← Tom Bilyeu's Impact Theory
Tom Bilyeu's Impact Theory
Neuroscientist On How To Achieve A Calm State & Rewire An Anxious Brain | Nolan Williams PT 1
01:37:29
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Tom Bilyeu
We all live inside of a simulation created by our brains. As such, your brain is without a doubt the most important thing in your life. Everything in your life is downstream of your brain. When your brain is functioning well, you're free to grow and chase your dreams. But if something goes wrong in your brain, everything in your life suffers. That's why I am really excited about today's guest. No Nolan Williams. Nolan is at the forefront of brain research, specifically your brain as it relates to anxiety and depression. In today's episode, we explore how things can go wrong for any of us. What to do when there's a glitch in our personal matrix and some of the cutting edge treatments like electromagnetic stimulation and psychedelics that Nolan has been exploring in his laboratory. The epitaph I want on my tombstone is that you're having a biological experience. If you want to optimize your life, you must understand your yourself as a biological creature. And today, we're deep diving into the complex world of mental health, bridging the gap between brain science, life experiences, innovative treatments, and the complex mechanisms of the brain. I think you're gonna love it. And if you do, please be sure to rate and review the show so that we can reach even more people. Now, without further ado, I'm Tom Bilyeu and I bring you Nolan Williams. We basically live in a simulation that's created by our biology. One of the most troubling glitches in that matrix is depression. You're an intersection of something that I think is really important with transcranial magnetic stimulation and psychedelics. What's happening? What causes Depression.
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Nolan Williams
If you take somebody and you stress them in the scanner and you cause them to have this, what they call social defeat stress, right, where you make them feel like they have this inability to control the external world, this inability to, this kind of sense or feeling of kind of social defeat in front of others, that sort of thing, then a certain brain region will go offline.
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Tom Bilyeu
What brain region?
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Nolan Williams
It's called the left dorsolateral prefrontal cortex. So that's the region that's involved in control and perceptions of control.
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Tom Bilyeu
Control or perceptions of control.
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Nolan Williams
So I'd say perceptions of control. Yeah, perceptions of control, that brain region goes offline. And the idea is that if you accumulate enough of that, you're sending a signal into the system that basically trains the system like a memory to keep that system offline.
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Tom Bilyeu
How are you knocking that out in the first place? Is that where we're using transcranial magnetic stimulation?
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Nolan Williams
No. So it's essentially this idea that, you know, external stimuli, you know, feelings of loss of control, feelings, you know, social humiliation, whatever it is, so you humiliate
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Tom Bilyeu
them while they're in the machine.
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Nolan Williams
I don't, I don't. But there have been studies that folks have done that, right? You social defeat stressors and different, through different tasks or watching videos you can make, you can induce sadness and normal, healthy controls. So I could put you in the scanner and make you experience sadness by playing like some of the most sadness inducing movies that people have ever seen. So there are experimental ways of manipulating emotions. Even normal, healthy controls. You can do it in people with illness and you can accentuate it. You can make folks experience more symptoms even than their baseline, say depressive symptoms. And, and those are ways of moving this network around and then understanding what it is. So we've been doing that for a long time, you know, since the mid-90s. One of my, my mentor that developed the original transcranial magnetic stimulation approach was doing experiments in, at the National Institute of Mental health in the mid-90s. And they were doing these sorts of emotional manipulation, sadness induction, sorts of manipulations. And so you can take somebody who's not sad, you can make them sad. And then another brain region comes online. It's called the subgenual anterior cingulate. So the left dorsolateral is kind of like right at the edge of your eyebrow, go all the way up to, you know, the natural hairline. And that's about where that is. The subgenual anterior cingulate is more in the kind of midline of the brain. It's under the corpus callosum. So it kind of sits, you know, more kind of behind my two fingers here. And that region will come online during sadness and in depressed individuals kind of stay online. And so the dynamic between those two brain regions normally is, and this is a simplification, there are more regions that are involved, but the core of it is the left dorsalateral clamps down on the subgenal anterior cingulate. In the case of mood regulation, there are other parts of the dorsolateral that'll clamp down on the other parts of the cingulate for cognitive control, like pure cognitive control. But essentially those two brain networks, those two brain regions within associated brain networks are involved in this dynamic of control. And if your external environment is such that it essentially trains through kind of a, essentially a memory process, these systems to be pathologically, in the case of dorsolateral turned down, in the case of the subgenual turned up, then it makes the individual much more likely to have a depressive episode and much more likely to stay in a depressive episode. And so we know from many different kind of epidemiological studies that folks with early life trauma, so they've had, you know, abuse, physical abuse, sexual emotional abuse as a kid, they're much more likely to, you know, experience depression and have harder to treat depression, what we call treatment resistant depression. Right. And so it's like those early life experiences wire in a certain risk within this network. The good thing to kind of get to our. Your question earlier in our research is that we're able to, with stimulation, reverse that dynamic. And we're able to do it not just with depression, but we can actually move around perceived control phenomenon and other parts of the dorsolateral cingulate combination. So we've been able to. There's a paper coming out soon where we were able to move around trait hypnotizability and make people more likely to suggestion.
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Tom Bilyeu
When you say move around, you're saying increase by altering what brain regions are online or offline or active or inactive. That's so interesting. Okay, so I, I really try to convey to people a very simple notion. You are having a biological experience. I've said a thousand times, if there's going to be an epitaph on my grave, I would want it to be that. Just a reminder to people that ultimately you exist inside of this simulation is a cool way to say it, but your, your brain, one light never touches your brain. And even if it did, the portion of the electromagnetic spectrum that we perceive is like 1,000,000th of what is actually there. So the, the thing that we think of as everything is this tiny, tiny, tiny, tiny, tiny fraction of what's actually there. And so in confusing your perception for reality, you don't realize how much your brain is basically communicating to you to say, oh, this thing is bad or this thing is good. It's not necessarily objectively bad or good. And for me, the. The big breakthrough in my life came when I realized, oh, wow, all. Everything that I'm worried about not being able to achieve in my life is, comes down to brain plasticity. Can I get better? Yes or no? If I can get better, then it's just about applying as much energy as I can. Do we have limits? Of course. And are all of our limits different? Yes. But at least focusing on that and so getting into the brain science of how this actually worked ended up unlocking literally the rest of my life. So when I try to explain to people, I didn't start rich success, didn't have entrepreneur parents, nothing. I started behind the eight ball. As far as I'm concerned, not many people had it worse. But I was not primed for the kind of success that I ended up having. And when I look at why, it really does trace back to the moment I decided to understand how the brain worked. And that allowed me to start pulling whatever levers I could, which, you know, 25 years ago, when I really started thinking about this, there weren't as many levers to pull on. But now as we start looking at things like this, it gets pretty interesting. So one thing that I try to communicate to people is you become what you repeat. Now, I have a thesis on this that you, as somebody who knows this far better than I want, wherever I go wrong, let me know. Your brain is just a caloric hog. It's just gobbling up resources. From an evolutionary standpoint, resources in the form of calories were very hard to come by. So your brain was like, all right, look, if you're going to do anything, a lot, I'm going to optimize that through a process called myelination. And I'm going to wrap fatty tissue around the neurons that you fire in, in groups a lot. And so those networks, I think if I were going to use your language, I would say circuits begin to form of these interconnected neurons where clusters, whether it's depression, like symptoms. Oh, you think this depressive thing a lot. And so this brain region lights up. This other one goes quiet. I'm going to make that easier. I'm going to Almost make that your default. And so because I have made the communication between those neurons easier by myelinating them now that it just takes less caloric resources. So now the state of being, depression becomes the easiest calorically state for you to be in. And that's how people end up just. You repeat your way to joy, misery, whatever.
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Nolan Williams
Yeah, totally. And you know, there's a kind of an old neuroscience saying what, what fires together wires the other. Which is essentially what you just said. Right. And so the one caveat I think that I'd put in there is for a lot of folks, you know, especially the early life trauma folks, it's, it's less. They're, they're not in a place developmentally if they're a kid or they're, Their, their cognitions are such that they even recognize that is that part of the problem.
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Tom Bilyeu
They don't have a defense, sort of thought based defense mechanism to recontextualize.
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Nolan Williams
Sometimes they don't know what's, what's abnormal and normal. I mean, if you're talking about a seven year old, you know, or a five year old, it's hard, right? It's hard to have that level of kind of context. But yet they're exposed to these events that create perceptions of not having control that are probably, you know, in that setting, accurate. Right. If you're, you know, if you're, if it's a kid experiencing some sort of abuse, you know, they don't have, they don't have control, you know. And so that's why, you know, it kind of sets those, some of those individuals up, you know, for future, you know, psychiatric illness. Some of those individuals have, you know, profound resilience, you know, and don't have that problem. And we, so there's been a big focus to try to understand why some people are resilient. They have these really bad early life, you know, trauma experiences and then they go on to be okay. Even despite all of that, others, you know, end up having, you know, a psychiatric diagnosis like depression. What's cool, I think and where, you know, we've really focused is this idea that just as you're pointing out that you can learn these things one way we can actually use neurostimulation techniques like non invasive magnetic stimulation where people are awake and able to talk and watch television and all that stuff while this is going on. And you can actually change the brain connectivity in such a way where you could reestablish dominance of the right brain circuitry. You can turn on areas that you Know, maybe have spent, you know, that individual spent a long time, you know, kind of wired up in a certain way, and you can change it so that they can actually clamp down, you know, say, the sadness region and have control over it. And that's been what's been really striking for me as we've been doing a lot of these. These experiments, is that, you know, I have patients all the time say to me, you know, I don't even understand how I'm able to do this right now, because I've never been able to do it.
