Dr. Nolan Williams: Psychedelics & Neurostimulation for Brain Rewiring
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Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I'm Andrew huberman and i'm a professor of neutral logy and optimal gy at stanford school of medicine today. My guest is doctor newlin Williams. Doctor Williams is a medical doctor and professor of psychiatry and behavioral sciences at stanford university school of medicine. His laboratory, ra, an clinic focused on depression and other mood disorders.

They focus specifically on the use of trans cranial magnetic stimulation, which is a brain stimulation technique that can either activate or quite specific brain circuits, as well as circuits within the body in order to treat depression and other mood disorders. Other laboratories in clinics use tms. What sets apart the work of nolen Williams and colleagues is that they combine tms with other treatments.

And some of those treatments are among the more cutting edge that you've probably heard about these days, including I begin suicide on m dma, cannabis, d mt. And other drugs that at this point in time are experimental in terms of clinical trials, but that, at least the preliminary data show, hold great promise for the treatment of depression and other mood disorders. In the course of my discussion, when doctor Williams, we covered things such as the history of each of these drugs, how they came to be, and there are current status in terms of their clinical use and legality.

We also talk about their safety profiles, both in children and in adults. And we talk about what the future of psychiatric research and clinical use really looks like. For instance, we discuss how a number of laboratories and clinics are modifying psychodeviant ics to remove some of their allusions agent ic properties while maintaining some of their anti depression or anti trauma properties.

You're also learn about some fascinating research and docker Williams laboratory focus on academy, which is a drug that is increasingly being used to treat depression. And contrary to common belief, the effects of cademy in terms of relieving depression may not actually arise from its dissociative effects. One thing that you'll find extraordinary about doctor Williams is that not only does he have vast knowledge of the various treatments for depression, but that he and his laboratory are really combining these treatments in the most pots way.

That is, combining psychiatric treatments with brain machine interface, or combining brain machine interface with particular learning protocols, that is, neuroplasticity protocols, which can directly change the brain in specific ways. So today you're going to learn a tremendous amount about the neural circuitry underlying depression as well as positive moods. You'll also learn about all the various drugs that I described, and you're really going to learn about the current status and future of the treatment of mood disorders today.

You'll also learn about a number of ongoing studies in dr. 点 wu ams as laboratory。 As you mentioned that they are recruiting subjects for these studies. If you go to bsl, which stands for brain stimulation laboratory, so that the bsl, not stanford, that eu, you have the opportunity to apply for one of these clinical trials for the treatment of depression and other mood disorders.

I confess that the conversation with the will liam's was, for me, one of the more stimulating and informative conversations i've ever had about psychiatrically, which is simply to say that his bread and depth of knowledge on that topic is incredible, and his bread and depth of knowledge in terms of the underlying brain science and how we can all be combined with clinical applications is also extraordinary. I'm sure that by the end of today's episode, you're going to come away with a tremendous amount of knowledge about the clinical and non clinical uses of those substances, and you're going to understand a lot more about how the healthy and disease brain work. Before we begin, I like emphasize that this podcast is separate from my teaching and researchers at stanford.

IT is, however, part of my desired effort to bring zero costs to consumer information about science and science related tools to the general public. In keeping with that theme, i'd like to thank sponsors of today's podcast. Our first sponsor is element.

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Again, that's waking up dot com slash huberman to access a free thirty day trial. And now for my discussion with doctor nolen Williams. Thanks for joining today. I'm really excited to have this conversation. It's been a long time coming, and I have a lot of questions about different compounds, psychedelics in particular.

But before we get into that discussion, want to ask you about depression, broadly speaking, intractable depression, how common depression is, or isn't? I heard you say in a wonderful talk that you gave, that depression is perhaps the most debilitating condition worldwide. And 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. So if you could educate us on depression.

i'd really appreciate absolutely. so. Depression is a condition that IT has a lot of a lot of manifestations, you know. So you can have kind of a depression that's primarily loss of interest. You can have folks who feel very anxious, they're kind of overactive. You can have people who don't have any anxiety at all and they're very interactive and they have no motivation to do anything. So you have this huge range of symptoms that are in that umbrella of depression.

And some of our work is to actually work with with folks are counter listening cornell and try to actually get biotype es based off of new imaging to see if we can purse out the different depression kind of presentations in them and see that clinically and also see that in the brain, depression is the most disabling condition worldwide. Um what's interesting about depression is it's both a risk factor, four other illnesses and IT makes other medical and psychic c illnesses worse, right? So recently the american her association added depression is the fourth major risk factor for corner early disease.

So at alongside the rise factories that we know, hypertension, hy blood pressure, hyper lip deia, high cholesterol and and diabetes, high blood sugar, those three have been on the list for a long time. And depression and that, you know, being added list is the fourth one and you know really interesting routes. So in addition to taking medications to address those other three risk factors we really have to be thinking about um how do you treat folks with depression to reduce the risk of having a heart attack in the future and you know there's some of that being worked on now, but we don't have a complete solution to thinking about that at this time.

And then the other thing that's interesting is once you have our heart attack in the individuals and having a heart attack, the risk of having depression after the heart attack is higher than the Normal population, right? And so a lot of what we're doing in the lab actually is, is measuring kind of brain heart connections. And we can actually, with transgender or magnetic stimulation, a form of a brain stimulation, we can actually decelerate the heart rate and after that heart rate deceleration um over the mood regulatory regions.

And so actually a direct probe of that connection. So it's interesting. And so you know as you said a second ago, you know it's it's a very disabling condition, moderate depressions about as disabling is is having a heart attack, acutely having a heart attack. Severe depression is disabling, is having cancer without treatment, you know, in dying from a cancer without treatment. And so you know it's it's kind of underappreciated, just how disabling depression is that way.

I think important as stigma is consistently kind of being reduced over the years for minor illness, for minal illnesses, than the idea that we can start really putting more funding and putting more focus, the federal level, you pride foundation level, whatever is at a given university to thinking about um developing treatments. We've been very interested in a very particular um clinical set of problems around the most severe and the most high acuity settings that focus with depression end up being in and that you emergency settings where they go into impatient units. And you know in the rest of medicine, if it's talking about heart attacks, if I start having chest pain right now and and you bring me to a primary care doctor's office, you're gonna a certain number of tests and treatments, right? But very limited because it's an outpatient.

Facility, if you bring me the emergency after that, there are more tests and more treatments. If you put me the ice to you or in the cafe lab where they do um invite the procedures, the heart there are more tests and more treatments in psychiatry, as we alleviate the acuity of an individual, you go from being just depressed to being depressed and now thinking about in your life the number of treatments actually go down on average. I mean some scenario they go up, but on average they go down and their own no test, right? And so we've been very focused on that particular problem, somebody that maybe was doing fairly OK with a pretty moderate depression and then the depression is worse and then they end up in an emergency setting.

And the field really hasn't developed a way of consistently being able to treat that problem folks in up getting the same standard oil entity presence that they have been getting out patient and and I came to this because of, you know, dull train is an error gist. In syria, rist went back and fourth between neology and psychiatry saw that in neurology, we have all these ways of treating acute brain based problems, and really wanted to emulate that in syria. Try and find ways to develop an engineer, new brain based solutions.

There's a lot to him. Pack there. One thing that you said. D like to fox on a bit more because I think we hear that the brain and the heart are connected but you described believe A A direct relationship between areas of the brain associated with emotion and heart rate yes, and that makes perfect logical sense to me but I think um at the same time many people out there, but we think of the relationship between the the heart in the mind as kind of wu or kind of a soft biology. But here you're talking about an actual physical connection between what area .

of the brain is IT. You know, the first place for the stimulation goes is called the door's atter al prefrontal cortex. It's kind of the sense of control, kind of governing of the brain.

And then, and then what we know is that when you use a magnet, use kind of what we call fair day's law, this idea of um using a magnetic polls to induce uh an electrical current in electrically conducting substances, so in this case brain tissue, but not skull or Scott, a scalper of that. Or here you avoid all that, just the brain tissue and you have a direct depolarization of cortical neurons, you know, the surface of the brains neurons in this store, lateral preferable. And if you do that in the actual scanner, which we can do, you can see that that distributes down into the enter singular in the insular and the amiga.

And ultimately, the track goes into something called the nucleus track of solitary arias and ultimately the biggest nerve into the heart, to the the heart um very consistently seems to be the end organ of the dorsal lateral, preferring cortex. If you measure heart rate in standard ways that cardiologist manager heart rate and you stimulate over the left or slatter al, you get a deceleration of the hurt rate is very time lock to the stimulation. So it's a two second train of stimulation.

At one second you see the deceleration IT goes down about ten beats per minute. And the new drift backup moves a break for eight seconds on the stimulation and drift back up, and the stimulation goes back in, and then the heart rate goes back down. So you see the hearts rate, just do this ten beats per minute every train.

And so we know if you do that over visual cortex ks, you don't get that a motor corporation won't get any of those findings. It's really specific to this kind of control region of the brain. And so yeah seems to you know that were other other folks work Martin arms in in in europe, the netherlands, work showing the same connection. And things been replicated like four, five times.

So you mentioned left dorso atter al preference to cortex. Any time I hear about lateralization of function, I get particularly curious, because obviously we have two, a mirror mm tric sides of the brain, rare exception to this, like the pinion and that sort of that are are only there is only one, a piano.

Um what is special about the left doors salado proto cortex? That does this have anything to do with handles, right hand or left hand? Because we know right hand and left endless has a lot to do with literalities ation of function for language um topic for another time. But um why do you think that left door salado prefrontal cortex would be connected to the heart in this way?

Yeah yeah I think so. So left to or saturated is thought to be the the side that when you excited, when you kind of do excited tory stimulation potential sort of stimulation that you can reduce depressive symptoms and go about my fox at harvard demonstrated if you have strokes in the brain that um that cause depression, you put them on the human connector, a hundred thousand patient map and you ask the question what they're all functionally connected to.

Left your catering if you take lesions and cause mania in individuals and you put those all in the human connective map and asked what they are all the one common area they're all connected to its the right dorsolateral. And so there seems to be hemispheric, you know, uh you balancing of mood of between these two brain regions. And we know this from an experimental standpoint.

Two, because you can take individuals with depression and you can excite the left or you can inhibit the right and they they're both anti a present. You can um excite the right in that antimony consumers studies. And so this idea that there is this hemispheric balancing of mood is is .

quite interesting, right? It's incredibly interesting and just um people know if if you're curious what the connector is, a connector is determined. There was built out of this notion of genomes are being a large collections of sequencing and mapping of genes.

There are proteome of proteins of uh connectors as uh so all connectomics of connections between so the human connector project is ongoing um and I find that incredible that within the connectome project that can identify these regularities of right versus left or seattle preferences cortex, especially since um i've looked a fair number of brains um from humans and certainly as many as you have um and if you look at the architecture, the layers, the cell types and even the neurochemicals of which cells are expressing like dopamine serita and a receiving input from areas that make dopamine look that different on the right and left side and yet here we're talking about a kind of an accelerator in a break, if you will, on on depression, in mania, using what, at least by my eye. And I think other people, I looked to be basic, the same set of bit, the same parts list, more or less. So what gives the these properties um to the right and left doors frontal cortexes the inputs they receive? Is this something that we learn during development? Or do you think that we come into the world with these hemispheres biases?

Yeah it's a great question. You know IT hasn't been worked out which your original question was around in a left handed individual, which is, you know twenty five percent of those folks end up having a right brain dominance for one percent of right, hundred of people have a right brain dominance if it's flipped right.

And that you know unfortunately, that studies still hasn't been done at the level because that would be probably pretty helpful for teasing some of this out. But it's it's still still being sorted out, right? We we know enough to know this phenomenon exists because we can use tms as a probe and do this sort of these sorts of manipulations.

But to my knowledge, there hasn't been anybody that's got ten so interested in IT. They've been able to get a mechanism of why that is. But but you know it's kind of empirically true in the sense that you can push and pull on those systems, or in this, in the case of of strokes that folks have, and then you kind of get their brains and their brain images and look at where the strokes landed. Those kind of castle bits of information point to this, this a symmetry thing.

