Essentials: Psychedelics & Neurostimulation for Brain Rewiring | Dr. Nolan Williams

- Welcome to Huberman Lab Essentials, where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. And now for my discussion with Dr. Nolan Williams. Thanks for joining today. I'm really excited to have this conversation. I have a lot of questions about different compounds, psychedelics in particular. - Yeah. - But before we get into that discussion, I wanna ask you about depression, broadly speaking. I heard you say in a wonderful talk that you gave that depression is perhaps the most debilitating condition worldwide, yet in contrast to other medical conditions like cancer, we actually have a fairly limited number of tools to approach depression, and yet the number of tools and the potency of those tools is growing. - Depression is the most disabling condition worldwide. What's interesting about depression is it's both a risk factor for other illnesses, and it makes other medical and psychiatric illnesses worse, right? So recently, the American Heart Association added depression as the fourth major risk factor for coronary artery disease, right? So alongside the risk factors that we know, hypertension, high blood pressure, hyperlipidemia, high cholesterol, and diabetes, high blood sugar, those three have been on the list for a long time, and depression ended up being added to the list as the fourth one. A lot of what we're doing in the lab, actually, is measuring kind of brain-heart connections, and we can actually, with transcranial magnetic stimulation, a form of brain stimulation, we can actually decelerate the heart rate. We can capture that heart rate deceleration over the mood regulatory regions, and so actually a direct probe of that connection. We've been very interested in a very particular clinical set of problems around the most severe and the most high acuity settings that folks with depression end up being in, and that's in emergency settings where they go into inpatient units. The field really hasn't developed a way of consistently being able to treat that problem, and folks end up getting the same standard oral antidepressants that they've been getting outpatient. And I came to this because I'm dual-trained as a neurologist and psychiatrist, and went back and forth between neurology and psychiatry, saw that in neurology we have all of these ways of treating acute brain-based problems, and really wanted to emulate that in psychiatry and find ways to develop and engineer new brain-based solutions. - Many people out there probably think of the relationship between the heart and the mind as kind of woo or kind of a soft biology, but here you're talking about an actual physical connection. - Yep. - What area of the brain is it? - You know, the first place where the stimulation goes is called the dorsolateral prefrontal cortex. It's kind of the sense of control, kind of governor of the brain, and then what we know is that when you use a magnet, kind of what we call Faraday's Law, this idea of using a magnetic pulse to induce an electrical current in electrically-conducting substances, so in this case, brain tissue, but not skull or scalp or any of that, or hair. You avoid all that, just the brain tissue. Then you have a direct depolarization of cortical neurons, you know, the surface of the brain's neurons, in this dorsolateral prefrontal, and if you do that in the actual scanner, which we can do, you can see that that distributes down into the anterior cingulate, and the insula, and the amygdala, and ultimately, the tract goes into something called the nucleus tractus solitarius, and ultimately into the vagus nerve, into the heart, so that the heart very consistently seems to be the end organ of the dorsolateral prefrontal cortex. If you do that over visual cortex, you don't get that, or motor cortex, you don't get any of those findings. It's really specific to this kind of control region of the brain, and so, yeah, it seems to, you know, it's our work, other folks' work, Martin Arn's in Europe, the Netherlands' work, showing the same connections. I think it's been replicated like four or five times. Where I think TMS is really interesting, actually, because I've had a lot of patients who've told me, like, my therapist told me that I wasn't trying hard enough in therapy, these are moderate to pretty severe depressed patients, and as soon as we get them well with the TMS approaches, you know, kind of rapid, you know, five-day approach, and the next week, we come in and see them, and they'll say, you know what I did all weekend is I looked at my therapy books, and now I can understand it. And so, you know, I actually see TMS as a way of having kind of exogenous sorts of cognitive functions, that in milder forms of depression, we can pull off with psychotherapy, you know, this idea of being able to kind of turn that prefrontal cortex on, and have it govern these deeper regions, and depression, the deeper regions govern the prefrontal cortex. - In one case, it's like the coach telling the player what to do, and in the other case, it's like the player telling the coach what to do, and you restore order to the game. - You restore order to the game. And what it looks like is depression is a bunch of kind of spontaneous content that's semi-volitional, that's being kind of generated out of this conflict detection