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Tom Bilyeu
What's this?
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Nolan Williams
Whatever it is, you know, I had a patient who told me that she put her feet on the dashboard of the car every single time her significant other would drive her somewhere. She was so afraid of getting in a car accident, scream at him and be really anxious and really upset and, like, hated being in the car. And a couple of days into our really rapid stimulation approach, she knew that she was better because she sat down in the car, they started getting ready to go. And the significant other is like, you're not going to put your feet on the dashboard. This was literally every time she get in the car, and she's like, I guess I don't need to roll the window down and let the wind come in. You know what I mean? So it's one of these things or patients who've come to me after receiving their week of stimulation, and they come in the next week and they say, they told me before they started, all these psychotherapists told me I wasn't trying hard enough to do the psychotherapy. And this weekend, instead of going to the beach or whatever you'd think they do now that they're feeling well, they went and spent the weekend reading the cognitive behavioral therapy workbooks or the mindfulness workbooks or whatever, and they're like, yeah, I just like, whipped through it in two hours and did the whole workbook or whatever, you know. And you're like, you know, one like, like, how did you do that? Why did you do that? You know? And they're like, because I. I knew that I couldn't, you know, and it was something kind of inherently not fully functioning in my brain now that it is. I needed to prove to myself that I could do it, which I thought was really, like, important. And kind of anecdotally, I saw enough of that, you know, to where it was like, pretty. It's been pretty clear to me that turning these systems on restores folks ability to have kind of full volition and be able to do, you know, have real control through choice, to your point. And I think kind of at the experiential level, that is what's kind of functionally wrong with depression, you know, is in the more kind of moderate to severe states that control is lost. There's too much kind of repetitive behavior based off of avoidance of pain or fear or whatever it is.
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Tom Bilyeu
Whoa. Okay, so this is very interesting. One thing that I'm particularly interested in right now is AI and I've seen some of the AI, basically neural feedback setups that are being developed. As you were talking, I was like, I have a hunch that what we're going to find over time is that this is really patterns of firing in the brain more than like one region. It's going to be a symphony of things. Like there, there are times where you want, you know, the, the anxiety region to be active and the control center to be low, but you, you want those to be appropriate to the given situation. And if I had to guess, over time with AI, we'll be able to start matching just like thousands, tens of hundreds of thousands of people in these devices, seeing the different setups that they're in. So we know, oh, you're trying to learn right now, being in the stressed out state, that's not going to be optimal for learning. You need to get into this state now if it's like biofeedback. So I used to have a really bad problem with my. It was actually manifesting in my scalings, but it was a mid back problem, which I never would have guessed. Once I had a biofeedback device that would beep at me when I was firing my mid back. I learned to control my mid back and then I could solve my problem with my scalings. Super weird. So I have a feeling it's going to be similar. Like if you can learn to control a region of the brain, which I love saying things like this in front of people who can tell me if I'm crazy, but I can, I can actually capture the sense of joy or elation in like little small bits just by thinking about it, by knowing what it's like. And so I can like put myself in that state. I can't take myself from like, I'm legitimately depressed to, oh my God, I'm on cloud nine. But I can grab these little moments consciously on purpose. And so my hope is that if you have a device that is able to track your brain waves and you know what your target brainwave pattern is and you can sort of grab you can train yourself to be in a certain. A learning state or a joyful state or whatever. And one. Does that sound crazy? No. Yeah. So that to me could be. Obviously we'd need data, but that could be really transformational.
- [18:16]
Nolan Williams
Absolutely. No, I think the technology kind of device space within mental health and brain health, it's just right. We're kind of scratching the surface. I mean, the tech that we've been developing to your point is both a location derivation that's individualized the person using machine learning, but then also it's a pattern of stimulation that in that case sends a message of turn on, stay on. Remember to stay on in that brain region, essentially mimicking the sort of learning that you do with, say, note cards. You write out 60 note cards and you look at it one every minute or something and you get back to the first one about an hour later. So we call space learning theory. You don't just write one out and look at it 50 times and set it down. Right. People don't do that. They have a stack of note cards. Stimulation can be the same way you stimulate. You give a certain amount of time for the dendritic spines to enlarge and prime, and about an hour later you stimulate again. It emulates that same exposure re exposure thing that you see with being exposed to a piece of information on the note card. And then about an hour later, you get back to that first note card and you see it again. These are not different. Right. It's that idea of being able to kind of lock those memories in. But it's very simplistic. Right. We don't. All we kind of know is we can turn this system on or off and kind of send signals in timed patterns to really reinforce turning it on or reinforce turning it off. But to your point, ideas around using machine learning AI to develop new parameter sets that send more sophisticated signals, send Morse code from the stimulation operator into the brain that's giving actual information is going to be important. And then to your point, also learning how to pick this stuff up and have behavioral techniques to reinforce it before you have to get to a place where you're putting dense amounts of stimulation to the brain and we're calling it a diagnosis. Right. I think we're only doing that because we're not good at picking it up early enough and doing more preventative stuff. So things get to some moment where people are not doing well and they're in a high risk situation. And then we. And then we kind of, you know, jump in and treat them with These, you know, technologies. But my hope is that we figure out a way to kind of move it back to your point, find less, Less and less invasive things that can train the brain in a way that you didn't. You don't. You kind of never get there or whatever, you know, but, you know. But that's the hope. Yeah, man.
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Tom Bilyeu
If that ends up working out, that'll. That'll be transformative. So I'm. I am both terrified of AI and probably unreasonably optimistic. I. Yeah, I. There's patterns, Patterns. Everything is patterns. And if we can learn some of those patterns and can. Can lock into those patterns in a way that becomes useful. I think this really gets interesting. I think you were just talking about this, but I wouldn't have known to pick up on it except for the fact that I've done a lot of research on you. But you were talking about Morse code, like actually being able to play back into the brain. And one thing I've heard you talk about is that we can. And I don't know the method by which you do this, but you can basically record biological patterns for a given state, play that back to the brain in some way through frequency.
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Nolan Williams
Yeah, frequencies.
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Tom Bilyeu
And the brain's like, oh, I know what to do with that frequency pattern. Tell me about that. Because if what you're saying is that a lack of control, and you may hate me putting these words in your mouth, but if a lack of control is depression, that. That the. When you put somebody in the state where they feel they have no control, it is the setup that leads you to sort of negatively interpret the world, then being able to memorize the playback of the opposite of that, lay it over the brain, pull you out of that into a new region, would be phenomenal.
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Nolan Williams
Yeah. And that's. Yeah, you basically have it. So I think we had a paper that came out in the Proceedings of National Academy of Science, like, a month ago. One of my superstar was a postdoc and a research fellow within psychiatry residency. He's faculty now, so he's already kind of moving up the food chain. But Anishmitra. And So he spent 10 years looking at this phenomenon of brain connectivity is reflected in the fluctuations of the blood within a given brain region. And so that's reflective of electrical activity. It's a surrogate of electrical activity that we could measure really easily with mri. And so he was able to find that in brain regions that are connected, where we kind of average over how the fluctuations occur within time within that brain region, that there's actually a subtle offset between a connected brain region, suggesting causality. So if this area is slightly in front of this area, it's likely that this area is signaling to this area. Right. And so what he found was that cingulate area and that dorsolateral area, you know, have a temporal offset from each other. And in normal, non depressed individuals, essentially everyone, the left dorsalateral, that control region is temporally in front of the cingulate in depression. Some, in this case, 70% of the sample, the cingulate was in front of the dorsolateral anterior insula. In the individuals that responded to our stimulation approach, essentially all of them had this flip. The people that didn't respond, none of them had the flip. And on the post scan flipped back to normal on the people that had the abnormality to begin with and had a clinically relevant change in their symptomatology. And so what we call. The other kind of interesting thing is what we call depression is probably a, you know, a combination of multiple things, right? And we saw this 100 years ago with idiopathic Parkinson's disease. What we think about is, you know, true to form, Parkinson's, right? There's actually a bunch of other things that look like Parkinson's. And historically they were all lumped together. Lewy body dementia, progressive supernuclear palsy, idiopathic Parkinson's disease, other things all lumped together. And then over time, we figured out how to separate them based off of techniques of, in this case, being able to do kind of postmortem studies of people. But in the case of depression, I think we're going to use non invasive biological techniques to say, okay, this group has this particular signaling abnormality and this group has something else. And trying to kind of separate that out. But at least in a subpopulation of people, to your point, it's this flipping of the signal. And so the kind of sadness region and areas around it are signaling to the control region, probably having dominance over it.