Well, that case, going with what we do know, that stimulation adore sator prefrontal cortex, slows the heart rate down, transiently close IT down, and seems to alleviate at me some symptoms of depression, leads me to the question, why would that be? The case is IT does IT tell us anything fundamental about depression, that a anxieties inherent to depression, I think of faster heart rates, you know, part in parcel with with anxiety.

In my laboratory, we've studied fear a bit in animals and in humans. And we often observe bRicky cardio, where somebody or an animal is afraid of something, and rather than the heart rate speeding up and actually slows down something that most people don't think about or recognize. But given that stimulation, a dorso ador prefrontal cortex slows the heart rate down and can alleviate depressive symptoms, and that there are other ways to slow the heart down.

I have two questions. What do you think this? This tells us about the basic architecture of depression and its physiology at the level of the heart. And does the circuit run in the opposite direction too, if one word to have or find other ways to slow the heart rate down, say with a bata blocker um does that help via depression?

And that question um I asked the second question first. Um so we know that we're ongoing trials of this.

If you stimulate in the vegan st nerve um in an implanted biggest nerve stimulator, you can actually um you know have this afferent um parts of the the vegas um project, ultimately up to the D L P fc of the singular ate through these entering loss so that same that obviously the same track right and you can stimulate there an alleviate depression, which seems very unusual right, you're stimulating a cranial nerve down on the neck, but if you you can get up into the brain, you actually can improve depressive symptoms. And so no more evidence that this is a kind of a whole track in system. And um if you stimulate in part of that system, IT appears that you can improve mood.

And what if I were somebody who did not have a stimulating electrode in my vegas nerve and I was dealing with minor depression, and I decided I wanted to take some other approach to slow my heart rate via the biggest, for instance, excel emphasized breathing or deliberately slowed breathing. Things of that sort is there are any evidence of behavioral interventions of kinds can alleviate depression or some symptoms of depression? And is there any evidence that IT doesn't deed feedback to the door salad or prefrontal cortex to achieve some of that alleviation?

Absolutely the number of studies um implicating deal the dorado al and and say meditation, mindfulness that sort of thing in in their small studies but but pretty well designed studies suggesting that. Behavior and interventions in mild depression actually work quite well. There seems to be a volitional thresh hold for depression where at some point you you start losing IT.

You you go from being completely in total volume to having come simi volition. You have thoughts that you really have a hard time controlling and that sort of thing, and you go through that thresh hold at some point. IT gets harder and harder for those sorts of things to kind of kick in and work in the extreme form that catatonia right where people in a very severe former depression get kind of stuck mottka ally, right? And they obviously can't.

They have no control, and so are a very limited control. And so, you know, I think there's a thresh hold in which these sorts of interventions will work. Exercise seems to really be a good treatment for for mild depression and IT may work with the mechanism you describing, right.

As as we all know, you know athletes hold the lower resting heart rate. Then folks that aren't. If you an athlete you had a lower resting heart rate, you stopped you know exercising and a couple years later, a resting heart rate in many cases goes up bright.

And so maybe that's maybe that's part of the process. I'm not aware of any studies specifically um looking at door cell atrial referral physiology proposed exercise, but that would be a great study. I think that would be really hopefully understanding this, especially if you had a correlation of changes and kind of lowering and say, heart rate with mood improvements there.

There's been a lot of work with heart rate variability and in depression. And you know studies are kind of point towards IT. It's not not every study is you know positive for this. But but quite a few studies say basically that lower heart rate variability is associated with moderate to severe depression and that may be part of that mechanism of that hurt brain risk.

So i'm both intriguante bit by this relationship between heart rate and depression. On the face of IT, I would think of depression is depressed to a lower heart rate might make somebody more depressed, even mention catatonia or somebody that just doesn't seem motivated or excited to do anything. I think a mania has elevated heart rate.

And being excited, on the other hand, I realized that anxiety, which you know brings about ideas, elevated heart rate is also built into depression, which brings me back to to what you said earlier, which is that when we say depression, are we really talking about four or five different disorders? I, for lack of a Better word. And for what percentage of people that have depression does some approach to reducing heart rate work, whether not a stimulation of the door, left door, lattle prefrontal cortex, by way of transcranial, my excuse, lation, or by taking a big blocker or by stimulating the vegas, can we throw out a number? A rough number.

Does that help? Thirty percent, fifty percent. how? How long lasting is that? That relief?

yeah. And to be clear that the deceleration, the heart rate is in the moment when the stimulation is happening, but it's not something that necessarily maintained chronically. It's more of an indicator that you're in the right network more than its than IT appears to be itself in central the mechanism, herry variability, peace may be.

And there are some studies that link the two, but the actual deceleration seems to be much more of a marker that you're in the right system. But very well could be that the heart rate system in the mood system to sit next to each other in the stimulation hits both. If you look at how much of the variance in the mood is explained by the heart rate, deceleration is not it's not a huge you know it's not a huge amount, right? So IT only explains a small percentage.

And so it's it's unlikely that simply the sult, you simply reducing the heart rate and in fact, you for many years per panel, all in these sorts of drugs actually were implicating, causing depression. And so that's been kind of debt. But it's it's unlikely it's simply decelerating the heart rates can improve depression.

But what IT does tell you is that if you're in that area, that is the mood regulatory area, there is some parties MPA. There's critical kind of process that's going going on that gets in and causes this to happen. And it's you know it's independent a mood. You'll take a Normal healthy um individual and you can do this and they're going to accelerate their heart rate.

And so glad you mention the paris sympathetic nervous system, which of course the most people think of is the rest and digest for the kind of coming side of the automobile nervous system as i'm hearing you say all this and in particular what you just told me, which is that it's not as if having a lower heart rate protects you against depression or a higher heart rate is associated depression, although I think extremes that might be true.

But rather it's something about the regulatory network, the ability to control your own nervous system to some extent. And when I think what the author ic nervous system I like to think about as A C saw ernst and common and when you're sleep, it's a lot of common. When you panicking is a lot of alertness to the but that and I don't think this has ever been defined.

And when I teach the medical students at stanford atomy, I my wishes that someday i'll be able to explain what the hinge in that process would be, right? Not the end of the season. We know what the sympathetic al system isn't, want to to wake us up and make us panic or make us feel nicely and calm. We know what puts up someone to sleep or a coma or make them feel relaxed.

But what shifts from one side of the sea to the other, and the tightness of that hinge seems to me what you're describing, that that depression is out of a lack control over inner states, so that when i'm stressed, I can't get myself out of IT, but when i'm feeling completely collapsed with exhAusting, I cannot get out of bed. And they get motivated to do the very things that would let me get out of depression like a workout or social connection, or think the equality meal, these kinds of things. So this is perhaps the first time that i've ever have heard about a potential .

circuit .

for the hinge.

as i'm refer to IT. Does that the same identical stimulation on the right doors slatter? Or you get an acceleration? You know, just kind of further confirming this idea lateralization right, that that even IT appears that even the preference al cortical areas seem to be lateralization. And in this way, and you know it's it's less the right finding is is more variable depending upon the study, the left very consistent in this way.

So so we've touch about china. Chino man made its stimulation for getting into these networks. And and I also just want to take a brief t agents say I because i've heard you say this before, I think it's so vital what you're saying that it's really not about stimulation of areas.

It's or any specific brain area or vegas nerve being important per say. It's really about a network of connection, a series of connections. I think that's really important for people understand and is a kind of a new emerging theme really.

The the other thing that to me seems extremely important for us to consider is what what are these latter prefrontal courtesy doing? Are they involved, for instance, in sensation sensing the heart rate? Are they involved in thinking and planning? And this gets down to a very simple question that I know a lot of people have, which is, can we talk ourselves out of depression if it's mild? Can we a hog ourselves into a manic state or an excited state, a positively excited, say that doesn't qualify as many, you know, other areas of the brain I I think of the is responsible for perception, or for for motor control.

But here we are in this mysterious frontal cortex, which people say, executive function planning. And that, are we talking about thoughts? Are we talking about structure thoughts? Are we talking about dream like thought? What in the world is going on in the prefrontal supporters? yeah. And here I been my career. You know, in neuroscience, I still, I still can't really understand what it's doing and maybe is doing fifty things yeah that's .

a great is a great question. So you know to so one of the one of the studies that that we have been working on, addition to the depression work, is actually trying to change trait notiz abilities.

So David, people and I have been working on this and you know he's found and policies ten years ago that a different part of the left dorsal erl um is functionally connected with the enter the doors entire singular uh with a lot of functional connectivity in high remote zable and not much in low, have notice ables. And that's a different kind of a different sub region within this bigger brain region we call left or slight cortex. Then the part that seems to be important for regulating mood.

And so the left to or slatter al seems to have connections that are locations specific within the overall kind of named brain region that connect to various parts of the single late and seem to regulate right. And so if you knock out the left to oratorial prefrontal cortex, and you have people do a striped task, for instance, which is a task where you have is a simple task. But you know this, you have people name the color of words. And so if I if I look at up, but if I look at one of the cards that they'll show you, it'll have the word red and red. That's very easy and that's a call the kingerie and then the incongruity red in the color blue and you have to name you have to say the the word you don't named the color.

You have to suppress .

the response yeah yeah exactly. And so um i'm sorry you do you name the color and and you see the word written in a different way. So basically, if you if you stimulate in a way that inhibits the left doors letter or prefrontal courter or either one, you can actually knock out the ability to do that well and it'll take a longer for people on the incongruent cards to a to be able to name IT.

And so they have they have a kind of a time delay that's greater than they had before they got stimulated. So that's the part of the the preferences cortex that's different than the part of the prefrontal cortex that's involved in mood regulation. The next thing about T M S as that you can go through, you can find these areas they're functionally defined through brain imaging, and you can perturb them and answer the question you're talking about.

How do I understand this part of the prefer renal cortex and its function, this part? And so we were able to stimulate an inhibitory ory way within the left dorsal atal prefrontal cortex that's involved with. You know this sort of cognitive control um area and we were able to knock that area out and um an increased trade notice ability.

So people had greater humidities ability after they got active stimulation verses when they got sham. And so IT suggests that that brain circuit is involved in the in the process of what therapy to kip nosis is up being. But it's a very different region within the left horsa old and say, we do when we do this very intensive stimulation approaches to treat severe depression, and we're able to get people out of depression. Um you know with the part of the of the doors later that seems to be lower in the you know of more lateral um in and um in fear on the D L P F C and connected with the subject ual entire single TTS to the party entire single tt that processes a motion.

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You saying in one moment, the rule is you read whatever the word says and then then you switch and you say the rule now is you tell me what color the word is written in and you suppress whatever is the word says. 好。 okay. A rule in some sense is a, uh, like that is a transient we adopted belief system.

So I could imagine that in depression, which has all sorts of back story to IT um that of course the psychiatrist or psychologist or friend can pull on that though i'd like for incident somebody might believe that they are bad or that they don't deserve love. I'm trying to bring this into the typical language that or they will never succeed or that even if they keep succeeding, it's just going na get harder and harder and I will never feel good. These are sort of rules like the truck task and some levels there are rules that are more pervasive over time, unfortunately.

But I could imagine that if the psc is also contains some sort of maps of algorithms related to rules of emotionality or self representation or things that we've heard, I think there must be date out there the same that yeah whenever we heard in middle school when someone made fun of us, we can remember that because I can remember things that people said about a jacket I wore one day or something in the fourth grade. crazy. I didn't even like the jacket.

Um now I think he's going to cool. But anyway, the point being that we have an intense memory for these things, set up a sort of rule or a question like maybe I don't really know how to dress for sense, maybe that's why I always were the same lecture. But in all seriousness, seems like the doors allowed frontal cortex is in this amazing position to access rules, which are beliefs and believe our rules, and then for moments or longer, to switch those rules.

没有。 And so for somebody who's depressed to just simply look themselves in the mirror and say, you are great, you are fantastic that IT feels like a lie. If you feel like garbage to say that IT doesn't fit with the rule, it's like saying that card is not red. That card is Green when your eyes is tell you that it's that is red and .

and .