system, the cingulate. In depression, it looks like the left dorsolateral does not sufficiently clamp down on it, and what therapy appears to do is to kind of restore that. What we see with TMS, over that region, is that we just exogenously do the same sort of thing. We restore the governance of the left dorsolateral, over the cingulate area, and that is correlated with treatment improvement. So the degree in which you can re-time, re-regulate in time the left dorsolateral over the cingulate, the more of an antidepressant effect you have. TMS is almost like exercise for the brain, right? You're kind of exercising this region over and over again with a physiologically relevant signal, and kind of turning that system on. And what's interesting for this show is, you know, we had a couple of folks, probably five or six folks, that have actually told me this, where if they remit early enough in the week, we have this very dense stimulation approach where we can stimulate people really rapidly over a five-day block. By Wednesday, they're like totally zeroed out on the depression scales, you know, even better than most people walking around, like really no anxiety, no depression or anything. By Thursday, the first guy that told me this, he came in and he said, "You know, I was driving back "to my hotel, and I decided to go to the beach, and I just "sat there, and I was totally present in the present moment "for an hour." And he's like, "I read about this in my mindfulness books, "but I experienced it last night, and I've never "experienced anything like this before." And I was like, "Hmm, that's interesting," but kind of wasn't sure, and then I didn't tell any, you know, obviously any more patients about that. And then about five over the last couple of years, when they remit early in the week, by the end of the week, they're like going to the beach, and they're like totally having what people describe as a pretty mindful, present, moment sort of experience, which is really interesting, you know, what that is. I mean, I don't have full-on scientific data to tell you, but it's just, it's an interesting anecdote, right, that folks, when you push them through this point of feeling kind of clinically well, that some people end up reporting this additional set of features, so. - I'd like to take a quick break and acknowledge our sponsor, Function. Function provides over 160 advanced lab tests to give you a clear snapshot of your bodily health. This snapshot gives you insights into your heart health, your hormone health, autoimmune function, nutrient levels, and much more. They've also recently added access to advanced MRI and CT scans. Function not only provides testing of over 160 biomarkers key to your physical and mental health, it also analyzes these results and provides recommendations for improving your health from top doctors. For example, in a recent test with Function, I learned that some of my blood lipids were slightly out of range. 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To learn more, visit functionhealth.com/huberman and use the code Huberman for a $50 credit towards your membership. Again, that's functionhealth.com/huberman. I want to make sure that before we dive into ketamine and psilocybin that we do touch on SSRIs, selective serotonin reuptake inhibitors, because we can't really have a discussion about depression without talking about SSRIs. My understanding is that the SSRIs are powerfully effective for certain forms of obsessive-compulsive disorder and may also be effective for treatment of depression. Is that right, and how should we think about SSRIs? Are they useful? Are they not useful? SSRIs clearly work. You know, many, many meta-analyses kind of proving that out, right? That in a sub-population of individuals, they achieve great benefit for depression, for obsessive compulsive disorder, for generalized anxiety disorder, panic, you know, all these things, you can see an improvement in those symptoms with what we call SSRIs or selective serotonin reuptake inhibitors. The issue is that they don't work immediately, right? So they don't work like the same day you start taking them. And that suggests that probably it's not exactly the serotonin being in there that's directly driving it, that it's much more likely that it may have some brain plasticity effects, right? There's not a deficit of serotonin. You're not born with what people call a chemical imbalance. And psychiatry has known this. This is not actually new information to anybody. You know, it's kind of a rehashing of a bunch of information we've known for a while now. But in the lay press, it's kind of hit in a way that it didn't seem to grab attention before with previous publications. But this idea that this chemical imbalance idea is not going to work. And so, you know, it's not going to work. And so, you know, it's kind of a rehashing of a bunch of information we've known for a while now. But this idea is wrong. I really think that part's important because I think that what I'll call psychiatry 1.0, right, this kind of idea of Freud and psychotherapy and its origins, it was a lot around, you know, your family and those experiences and psychotherapy kind of going in and correcting or helping you to figure out or, you know, show you being able to see or people hear you so that you can eventually come to the conclusion