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Tom Bilyeu
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Tom Bilyeu
Yeah, man. Perception is everything. So going back to why we have such an epidemic of depression and why Covid really kicked it off, is this so lack of control? Yeah. So that makes sense to me in terms of why Covid would exacerbate it. I. I have a broader theory that I would love for you to dismantle and help make me smarter that I would have thought was true leading into Covid. And that is Lisa Feldman Barrett. Is she at Stanford? Do you know? She wrote a book called How Emotions are Made? I don't. I don't remember now where she's from, but she talks about how the emotions that we have we perceive as coming from our thoughts, but in reality, it's a confluence of thoughts. The body, largely the gut, and then the brain sort of going back and forth in this communication. You sort of never know which started the whole conversation, but they're going back and forth. And the brain will ultimately create a narrative about why you feel the way that you feel. And having spent a lot of time looking at nutrition, I think a lot about nutrition, obviously the impact that that has on the gut, then if the gut is involved in emotion, in communicating with the brain. I was looking at the modern world going, okay, our diets are just absolute tragedies. We no longer have to exercise to survive. So now exercise becomes completely optional. Modern life, especially with social media, is pushing people into isolation. Even if you're around people, you're emotionally distant, you're emotionally isolated. And so you start putting all of that together and everything just deranges. Just enough that, especially if you're already predisposed to this because of childhood trauma, now you're just. You're way out of whack. But only some of that I would liken to control, like diet. And that's, to me, sort of a bodily communication that's microbes that are sort of derailing or you may also. And this part, I don't. I don't have. I don't even have another person that has said something along these lines that makes me think this. But when I think about mitochondria, mitochondrial dysfunction, if there's any sort. I mean, there has to be signaling of some kind. So it's like, where are we picking up on that signaling? Is that also part of the body telling us that there's a problem? And if your diet's off, you're going to feel it in the Gut and in the mitochondria. So do you think any of that played into pre Covid and then Covid just exacerbates it with control? Or is depression really just you feel out of control. That's the pattern. And when you have it, you're in real trouble.
- [29:19]
Nolan Williams
I mean, and that gets back to the, you know, the statement I said earlier around, you know, there are probably multiple things that kind of get lumped into depression. Right. Not everyone, you know, some people kind of are in an over control phenomenon, you know, so it's not everybody necessarily has. This has a kind of a perceived loss of control necessarily. Right. And that may be more of a problem of us being kind of lumpers instead of splitters on the diagnosis. But to your question, I mean, what's hard about understanding any psychiatric condition is that you need to establish some level of causality. Right. And so the reason why psychiatry is over here, neurology is over here is because in neurology, you know, the game is where's the lesion? You know, and in psychiatry historically, there is no lesion, right? There's no kind of lesion that we can pick up on standard imaging methodologies that are employed for.
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Tom Bilyeu
Because the dysfunction just isn't tied to a lesion.
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Nolan Williams
Well, it's electrical, you know, effectively. So what we think about as a lesion really ends up being, you know, in the case of that paper I talked about earlier, flipping of the signaling directionality, it functions kind of like a lesion. So if you take people that have depression from a stroke and you look at, you know, you look at where all those strokes fell on a common brain atlas, like functional atlas. You know, Mike Fox and others at Harvard found that, you know, brain lesions that are functionally connected to that same control region are, you know, are associated with depression and, and brain lesions that don't fall within a network that's connected to that control region don't have, you know, those individuals.
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Tom Bilyeu
So if you saw, if I had a stroke and you looked at it, you would determine by the region of the brain that I had the stroke and whether I'm now at higher risk for stroke related depression or not.
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Nolan Williams
Yeah, so they, I think they're doing those prospectively now, but in a retrospective way at a group level. You can put all those lesions on the brain and the vast majority of them would, if you had depression from stroke, would be functionally connected to that same control region. And so it looks like a lot of what we think about as depression ends up being that sort of a problem. But to your point, right, it's a complicated thing, right? If you stimulate on the vagus nerve in the, you know, in the neck, you can, you know, produce signals up into the brain and treat depression, right? And, and there's a huge Medicare funded study going on right now to, to start paying for something like that where you actually stimulate a cranial nerve, you know, that, that also, you know, propagates down to the gut, propagates to the heart, you know, and if you stimulate and go up, it'll, you know, it'll affect those same core brain regions. To your point, the brain and the gut and the heart are all, well interconnected. And so causal mapping and understanding of some of the questions that you're talking about is exactly kind of the way to do it. And you can actually, it's not a hypothesis. You can actually test it, right, because you can cause interruptions or you can accentuate signals in any of those spots and then see how it changes the mood. You can do the same thing with functional, with neurostimulation, either invasive or non invasive. You can look at the same sort of thing with lesions like stroke lesions. And with all of that information, we've been able to develop maps that tell us kind of what is connected to what and what systems are signaling. But it's still really early days. I mean, I tell people this is like 1950s, 1960s cardiology. You know, it's not developed at the level where there are 10 text, you know, 10 chapters, I'm sorry, 10 volumes of a textbook like in cardiology, where you see a rhythm on an EKG and you know exactly what it is, what's causing it, what it's called. That whole thing, like psychiatry is very far away from that reality. But there's definite inroads in the last 10 years to where we're headed in that direction. There's a clear signal, I think, that we're, we're going to go there and that we're going to be able to map it out. And to your point earlier about where AI, I think is really useful is that this is such a complicated process and it's so much more complex than just simply what's going on, measurements in the heart. But it's these complex dynamics between the heart and the gut and the brain that it's going to take a lot of dense data collection to really also understand at the behavioral level what's going on. I think Covid exacerbated kind of a cultural problem that we're having around being separated Being on Facebook instead of seeing somebody in person, that whole piece of things which also contributes to depressed mood, and then it kind of take away the control factor, take away the ability to see people in person wearing masks, being kind of stuck at home for a period of time or whatever it is. And I think that sense of control goes, goes further and further down. We think about depression like we think about how many fingers you have on your hand or something, but it's actually on a gradient. We just draw a line and say this is the syndrome that is depression, and below this it's normal. But if you look at it, the scales that we use for what's normal, people can be reasonably symptomatic. At the high range of that, somebody can be what we call in remission or no depression and still have 10 points on a 60 point scale. And I'd argue that actually most people aren't a zero. Most people.
- [35:40]
Tom Bilyeu
I'm not.
- [35:41]
Nolan Williams
Or not. Yeah, I mean, we see people. I mean, it was funny the other day, one of the patients running through our trial, my wife works with me at Stanford too, and she's a psychiatrist and runs a lot of the clinical operation. And so one of the other guys that's working with me sent a message and said, this patient's a zero. And then the conversation was, oh, how great would it be to be a zero? Because nobody a zero means you slept eight hours last night, you fell asleep immediately, you slept all through the night, you woke up rested, you're completely not anxious, you're completely optimistic and in a good mood and you got up without any problem and you got going. So it's hard to, when you get down to it, I think a lot more people even than the percentages that we think about that are in true to form depressive episodes or having some, you know, kind of mild symptoms. And you know, the number of those people that, you know, number of people that were experiencing those mild symptoms, I think in Covid probably went up too. We don't track that, but I think that would be my suspicion as well. What's interesting and kind of, you know, one of my theories I think will happen in the future is just like with blood pressure and cholesterol and all these other things where we say, oh, this is the bad number, and then we're going to, we shift it. Oh, and we're now we're going to be more conservative. This is actually the bad number. And you need to have your LDL even lower or you need to have your blood pressure even lower or Whatever it is, I think that we're going to get to a place as we get better at this, tracking it and treating it, that, you know, the number of what's acceptable, what's normal or whatever may move a little bit too, because I think somebody on a 10 points, on a 60 point scale, it's. That's probably not ideal either. Right? You know.
- [37:32]
Tom Bilyeu
Yeah, I was gonna say I haven't been a zero since I was like nine.
- [37:35]
Nolan Williams
Yeah.
- [37:35]
Tom Bilyeu
So, yeah, getting to a zero would be amazing. In fact, I have struggled pretty profoundly with anxiety. Part of why I came up with a thesis around diet was that was the big fix for me. It didn't take me to a zero, though. I would say it. It alleviated my symptoms by 70%. It took it from completely unmanageable. What the hell is going on in my life. This is really a problem to. Okay, back to, you know, where I've been since I was a little kid, where I would say I'm probably more prone to anxiety than the average person. But from a. I don't need to take medication or anything like that. So that is. The thought of being at a zero is like somebody saying that I could be a superhero. So that would. When I was researching you, I was like, yo. Transcranial magnetic stimulation is something I would very much like to try. I want to do your five day process. I don't know how hard that is. If that's like I can just roll up and we zap me or like,
- [38:32]
Nolan Williams
yeah, we can chat about.
- [38:33]
Tom Bilyeu
But that, that would be crazy because I've told my wife when I'm. When I'm anxious, I feel like a mortal. And when my anxiety is at a zero, I truly feel like a superhero. And it, and it does happen every now and then. I'll be just in a perfect zone of comfort where I'm supremely confident in my abilities in something. The stakes are really low, you know, and it's like, okay, yeah, this, this is how I want to feel. All. And the fact that I almost never feel like that. It's. It's been sort of the holy grail of what I've been chasing since I started researching the brain. And it's interesting because I never put my finger on control before, but that really would be a very easy way to recontextualize. What brain plasticity allowed me to believe in is that I controlled my future. My future wasn't controlled by my current level of intellect, which was my big struggle. I didn't think I was smart enough to do the things I wanted to do. And, and once I realized, oh wait, I can get better, then it was like, okay, now I felt in control. I didn't, I didn't conceive of it that way. I just felt like there's something I can do. But that's really, really fascinating. Okay, so keeping it very tangible for people for a minute. So Covid hits people are getting isolated. They are freaked out about what the future feels like. They definitely feel completely out of control. Did you have a. Or do you have a best practices for people in hard times like that to avoid sliding into depression?