IT seems like there's something about prefrontal cortex that that in principal gives flexibility to rules based on what we know on the stroop task.

So given its connectivity, can we assume that the talk therapy that occurs in a the psychiatry office or with a friend or through journal out something um because we do know that reporting things about trauma, difficult circumstances are the rules that we contain and attend to hide inside of us about how we feel miserable about ourselves or anything really that in the scripting that that somehow IT allows us to do a sort of stroop task on our beliefs is that is a tremendous sleep. Just trying to put frame this in the context of what I and mostly will think of as depression yeah. So because the network components are vitally important. But I guess what I have traffic red out is like what the what are the the algorithms that govern prefrontal cortex?

Yeah absolutely in a of standard cognition hav oral al therapy session right? What what the therapist just trying to do is identify those beliefs and um and you to determine how how fixed they are if their flexible, as you're saying, and then then help folks to find another explanation for them and to into kind of reintegrate the potential other explanation into their their memory system, right? Um I think T M S is really interesting.

And actually you heard a lot of patients who've told me like my my therapies told me that I wasn't trying hard enough in therapy and and you know and I I really am trying hard, but these are you mother to pretty severe depressed patients. And as soon as we get them well with with the T M S approaches, you know, kind of rapid, you know, five day approach in the next week, we come in and see them and we'll say, you know what I did all weekend as I looked at my therapy books and now I can understand IT. And so, you know, I actually see tms is 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 preferences cortex on and have IT govern these deeper regions and depression, the deeper regions govern the referral cortex. They they proceed the preferences cortex. Timing wise may be at some data in review now, or we're seeing that in depressed individuals that are responsive to a rapid T M S approach.

We called steam ford accelerated intelligent or modulation, or or S, N, T. Or say, if you look at the brain before people get this, they will, they will have a temporal delay where the singular is in front of the deal. P, F, C.

And in people that are Normal, healthy controls, no depression, the dorsal ral preferences cortex is temporarily in front of the entire single late. With effective treatment, we can flip the timing of things. So the dorsolateral is in front of the entire simulate, just like an a Normal person.

So you're not talking about obviously physically moving these structures, driving about in time your activation. So in one case is like the coach telling the player what to do and like the player telling the coach what to do. And you restore order to the game.

You restore order to the game. And what that looks like is depression, to your point, is a bunch of kind of spontaneous content that's semi violation that's being kind of generated out of this conflict um detection system. The singular seems to to uh to since conflict and kind of feed that information, it's overactive in depression and um and then in depression IT looks like the left or lateral does not sufficiently clap down on IT.

And what therapy appears to do is to kind of restore that. What we see with ts over that region is we just exogenous sly do the same sort of thing. We restore the governance of the left or saturated over the single late area, and that is correlated with treatment improvement. So the degree in which you can time reregulate in time the left, or scatter over the singing late, the more of an antidepressant effect you have.

Can we therefore saying in crude terms that the dorsal lateral profondo cortex really is the governor of how we interpret physiological signals and spontaneous thoughts?

IT places a lens that the rest of the brain sees things through. And and you can, you can do these experiments for you. You can put a Normal, healthy control person in the in the scanner and you can make them feel like they have a loss of control.

And then you can see that region come offline. It's you experimental manipulate the system and so kind of buffing IT up and it's like almost tms is almost like exercise for the brain, right? Your were 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 um I think really interesting for this show is to we had a couple of folks um pride five or six folks that have actually told me this where if they remit early enough in the week, we have this very dense simulation approach where we can stimulate people really rapidly over a five day block. We don't discriminate when they get Better to when they stop. So they they get Better on day one.

We still give them the other four days because it's in the protocol to do that. We can we're getting to a point. We can tell how long I was going to take.

We're not there yet. And so you know, every time somebody gets Better at, they wanted to at the beginning, when we first started doing this, we'd say, no, not sure. You know, we think this is safe to keep going, but you know, what do you want to do? And everybody was like, no, I want to keep going.

And so there by wednesday, they're like totally zero down on the depression scales, you know even Better than most people walking around like really no anxiety, no no depression, anything. By thursday, the first guy, the toomas, 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 is like, I read about this in my mindfulness books, but I experienced IT.

Last night, I ve never experiences anything like this before and I was like, that's interesting, but kind of wasn't sure. And and then I didn't tell any obviously any more patients about that than about five every last couple of years when they get the 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 describes a pretty mindful present moment sort of experience is really interesting.

You know what that is? I mean, I don't have full on scientific data to tell you but IT just it's it's an interesting anette right that that folks when you push them through this point of of feeling kind of clinically well, that some people end up reporting the traditional set of features. So you mention .

the single and the entire singular in particular um because now I feel like for the first time in my career, I have some sense of what prefrontal cortex would actually be doing um sides providing a bumper for for the rest of the brain is the single late IT seems is a more primitive structure in the sense that it's it's under the ideally it's under the regulation of this top down control from frontal cortex.

But what's mapped in the singular in the end for the non neth scientists out there. When I say mapped, we were to puts on in the scanner and focusing on single late, or put an electricity in there. What makes the neurons in their fire of things, in the body and in the mind and out in the world light up, for a lack of a Better phrase, to simulate? What does the single late like?

Yeah, yeah. So so that strip task is inconsequent word color associations the dorsal part of that um you obsessive compulsive disorder patients certain you know certain kind of trigger you you'll see some some of them their imaging studies point to to enter a singular in the kind of very crude psychosurgery world.

Fifty years ago, the entire single atomy was a way of treating obsessive compulsive disorder, right? Is that area seems to be overactive in people who are experiencing obsessive compulsive disorder. You can kind of walk that the singular raps around, you know this White matter track you like bungles that wraps around that. And so there's a part that's above that, around that and below that and depending upon how a much how much of the um the conflict task has an emotional component, the more um venturing and sub general that um that activation is.

So the dorso part of the entire single that seems to be kind of more of a pure cognitive maybe um obsessive compulsive disorder sort of area where as when you start getting in the mood sorts of trigger like facial expression um conflicts we are supposed to there's an emotional stroop task where you show the word happy and then you have a face of of a person that looks mad then that's another way of having the same sort of strip conflict that seems to be more very general sub general areas, right? So you can kind of you can trigger the singing late based off the level of emotional violence from none down to a lot. And and that seems to be how the how it's distributed there are you know heart rate kind of components to an automated ic components in there.

Two, there's something called a connected mutism, a board certified USA behavioral neurologist. And i've seen know a lot of these, what we call zeeba cases in neurology, where people have, you know, these unusual neurological presentations, and one of them is connected mutism. So you have a glioma sitting in the inner hemispheres, Fisher, and having a pressure on the singular ate.

People can get into an almost catatonic looking state where they kind of get stuck and they don't speak. And so that tells you something about how the how the single that works as well, right? It's it's like if it's um if it's not functioning, then people have a hard time kind of connecting with reality. IT seems to need to be constantly on you online to be able to interact to the world.

Is IT involved in some of the dissociated states that sometimes people who are very stressed or or depressed experience he said cattanach being an extreme one but um I know someone for instance that when they get really stressed and IT can even be if someone um yells at them or someone to angry even if someone to angry with them or they perceive someone's angry them there's a developmental back story to why they they likely feel this way um they sort just can this is a high, high functioning individual Normally and they they just kind of kind of function. They can't complete simple things like email or or groceries or things for a short while. It's almost like a catatonia and they refer to as a dissociative state um do you see that in depression and mean we're speckling here as the whether that involves a singular ate, but what you're saying there has A.

A lot of a there see catatonia is an extreme outcome of depression and of and sometimes schizo reni and other illnesses. Association is an extreme outcome or even some cases a less extreme outcome of ptsd in trauma and you know and it's also a phenomenon that happens naturally in some people that are highly hippot zable.

And so if you asked David, be able to say that some of the work that he's been working on is around post your singular in in the capacity to associate. But with our stimulation approach to to del pfc dorsal tier singular, one of the sub scales that move the most was the associated subscale for for him, tize ability. So even in a Normal individual, you know, you see that that change in that kind of experience of association.

I am highly, David criminalize me a number of times. In fact, we have a clip of that on the people life channel. I've always um well always starting my really teens.

I started expLoring him. No, i'm extremely have noticable and um self hip nosis or assisted hip nosis. I don't know that I ever go into service of states. I'll trying avoid forcing you to running a clinical session right now but to assess anything like that.

But this brings about something really um interesting I think which is i'm aware that some of the more popular emerging treatments for depression include things like kadee which is a decisive anesthetic that right? And yeah and my assumption is that as a decisive anesthetic, that IT leads a decisive states where people can sort third person themselves and be so feel somewhat distant from their emotions. I've also been hearing that there are emerging treatments still alive in being one of them.

But some other treatments, M D, M, A at her, that will pass each of these in in detail, that lead to the exact opposite state during the effect of the drug, which is a highly engaged emotionality and heart rate and sense of self, and can also lead to relief of depression. Now, whether not this, again, reflects that depression, as many conditions are supposed to just want, or whether or not somehow tickling, or in some cases, is pushing really hard on the opposite ends of the scale, really matter. I am absolutely fascinated, and again, also perplexed by this. Why would I be that a drug that induces associated states and a drug taken separately that induces hyper the states would lead to relief for the same condition?

Yeah now a great question. yes. So for for kadee and you know that the level of association appears to be correlated with the therapeutic effect IT appears to be necessary but not sufficient to produce an enter press effect. And so folks that they don't have any any psychological change um from the cademy or or don't experiencing association typically tend to have less less potent entire press and effects from academy. We did study a couple of years ago is really interesting. So we if folks now track zone, which is an opiate antagonist, a meal and capper opt receptor tag onest, and we we gave folk the same individuals, a pill of that or a pill of pluizer, they had no idea which, when they were getting .

with this low to smell truck zones.

fifty milligrams, that's pretty high dose. okay? And so we gave a typical therapeutics dose, and we gave fifty milligrams of no trick, sound or policy o and then in the same individuals, we gave two in two infusions, one with each of those conditions. And if they had entered a pressing effect, we waited until they relax, then we gave in the other condition, and then we look to see what what effect of blocking the opposite cept.

Um what fact would you see on the entire pressing effect of block in the other receptor with the idea that if kadeem works the way that a lot of researchers at the time thought that IT completely worked in, which is the glue mate system, then you would have no effect of no tricks and no tricks and just interact with the opposite system. IT doesn't do anything with any other systems. Kadee has a lot of effects over you know IT has clear option effects um in my in various ways of looking at that um and in M D A receptor and tagged ism and glutamate effects.

And so if it's just that the glutamate part is is the part driving the entire pressing effect, you shouldn't have any difference in the entire depression effect between the two conditions if however, the anti depression effect is primarily is the the opioid properties of kadee are necessary for the entire pressing effect, then you should have a loss of antidepressants fect during the cademy plus now track oin condition that you observed in the kadee in plus plus bo condition. And what we what we saw was that there was a dramatic blockade, the entire press and effect when now track son was present in in the people that had a had an entire present um effect with keamy plus plus evo alone and and then some friends of mine that A T M S study with pain and they stimulated over the left or sled or prefrontal cortex and they gave no ox ivy nooks in which works basically the same way as now track on, and they were able to block the anti pain effect of tms with the opiate blocker. So this idea that another kind of convergent point, right, this idea that the opposite recept may have a role in mood regulation was also interesting as if you look at people are getting a total new Operation, very painful Operation, right um totally replacement.

And you you age, sex, know everything match the individuals that are going to through that. But you have a group of people that don't have depression and a group people do have depression. The presence of depression triples the oil oppoi dose by day four.

That's required.

that's required to to cover the pain. But what may be happening is it's not just treating physical pain, maybe treating emotional pain as well, right? At least transiency IT seems to have a pro and anti oppressive effect.

Chronically IT seems have a very prodesse effect, can make people. Treatment resistant. But you know it's it's an interesting phenomenon.