of certain cognitions that aren't helping you. Right. Things like the schizophrenogenic mother and all that, you know, that was a concept at some point. Right. And so we've transitioned from that to the, you know, for a long time, the chemical imbalance, which I'll call psychiatry 2.0, you know, this idea that there's something chemically missing. The trouble there for a patient, right, is that it's telling it's sending a message of there's something missing with me, whether it be my experiences I had no control of over when I was a child or. A chemical in my brain. What I think is really powerful with with TMS, you know, really powerful TMS and a level even powerful, the psychedelic story, is it saying something different? You know, TMS works and there's no serotonin coming in or out of the brain. Right. And we're doing a rapid form of TMS that works in one to five days. There's no there's it's very unlikely that there's some long term kind of upregulation of serotonin that's driving that. So our work actually kind of pushes back on this serotonin hypothesis as being kind of the center of depression, because it says, look, we're not giving anybody any serotonin. We're simply turning these brain regions on and we're focused on the circuitry. And that's psychiatry 3.0. It's not just like neuromodulation. Neuromodulation is a really nice, you know, use case for psychiatry 3.0, because it's a way to focally and directly perturb brain regions in whatever modality you're using. But, you know, there are a lot of. A lot of groups that are actually doing neuroimaging before and after, and they're able to see circuit level changes for something like psilocybin or ketamine long after the drug is gone. Right. Suggesting in those same brain regions converge. So the subgenual default mode network connection that we see is changing with our Stanford neuromodulation therapy technique. It's that same set of brain regions that ketamine and psilocybin seem to act on these connections between brain networks that seem to shift. And so it refocuses the story on something that's highly correctable. And it's basically electrophysiology. And it's basically kind of recalibrating a circuit that is recalibratable instead of I have something missing or have some set of experiences early in life that are that are going to forever trap me in these these psychiatric diagnoses. And so it kind of challenges that idea. And I think that's what's so powerful about psychiatry 3.0. This idea of focusing on the circuit because it gets us gets us into thinking about psychiatry and psychiatric illnesses is something that are recoverable. People can get better people. You know, we've seen with our TMS techniques, we've seen it with some of the psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time. Within five days. Within five or less days. And in the case of the psychedelics, within a few days, right? So we can get people out of these states. They're totally well. There's no drug in their system at that point. In the case of psychedelics, it was never a drug in their system in the case of of TMS. And it just tells us that that it's it's it's fixable. It's just like an arrhythmia in the heart. It's like a broken leg. We can go in and do something and we can get somebody better. And I think what's what's empowering and what a lot of patients have told me is they say, you know, I've gotten to, you know, some people will relapse and need more stimulation or need more psychedelics or whatever it is. But they'll tell me I don't fear that I'm chronically broken. I don't fear that the chemical imbalance is still imbalanced. I don't fear that these things that I couldn't control in my childhood, you know, are going to be there and drive this problem forever. And I think that's that's what's so powerful about this. And that brings me to this question about psychedelics and and the effects, frankly, the altered thinking and perception that occurs in high dose psilocybin clinical sessions. Many people do report improvements in trauma related symptomology and depression, as I understand it from my read of the clinical trials after taking psilocybin, because during those sessions, something comes to mind spontaneously. They will report, for instance, a new way of seeing the old problem. That's right. The old problem could be the voice that they're no good. They'll never nothing will ever work out or could be even more subtle than that. Why do you think the brain would ever hold on to rules that don't serve us? Well, I think it's it's an it's an evolutionary neurobiology answer, right? I think that we end up being a result of of probably a lot of biology that's not that useful in the modern era. And I think in the brain for for, say, let's say PTSD, right? A lot of a lot of veterans come back and they experience these PTSD symptoms and they're not at all useful back home. Right. They hear some loud noise and all of a sudden they're behind a car or they're behind a, you know, I've heard of folks, you know, jump and run behind a trash can or whatever in the middle of San Francisco when they hear a loud noise. But if you put them back in the battlefield, you know, that's highly adaptive, right? We hold on to those things from, I think, an evolutionary neurobiology standpoint. But what seems to, for whatever reason, kind of alleviate that are these