- [40:05]
Nolan Williams
Yeah, it's tricky. I mean, I, I think, you know, the kind of standard answer there would. Right. Would Be that folks, they had a therapist to go and you know, chat with their therapist about what's going on.
- [40:18]
Tom Bilyeu
How, how does, how do we make therapy work for us? Is this cognitive behavioral therapy, talk therapy?
- [40:23]
Nolan Williams
Yeah, I think that's for all. Like a lot of the digital therapeutics work that, that folks have, you know, because therapists are hard to get. There's, you know, many times you're paying out of pocket, they're expensive in the Bay Area. I'm sure in LA it's the same thing. Like, it's, you know, it's a complicated process to get a hold of a therapist. So trying to figure out ways to scale that through digital means makes a lot of sense. You know, there hasn't been a whole lot of preventative work that's been done in psychiatry. You know, it's mostly been you have, you now have this diagnosis, now we're going to start doing something. I don't think that's the fault of anyone. I don't think that's the fault of the field or anything. It's just like it's hard enough to treat it when it gets to this point. But I'd argue actually it may be better to try to intervene earlier. We try to do this study with orthopedic surgery at Stanford. It was just very hard to coordinate and kind of figure out how to do it with everything else that was going on. But people that had motor vehicle accidents, broke their leg or broke their hip or whatever, they have this huge conversion rate to PTSD and depression later.
- [41:40]
Tom Bilyeu
Whoa.
- [41:41]
Nolan Williams
Yeah.
- [41:42]
Tom Bilyeu
Why ptsd?
- [41:43]
Nolan Williams
They just went through a traumatic event with a car accident. They thought they may die in that moment, that they're head to head collision or whatever it is. And so they have these traumatic experiences and it's an opportunity to try to prevent. To your point, could you Use brain stimulation to try to get in there and prevent this future symptomatic event from happening. There's been some work. We know that heart. Heart attacks, myocardial infarctions. You, you know, you have this post MI depression risk, you know, and so there's been some work there trying to think about SSRIs. And.
- [42:25]
Tom Bilyeu
Okay, so hold on. Do you think that that's happening because of the brain, Heart, like physical connection? So it's not a psychological thing of. I'm terrified I had a heart attack. This is Yo. There's a real physiological connection between these two and they are communicating that something is bad and that leads to the depression.
- [42:43]
Nolan Williams
Yeah, I mean, that'd be my suspicion.
- [42:46]
Tom Bilyeu
Like, is that counterintuitive for the field or is that like.
- [42:51]
Nolan Williams
Yeah, yeah.
- [42:51]
Tom Bilyeu
Everybody assumes that to be true.
- [42:53]
Nolan Williams
You know, we've done some work on this. There have been a couple other people that have done work in this where actually like the stimulation approach that we're using, you can decelerate the heart rate. So we know actually that it's a direct connection because you decelerate the heart
- [43:06]
Tom Bilyeu
rate by starting at the brain.
- [43:08]
Nolan Williams
Yeah.
- [43:08]
Tom Bilyeu
Whoa.
- [43:09]
Nolan Williams
So you stimulate here and you can very reproducibly drop the heart rate.
- [43:14]
Tom Bilyeu
Are you mimicking a condition of all is. Well. Whoa. Okay.
- [43:21]
Nolan Williams
Yeah. So if you turn this system on, it's involved in the parasympathetic control of the heart. You kind of drop the heart rate. Right. So you end up having a reduction of heart rate by toning up control, which makes some level of sense because our parasympathetic system is set up to where we're perceiving that everything's okay and we're able to digest our food and have a lower heart rate and counterbalanced by the sympathetic system, which is this kind of fight or flight process. Right. So, yeah. So you can decelerate the heart rate from the brain. It's mechanistically, I think there's been some work on this as far as trying to understand exactly why that happens. But it definitely happens. I mean, people that have heart attacks have a much higher risk of post heart attack depression. Depression is now one of the four leading risk factors for having a heart attack.
- [44:25]
Tom Bilyeu
I'm sorry, why? I mean, it's just that two way communication.
- [44:30]
Nolan Williams
Yeah. I mean, we don't know enough for me to be able to.
- [44:33]
Tom Bilyeu
Being depressed increases your risk of heart attack.
- [44:37]
Nolan Williams
Yes. As much as diabetes, is it ramping
- [44:40]
Tom Bilyeu
your heart rate over time or. Because I always think of a heart attack as being about an occlusion, like blood has been blocked by physical blockage. So is the. In fact, this is. We're going to fractal here very fast. There's two things now that are tied in my mind. I'll let you tell me how we're going to tease them out. So the fact that depression increases your risk of heart attack, but that I assume heart attack has a physical reason for happening and it's not purely psychological, but maybe you're going to tell me that's not.
- [45:13]
Nolan Williams
Well, I mean, I don't think anything's. You know, we. This kind of brain mind dualism thing, it's like we've divorced these things that aren't really divorced conceptually. You know, Freud kind of started that process, but it's not actually, you know, they're not actually separated. Right. And so what we feel and those negative emotions and all of that are just, to your point, playing out in brain networks that are ultimately connected to the heart. We know if we can, we can slow the heart rate down by turning this region up. They're connected. So whatever. If this isn't sending signaling down to the heart, then the heart's not receiving a signal that it normally receives in wellness. Now why from the vagus into the heart and the coronaries, why that happens, we don't know, but it definitely happens. There's something called Takotsubo's cardiomyopathy. So this is another interesting one.
- [46:13]
Tom Bilyeu
I was just going to say that.
- [46:14]
Nolan Williams
Yeah. You know about this? Yeah.
- [46:16]
Tom Bilyeu
Never heard of this in my life. I don't even know what you just said.
- [46:19]
Nolan Williams
Yeah, so it's, it's, it's this Japanese word and it's. I think it's like, I don't remember the translation. I feel like it's like some sort of basket or something. But, but essentially it's a ballooning of the heart. And so it can happen from a stroke in the brain in the same, same connected brain regions. It can also. It's also called the broken heart disease. It can happen with an intense emotional experience.
- [46:47]
Tom Bilyeu
What?
- [46:47]
Nolan Williams
Yeah.
- [46:48]
Tom Bilyeu
So when you say it's ballooning, is it adding muscle fiber to the heart?
- [46:52]
Nolan Williams
Like the heart kind of dilates and they go into heart failure. So you have to, like, do all sorts of heart failure maneuvers.
- [46:58]
Tom Bilyeu
It dilates, meaning the empty space grows larger.
- [47:01]
Nolan Williams
Yeah. You have a cardiomyopathy. Yeah. You have this, you know, problem with your heart pumping.
- [47:05]
Tom Bilyeu
And you can actually get that just from a. What we would sort of colloquially call a broken heart.
- [47:10]
Nolan Williams
Yeah, I mean, it's extremely rare, like for listeners. Like, like it's a very unlikely event. You know, it doesn't happen very often. But if you. There was a study that came out a couple of years ago that I think 85 or 90% of the people that had it had a pre existing psychiatric diagnosis, right? And then they had some, you know, somebody died or something like that, a major life stressor and then all of a sudden they ended up, you know, on the cardiac unit with takotsubos. And so yes, you can have physical things that happen in the heart from things that are happening in your brain. And the idea that somehow the a psychiatric illness is less real, just like that's like a fiction, right? Like it's just as real, right? It you, you wouldn't be able to have a post stroke depression if it wasn't just as wired in as having a post stroke hemiparesis where you can't move your arm. It's just that they're more complex systems, right. And there's a level of semi volitionality to it, right? Like I'm depressed, but in certain circumstances house is on fire, I can run out of the house even if I feel like I can't really move or do much. In the extreme case of catatonia, you can't. But most people depression can, can amount enough energy to be able to leave a burning building or something like that and they're kind of back to their base state. And so I think folks, it's very wired in, it's very biological. It's just as, I think just as biological as many other things that we think about as purely biological. It's just a matter of really discovery and understanding and coming up with tools. So that's what we've been focused on is just like how do we build, how do we build tools? And I'm a very agnostic tool builder. I really don't care what the social perception of the tool is. I really don't care what we got into psychedelics, study ketamine, do neurostimulation. If it's safe for the patient and it's acceptable for the patient and it's something that I would suggest to my mother, brother, spouse, then, you know, and the risk benefit is, right, do no harm and all those things, right? Then we'll look at it. You know, we don't have any, we don't have any kind of off limits because I have some conceptual problem with something, you know, and so I think that's been very useful and it's Given us the ability to ask a lot of interesting questions because we're willing to go into these spaces that, you know, not, not so many people are willing to go in within the mental health kind of research space.
- [49:58]
Tom Bilyeu
So yeah, I'm, I am incredibly eager to pursue that path and figure out what theory led you to psychedelics. But first, there was another thing that feels related to the, the emotional trauma, creating heart trauma connection that I wanted to talk about, which is what you call psychiatry 3.0. So this idea that in fact you don't mind walk people through psychiatry 1, 2 and now 3.0.
