this is, as we described earlier, such a high risk phenomenon that a one in 300 risk is not
Is it one in 300 or one in 100? One in 100 risk of a yes, it can be a trivial just blood on the tip of the electrode, which is asymptomatic about a third of those people are going to be, you know, in a more complicated, you have a role complication. So, and then you get about one in 300 risk of a torsades risk with Ibogaine.
Right, and so next door in Kentucky, similar odds. Yeah, you got a similar odd concern, you know, both of which can be kind of dealt with in the hospital. I'd argue that the Ibogaine risk is probably a little less actually than the DBS risk if you just kind of look at everything.
And they're having these significant hearings. There's a lot of opinions about this and a lot of shocker, right? And I'm, you know, I'm one of the few people that does all this stuff. So I can kind of, and you juxtapose part of the reason we're having this conversation because you like, you bridge a bunch of interesting, often separate worlds. So anyway, thanks.