substances, some new like MDMA, some that have been around for thousands of years, like psilocybin seem to have a therapeutic effect that seems to be pretty long lasting for these phenomenon. And so it's just curious, right? It's curious that in the absence of that, these things will keep going on and on. But in the presence of that exposure, then all of a sudden you see a resolution of the problem. And we have some work now. We're treating folks with Navy SEALs. The anecdotes that we're getting, right, are folks are coming back and they're saying these set of PTSD symptoms are finally gone. And so this idea that for whatever reason, going into what's probably a highly plastic state and re-experience memories, and then as you know, you know, we re-consolidating it in that state for whatever reason may drive, drive a therapeutic effect. My business is to find treatments that help people. And so I'm much more like pragmatic about it. You know, if, if this sort of thing, which has a lot of cultural baggage but if this sort of thing ultimately ends up being therapeutic, if we can design trials that convince me and others that it is, then we should absolutely use it. And if it doesn't, then we clearly shouldn't use it, right? The work that's been done so far, the first psilocybin trial, the first MDMA trial is published in Nature Medicine recently. And what do those generally say? Let's, let's start with psilocybin and MDMA. So MDMA appears to in, in you know, one to a few MDMA sessions have an anti-PTSD effect that seems to be, you know, outside of the kind of standard assumed levels of PTSD improvement that you can observe in individuals with this level of PTSD, right? So, so does that mean that for people that have trauma who do a, and again, we're talking about in a clinical setting, they, they take a one or two doses of, of MDMA. I think the standard MAPS dose is a hundred and fifty to 175 milligrams, again, doing this with a physician, et cetera, control clinical trial, legal. Exactly. They do it once or twice. And broadly speaking, what percentage of people who had trauma report feeling significant relief from their trauma, trauma afterward? It's about two thirds of people had a, had a clinically significant change in their PTSD. That's impressive. And how, how long lasting was that? It appears to last for a while. In the earlier trials where they followed people out, it seemed to last for kind of in the years range for some people. And so it's, you know, it's pretty, it's pretty compelling in contrast that with ketamine, which only on average lasts about a week and a half for a single infusion. So it's a much shorter. So they have to get repeated infusions of ketamine every 10 days or so? For some people, or they end up getting like, like, like a bunch of doses for a couple of weeks. And then for some people that seems to last a while. You know, that's where I think, I think the, the psilocybin story for depression and the, in the MDMA story for PTSD seemed more interesting to me. psilocybin? What is the rough percentages on, and this would be relief, not from trauma, but from depression. Yeah, exactly. So it's, you know, in open label studies, it's closer to like half to two thirds of people end up getting better depending upon their level of treatment resistance in the, in the blinded trials, it was more like a third or so of people. I'd like to take a quick break and acknowledge our sponsor, BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. I've been doing therapy for a long time, and I can tell you that it's a lot like physical workouts. There are times when I want to do it, and there are times when I don't want to do it. But whenever I finish a therapy session, I come away feeling better. And I have specific actionable items that hadn't occurred to me that when I implement improve various aspects of my life. 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Again, that's BetterHelp.com slash Huberman. Since you mentioned psilocybin, let's talk a little bit about the neurochemistry of psilocybin. What's going on when one takes psilocybin and why is it interesting in light of depression? Yeah, definitely. So David Nutt and Robin Carhart-Harris' work around neuroimaging psychedelics are kind of some of the first folks to do that work. And to their great surprise, they thought there was going to be an increase in activity on psychedelics. And what they found is the opposite, right? There's kind of an overall decrease in the level of activity in the brain with psychedelics. But they've also looked at connectivity. And there's this kind of small world, you know, large world connectivity that you think about. And so, you know, small world meaning there's a lot, there's kind of a much more kind of focused kind of cortical function or, you know, subcortical function or whatever it is. And what you see is a difference in that. In that level of engagement of brain regions, the connectivity, kind of global connectivity kind of increases. And so it's interesting, you know, I think to kind of have a convergent theory on this, it's still, you know, to be determined, there's still a lot of work, I think, that needs to be done. But it's certainly suggestive that there's pretty profound changes in brain activity and brain connectivity after. And what we've found is that there's a lot of work that needs to