- [50:29]
Nolan Williams
Yeah, definitely. And this is a concept not just for me. Buddy of mine, Jonathan Downer has been talking about this as well. It's a concept of. We've basically had three major epochs within psychiatry and kind of modern psychiatry with Freud, Ford. The first one being that the problem is inherently a content problem.
- [50:56]
Tom Bilyeu
Content of your thoughts.
- [50:58]
Nolan Williams
Yeah. And psychotherapy effectively is the ability to introduce different ways of looking at the information or different points of view or framing of it, or introducing new relationships in the case of the patient therapist relationship, where the dynamic changes so the person can have insights. That's basically psychiatry 1.0, the transition between 1.0, which is psychotherapy focused, and 2.0, which is psychopharmacology focused. There was a major kind of historical issue there, and there were two camps. There were the analysts, psychotherapists, and there was psychopharmacologists. And that happened over the 50s, 60s, 70s, even into the 80s. And some of this still extends into today.
- [51:51]
Tom Bilyeu
And this is going to be SSRIs and things like that.
- [51:53]
Nolan Williams
Yeah, like Thorazine, the early antipsychotics that took the schizophrenic patient out of long term care. So there's a big exodus of patients, early monoamine oxidase inhibitors and tricyclic drugs that were the precursors to SSRIs. Those drugs really, you know, kind of jarred the idea that it was totally content. Because if you can just take a pill and then all of a sudden, to kind of your point, the person has a total change in perspective. How could that be if it's a content problem? And then what I would say, psychiatry 3.0 kind of circuit based thinking about mental illness, aligns it with neurology, neurosurgery and all of those specialties into kind of a common circuit language. You know, I can have, I'm trained as a psychiatrist and neurologist, but you know, kind of I can have a psychiatric dialogue on the circuit level with a, you know, fellow neurologist or a neurosurgeon, and you're speaking the same language. And we've never really been there. We haven't been there since pre Freud, you know, with the kind of discussion around what the problem is with a patient with psychiatric illness, with epilepsy, whatever. And so what's useful about psychiatry 3.0 is it embraces the first two, right? Because it takes the first two into account and says, okay, if your psychotherapy or if your drug moves this circuit, then our stimulation moves the circuit. We can have what we would call a modality independent kind of predictive biomarker, right? Something like this or area that changes or however you want to think about it. And so it's more about the end product of the kind of biological change. And that as a tool maker and as somebody who thinks a lot about building tools and building measurements of those tools, it makes you very agnostic, like how do we figure out what the problem is? And then how do we move the problem circuitry around such that we understand we can even further confirm it? And then it's just a simple thing of does this move that circuit? And it gets us out of all these theories and stuff, which I'm less inclined to necessarily be thinking about. I'm much more just trying to figure this out. And I think that's what psychiatry 3.0 effectively is, the ability to develop a circuit based understanding and then develop new treatments based off of circuit measures and then think about the existing treatments based off of those same circuit measures and really get us away from the negative. Framing in psychiatry 1.0 was the framing of the schizophrenia mother. This whole idea that somehow you're parenting a lot of schizophrenia, that person's parent led them to develop schizophrenia, which has been totally debunked. Right, Interesting.
- [55:00]
Tom Bilyeu
So what was that original theory?
- [55:03]
Nolan Williams
Yeah, no, there was a, you know, kind of over controlling mother and all that sort of thing. And then all of a sudden this patient had, you know, had schizophrenia.
- [55:14]
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- [55:45]
Tom Bilyeu
Do you think there's anything in the Wives tale of that, that it's early trauma, you feel out of control because the mother's controlling you. So it ultimately it ends up being a circuit thing because my, my next question in understanding the circuits is, is the circuit the manifestation of another root cause or is the circuit the root cause? And I couldn't do anything to influence it because I can influence it from the outside. So it seems like if I can fix it from the outside, I can probably break it.
- [56:15]
Nolan Williams
Oh yeah.
- [56:16]
Tom Bilyeu
From the outside. And certainly if you let me control diet and things like that, I can probably really do some damage. So I'm curious, I get it that it isn't just mom is what made me this, but is there some element of what they're groping for? Is that person with a mom that was that unhinged. They're probably this cascading set of problems that are relatively predictable.
- [56:40]
Nolan Williams
Yeah. I mean, you know, that particular idea has been debunked. You know, the, the next thing I was going to say was this, you know, chemical imbalance kind of idea, which has essentially been debunked. The idea that our environment.
- [56:54]
Tom Bilyeu
Wait, I think we shouldn't blow past that because even for me, that stops me. So you're saying psychiatry 2.0, this is a serotonin imbalance. False.
- [57:02]
Nolan Williams
We've, it's, it's not a, it's not a problem where there isn't an, you know, the messaging historically has been, there isn't enough. Your brain is faulty because there isn't enough of X neurotransmitter in place. And then therefore you need this drug. And it's not really, you know, there's no evidence of that. Right. And so we've not. Yeah.
- [57:27]
Tom Bilyeu
So but to plant a flag, which I'd love you to speak to, SSRIs, selective serotonin reuptake inhibitor. They work to some percentage of people, but it isn't because of the way that it's balancing your serotonin. Is that the.
- [57:43]
Nolan Williams
Yeah. So the idea, I mean what we think is really going on there because it, you know, as, you know, it takes kind of a while for it to work, a month, two months, whatever, is that it's actually up regulating plasticity to your point. Right.
- [57:55]
Tom Bilyeu
Specifically bdnf.
- [57:56]
Nolan Williams
Yep. Yeah.
- [57:57]
Tom Bilyeu
And so for people that don't know,
- [57:59]
Nolan Williams
brain derived neurotrophic factor. Yeah. So it's just like a brain, you know, kind of growth promoting factor. Right. So, you know, it's probably more like that or more like it's having an interaction with Some of the, you know, kind of dendritic spines, that sort of thing. Much less about acutely upregulating serotonin. Because if it. If it worked like that, then it would work in a day or two days or three days. Right. It actually takes time for it to work because there's something else more complex going on. And the problem at a fundamental level is you put a drug in your body that upregulates. Also, to your point earlier, GI serotonin, like gut serotonin and all that. We don't have conclusive human studies saying this is how this works for SSRIs. We've done that with ketamine. Right. My lab, in collaboration with Alan Schatzberg and Boris Heifetz at Stanford. To my knowledge, the only study that's totally blocked an antidepressant effect, and that was with ketamine, where we were able to use an opiate blocker and actually block the antidepressant effects totally of ketamine with co administration of an opiate blocker. When you give somebody that same person ketamine with a placebo pill, they have a perfectly good remission from ketamine.
- [59:22]
Tom Bilyeu
So what I'm drawing from that is that ketamine is not working at the disassociative level, working at the opiate level.
- [59:30]
Nolan Williams
The opiate level is necessary. It may not be sufficient, but it's necessary. And those people had the same amount of dissociation when they had the naltrexone. So that's not sufficient.
- [59:42]
Tom Bilyeu
The naltrexone being the thing that blocked the opiate. That is very interesting.
- [59:47]
Nolan Williams
Yeah. But to get back to the SSRI thing, I think that the big messaging there, which I think, you know, the field is known for a long time, but I think optically there's been, over the last couple of years, a real intent to walk back from is that there's some missing thing in your brain that pharma is somehow going to, you know, that these SSRIs, or whatever it is are going to replace. And I'd argue that the neurostimulation work that we're doing even further accentuates that if depression is a serotonin problem in that way, stimulation shouldn't be the answer. Right. It'd only be replacement of neurotransmitters that are lacking or whatever. Right. It's this idea that it's really a circuit problem. And that's kind of what psychiatry 3.0 gets into. Now. Stimulation of circuits releases neurotransmitters so it's not divorced from that idea. It's just much more complicated than that idea, but also empowering because it doesn't seem like you need any of that stuff in your system to get better. You can get better without any of it in your system. It's just really about engaging the brain circuitry that's involved. So, yeah, I think each era kind of debunked the last era and recontextualized the last era to understand it more. But it's not kicking any treatments out. To your point. SSRIs have saved lots of lives. They're introducing SSRI into a country and the suicide rates go down. So we know that those drugs do have an effect. The issue ultimately ends up being that not everybody responds to them. What we call treatment resistance or hard to treat depression or whatever term you want to use. And in those individuals, those are the individuals that we study. We don't study treatment naive people. Those are.
- [61:50]
Tom Bilyeu
Do you have any sense of what the treatment resistant people have in common?
- [61:55]
Nolan Williams
Yeah, that's part of what we're trying to figure out now. Some of that flipping of the signal that I was talking about earlier is one potential.
- [62:02]
Tom Bilyeu
How easy it is to flip the signal for them.