But yeah, the opioid system seems to be pretty, pretty involved. But what's interesting there with the academic trial is that we didn't see any effect on the association. And so the association was the same each time. So the psychological effect of what we call the trip, the kind of associate effect of people, are having a psychological phenomenon from keaveney that was identical both times.

And so IT IT kind of IT also chAllenged this idea that the psychological experience of the psychological effect may be all the necessary to produce an effect that the pharmacology doesn't matter as long as you can achieve that state. And so you know we think we pretty clearly debunk that idea that the underlying pharm ology and the state um you know seem to be important. We don't know for sure if you can a lot of people are working on this.

If you can take out essentially the psychological effect and still have a drug that works to to treat the the illness that you are trying to target. And a lot of there was a mouse study out this week where where they had an elless analogue and they were able to see some, some animal level data to suggest that could be true. But but until we figure that out humans, it's kind of to be determined. But IT is IT is curious, right, being able to kind of use experimental manipulations to try to separate you know, some of these phenomenon apart, really understand what's what's doing, what it's so critical .

and it's so critical to the other conversation that will surely get to, which is the progression of psychedelics from illicit legal drugs to clinically validated and and presumably at some point either decriminalized or legal drugs which has not yet happened, at least not in the us um but just to make sure that people are getting this um and how crucial this is what we're really talking about here is the fact, you know, somebody takes a multigrain dose of Sullivan or somebody takes A M D M A, or they take Kevin and they experience relief from their trauma, the depression, their addiction or any number of the other things that indeed those compounds shown to be useful in certain context, clinically supported at seta.

There's this gravitation poll to the idea that, oh, IT was the hlubis ation. IT was the dissociated state, IT was the feeling of connectiveness. And what we're really saying is that, well, that certainly could be true. IT may be the case that a major source of the positive shift that occurs after the effect of the drug is some underlying biology, like shifts in the mule bio ID recept ala, your experiments with now truck zone, or a change in the underlying or modulation that had anywhere from nothing to something to do with the real shift.

And I know there's a group up that you see, Davis, that published a paper in nature about a year ago also looking at um these are is a chemistry lab essentially modifying psychiatrically to remove the the hallucinogenic properties, the mood altering properties and actually seeing some pretty impressive effects and shifts in mood after the drug wears off. And I know this, this gets people upset when they hear IT. A lot of this gets a lot of people upset really because people think, oh, no, it's it's the intensive experience that matters but um in fact, uh that may not be the case at all.

In fact, it's so powerful for people that sometimes I like in in my mind to you will take somebody is like the birth of a new child and it's such an incredible experience and then people feel so much connection and then they sort connect the the experience of of the actual birth to the connection when in fact, that's true, IT turns out. But there are a bunch of other things happening to that. Are that simply the reflection of the fact that you're holding a child and the vermont effects that so anyway, I I think it's very important that these different um variables be uh figured out along those lines.

I want to make sure that before we dive a bit deeper into cademy and suicide de and um that we do touch on really important topic that has been in the press a lot lately, which is s seri selective a reuptake ken hires because we can't really have a discussion about depression without talking about then I went to circle back to um kadee in and suicide von IT seems that um there are now data that essentially say state that there is no direct link between seaton and levels and depression. Although I my understanding is that the S S S are powerfully effective for certain forms of obsession, obsessive compulsion disorder and may also be effective for treatment of depression, but IT may again be through some effect unrelated to serotonin itself. Is that right? And how should we think about S R eyes are useful and not useful. Um what's what's going on with us arise in neuro patients and other other people as well.

Yeah that the experiment that I described a bit ago around the now track, son and and Kathy, is the first time i'm aware of where we were able to essentially eliminate an entire presence effect by using a second drug as an kind of a block aid highlights a bigger issue, right? The issue that we haven't had a good way of really understanding how these drugs work.

And so it's the difference I think a lot of the the controversy there is that um it's been difficult, they think, for folks to see that something can in one hand work and in the other hand we don't know how that works. So um and so um necessaries clearly work. You know many, many more meat analysis kind of proving that out, right? That in a sub population of individuals they achieve great benefit from depression.

Uh you for depression, uh for obsessive compulsive disorder, for journalizing anxiety, panic of all these things, you can see an improvement in those symptoms um with what we call accessorize or selective serotonin reuptake king headers. The issue there is that these selective serotonin reuptake inhibitors end up um blocking the the reuptake of serotonin, leaving the the serotonin you know in this um in this kind of in between um between two neurons um for a while and allowing for more serotonin kind of be there. The issue is that they don't they don't work immediately, right? So they don't work like the same day you start taking them.

And that 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 say, play brain plastic city effects wrote, we know that things like brain derived trophic factor get up regulated with chronic um oil enter the present use in and so that that's kind of the ideas that um is that these things work. But what's powerful and I think with the authors of this paper is extremely controversial pay paper in part trying to say was that there's not a there's not a deficit of serotonin and you're not born with, uh, what people call a chemical and baLance. Cce psychiatry is known this this is not actually new information.

Anybody you know, it's kind of 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 um before with previous publications but this idea that this chemical imbaLance ideas wrong um I I really I really think that part important because I think that um you know for a while I think I three you know what i'll call psychiatry one point now right this kind of idea of royd and in psychotherapy its in its origins um he was a lot around your family and those experiences and psychotherapy kind of going and incorrectly or helping you to figure out or and you know show you being able to see or people here are you so that you can eventually come to the conclusion of certain cognitions that are in helping you, right? And there is a huge there is a huge importance there, but there is a history where, you know, things like the skids, frenzy, mother and all that, that was a concept at some point, right? And so we've transition from that to the you for a long time.

The chemical imbaLance, which are call psychic two point O O. This idea that there's something chemically missing and and and I I think that the trouble there for a patient who's not a physician, who's not someone who's you know um who's who's steeped in these sorts of ideas, who's you know more of a person of average american out there, right, is that it's telling is sending a message of there's something missing with me, whether be my experiences I had no control of over when I was a child or a chemical in my brain. What I thinks really powerful with with tms um you know really powerful T M S and a level even powerful.

The psychiatric story is saying something different. You know tms works and there's no serotonin and coming in around the train, 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 up regulation of theatre and it's driving that. So our work actually kind of pushes back on the hypothesis is 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 circuit tree.

And that psychiatry three point, it's not just like neuromodulation no modulations are really use case for psychic three points because it's so a way to vocally, indirectly perturb brain regions and whatever modality you're using. But you know there are a lot of a lot of groups that are actually doing. They are imaging before and after they're able to see circuit level changes for something like suicide or kadima, long after the drug is gone, right, suggesting in those same brain regions converge.

So the sub general default mode network connection that we see is changing with our our s stanford modulation therapy technique at the same set of brain regions that the kedem and a suivant seemed to act on, 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 electrophysical logy and it's basically kind of retaliation ating a circuit that is regalia able instead of I have something missing or have some set of experiences early in life that are um that are onna forever trap me in these these psychiatric diagnoses. So I kind of chAllenge is that idea, I think that's what's so powerful about psychiatry.

Three point o the idea of focusing on the circuit because IT gets us, gets a set of thinking about psychiatric and psychiatric currencies is something that are recoverable. People can get Better people. You know, we've seen with our T M S techniques.

We've seen with some of the psychology ork that we've done where people are actually in Normal levels of mood for sustained periods of time or within five days, within five or less days. And in the case of. Of the psychology s within a few days, right? So we can get people out of these states.

They're totally well, there is no drug in their system in that point in the case of psychiatric was never a drug in their system in the case of of tms and and IT just tells us that that it's it's it's fixie, it's it's just like the heart, it's just like just like any raise me in the heart. It's just like these other illnesses that so like a broken leg, we can go in and do something and we can get somebody Better. Then I think what what's empowering and what a lot of patients have told me as they say.

I gotten to know some people will relax and need more stimulation or need more psychiatric, whatever IT is. But we'll tell me I i've really laps and i'm depressed again, but I never think about killing myself again because I know that if I go get stimulated again IT IT improves IT gets Better IT IT IT will I will be able to reaction? Eve IT and I can't and I I don't fear that i'm prony ally broken.

I don't fear that the chemical baLance is still imbaLance. Ed, I not fear that these things that I couldn't control of my childhood, you know, are gonna be there and drive this problem forever. And I think that's that's what so powerful about this, the sense of control, the sense of control, the sense of they're not doing the stimulation themselves, they're not administering the drug and these trials themselves that probably never will. This will probably be medical treatments, but they're choosing to do IT. And in that since they are in control.

yeah i've A A good friend that I won't out him for for reasons he'll become clear a moment who was quite obese um and lost a lot of weight and was really proud of himself and then we could say he sort of a lapsed ed in a sense not not not all the way but but far along but his tone around IT was very different. He knew he had accomplished what his goal once before. He was disappointed in himself, but he knew exactly why he had relaxed.

IT was very clear. He had essentially relaxed to the previous set of eating behaviors and lack of exercise behaviors and is now brought himself back again. And IT just resonate with your story that you know once somebody underthings, they can do IT because they're been there before. This idea of of considering new rules that that um and and that brings me to this uh question about psychiatric and and the Frankly the altered thinking and perception that occurs in in hyde so hbi on clinical sessions um IT seems that the disorder thinking even though I could um be random right h hearing hearing colors and and seeing sounds is always cliche statement of the tim area also right there.

That's a stroop task of sort a it's a synthetic sia to combining of perceptions but it's it's sort of stuck task ish in that it's a new set of rules for the same stuff right? And um people do many people do report improvements in uh trauma related some tomato gy and depression as I understand IT for my read of the clinical trials after taking suicide van because during the session something comes to mind spontaneous ly as um you and I were talking about earlier. Um they will report, for instance, A A new way of seeing the old problem.

And the old problem could be the voice that there are no good they'll never nothing will ever work out or could be even more subtle than that. So um that raises two questions. One is about the basic functioning of the human brain um which is why do you think um the brain would ever hold on to rules that don't serve us well? That's one question. And then the same question is what is IT about solicited and related molecules? What in terms of their chemistry, in terms of the ways they disrupt thinking and feeling at that during the session that allow this a novel rule and .

domino yeah so the first question, I think it's it's an an evolutionary neurobiology answer, right? I think that at the individual person level, you know IT doesn't make a whole lot of sense that when we really stressed out, some of us want to eat more, right at the individual person level is like that's not particularly that good for my health a long term. But if you think about IT, like you know, in some five hundred years ago, a thousand years ago, i'm highly stressed out. It's most likely that about to not have food at some point.

And I should have a bunch food that is high fat, high sugar, high car food to put on weight for that new next phase, where in the stress I may be in battle and I don't have food and I have enough fuel on board, right? And so we we end up being you we end up being a result of probably a lot of biology that's not that useful in the modern era. And I think in the brain, for for, but say P, T, S D write, a lot of a lot of veterans come back and they experienced es P, T, S D symptoms.

They're not they all useful back home, right? You know you know they hear some loud noise and all the sudden they're behind a car or they're behind, I heard a fox, you jump and run behind trash can or whatever in the middle, and ford sisco when they hear a loud noise. But if you put them back in the battlefield of the adaptive.

that's highly adaptive.

right? And so I think what what the what's interesting is that um we, in the absence of using substances like psychedelic, end up having these very persistent memories that are attached to negatively violence to motion, predominantly as you are sent earlier the jacket and elemental. Could we you know at various things like that for me too right? You you remember these things and and we we hold onto those things from, I think, an evolutionary neurobiology standpoint.

But what seems to, for whatever reason, kind of alleviate that are these um are these substances some new like M D M A, some have been around for thousands of years like suicide ben and used um in in kind of screen tal as a sacrement in ah in traditions um seem to have a theraputics fect that seems to be pretty long lasting for this phenomenon and so it's it's just curious, right it's curious that 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 or treating folks with navy seals. Data is still being you being analyzed, but the anodos that we're getting ready to folks are coming back.