be done to be really interesting is the antidepressant effects of psilocybin have a particular connectivity change that we also see with our TMS approaches, right? And it's this connectivity between the subgenual anterior cingulate and the default mode network. And so when we do this effective Stanford neuromodulation therapy stimulation, we see a down regulation, the connectivity between the negatively valenced mood state, in the case of depressed individuals, and the self-representation of the brain. And you see that same connectivity change occur post-psilocybin, you know, suggesting there's a convergent mechanism. And it makes sense, right? You've kind of got an over-connected, negatively valenced system, conflict system that's kind of, you know, kind of attached onto the self-representation and people feel stuck, right? And then when you do whatever you do that's effective, it unpairs those two systems. I want to ask you about ibogaine. Is it legal in the U.S. as a clinical tool? Who's using it and for what purposes? Ibogaine is one of the alkaloids that you can extract from an iboga tree root bark that's typically growing in the country of Gabon, Africa. So what individuals taking ibogaine will say is that open eyes, they don't see anything, but closed eyes, they'll go back through and re-experience earlier life memories, and they will be able to experience it from a place of empathy, not only for themselves, but from others, and kind of a detached empathy, and being able to see this as almost a third party, even though they were there. Ibogaine is in no way a recreational substance. You're essentially having this, what they call a life review, they also call it 10 years of psychotherapy in a night. So these are the terminology that people talk about. How long does it last? Is it truly one night? Depending upon how fast you metabolize it, sometimes 24, sometimes 36 hours. Sometimes it can be shorter, but it is a long time. It's a very long time. So it's definitely the longest acting psychedelic substance I know of. And so we have over the last couple of years been able to do this first. In human, kind of full neurobiological, clinical, neurocognitive evaluation of what Ibogaine is doing. In this case, in special operations, special forces, individuals, former Navy SEALs, former Army Rangers, that kind of crew of folks, and look at the pre-post changes that they're experienced to be able to totally quantitate all of that. And so we've been able to capture all the clinical scales, depression scales, PTSD scales, all that standard stuff, neurocognitive batteries. So how does your executive function work specifically? How does your verbal memory, all of that? And then neuroimaging and EEG. So this will be the first human study of Ibogaine for those. And the reason why is because Ibogaine is kind of the, both seemingly the most potent and most, seemingly to me at least, most powerful psychedelic, but the one that has the most risk too, because it has a cardiac effect. It seems to be that you can screen people out that have risk off of their electrocardiogram and reduce the risk quite a bit. And that's what we all did. But that's why people haven't really studied it as much. And it isn't as, in addition, there's no, right, nobody goes to rave on Ibogaine. There's no recreation at all with it. It's not fun. People say that it's relieving, but it's hard work, right? Because yeah, you're re-examining things. So then we see these folks after, and I'll tell you, you know, I haven't fully analyzed the data yet, but I'll tell you that from what my folks are telling me, it's pretty dramatic. You know, people come back and they're doing a lot better. Soldiers experience something called moral injury, right? Where they, maybe they accidentally blew something up and it had a kid in it or something like that. You know, you know, if they're in Afghanistan or Iraq, maybe a child died on accident or maybe, maybe, you know, a civilian died or whatever it was, right? And then they suffer these moral injuries as part of the job. And it's almost one of the kind of, organizational risks. They come back and say that they've forgiven themselves, you know, which is huge, right? And then part of that is being able to see themselves in a different light and having empathy finally for themselves and being able to kind of have that experience of forgiving. And so there's this kind of Timothy Leary kind of sociocultural construct that ends up being overlaid over psychedelics. And what I think is that if you rid yourself of all of those preconceived notions of what it is and isn't and the counterculture movement, all that stuff that neither of us were ever involved in, neither of us are ever partaken, you know, it's kind of straight scientists looking at this, right? If you can kind of rid yourself of all those sociocultural constructions and then re-examine this, these, if we just discovered these today, we would say that these sorts of drugs are a huge breakthrough in psychiatry because they allow for us to do a lot of the sorts of things we've been thinking about. With SSRIs, with psychotherapy, but kind of combined, right? Psychotherapy plus drugs in a substance that kind of allows you to re-examine these things. And so it's interesting, it'll, you know, there's a lot to do to try to figure out if that's true, you know? And