- [62:04]
Nolan Williams
Oh, just the fact that it's flipped, you know, we don't know. We know in a highly treatment resistant population that most of them had it. But, but going back and looking actually at the broader treatment naive depressive population, understand that. To understand it in the context of people that are treatment resistant versus treatment responding with a given oral antidepressant. Leanne Williams and others have been trying to look at that as it relates to earlier stage treatments and how to do predictions with brain, brain circuitry. But it's, you know, it's a very hard problem to solve because we don't know how the treatments work. And we, you know, at least the oral antidepressants, we don't fully know how they work and we don't fully know in a given individual what the brain circuitry differences are. And so you're, you're kind of, you have two variables that aren't well controlled. And so that's why we've focused primarily on things like stimulation, where you can say, okay, I'm stimulating here. I know this isn't going into the rest of my brain. I know it isn't going into my body. I'm just stimulating here. Then I'm trying to figure out what's different about the people that get well from just stimulating here versus the people that don't get well, it controls a lot more of it so that you can derive some sort of answers in humans, in mice. We have a lot of really cool science around that. But translating that's been hard as far as drug effects and all that, man.
- [63:40]
Tom Bilyeu
One thing I'd be very curious to see people look at would be bdnf and specifically BDNF and recidivism. So as you're talking about it, one of the things that if somebody came to me and they said, hey, I'm depressed, the first thing I'm going to say is get your diet under control. Meaning basically don't eat sugar, whole foods. And then exercise. Now exercise, I never really knew, I have no idea why it works. But certainly exercise spikes bdnf. I've heard BDNF referred to as miracle grow for the brain. And if what this is, and the reason I would love to see it looked at with recidivism. So let's say somebody does your five day protocol. So for people that haven't sort of put it together yet, you have transcranial magnetic stimulation. You put a device in the head that zaps them, basically gets the circuits to go in the right order again. So we're doing that. But then my question is at the end of the five days, what do the people have in common where that lasts for a long time and what do the people have in common where that falls off really fast? Now, I have no idea, but this at least would be testable is what are the. Either the BDNF response rate to the treatment or the baseline levels of bdnf. Like are they BDNF super producers low? They're probably low already or they wouldn't be in the study if my hypothesis is correct. But then as we test them, we can see like, of that population like which, like pumps that harder, which lower. And then if the people that were in the, the responder BDNF group, meaning they, they create more of it, if they had a longer shelf life of efficacy of the protocol, then it's like, oh, maybe there's something there, right? That's really interesting. That would certainly explain because it's my understanding I could be wrong about this, but it's my understanding that exercise has a higher efficacy rate than SSRIs. Is that true?
- [65:42]
Nolan Williams
You'd have to look. I'd have to look at the study. I mean, I think that there is definitely in mild, kind of mild, even maybe moderate depression. There's good evidence that exercise Is very effective. You know, aerobic exercise mind more than weightlifting. So I haven't seen, you know, there haven't been any studies at scale. You know, there's. It's usually like single site studies sort of thing. And they're comparing, like a standard treatment versus, you know, one exercise regimen. I'm not aware of multiple different. You may have this study at your fingertips, but multiple different exercise regimens versus, say, a standard treatment, like an oral antidepressant.
- [66:29]
Tom Bilyeu
I don't have it at my fingertips, but that is a very worthy thing to look into. I'd be super curious to see what that is. The other thing about exercise. So this goes into your psychiatry. 1.0, 2.0, 3.0. So if content is part of the problem, it just. It's not sufficient to explain the phenomena. If I were. If I really wanted someone to feel good about themselves, like, I literally just had a woman come to me. She was really upset. She had just had. She got scammed, basically, and lost, I don't know if everything, but lost a lot and was at a dark place in her career also got scammed. And so she was just, like, really down on herself.
- [67:07]
Nolan Williams
Yeah.
- [67:08]
Tom Bilyeu
And I was like, look, if I had just lost everything, the first. This is so weird. I'm putting things together in real time. Thank you very much. What. What I said to her is, if I lost everything, the first thing I would do is start working out. Because when you work out, you realize you have complete control over your body, over what you eat, over the way you look, how you feel, which, again, man, you really put something together for me. So that is interesting. So working out will make you feel better about yourself. One, because you'll just start improving. Two, you have control. And that sense of, like, I can do the right things and I can end up in a better situation. I can change the way I look, which, hey, people can. I'm agnostic. Like, you're agnostic about what the tool ends up being. I'm agnostic as to why looking good makes people feel better, but it does. So you can whine and cry that people shouldn't want their ass to look great in jeans, but it is super motivating for humans, man. That's interesting. I will be very curious to see what comes of all that.
- [68:11]
Nolan Williams
There was some studies where they Botox Glabella right here, this muscle here, and treat depression because they can't scowl. Yeah, I mean, well, I mean, that's one idea, right? Is that if you, you know, there's some feedback Kind of where the more you smile, the better you feel, you know, that sort of thing. And if you can block kind of frown muscles, maybe, and these things are kind of wired all the way back into motion circuitry. So it's. It makes some sense that intervening even in those places would make sense to have a mood improving effect, but still kind of grounded in this idea of it being ultimately seeable within the brain circuitry.
- [68:59]
Tom Bilyeu
That idea of the expression you wear on your face, controlling your emotions is one of the things that got me to start saying to myself at first, you're having a biological experience was my. I. I work a lot. And this was also true when I was younger and my wife and I were just married, and we would inevitably get in arguments on Saturday. And it was like the only day that we had to spend together. And so I. I am slow to anger, but once I get angry, it's not as true anymore. But it used to be once I got angry, I would stay angry for a very long time. So I ended up writing this note and giving it to my wife. And I said, the next time I get mad, just read me this letter. And in the letter, I said, hey, me, it's me. There's no ulterior motive here. You know that if you stay mad all day, you're going to regret this. You've never once stayed mad and been like, I'm so glad I was mad all day. So what I want you to do right now is laugh out loud, because you know that if you force yourself to, because it's from that study where they put a pencil in your mouth and you bite down and it sort of forces you into this faux smile. And I would not be surprised if there's a replication crisis around that. But laughing for sure will change your neurochemistry. And so I did it. She only had to read me the letter once, because when I burst into laughter, I. It changed my neurochemistry so rapidly, partly because I just felt ridiculous, but in an amusing way. And it changed my neurochemistry so fast and so profoundly that I was like, oh, my God. Now, at the time, what I said to myself is, you're just a neurochemical processing plant now. Maybe I'm just a circuitry or circuit board and, you know, I'm turning on the right circuits. But that was like, whoa. That little thing has had such a big impact on my marriage that realizing how by manipulating my face, I can make myself feel differently, that's just weird to me. But it's so Useful?
- [70:59]
Nolan Williams
Yeah, I mean, I think that we're this reverberating system on itself. Right. And if you can impact some aspect of it, then you can change the system. And so it makes a lot of sense that, yeah, those are essentially psychotherapeutic techniques in many ways, like a CBT sort of technique. So. Yeah, that's awesome.
- [71:21]
Tom Bilyeu
Now, when you're not on camera, do you have a secret hypothesis about how this all adds up from a root cause perspective? Like, what is all of this? I know you need data and I know you don't. Nobody knows right now, but do you have a sort of mental map in your brain that you know will probably get debunked over time, but that anchors you to what you look at next?
- [71:41]
Nolan Williams
One of the most provocative papers that's come out over the last couple of years as it relates to thinking about psychiatric illness and serotonin, and that whole story is this. This paper that came out of UC Davis a couple of months ago in Science, where they. They showed that in. If you were to kind of agonize the 5a, the intracellular 5ht2a receptors within neurons, you're able to produce changes in dendritic spine and producing dendritic spine enlargement. But they weren't able to see that with extracellular 5ht2a receptors. We think about these as serotonin receptors, but the problem with that kind of conceptualization of them is that serotonin doesn't cross through the cell membrane. So it doesn't seem to get into the five HT2A receptors that are intracellular and agonize them because they're not lipophilic enough. And so the substances that do cross that are lipophilic and seemingly agonize these intracellular receptors, the only ones that seem to be responsible for producing these dendritic spine enlargements that we think are probably linked to antidepressant effects are psychedelic compounds. And folks have, over time, theorized, although this is completely unproven, that the brain actually has its own endogenous, at least dimethyltryptamine production?
- [73:19]
Tom Bilyeu
I've heard that.
- [73:20]
Nolan Williams
Right. And there have been a number of animal human studies and epilepsy patients and CSF and all this stuff trying to look at that. None of it's been particularly conclusive. But it's interesting, right? Why would you have a receptor that we were thinking about as a serotonin receptor in a place that's inaccessible to serotonin and you end up, you know, is that like A vestigial receptor. Right. Like our appendix or tonsils or whatever. It's just vestigial, and it's not, you know, nothing endogenously activates it. Which is probably the least provocative thing to think about. If that science paper replicates. And that's a real. That's a real consistent finding. If we endogenously make DMT, that's kind of wild. Right, because it's a Schedule 1 substance. It's something that US government officials have blocked us from getting from a plant. But if the brain makes it kind of turns that whole thing on its
- [74:31]
Tom Bilyeu
head, don't we also make opioids and cannabinoids? Yeah, certainly. They have a long history of blocking things that we already make in the body.
- [74:39]
Nolan Williams
Yeah, that's fair.
- [74:41]
Tom Bilyeu
Okay, that's super interesting. So I'm going to put it in my words. So there is potentially a receptor in the brain that is designed for psychedelics, at least some subset of what we think of as psychedelics.