And they're saying, and finally, that's finally gone, right? This kind of these set of P, T, S. These symptoms are finally gone. And so this idea that, for whatever reason, going into what's probably a highly plastic state, like we're talking about earlier, up regulation of binder, a tropic factor, in the case of I began glial eutrope c factor, this highly plastic state, and the ability to kind of reality ced memories and then as you know, we we always reconsolidated memory when we bring you back up, we always reconcile but reconsolidation IT in that state for whatever reason um may drive um drive their beauty effect um and you know the the jury still out there's am I would say that I am kind of a i'm an Austin to what tool i'm using kind of guy like i'm my businesses to find treatments to help people and so i'm much more like pragmatic about IT. You know if if this sort of thing which um has a lot of cultural baggage um but if this sort of thing ulto millions are being therapy of design trials that convinced me and others that IT is then we should absolutely use IT you know and uh and if IT doesn't then um then then we clearly shouldn't use IT right and I think that's a big that's a big question that feels going to have to work out. We have a hard time binding these trials because the polyvore condition is not easy to to pull off A A posible .

for a suicide and journey is is hard to imagine.

We've got we've been thinking about this and maybe that academic study that I was talking about earlier, if we could give people now truck zone in kadee, maybe that's a good you know A A good sort of plus ibo condition recks. We know that we can block any of the actually and had a Price effects academy, they still have an experience, you know so that's one way of doing. But thinking about ways to do that really kind of proving this out and that's been um yeah I think that's been kind of central the way i've been been thinking about this yeah I think there's the work that's been done so far. The first so ivan trial um the first D M A trial is publishing medicine recently.

And what do those generally say? I mean that they are effective for a number of people after one session, two sessions. What's the general? Let's start with self. I an an M D M A.

yeah. So M D M A appears to, you know, one to a few. M D M A sessions. Have A N antip. T S. The effect that seems to be, you know, outside of the kind of standard assumed levels of P T S D improvement that you can observe an individuals with this level of ptsd, right? So what we call the effect size, which is essentially like A, A, A measure of coins, the effect size, the measure that allows free to to compare different treatments each other for different conditions that are no agnostic to what the actual illnesses is, you know um the effect sizes is there approach effect sizes, the of things that are pretty effective, like antacids for heartburn, right? And you see that with with with the M A treatment.

So does that mean for people that have trauma who do a and a? Again, we're talking about in a clinical setting, they they take a one or two doses of M D M. I think the standard maps doses one hundred and fifty thousand and seventy five milgram again doing this with a position it's said a control .

clinical gal um .

exactly they do at once or twice. And broadly speaking, what percentage of people who had trauma report feeling significant relief from their trauma afterward?

About two thirds of people had a had a clinical significant uh, change in their P T, S, D. And impressive, which is impressive.

right? And how how long lasting was that? I mean, these trials were ended pretty recently.

So IT appears the last for while. In the earlier trials where they followed people out, IT seemed the last for kind of in the years range for some people. And so you know it's pretty it's pretty compelling still sivan.

Um you know that in contrast, that was kedem in which only on average last about a weekend, have for a single. infusion. So it's a much shorter .

safety of repeated infusions. Academy an every ten days .

or so yeah ever. For some people are they end up getting like like a bunch of doses for a couple of weeks. And then for some people, that seems the last a while. You know that's where I think I think the the Sullivan story for depression and the um in the M D M A story for P T S D seem more interesting to me.

So for suicide and what is the rough percenters on? And this will be relief not from rama but from depression. Yeah yeah exactly.

So it's you know an open label studies. It's closer to like half two thirds of people end up getting Better depending upon their level of treatment resistance in the in the blinded trials that was a third or of people you know experience um relief and and and and this is this is the press release of of the data you know so IT hasn't to my knowledge IT hasn't been published yet and so i'm looking forward to see in the full paper on that one but but you know separated from from placebo and looks you looks pretty pretty good as well. Looks like you know the first of two trials and need to be done to get this thing um approve for treatment resistance depression and so um so that .

stuff looks looks good in terms of M D M A, for many years IT was reported in the popular press and there was a paper, political science, that M D M A was neurotoxic that I would kill serao in neurons. This was was always said. Then I saw another paper published in science that wasn't a retraction of the previous paper, but rather was a second paper in the same group that essentially admitted that the first time around they had in injected these monkeys because with not M D M A, but with Matthew federman, which is known to be in the attack so IT was kind of a public administrator s or big like really big screw ups of oops um but never attraction and then never really a publicly acknowledge um correction in the in the popular press. So IT seems that in the appropriate dosage range and with these one or two sessions, my assumption and his sgherri an assumption tell me from writing wrong here is that M D M A is not neurotoxic for certain gic neurons at appropriate dosing with appropriate sourcing .

and is an interesting study that um I think guys name's helping. The last name is helping IT, not casey helper. Not a different. I think josh help and i'm buying on his first name but .

casey helping was a guest on this podcast and as a former colleague of ours at stanford, who unfortunately we lost to university pennsylvania, maybe someday will .

will bring yes right so this this individual um you received some I H funding to actually niter know national city for drug abuse funding to to explore a individuals um of the morning faith in utah who who partaken only dma so um the way this works is that uh D M A um happened kind of after a lot of the religious documents were were developed and so edna isn't on the prohibited drug list.

The band subs, substance list. Have some good friends .

who are you do as well um you know just a kind of set of facts you know and so um so these folks um only use M D M A, but they don't they're not you know the problem with some people using drugs in poli substance users rates. You can't you can't say it's the M D M A if they've also taken other psychologists and you've taken opiates, they've taken cocaine and you have this picture where you can't really tease out that problem.

But but with this thread, IT was just individuals that were part of the morning faith. And so they they were um kind of purist in this since they only used M D M A, and he confirmed all that. And and IT was a brilliant study, right? Because then he was able to go in and look at their cognitive profiles, verses individuals, you know the same geography, the same faiths, all of that that happened did not take md, mn, found there were no neurocognitive a differences.

So IT IT. Does that mean that IT IT was not damaging?

IT was not damaging? It's hard to know. Because to really do this study, well, you'd have to track these focus down before they ever took him.

D. M. A, and you are prepared post and compare to people that didn't. But you know, this is about as good as a study as you can do, given given the situation to be able to check this out. Additionally, when I was back in tro son and working in the medical universal south CarOlina, I one of my mentors um there after wagner um was a nurse psychologist in museum was also the the neurobiologist for the early mda trials and so he did all the neuro gn tive batteries for individuals post and similarly did not see any changes in new recognition profiles in a negative way. And so you know there's there's data from experimental patients receiving this. There's data from people that chronic users you know who only take M D M A um and that the combination of a of data suggests that there's no there's certainly no apparent risk in the kind of one to two to three dose range and it's it's probably unlikely that at least you know modest dose exposure over a lifetime doesn't appear to have A A profound or cognitive um damaging effect.

Yeah interesting. Yes, I know that sourcing is key in the way here are time my clinical trials or purity is assured. And you know, years ago, when so called raves were really popular, maybe they're still popular. Never been been to once.

So well, no, they're happening or not not how in the no I am but um IT was clear that you know testing for purity was important because that sometimes the drugs um are made such that there are contaminants like math photo in which we know is highly neurotoxic. I think that one reason why people think that M D M A might be in a toxic as the the reported drop in energy or serve feeling fatigued. A few days afterward, I spoke to a physician colleague of hours who said that that, uh, very likely has something to do with the surgeon protein that arrive subsequent to the big dopamine search that occurs um in M D M A.

And I mention that because I know a number of people um talk about sro on depletion after taking M D M A. He has IT in mind that well that could be true. It's likely that any time somebody takes something or he does something where there's a huge lift doping, that there's very likely a huge compensate increase in product that follows in product has a kind of sensitive effect nummi effect on mood in the beto at sara that eventually also wears off. Does that makes sense? You as a position.

yeah makes sense, mean the difference between C M dma. And so sivan is that M D, ma is kind of an effect me of sort rate. So IT has IT has effects in doping in the in Sullivans. You prety pretty neutral and know maybe a little bit of doping effects, but kind of much more of a set error focus drug. And so yeah, I think you're going to see a kind of a different profile afternoon and that makes I haven't heard that story, but that makes sense to meet too.

since you mention suicide de and like global about the neurochemistry of suicide and as a magic agent, my understanding is that um Operates on these uh is that the five H T sera and two c recept to me a receptors and that i've seen a bunch of different reports in terms of what is actually doing to the brain while people are under the effects of the drug.

And this is important for us to segment out because there are the effects that happen while people are under the influence, and then the more long lasting effects, but some of the effects i've heard about our, for instance, and tell me again if these are right wrong, that there is increased comic activation of lateral connection, sort of broader areas of the brain being coache then would Normally occur. Maybe that explain some of the sydney and seeing sounds and and hearing collars and as the trivial example, but rule breaking within the mind. But then I ve also heard um that perhaps its lack of gating of sensory input. So Normally if i'm looking at something, i'm not thinking about the sensation in my right toe unless it's relevant, but if i'm thinking about the sensation in my right to m generally not thinking about the truck around the corner. So we have these attentional spotlights, but that somehow IT create a more IT add spot lites.

the gates, the debates, the film.

right through the particular pillai ics structure. So um what is the evidence that any of that is true? And h are the other phenomena is their involvement of our seattle cortex that we are aware of.

And when i'm really headed here are in a few minutes is um you know is there a place for combining directed stimulation of the brain with psychedelic so that the effects of serotonin could be um primarily within the structures that you know from your work to be relevant to depression? So so but to simply by at first what's going on when one takes sellers? I and um why is IT interesting in light .

of depression? Yeah definitely. So um David nut and Robin card to work around new imaging psychiatric x are kind of some of the first folks to do that work. And to their great surprise, they thought there was going to be the increase in activity on psychiatric. And what they found as the opposite, right there was kind of a and overall decrease in the level of activity in the brain um with psychiatric s 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 small world, meaning there's a lot there's kind of a much more kind of focused kind of critical function or you know a subcritical function, whatever is and in what you see is a difference in that in that level of engagement of brain regions of the concept vy global connectivity, to your point, kind of increases. And so you know it's it's interesting, you know I think to can have a conversion theory on this is still you know to be determined. There's still a lot of work, I think that needs to be done.

But but it's certainly um suggested that there's pretty profound changes in in brain activity in brain connect vy after and what we've found to be really interesting is that the antidepressant fect of Sullivan have a particular connectivity change that we also see with our R T M S approaches, right? And it's this connectivity between the sub general and to a singular and the default mode network. And so will we do this effective stanford and modulation therapy?

Stimulation, we see a dow regulation, the connective tivy between the negatively violence ed mood state in the case of depressed individuals in the self representation of the brain, and you see that same connectivity change occur post solve and suggesting there's a convergent mechanism and IT makes sense, right? You've kind of got an over connected negatively violence ed system, conflict system that kind of kind of attached onto the self representation and people feel stuck, right? And then when you when you do whatever you do, that effective IT IT unpaired those two systems.

I want to ask you about this phenomenon I heard about during suicide and journeys. I heard about this from doctor Matthew Johnson, who, running a lot of the clinical trials, h john's hopkins and h has been a guest on his podcast. He said that there something seems to be important about the patient whose depressed or whose is under the the influence of suicide bin, or the patient who's trying to get IT over smoking or a needing disorder, who's taking solicited and and is in the clinic that they're something important to this notion of letting go, that people will feel as if their thoughts and their feelings and maybe in their body aren't under their control.

And that the clinical job under the those circumstances, of course, to make sure that they are physically safe, that they don't jump out a window or china actually give an example of a patients who thought, I think IT was that he could move into the painting in the wall. And obviously that wasn't true in the real world, although was true in her mind. So they prevented her from doing that.

But that letting go, that somehow um untethering from the automatic ousel that occurring is important um which brings us back to this idea or me back to this idea of like a sea saw where you sort letting go of the hinge. Just you your heart rates going up, like just go with IT and trust. You know, your heart rates going down, just go with IT and trust.

You're thinking about something very powerful and depressing related to your childhood. You're supposed to go there without fear. You're thinking about what possible in terms of what could happen. So anyway, you get the picture.