I can say that as it stands right now, we don't know if it's that statement is true, right? There's a lot more work that needs to happen for that statement to be proven to be true. But the hypothesis is if it is true, then it's very likely that this will be seen as a breakthrough because it allows you to do these sorts of things that you can't do with normal waking consciousness. But also why we have to really think about this and, you know, these drugs can't be recreational drugs. They really shouldn't be recreational drugs, right? They're really too powerful to be used in the context of psychotherapy because they can put you into these states. And this generation of psychedelic researchers are really clear about that. You know, I think the 60s folks were not clear about that and they felt like there was this whole kind of cultural thing that was going on there. But I think this cohort of individuals really understands that in order to really make this happen, we have to understand that if you need a prescription for an SSRI, which doesn't change your consciousness a whole lot, and we don't have a prescription for an SSRI, we don't have a prescription for an SSRI, And we're very worried about that. And the doctor has to evaluate you for that every week, that the idea that some of these substances would go outside of very strict medical supervision is kind of preposterous, actually. It's kind of a dumb moment, I think, for all of medicine to say, look, we've, you know, if we're going to do this right, we've got to do it in such a way that's so protected, that's so safe, that we make sure people know these things are not recreational and they're really for the pure purposes of really powerfully changing cognition for a while and letting people have these, what seem to be, you know, relatively therapeutic states. Tell me about ayahuasca and as a plant, is it useful for the same sorts of conditions that we've talked about thus far? And if you could perhaps tell me a little bit also about the Brazilian prisoner study. Yeah, yeah, definitely. Ayahuasca is another psychedelic. It's used as a sacrament. In Brazil and in Peru and Ecuador and Colombia, so a lot of the South American countries. And what they do is they combine two plants together where one plant of the two plant combination would effectively do nothing. But the two plant combination together is capable of producing this very profound psychedelic effect. And what's really kind of curious. Is that there, as I understand it, 10 to 20,000 plant species in the Amazon and somehow somebody tried them all combined these two plants together and certain proportionality and cooked this for five, 10 hours to the point where you cook out the dimethyltryptamine out of one of the plants and cook out the reversible monoimmune oxidase inhibitor out of the other plant. It's such a way that the reverse. Reversible monoimmune oxidase inhibitor prevents the GI breakdown of the dimethyltryptamine in such a way that it's then allowed to cross the blood brain barrier and get into the brain. And if you didn't add the reversible monoimmune oxidase inhibitor plant derived into this combination, then it would never cross the brain. If you put people on a standard psychiatry prescribed monoimmune oxidase inhibitor that wasn't reversible, you'd throw them into serotonin syndrome. Right. So this kind of like sweet spot that somehow ayahuasca practitioners have found being able to get DMT into the brain from an oral source with this combination of a monoimmune oxidase inhibitor is curious. And so that that substance has been explored as an antidepressant agent. And some studies have looked at that. It also seems to be very safe. There was a psychiatrist down at UCLA. Harbor, who's done a lot of work with this, where where he's looked at children even that have been exposed to small doses of ayahuasca is kind of a sacrament within Amazonian tribes and found no neurocognitive effects, no neurocognitive effects in adults. And so it appears to be safe. It's kind of part and brought into various religions, including kind of merged with Catholicism in South America, which is kind of very interesting. And so, you know, in some. Sects of Catholicism in Brazil, it's used as a sacrament during religious ceremonies. And so it became interesting to Brazilian researchers as to whether or not they could affect recidivism rates for prisoners in Brazilian prisons. Right. So they gave half of the prisoners, you know, some sort of inert substance and half of the prisoners a ayahuasca session. And the. Recidivism rate of the return to prison rate in the ayahuasca exposed individuals was statistically significantly lower than the recidivism rate in the in the control group, suggesting that, you know, whatever is going on there seems to have an effect on whatever drives criminal behavior, whatever criminal behavior that happened to be. And I don't have the details on the exact nature of the crime. You know, I am also in no way saying that we should just be giving psychedelics to to folks in prison and all of that. I think that that is a very edgy thing to do and probably not something that anybody should try. But but it does it does kind of bring up this this curious question of of what is it about that that would drive people to to change those behaviors and why why do people make those behavioral decisions? As many of you know, I've been taking AG1 for nearly 15 years now. I discovered it way back in 2012, long before I had a podcast. And I've been taking it every day since. AG1 is, to my knowledge, the highest quality and most comprehensive of the foundational nutritional supplements on the market. It combines vitamins, minerals, prebiotics, probiotics and adaptogens into a single scoop that's easy to drink and tastes great. It's designed to support things like gut health, immune health and overall energy. 