- [74:54]
Nolan Williams
It's. Yeah, I mean, it's. Yeah. And that would be. The third idea, is that it's there because of some exogenous use. Yeah, it's definitely.
- [75:02]
Tom Bilyeu
Oh, whoa, whoa, whoa. I wasn't even thinking about that. So that from an evolutionary standpoint, it's possible that we pass through a period where use was common enough that the brain evolved to use it, for lack
- [75:17]
Nolan Williams
of a better word. Yeah, that would be the third idea. And. And, you know, the number two and number three, obviously very provocative, but it's not really explainable that this is. It's not.
- [75:31]
Tom Bilyeu
And can we see. Have. Has there been any study done where we give people a psychedelic and then look at if it's binding to those receptors?
- [75:38]
Nolan Williams
Yeah, that was part of what the UC Davis folks were doing. Right.
- [75:42]
Tom Bilyeu
So they see it. It is happening.
- [75:43]
Nolan Williams
Yeah, yeah. And. And, you know, only the dendritic spines
- [75:46]
Tom Bilyeu
do grow as a result.
- [75:47]
Nolan Williams
Yep. Yeah. And. And you can get it if you make. If you kind of. So the experiment that was interesting that they did was they also used chemical agents to make the cell membrane more permeable, something that you couldn't do with a human brain because it'd be problematic. But for the purposes of understanding this at the cellular level, they were able to make the cell membrane more permeable so that serotonin could get through. And then if serotonin can actually get through, then it does agonize that receptor, and it does also do that and change the dendritic spines. But it's one of these things where that's probably not what's actually going on. And you normally. Because it's not actually permeable. And so then it draws up these other questions of is this effectively a receptor that receives input from other non serotonin sources? And yeah, I think figuring that out is going to be very. If that's true, figuring out why that is is going to be really central to understanding a lot of kind of socio cultural reasons for mental illness, why they're there, what it is, why that receptor is in that particular place. I mean it just opens up a whole host of questions that, that we definitely don't have any answers to.
- [77:19]
Tom Bilyeu
Okay, so did people start deciding that there must be DMT endogenously produced because they saw these receptors and knew that it would fit in?
- [77:30]
Nolan Williams
No, that's, this was way before it was theories about why people have these near death experiences or these kind of phenomenon in and around death.
- [77:38]
Tom Bilyeu
And so we have never been able to validate that.
- [77:42]
Nolan Williams
There have been studies, CSF studies in humans and various animal studies, but it's not well established. Rick Straussman, who's a psychiatrist, I think he was at University of New Mexico, did all this work with DMT in the 90s and early 2000s, published a book on it, trying to understand what DMT is. And in his book he theorizes about endogenous DMT and the fact that the idea that it may be present but yeah, hasn't been enough work to kind of conclusively establish it. And there hasn't really been a real reason to do it before this UC Davis paper because it was like, yeah, that may be there, but it's not like there's a lock without a key. And now all of a sudden it's like, oh, there may be a lock key, there may be a door that you can only get to in a certain way. And it's, you know, I think it's a pretty important question to answer if that really, if a couple more labs can replicate this and show that that's the case, then it's going to be important to understand that because that means something inherent about ultimately about how our brain plasticity works. Right. You know, and, and curious, right. If you did have endogenous dmt, when does endogenous DMT get released? You know, does it, people think it's released during these near death experiences. Does it get released during sleep? Does it get released during high, you know, high exertion exercise? You know, where you hit these kind of flow states? You know, I mean these are all the sort of Questions, you know, that, that we have no answers for but are just kind of interesting, you know? Yeah.
- [79:32]
Tom Bilyeu
All right, so I want to talk about treatment. Treatment resistant depression and psychedelics. So I, I have never done. I, I've micro dosed psilocybin. I noticed effectively nothing. And then as I pushed it, pushed it a little bit, it started to feel a little bit like I was drunk, but like.
- [79:52]
Nolan Williams
Yeah.
- [79:53]
Tom Bilyeu
So I've never done a macro dose where I expected something to happen.
- [79:57]
Nolan Williams
Yeah.
- [79:58]
Tom Bilyeu
But nonetheless, when somebody comes to me and is like, yo, I've been struggling with this for a long time, like, I'm really scared I'm going to take my own life. One of the things that obviously go get therapy immediately, do not pass go. I'm not the guy to talk to. But as by way of making a checklist to run by your therapist, here are things that I would say try all the things that we know work and if none of that works, then I would, I personally in my own life would not consider myself to have tried everything until I had tried. I'd start with mdma, which I know is out side of technically being a psychedelic, but it's just from my, my whole theory around, it's the context, it's your frame of reference, it's the simulation is glitching. And it's a way to rapidly reorient the simulation. Everything is good. And to revisit whatever problem you're having through that lens of like, everything's good. I love everyone. I'm hopeful. If that also didn't work, then I would move on to like more traditional psychedelics. I'm curious and I only say that because I've read enough headlines. I haven't really gone into the studies, but I've read enough headlines to know there's. It seems like there's really something there, obviously warrants further exploration, but really seems to be that treatment resistant depression seems to yield in a very substantive number of cases to psychedelics. Obviously you gave us a little bit of a forerunner there with DMT and the possible key to the lock of the receptors in our brain. But what is coming out of that research? Where do we think that goes? Why does it seem to work and how often does it work?
- [81:37]
Nolan Williams
Yeah, that's a great question. So I was at the Psychedelic Science Conference in Denver a couple of weeks ago. I was at the 2013 one. Really? Tell anybody? I was going to the 2013 one, but I was able to tell everybody I went to the 2023 one. So things have changed quite a bit in the last decade around this topic and you know a lot more data, right? We know a lot more about what, what these things can do. MDMA seems to be a very profound, you know, anti trauma sort of substance, ptsd, that sort of thing. There's been one positive trial that was in Nature Medicine a couple of, I guess a year or two back. One of my best friends who's in my wedding was one of the investigators on that paper and they did a great job on that work. There's another positive study that's going to come out soon and people expect FDA to weigh in on this soon. And they actually released guidance for doing studies in psychedelics during the last day of the conference. Ironically, psilocybin has been studied to your point in both major depression, that's not necessarily treatment resistant and in individuals with true to form treatment resistant depression. The major depression data, Robin Carhart Harris had some of that went into New England Journal. There's another paper that is going to arise from Chuck Raison and that group and he's holding that data close to his chest. So we get the sense that it's good but haven't seen it. And that's in more non treatment resistant major depression where you see higher response remission rates. And the compass trial, that was the treatment resistant trial. The data was good. It was, you know, it wasn't as profound as what we were able to see with the less treatment resistant folks. But you know, about a third of people had benefit from it that was clinically relevant.
- [83:54]
Tom Bilyeu
And what dose were they giving people? Like is this a full blown hallucination or.
- [83:59]
Nolan Williams
It was all the benefit really was only observed in like the full dose. Right? Like with the 25 milligram dose, which is 25 milligrams of pure psilocybin, the active ingredient in magic mushrooms. When you think about or psilocybin mushrooms or however you want to talk about it. If you think about actually ingesting the mushrooms themselves, you're talking about grams of mushrooms. There's a certain conversion factor of grams of mushrooms to actual psilocybin. The problem with the grams of mushroom thing is that the depending upon if you're getting mushrooms from this place or that place or this person or that person or whatever it is, the mushrooms end up being different concentrations of psilocybin compared to, you know, how much. Which is why I'm pretty supportive of the kind of medicalization of this because especially for treating diagnoses I think it's important if you've got somebody that's to your point, suicidally depressed. I want to. If I'm going to give them something that has psilocybin and I want to know actually how much psilocybin they really are getting. Because the 10 milligram group, which is still not a trivial. That's over a microdose you're feeling that didn't experience the same clinical benefit as the 25 milligram group, which is pretty heavy.
- [85:21]
Tom Bilyeu
Are we at heroic dose at that point?
- [85:26]
Nolan Williams
I don't use that term medically, but that is what others would call a heroic dose. At 25, 10 would be a dose that you're having, you know, a psychoactive drug. Effect one, which was another dose in that study is essentially a micro dose. So there's nothing there. Not that much for the 10 clinically relevant effect and about a third of people for the 25, suggesting that you have to have this full experience. You know, I, you know, I have, I don't have like a. I'm agnostic to all. These are all tools. I think they're all going to be used for different things. Going to skipping neuromod, you know, especially the stuff that we've been doing with accelerated tms. Skipping that and going on to psilocybin is tricky. And, and I always kind of bring people through STEM first because the risk benefit profile and the like prep, it's functionally just boring, right? The prep to get somebody on board to do that and to. For them to be psychologically ready to do that is so low. I mean, I tell people, if, if your doctor thinks that your treatment is boring and you think your treatment is boring, that's great because that boring from the standpoint of what's going on, not the outcome, because that means that it's low risk, right? And you know, TMS and what we call saint, this accelerated stimulation approach, these are incredibly high risk benefit profile sorts of things where there's a theoretical risk of seizure. We've never actually even seen it with a stimulation approach. That's it. Headache in some people, it's Tylenol responsive and the benefit can be huge. The problem with psilocybin isn't the people that got better. You know, there are people that got better, they got better and it was good. If you look at the adverse event list in that study, that New England Journal study, there was a decently high risk of emergence of more suicidal ideation or suicidal ideation, particularly in the individuals that didn't get better. And it's not necessarily from the drug it's from this phenomenon of disappointment and hopelessness. Interesting, right.