Can we think of that as as just the willingness to um do a million different variations on the the emotional stroop task? You will entertain the full full array of rules within your head and consider them where is there's something more to IT you know IT and again, that we're we're in the the outer margins of understanding here. But what your thoughts on this notion of letting go as such a key variable for relief from depression during the psychology journey?

yeah. So i'll talk a little bit about something called exposure and response therapy that a typical kind of gold standard treatment for A C. D. And i'll help help this a little bit conceptually. And so what that really is, is a letting go therapy. And so you know, exposure response prevention in the idea is that you have to expose the individual to something that you something that trigger an obsession that they then want to do whatever the compulsion is right? And so i'll give you you my first exposure response prevention patient.

When I was a resident, um he was very concerned about um leaving the lights on his car and and so what we did is we went out and we turn the lights on in his car and locked the door so he likes her on and he was super worry that is kind of kill battery um then we went and we spent an hour talking about things and we went back out to his car and his battery was fine and his lights were run and he crank the car and we did IT maybe one other time and then all the sudden that was gone right? And that's the idea is that you know you're essentially exposing and you want to do IT at levels that are from an anxiety standpoint tolerable, but exposing the person is something and then letting them see that that exposure ends up being fine, right, and is up not causing the thing that that they end up being worried about. Um and so you know in some sense being in the psychiatric state and we are all we are all taught at a level to retain some level of control.

You know people have more or less of that, but we are all effectively retaining some level of control. We all wake up in the morning and put close on to go into society. We all try to say, know, most people try to say the right things. They don't try to do things. They are outside of cultural norms when they're in conversation. And so we're constantly, at some level, controlling the situation that were an and so it's you know it's not makes a lot of sense that in that state, part of the therapeutic effect that may be linked to the neural circuitry is the idea of letting go and essentially letting the system, you know, the network configuration, maybe whatever IT is, assume a state that youth essentially been fighting the whole time, the same way that my ocd patient was fighting. This need to click the off button on the lights of his car fifty times before he would go and do whatever he needed to do and in some of of letting go there, meaning letting us just turn the lights on and him not do anything, or letting go, meaning in the psychiatric state you're just letting go of whatever IT is you're holding onto negative the violence. Think thoughts about yourself in the in the you know setting having depression or you know we experiencing a trauma um you know memory and allowing that to just happen and reseeded IT again through a different light feels the same in the sense that that's allowing for whatever is going on with this psychotic states to do whatever they do.

fascinating. You said exposure response therapy is .

the traditional reinvention .

therapy done outside of the of the psychiatric journey.

is done outside the psychology journey. But that idea of letting go is present both of those psychotherapy of straight up, totally sob, non psychiatric, non anything psychoanalyzed that psychotherapy that we know works really well for ocd and then in that photo state, so people have done studies with with still sipping and some studies of the dma trying to look at, um you're treating O C D um you know with the same sort of idea letting go, right and how do you how do you have an O C D patient kind of let go, maybe even letting go, of not washing your hands anymore, of accepting the idea they're not onna get germs on their hands or whatever IT is is you know and so it's kind of part of that part, partly that same sort of thinking.

When I was in college, I developed a compulsive superstition. I'm not afraid to admit this. I am somehow developed a knock on wood superstition.

And I would, I was actually kind of shamed by of IT because IT rationally made no sense. I don't consider myself as superstitious person. Never was a supervised kid. I step on the sidewalk cracks i'd walk under latter, even try walk under a latter I don't suggest um but somehow I picked this thing up and um and I used to sneak IT at times I told my girlfriend at the time I had IT and hopes that that would prevent me from doing IT um and it's tRicky sometimes that I actually comes back right I think cash I didn't say you know not on wood.

I didn't not on word, I hope that doesn't actually happen and and it's crazy right but I crazy the sense that that makes no sense rationally why the the events would be linked and yet I think a lot of people out there do have internal superstitions um maybe by talking about IT now and will go away, I just clearly I just need to chAllenge IT. You know it's anyway I mention because I might concern myself you know generally rational person but it's interesting of these motor patterns um get get activated and and this notion letting go because I don't actually know what consequence I fear and the fear, as I was hearing the example you gave on the fear, the car running battery running down, I was about to say, well, what if the battery actually did run out? Then the therapy would be undermined and yet that could also be interesting too because it's not that big video you jump the car but in my case, I I need to think about what the ultimate fear is yeah .

you know I think I think a lot of people. So there's it's interesting if you look at, say, the O C D scale or the depression scale or whatever, we don't define Normal as zero. We define Normal as some number range above.

So zero two. In the case of the mongery expert depression rating scale, one of the depression scales, we use ten, right, that's the Normal range, and so people could have some sadness and still be considered Normal. In the case, the ocd scales, about the same ten right, where we say it's kind of starts to be know mildly Normal or something.

And I always, I always tell the medical students, look, my friends that are surface structure, they're more like a zero on the y bog, people that are professionals that are non zero. But you are still in the Normal range, especially in the case you're talking about IT doesn't sound like a got in your way. IT doesn't sound mean obviously highly successful tenured professor at stanford and do all of the great things that you do.

Um and so it's it's very much kind of within the Normal range index. I think totally um totally assumed that a lot of people have have these sorts of things and a lot I think something a psychiatric diagnoses when IT severely empires your ability to function and that's when we kind of cross that threshold know. I think that I think that a lot of people, and it's great that are bringing this up.

It's very antistius matiz ing that you're bring that up, right? Because I think a lot of people hold that stuff in and they don't want to talk about IT because they are worried that somebody else may think something. But the reality is a psychiatrist that talked a lot of patients, a lot of people, you know family members, you know folks are just going through a death.

And in the family, whatever IT is. And what you figure out is like everybody's got a little something here and there. Everybody has the knock in some way, if that makes sense.

And it's just and we're just all we're all just kind of more pretty exposed not to talk about IT, but I think it's important to talk about IT because I think that when we start all talking about IT, then we realized that we're all kind in this together and away and that were then some folks that you know have, you know have to knock one hundred times, we call that O, C, D. Or, you know, and they have all no germs. They worry about germs and all these other things. We call C, D.

And then in that circumstance, you they need treatment, right? But but IT is really on just like blood sugar, just like blood pressure is on a range. You know, it's not just these discrete diagnoses.

You have them or you don't. It's good to know I actually feel some relief just hearing this slightly I I would say a shame I were embarrassed by but I I offered IT as you know, that you know IT IT is what IT is as they say and IT certainly doesn't seem to hinder hinder my my life much not on wood.

So if we could talk a bit about i've again I don't know much about I begin although in time I hear the you know A I, I, I, I begin I think of an ah and going to the dentist which is an unpleasant experience for me generally what's I what is I begin? Um does this have anything to do with the so called tode? Um you know people talk about smoking, frog skin, told skin.

Um what is IT used for clinically is IT legal in the U. S. As a clinical tool who's using IT and for what purposes if could educate me on I be again I truly know nothing about IT. I think I know how to spell.

Yes that's so so I begin is the um is one of the alcohol ids that you can extract from a um I boga tree root park that's um typically growing in the company of in the country of gabon, africa. So good bon is one of the west african countries can middle of africa on the west coast and in gabon is has A A group of a fox you call the beauty um it's a religious kind of sex mental um group that h sacramentally uses.

Um I boga root bark is part of of that the sacrement um and they uh they've been using I bog root bark for a very long time um and it's it's part of the tradition. There is a whole um there's a whole set of of kind of ceremony around IT. Um if you're interested in this, there is a book called breaking up in the head by Daniel pinchbeck that goes go through and talks about this um this whole process but essentially um the cabin ism and using this for a long time and it's it's a kind of an a typical psychiatric it's not it's not a psychiatric that we Normally think about with solicit an analysis where the visual perceptual changes rates.

So if if you take so and what you what you experience you experience this kind of visual um perceptual differences in the external world right on enough lst or sul, an individual can actually perceive something visually in the external world that isn't there, as we talked about earlier. Um I begin doesn't do that. I begin does something different.

It's it's kind of like if you are seeing minority report with you know, the movie with tom twenty years ago or something to a dates a little bit. But IT was this IT was this movie where he would be able to go and see these kind of precise, and he had this big, this big screen where he could look at scenes from from time, and like, kind of go through that scene and see IT. And so what what individuals taking, I begin will say, is IT open eyes.

They don't see anything but closed eyes. They'll go back through an rex ence earlier life memories, and they will be able to experience IT from a place of empathy, and only for themselves, but from others in come detached empathy, and being able to see this as almost a third party, even though they were there. But they're able to see IT, you know, as the third party.

So clodion nan, how was the chief is from argentina? Describe this a lot of books that that he wrote. I think the eighties and nineties around this.

And so, you know, i've begins been around for a long time. Howard, lots of american guy that brought IT over from from africa, is a police substance user, used every drug. How the hands on took I begin, and including a lot of other psychiatrically, by the way, I took, I began.

And they never did another drug, supposedly because he had such a profound I begin experience I begin is in no way a recreation substance. It's not a recreational substance if you want IT to be a recreational substance because you're essentially having this, what they call life review. They also call IT ten years of psychotherapy at night. So these are the terminology that people talk about.

The issue does IT last is IT truly one night.

It's usually, you know, we can go depending upon if, if we do to anything, go sometimes, depending upon how fast you metabolize. Sometimes twenty four, sometimes thirty six hours, sometimes you can be short or but it's a long time, a very long time. So it's definitely longest acting psychedelic substance I know of.

And and so people, people, you will take this now to will have this reevaluation of the a given memory. And then is we are going early reconsolidated memory again. And then IT seems to have no an effective of that reconsolidation process. So you know, about five, four, five years ago, I was tapped by Robert milinko, one of the new senior neuroscientists we both know in the university. He says, well there's a you there's unnamed donor that's very interested in um in funding A A group you know a scientific can I open label study of um of these navy seals that have been going down to mexico in taking um I begin and and also five O D M T which i'll talk about in a second um to treat P T S D you know the claim of ramai brain injury, depression know that whole conStellation of symptoms you know and as I was described to me um by various people had done this by their spouses and what not um you know giant want to say gian gian coulton screw a light into a light like a light bob into a light fixture right they they were just so debilitated they couldn't do in a simple tasks where we call activities of daily living. And they were coming back and having news, really dramatic improvements in in in all aspects of life.

And so we have over the last couple of years, been able to um to do this first in human can full nearby ological clinical neurocognitive evaluation of what I begin is doing in this case in in a special Operations, special forces individuals, former nav seals for my army rangers, that that kind of crew folks and look at the proposed changes that we they are experience to be able to totally quantity all of that. And so we've been able to capture all the clinical scales in depression, scale, P, T, S, D scales, all that standard stuff near cognitive atterly. So how does your executive function work specifically? How is your verbal memory, all of that? And then the imaging in E, E.

G. So this will be the first human study of vivo game for those and the reason why is because I begins kind of the both seemingly the most potent and most um in in seemingly to me at least most powerful um psychologic but the the one that has the most risk too because that has a cardiac effect IT seems to be that you can screen people out that have risk of their electrical dio gramm and reduce the risk quite a bit. That's what we all dead. But but but that's why people haven't really studied IT as much as IT isn't as in addition, no nobody goes to arve on I is no recreation .

at all with it's .

people say that it's believing, but it's hard work, right? Because yeah you're reexamining things and you know and so then so then we see these folks after, and i'll tell you, you know aven't fully analyze the data, but i'll tell you that you know from from what my future telling me, it's pretty dramatic. You know people come back, they're doing um they're doing a lot Better. They're doing a lot Better. And um not nobody.

I'm not on what nobodies had any sort of a cardiac issue at all um in you know in the cohort that we've studied and and they look a lot Better and they feel a lot Better too and and they describe these experiences of being able to go back through you know soldiers experiences something called moral injury, right, where they maybe they accidently blew something up and and had a kid in IT or something like that there, afghanistan and iraq. Maybe child died on accident or maybe maybe you know a civilian diet or whatever IT was right and they and they suffered these moral injuries as part of the job. But it's almost one of the kind of, you know, vocational risks.