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Yeah, SAINT or what we're calling it S&T now, Stanford Accelerated Intelligent Neuromodulation Therapy, or now what we're calling Stanford Neuromodulation Therapy. The idea there is that TMS is a device that delivers. That delivers a treatment. And the treatment is the protocol. And the protocol is the stimulation parameter set in a specific brain region for a specific condition, whether it be transcranial magnetic stimulation or transcranial direct current stimulation or deep brain stimulation, like what Casey Halpern talked about. In all of those cases, the device itself is a physical layer conduit of a stimulation protocol that's therapeutic for a given patient. For a given condition in a given brain region. We decided, gosh, you know, this problem I talked about at the beginning of the show where you have these, you know, this problem that we don't have a treatment for people who are in these high acuity psychiatric emergency states, right? This idea that we're going to engineer a treatment where we can reorganize the stimulation approach in time to be much more efficient by utilizing something called space learning theory. And so you probably know about the space learning theory. It's the idea for the viewers. If I'm cramming for a test, what I do is I write out 60 note cards and I read each one for a minute until I get to the first note card and again, and that's about an hour later, right? That's space learning theory. It's this idea that you need to see it about every hour to an hour and a half. And that optimizes learning. What we found was that the old way of doing TMS, this idea of just doing it once a day, every day, five days a week for six weeks, didn't utilize the space learning theory. It's like studying for a month or two. It's like studying for a month, a little bit once a day. Like you remember some of that stuff, but it's like not as potent as that week where you're kind of cramming, right? And what we realized is that if we could reorganize the stimulation in times that we took the whole six week course, we actually figured out a way to do it in a day. And then what we also figured out is that people were under dosing TMS, because if you just keep going after six weeks out to month three, four, five, more and more people got better. So we figured out it's not just one day, we're gonna give five times the normal dose. We're gonna have seven and a half months worth in five days. Using space learning theory- - So every hour? - Every hour for 10 hours. - For five days? - For five days. So it's a 50 hour block. It's 90 minutes of actual stimulation, but spread out through the day in the same way of learning. What we've found is that folks will, within one to five days, in more cases than not, and depending upon if you're looking at this open label or in trials somewhere between 60 and 90% of the time, they will go into full on remission in the sense they're totally normal from a mood standpoint at the end of this. And like I said, with variable durability. So that's the part we have to figure out now about dosing and how to keep people well. But for some people, you know, we've had four years of remission, you know, a year of remission, and it's really that cramming of the test. It's really that idea that you're laying in that information in the exact right spot. And the signal is a simple signal, but it's a profound one, which is turn on, stay on, remember to stay on. You know, that idea that you're sending this memory signal into the brain and you're doing it in such a way that you're telling the system, you're kind of taking it out of the hippocampus' hand, your own hippocampus' hand as you're sending the same signal the hippocampus normally signals out. Now you're sending that signal into the prefrontal cortex and kind of utilizing the brain's own communication style to get it to get out of the state. And what's very cool about this is that is that people, when they kind of exit out of that, they end up, they end up saying they don't have any any side effects from it and they feel back to normal thank you so much uh for taking us on this incredible voyage through the neurocircuitry underlying certain aspects of depression the coverage of the different types of depression the various therapeutic compounds how they work we've talked about a lot of things today and you've shared so much knowledge and even as i say that i um i very much want to have you back to talk about many other things as well that we didn't have time to cover but to take the time to sit down with us and share all this knowledge that really is in service to mental health and and human feeling better and in fact avoiding often suicidal depression it's just incredible work and an incredible generosity and just thank you so much absolutely thank you