- [87:41]
Tom Bilyeu
So this thing that's supposed to be like the thing didn't work for me and now I'm really despondent.
- [87:47]
Nolan Williams
Yeah.
- [87:47]
Tom Bilyeu
And you.
- [87:48]
Nolan Williams
And that's not even specific to psilocybin. I'm not arguing that psilocybin caused that. I'm arguing that there's just a general risk in those sort of scenarios where you see that. Sometimes we see that with people that go through brain surgery for depression, like really, really worst of the worst. There's experimental brain surgery, sorts of moves where you can put stimulators into the head that people that don't respond to that have a suicide risk. We've seen that. And then, you know, folks who the, you know, on the esketamine product, kind of FDA product description post study, there were a number of suicides once people were pulled off of esketamine, which is really interesting to get back to the kind of.
- [88:32]
Tom Bilyeu
Once you get pulled off. So not while you're on it, but if you stop, is that a withdrawal thing or just the depression comes racing back?
- [88:39]
Nolan Williams
You know, certain individuals would not love it if I said that, but I think that that's an open question. Right. Because it's during the period after it comes off board. But I think it's this overall question of kind of mitigating risk. We see this less with neurostimulation or not much at all with a non invasive neurostimulation bit. And I think it's because people don't have to prep themselves to do it. It doesn't feel like such a risk. It doesn't feel like such a, you know, to take a psilocybin trip as a depressed individual that's never done it before, which is really who they're looking for. 50 year old, 60 year old person, they've gone through their whole life and avoided this and now they're taking this and they may have even had a bad experience with it and then they're still depressed. That's not a, you know, it's a tough thing.
- [89:35]
Tom Bilyeu
How do you prepare yourself for it?
- [89:37]
Nolan Williams
Psychologists will try to. We'll do some work to prep folks
- [89:41]
Tom Bilyeu
for psychotherapy, therapy or just explanation of what the trip is going to be like and how to handle it if it gets scary.
- [89:47]
Nolan Williams
Yeah, I mean, in some ways that's therapy too, right? In the sense that you're supportive of psychotherapy or however you want to think about it. But yeah, I mean, psychoeducation, that sort of Thing you're trying to get the person to be ready to when they go into this mental space. And then they end up feeling quite a bit different and in some ways kind of out of control, right? And then the kind of control comes back online when the trip is over, you know what I mean? And so that's, I think, and then processing insights. Psychedelics produce a lot of insights, so. Processing insights, processing, you know, the positive and the negative, you know. And for some people, with all those disclaimers, for some people, this is incredibly transformative, right? They come out of these experiences and they feel like they're a different person, you know, from like how, how I'm approaching, you know, my significant other, my friends, you know, they, they get out of the, maybe the mental health crisis or their depression or whatever it is. But, you know, we know that there's even lasting personality changes that happen. You know, if you give psilocybin to normal, healthy control individuals, they'll routinely rate it as one of the top five most important, like a full blown trip, one of the top five most important experiences in their lives up there with their wedding and their kids being born, you know, and that's, that's saying something, right? That's pretty hard to pull off a lot of people and into life where they're able to process their imminent death. So these tools are a little trickier than I think the stem tools are. They have the ability to produce broader effects because it's not just about affecting the illness now. You're affecting an entire perceptual, to your point, kind of perception of how the world works. You know, what we've been working on is a psychedelic that's a less known psychedelic called ibogaine. Its issue has been historically that has quite a bit of cardiac risk and so kind of 1 in 300 serious cardiac risk. Right? Those numbers come from individuals that have received ibogaine for the purpose of detox from usually end stage heroin addiction. So it's people who've probably had a heart infection before and all that sort of thing. So I got connected with a group back in 2018, vets, which is amber, Marcus, Capone veterans exploring treatment solutions for this case. Tbi, PTSD and depression. And so Marcus actually went down to Mexico after a buddy went down to Mexico and took ibogaine and his PTSD and traumatic brain injury symptoms got better. And Marcus.
- [92:47]
Tom Bilyeu
Whoa, whoa, whoa, whoa. His traumatic brain injury symptoms got better. What does that tell us?
- [92:54]
Nolan Williams
Well, in addition to being a brain derived neurotrophic factor, upregulator Ibogaine is a glial derived neurotrophic factor upregulator.
- [93:03]
Tom Bilyeu
What does that mean?
- [93:05]
Nolan Williams
That one has a role in regulating dopamine neuron health and other things. So it's a broader kind of neurotrophic factor upregulator than just what we see with psychedelics and what we see with SSRIs. And it's unique to ibogaine.
- [93:20]
Tom Bilyeu
If there are at least two, apparently growth factors that you can have in the brain. Are there only two? Are there a whole bunch more? What does that look like?
- [93:29]
Nolan Williams
Those are the main ones that people think about as far as regulating the kind of standard serotonin receptor, serotonin neuron, dopamine neuron. And in glial derived neurotrophic factor in particular, that's been a harder one to move. BDNF moves with a lot of different things. And so if you take a mouse and you get the mouse addicted to cocaine and you give it ibogaine, it'll stop being addicted to cocaine. If you give direct injections of GDNF into dopamine neurons, you have the same outcome. It's really interesting. Right? So that kind of effective ibogaine may be unique. So, yeah. So we've been running this trial. It'll come out in press in six, eight weeks from now. It's looking like human trials with ibogaine.
- [94:25]
Tom Bilyeu
Tell me more.
- [94:26]
Nolan Williams
Yeah, yeah. So we partnered. So it has been very difficult to do this in the US Historically because of the cardiac risk. So we kind of constructed this study where Stanford IRB agreed to this study, which is amazing of them, where we actually evaluated people at Stanford, sent them down to Mexico. So they were kind of already headed to Mexico, signed up to do this through vets. Then they came to see us and they went down to Mexico, received the ibogaine, came back, reevaluated them, evaluated them in a month. So we did the first neuroimaging study of ibogaine effects, first EEG study of ibogaine effects, blood full neurocognitive batteries. And it's an interesting phenomenon. There have been about a thousand Navy Seals and Army Rangers and special forces guys that have gone down and taken this African root bark extract drug.
- [95:29]
Tom Bilyeu
That's ibogaine.
- [95:30]
Nolan Williams
That's ibogaine, yeah. Got it. Ibogaine is extracted from the iboga tree that's native to Gabon and surrounding African countries. And the Gabonese group that has kind of used this as a sacrament is the boite. And they've been using this for millennia. And so, yeah, it was kind of long story that led up to it. There's a movie that. A documentary that I was in premiered at Tribeca about a month ago called Of Light and Night. Lucy Walker described, kind of went through and described this history of the last kind of 50 to 60 years of trying to get this studied in the U.S. but, yeah, there's been a difficulty in studying it in the US and so we partnered to do it. Those results are kind of pending, and I can talk about that at a later date. There's been a lot of interest kind of in the addiction treatment community in Kentucky. Kentucky, interestingly, ended up being the first state to. To have a lot of interest in this. And they have money from some of the opiate lawsuits and settlement money for. For a lot of the, you know, the. The opiate oxycodone, you know, cotton codone problems. They have, you know, I think like $800 million. And they're.
- [97:00]
Tom Bilyeu
Whoa.
- [97:01]
Nolan Williams
And so they're trying to. They. They're trying to earmark like, 42 million or so towards ibogaine research. And so they proposed to do this. So I was actually testifying in Kentucky earlier this week in front of the opiate commission about this. And so they. One guy in particular, Brian Hubbard in the Attorney General's office, put this up as, like, an idea for dealing with Kentucky's opiate crisis.
- [97:38]
Tom Bilyeu
And what did they want to know? Is it effective in help get unaddicted?
- [97:43]
Nolan Williams
Yeah, and that's what it's actually been known, like, what it's been more established to do. And so that, you know, this exploration of the veterans is a new application. And we, you know, we've explored kind of those effects. We've known for some time that it's a profound addiction interrupter. That mouse study I was talking about earlier, like, for, you know, 30 years, we've had case reports, but it's been very hard to study it in the US because of the regulatory concerns around the heart and because of concerns of studying psychedelics historically. So we're probably at a moment now where that's shifting. But, yeah, I think Hunter Biden in his documentary took ibogaine and then describes it. There have been a number of other celebrities and folks like that that have taken ibogaine in variable levels of optics, kind of. Of societal, you know, at a societal level of, you know, knowing this. But they're clinics that operate in countries where this is legal, including it's legal in Australia and New Zealand. But, you know, countries where this is legal where people will go and receive ibogaine treatment for, you know, hard to treat addiction. And so, and the numbers are really, really good for addiction interruption. So it's just been this issue of how do you, how do you deal with a heart problem? You know, we've, we've taken this, this kind of stance of co administration of cardiac risk reduction drugs. So you can kind of prophylax against potential heart problems before even ibogaine's on board. And then concurrently with the ibone with the idea that you could risk reduce. And we didn't observe any symptomatic cardiac problems during our trial, which was great. But yeah, it's interesting. We're at this precipice of really looking at these really interesting substances and ones that are really, really, I would say, technologically advanced compared to the drugs that man has made.