They come back and say that we've they ve forgiven themselves, you know, which is, which is huge, right? And in part of that is being able to see themselves f in a different light, having empathy finally for himself and being able to kind of have that experience of of forgiving. And so so very cool. The the study um you know what was happening was they were taking him again and then taking something called five O D M T people call the san um I river to I think it's like find these mexico, find an arizona um in in the back of the the the tode um produced something old five M O D M T which is um your flavor of emt that produces a particular psychiatric effect. Also used as a sacrement is .

a die method trip to me.

So IT IT is a five imo diametrical trip to me and so it's a kind of diameter D L trip to me in with with a kind of addition to IT the the deal there is um that IT last longer than traditional D M T know it's like twenty minutes at five, three or whatever kind of thing. And and so then so these guys were taken, I began. Then they would take the five meo d mt. After we had to kind of divorce those two things, be able to do this study and just understand what type I came was doing. And they go back down a month later and y'll do the five O D M.

Two completely separate sessions, two completely .

separate section.

And one quick question I began before a bit more on five mild M. T. Um is that I begin journey guided or the person just closes their eyes and they just start falling into the backpack logue of memories.

They have a bunch of preparatory sessions, and then they have a bunch of sessions after that. They kind of they're able to kind of rehash things during there's a pitter that sits there red and kind of sits for them um and helps them out. But it's not it's pretty.

The phenomenon of the drug seems to drive a lot of this. And so a lot of IT up being we call supportive psychotherapy being there. And you know maybe we hold the person's hand.

Maybe you're just saying i'm here. Maybe whatever IT is, you're make sure they know you're around. But you're not really is not really an interaction per say. And then the whole kind of goal there is just to to get focus to kind of go back through and reexamine these memories that ultimately look look like they reconsolidated in. You know, it's very interesting. I mean, there is a there is this kind of time, as you said earlier, Timothy, kind of social cultural construct that is upping overlaid over psychology s and what I think is that if you rid yourself of all of those preconceived notions of what IT is and is in in the counter culture movement, all that stuff that neither of us ever involved in, either of us never protein, you is kind of straight scientists looking at this, right?

If you can rid yourself of all those social cultural constructions, and then we examine this, these if we just discover 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 with series, with psychotherapy, but kind of in combined right psychotherapy plus plus drugs in in a substance that kind of allows you to reexamine these things. And so it's it's interesting at all. You know, there's a lot to do to try to figure out that's true, you know.

And 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 this 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 do with Normal waking consciousness.

But also why we have to really think about this in, you know, these drugs can be recreational drugs. They really shouldn't be recreational drugs, right? They are really too powerful to be used in the context of recreation, because they can put you into these states in in the this generation of psychology.

Researchers are really clear about that. You know, I think the sixties folks were not clear about that. And they felt like there was a this whole kind of cultural thing that was going on there.

But I think this coward of individuals really understands that in order really make this happen, we have to understand that if you need a prescription for an access area, which doesn't change your consciousness a whole lot. And we were very worried about that. And the doctor has to evaluate you for that every week that the idea that some of these substances would would go outside of a very strict medical supervision is is kind of proposed. Actually, it's kind of it's kind of A A dull moment, I think, for all of medicine to say, look, we're you know if we're going to do this right, we've got to do IT such a way that so protected, that so safe that we make sure people know these things are not recreational and they're really for the pure purposes of of really powerfully changing um cognition for a while. Letting people have these would seem to be meaning relatively therapeutics states.

I think it's great that you're doing the study in along the lines of the sort of the early iterations of psychiatrically and the counter culture of the sixties and seventies, some of which took place like one flow of cookies ness I think is actually based on um the menlo park V A, which is know in our neighborhood of stanford.

Um and things are quite a bit different now I know um you and I ve spent some time with the Operators and former Operators at an in last Better and stay in fact this called veteran solutions group that's um pioneer a lot of these psychological treatments for former special Operators and current special Operations. And what's interesting to me about that is in contrast to the counter cultural movement, the sixties and seventies, um that room was filled with people that are very much of a structure, the military right. So it's no longer um considered left wing, right wing, anti military, pro military here.

This is just about one group of people who is expLoring psychiatric s as a treatment for trauma, P, T, S, D. And other other things. And of course, you also other domains of society looking at this. And in fact, there were. But he was really interesting because they were both far left and far right politicians at that event, up on stage together, talking about, 嗯， in kind of lighter terms, heart medicine, but also talking about neutral biology and talking IT was just fascinating from from the perspective of somebody who's trying to learn about this stuff, that psychology therapies no longer sit within the entire establishment realm.

It's both it's it's independent to all that um certainly when people in the military adopting as a potential treatment, again still under exploration but also under exploration that universities like stanford and johns hopkins and U C S F and london um along the lines of tree barks and told skins um tell me about iowa a um in as a plant uh you know it's intriguing um and is IT process egil um drug like saban um and is IT uh useful for the same sorts of conditions that we talked about thus far. And you could um perhaps tell me a little bit also about the brazilian prisoner study. Yeah definite .

iowa is another psychotic like is used as a segment in in brazil and in peru and ecuador and columbia. So a lot of the south american countries and and what they do is they combine two plants together with where one plant of the two plant combination would effectively do nothing but the two plant combination together is capable of producing um producing this very profound psychic c effect. And what's really kind of curious is that there, as I understand, at ten to twenty thousand plant species in the amazon, and somehow somebody .

try them all.

combine these two plants together in certain proportionality, and cook to this for five, ten hours to the point where you cook out the diameter le trip to me out of one of the plants and cook out there were reversible monotone oxidize inhibitor out of the other plant is such a way that the reversible mommy, an oxygen inhibitor, prevents the the G I break down of the diameter d tripped to me 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 monitoring oxy and a plant derived into this combination than IT would never cross the brain. If you put people on a standard psychiatry prescribed monem, an oxy inhibitor that wasn't reversible, you'd throw them in a saton's syndrome. Wrote that this kind of like sweet spy that somehow I asa practitioner is have found being able to get the mt and the brain from an oral source with this combination of a moto me oxide inhibitor curious um and so that that substances has been explored as an enter to present agent and some studies have looked at that IT also seems to be very safe um there is a psychiatry um uc a harbor who's done a lot of work with this where um where he's looked at children even that have been exposed to to small doses of ioc is kind of a sacring within amazonian tribes and found no neo cognitive effects, no nereid gc effects and adults and um and so appears to be safe it's part of its kind of part and brought into various religions including kind of merged with cathos m in south americans.

Kind of very interesting and so you know in some sex of catholic m in brazil, IT used to sacrement during religious um ceremonies and so IT became interesting to brazilian researchers as to whether not they could affect recidivism rates for prisoners in brazilian prisons right? They gave half the prisoners some sort of earth substance in half of the prisoners a osa session and the the recidivism of the return to prison rate in the I osa exposed individuals were statistically significantly lower then the recidivist rate in the in the control group suggesting that um 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 the details on the exact nature of the crime um you know no I am also in no way saying that we should be giving psychiatric to fox in prison and all 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 that about that, that would drive people to to change those behaviors? why? Why do people make those behavioral decisions? In a lot of times, if you look at prisons in the united states, you know, you said people say this, what's the biggest mental health facility in in the united states? It's a prison .

yeah there's a lot of impact there for sure. Um you know the homeless issue, the prison issue um does lead to something that I heard recently, which is related all this, which is cannabis know we hear a lot nowaday about um people say what's safe for the alcohol and we did an episode on alcohol that at least by my read of the literature um indeed alcohol does seem to be um quite bad for our health, I think and it's pretty clear that not drinking is Better for your health than drinking at all.

And and here i'm not trying to tell you what to do with that. Those are what the data say. And forget the studies on red wine.

You'd have to drink so much red wine to get enough to d doesn't think anyway eeta. Nonetheless, cannabis is now available in a lot of very hypotension y forming. People are walking cannabis um people are smoking cannabis.

I certainly am not saying that cannabis bad for people necessarily. Although I think children, I would like to hope that their brain development would be be completed first. You get age twenty five. I know that sounds late um for a lot of people but um the T H C obviously taps into some industrial systems of of and the contaminant systems and is powerful. And i've seen this h this report that was in uh Lancet psychiatry this last year that said that early use of pot cannabis, meaning age fourteen to twenty or so, can potentially lead to an exasperation of psychosis later in life.

And I actually put this out on social media and a sort of exploded what I didn't expect to people are saying, well, that's not caught and obviously it's not caught um because people say, well, maybe people with psychotic tendencies are seeking out cannabis is although that sort of a weak argument in in the sense that there's a at least of four times for acting in these a psychotic episodes for people later in life。 But what are your thoughts about canvas? Because I do want to acknowledge that he does have medical benefits for in things a pain chemotherapy um so by no means trying to to knock on cannabis and its appropriate. Medicinal use but what what we think about cannabis in terms of this finding that I can make exacerbate psychosis in certain individuals.

Yeah so I think you know there's there's a couple of things right. So cannot is .

is multiple h because get yeah there's a lot.

There are time act. Yeah, there's a lot. But there two, there are two main, you know chemicals you think about kind of how things are are essentially bread, right? And so you know there's a lot of cannabis is really bad to be very high, very potent.

T H C. There is a lot. And there is cannabis where the T H bread completely out. So their stories from colorado, right this strain of of kenna is that T H C free.

There's no thc at all and it's all CBD and they is called sure its web um and a bunch of kid's parents, one kid and then kind of a string of parents after that moved to colorado. And cannabis was legal because legal lize, because CBD is anti palette. So C, B D is also antisemitic.

So they're been a number of studies. If you give C, B, D, high doses, it's anti security inst schizophrenic, established schizophrenic ic patients. The issue is that we've bread CBD out of marijuana selectively over time.

We get very good at figure out how to do that, right? Conversely, T, H C is proph choc in proelio tic, right? And so when you talk about is cannabis cause psychosis or is cannabis treat psychosis, IT appears to be more related to the proportions of C B D to T H C then that does to the kind idea of cannabis.

So for me, there's there's a kind I know stock in this or anything like that, but there is a company called gw arma ticals, and I haven't looked into them in a while, but they they have a lot of clinical trials for some culture vez syndrome a which is a seizure disorder. Kids sees a whole linux gas to syndrome, which is a seizures disorder. Kids are seizing three hundred times a day.

Both of these are like kids are seizing so much that they're basically in a seizure or in the post IT al phase constantly. And then they ve failed everything. They felt burpee tes, they felt promise, which we we don't use anymore except in these cases because of the side effects. And you'll give kids C B D.

And I think C B D is pretty safe drug compared to promote, right? And so this idea that the C B D in a kid is actually safe, it's, it's, it's a canoe, but it's C, B, D, and it's safe, right? So that to me is totally fine.

Also, giving C B D is a adjunct of treatment for for schizophrenia been some positive trials and negative trials and APP. But there seems to be no negative side effects that seems to reduce some of the meta lic syndrome issues in folks with schizophrenia a who are having side effects from the primary and psychotic, the converses. There's clearly cases where people that are taking very high doses of become psychotic, they get put into the psychiatric unit.

Nothing happens out of me. They kind of get this T H C out of their system, and then they resolve their psychosis, right? And so and a handful of people have had, you know, seizures related to hydas of T H C snap, all sorts of things.

And so this idea that T H C high doses of T H C can be proph choc is also not taking a shot at people that think that kind of us all is a good thing. IT just, IT just is what IT is. And they kind of pure.

If you I think if you zoom back, you say you're true naturalist. You think about natural medicines in the world. You should think, well, probably marijuana was baLanced.

T, H, C, C, B, D. At some point. Then we just, we humans messed with IT right in the most likely that was probably okay at some level. And then we pushed IT one where another and when I mean, by OK is in a forty five year old, it's okay kind of thing.

Now what I think is going on with the with the kids, with the teenagers, as you've got preferable maturation rate in the year, exposing them to a whole lot of high T H sea load. And while it's unclear if it's if it's cause the effect, it's certainly in the picture. And if I were apparent, I wouldn't want my sixteen year old smoking marijuana.

If I were apparent in my thirty year old, otherwise healthy um totally find you know whatever banker, lawyer, kid decided to try marijuana for the first time, I wouldn't scold them about IT right? So I think it's kind of a different thing, right? I would never want my up to twenty five years old to say you're saying before preferred al maturation.

Never want my kid to be exposed at all. But IT looks like, except in you know subtitle individuals that are subtitle a drug and new psychoses, IT looks like, you know it's it's a relatively safe thing, past preferences, maturation. You know, again, I can i'm not going to comment of cause and effect, but I but I would say that you know IT doesn't if you a parent IT doesn't make my sense right.

But you know you want to you never know what's ultimately going to hurt your kid. And my wife is talking about really my best pregnant SHE kind of avoid everything peculating. So right?

The idea that we just we want to be careful when our children's brands are developing, and I think that's really what you are saying and I think actually important. The bigger question you asked, which is relative risks of drugs, is an interesting one. So David, not published in, he was in the land set.

I'll have to look at up anything in the Lancet, an article about relative drug risks for the person in for society. And this was like he was on the the, the U. K. Like british drug policy group, were essentially what he showed was, if you took, if you look at societal risk plus personal risk, and you combine those too, you know what drug is the most dangerous drug in the world?

I guess alcohol .

l right behind heroin and cocaine and did and somewhere in the middle of marijuana and write on the tail end of the other, on the exact other end of this. Sullivan.

this caffeine usually doesn't like the list I .

may have bit on the list is part if IT was IT was probably pretty close to solve ban. But somewhere in the middle km somewhere in the middle was was um embedding somewhere in the you know little closer to sell aside anything that was in dma. You know but but if it's it's this combined personal you know kind of world risk of these things. And so alcohol makes IT because there is a huge amount of personal risk and is a huge amount of societal risk. Great drunk .

drivers kill x .

people in the world, sexual all the cancer and all that stuff. And so IT IT beats out cocaine, IT beats out heroin and IT beats out all of these things. And yet um yet we don't we don't as a culture, for whatever reason, we don't as a culture, see IT is a drug and that's the part that really baffles me, you know and I mean, they serve IT.

I mean, this is no knock on stanford at all course. I would knew that this is every institution i've been to. They serve of alcohol at the graduate student events and they serve alcohol.

They do a happy hour. I ve never been a drinker. I can take you to leave IT. So and I realized that some people, they really enjoy alcohol.

And you know um my former but I mean he just was in that ten percent or so of people who have a glass one and just feel great and the second one feel great. I I just want to take a nap after I have a bit of a alcohol so I never does much for me. I always feel poison.

I feel lucky in that sense. But it's it's unbelievable that IT is so prevalent and it's it's just it's baked into the medical even medical institutions that the pop by of champagne to celebrate the opening of a hospital. Yes.

it's really crazy. Yeah, you're absolutely right. You know, I think I think what's onna happen, but this is me, you looking at Christal ball a little bit. But I think what's onna happen is what happened with doctors and smoking.

If you look at the fifties and sixties, right, they're all these pictures of doctors smoking cigarettes with patients, psychiatry doing psychotherapy and smoking a cigarette with the patient sitting on the cow, you know, surgeon smoking a cigarette. In between cases, there are all these pictures that right? And now of a sudden smoking, totally ban.

I think it's totally banned from most of stanford campus. My suspicion is, as you're suggesting, right? You know, this is everywhere, and it's all kind of ubiquity at some critical point, some tipping point.

Everybody's gonna realize that just like with smoking, we've got a rid hospital systems in universities of alcohol. And at some point in fifty years, it's my view that will look at back at the scenario you talking about and and be like, you know what, we we were foolish about this. We can believe that we we gave people alcohol on the way, know when they graduated from whatever you know.

And I think we'll have a different take on IT, but it's going to it's going to take alonger time. I think I think people did a really good job tying smoking the lung cancer. And it's like very a very simplified c story.

Smoking lung cancer, you know. Now as you know, alcohol increases the risk of a lot of different cancers. Not so clear which one in there I know or like the throat tongue cancer, that's one cancer, breast cancer, you know.

So but it's kind of it's a harder story to tell, you know and I think that's why in everybody and then there's this whole know, my mom says this, I drink my glass of wine because my doctor told me I was hard, healthy. We were talking about this and I tried to, no, no, but doctor, so on, so said, it's hard, healthy. And so IT ends up being the thing.

We're like she's drinking alcohol because he thinks that it's it's good for heart and um you know and it's it's hard to have those conversations, that heart is hard to untie that. And I think that yet at some point, we're going to hit some, some threshold. Ld moment will be interesting if we really look at the data and we really look at what's safe and not safe from purely from this analysis, IT can IT can points to the right direction .

is really interesting, and also saying nothing of poor judgment under the influence of alcohol. I mean, I would venture that if we were to remove alcohol from university campuses, watch, watched, the students are gona lobby against me. If I said as well, if you were to remove alcohol from canvas, as I just think about the the what I suspect will be the improvement in good decision making.

And um that would occur or you know I have got stories from graduate school and put in IT IT was very different. In ten years ago, there was a lot more alcohol consumption. That was never my thing.

I know people being really bad decisions, you um in any case um there's a whole landscape their emerging I think you get your finger or right on the place of IT. I I want to touch on something slightly different than what we've been talking about but definitely related to depression. And this again is one of these intriguing but perplexing things, which is that sleep deprivation can improve symptoms of depression.

And yet, i'm impersonally very familiar with the fact that if I don't sleep well for one night, or don't sleep at all, in fact, I do have an ability to function pretty well the next day i'll do this non sleepy breast practice that I blab l out about on the people in that podcasts. Er is for me as tremendously restoration. But I like a good nights sleep. I think everybody understands.

Now, thanks to the great work of Matthew Walker and others, they're really got now into the world saying, look, the foundation of mental health, physical health and high performance, if that's your thing, being a functional human being, is to try and get enough quality, deep sleep, at least eighty percent of the nights of your life, if you can, that that something to focus on, just like good nutrition, just like exercise and social connection set a so sleep deprivation we know can in particular I think rapid eyes movement components of sleep deprivation can improve the symptoms of depression and yet um being sleep deprived can also really diregus ate our control of the automatic system I notice on two or nine three of poor sleep of on going through a stressful phase and that happening always said, my heart rate is chonkina elevated. My thought patterns become really disrupted. I can't then exercise do at my decision making us thrown off my emotionality is more labeled.

The hinge, as we're referring to earlier, feels less in control under my control. And maybe I wonder sometimes if I enter that state they refer to earlier, where the dorso ador prefrontal cortex is no longer leading the singular ate, but the singular IT is now in charge. The players are in charge.

Coach, yeah, not a good situation. So I know you have done some work on sleep deprivation and light and affects. Please tell us about that. And please tell us about this triple therapy.

Yeah, yeah. So front mine great salem one another. One of the professor at stanford very interested in sleep.

He did bunch, bunch of training asleep before we went to medical school. And gover interest in this idea. That is your thing.

If you sleep, deprive somebody one night in just kind of an isolated single night, in the the end of that sleep ed deprivation, they will have an entire press and effect. But as soon as they fall to sleep, they lose IT. So if it's a depressed individual, you get them to be less depressed acutely.

Soon as they fall asleep, they wake up eight hours later than they come. They come back into the same level, depression. And so the idea is that you needed to do some sort of circadian reset. And that part, what part of what depression is, is IT a deregulated circadian system. And so minor is a mindset.

Fe, if you just get the sleep Better, half the battle of dealing went depression because so many people have in soma around depression and have A A whole host of types of insomnia, having hard time, falling asleep, waking up in the midst night and waking up earlier, all symptoms of depression. And so what this does is IT sleep deprived the individual. And then there's a certain calculation of shifting their face and simultaneously exposing them to bright light.

So that's the trip of the phase shift, sleep deprivation in the bright light to try to get their circadian rythm. Essentially the theory is rein trained. And so um in in the trials that we've done and other trials um prior hours and after, you looked like there was a prety pretty profound anti depressant effect from this triple this triple therapy that seemed to be durable, meaning durability is this term.

We used to say that not only can you get kind of point relief, but that the relief ends up lasting. What's important to know about this is like you shouldn't do this home for sure, this what you would need to do this with the professional, because it's complicated. It's not just one thing.

And IT in sleep deprivation, while IT seems to be entered the present, its pro anxiety. So if you take a highly ancient person's not depressed, you sleep, deprive them, they get profoundly anxious. And so that's the other thing that, that you have to really realize is that this is like everything else that have talked about today, all things that you have to do under medical supervision.

But curious, right? I think you know that the question that always comes up as why isn't this used more? And I think the reason is that there's not really a mechanism for you know, ultimately in in medicine as sad as IT is you have to have a code to do a thing.

There has to be a code associated with a treatment. And it's hard to figure out how to make a code for this. And so I think that's part of IT.

And so if if there is a way and somebody he's gotta take that but on on that, but if there's a way to make a code for this, I think you could you could actually turn them into something was more widely widely utilized. And you know we pray, dream up ways have had to integrate A I passive since all that stuff to really make that work. Um but I think that would be that would be the the idea that be the trajectory. I'd say.

yeah, having a available to insurance code is fundamental. And a lot of listeners of this podcast, I think, have a background in engineering science. And we will put a link to that manuscript that talks about the triple therapy because here we're talking about one night week deprivation, some talk time, light exposure to the eyes and and then shifting in the circadian and clock in central to the themes of this podcast up often um I think for the typical person, can we say that trying to get a regular light dark cycle and sleeping yelm would be beneficial for overall mood regulation .

yeah I think for the typical person um you know really really kind of irregular your sleep and and tend to get you know a good night sleeping which you fall asleep, stay asleep, wake up in a set time every morning is gonna be pretty crucial. Um you know in mild depression, I think that one has a lot of control over that.

As we were talking about earlier, I think when you you hit some thresh hold depression, where things become kind of semi violation, it's harder took kind of wall yourself into that um there are therapies like um you know there's A C B T for insomnia, for instance, renew cognitive behavioral therapy to help in soma. Sometimes people and i'm no sleep expert that can pass this to greg to fully talk about this. But but, but some of what goes on that people kind of milder in somalia, experiences like blue light out of their computer and things like that, that they should use like blue light blockers to, and tricks your your brain you know Better than me, and trick your brain to think that still light outside.

And so people will, you'll have insomnia because their brain still thinks that it's light outside and then people will, you know the kind of strip cbt for sleep um you know um therapists will say there are only two things that you should do in your bed and if you're under a certain age and what not is really one thing that you should do in your bed, which is to sleep and be with your partner, right? So those are those are kind of the two um the two things that you should do in a bedroom and that's really the only things that you should do in a bedroom. If you're having sleep problems, you shouldn't watch T, V in a bedroom, eating bedroom.

hanging our phone out of the bedroom.

keep the phone out of the bedroom yeah .

um we should get great sale on the podcast. We the all just mention for people that want to regulate their sleep, we have a sleep tool kit that's available as a downloadable PDF at human lab outcome. Just go to the menu and a lot of the things in that tool kit are based on work from stanford sleep laboratories, including Jamie's sightings and others.

Lab, i'm not aimed at depressions specifically. Listen knowin doctor Williams, this has been an amazing voyage through the circuitry of atomic control. This landscape of the prefrontal cortex is, I find incredibly fascinating. And I I just to start off by saying, please do come back again and teach us more about that and your tms work. I before we wrap, however, I do want to give you the opportunity to talk about the same study is same or same plural?

Yes, same, so so same. Or were calling in S N T now say, has you know the intent was not to help you to kind of connect IT to religion, but but we may have accidently done so. And so we we abbreviated IT to S N T for the for the subsequent trials, which is initially stanford accelerated intelligent neuromodulation therapy, or now we're calling stanford neo modulation therapy.

But it's the idea there, which is a cool idea, that T, M, S is a device that delivers, delivers a treatment. And the treatment is the protocol, and the protocol is the stimulation parameter said in a specific brain region for a specific condition. And so what's cool about, nor modulation, whether to be transferral magics stimulation or transcranial direct current stimulation or the brain stimulation, like what casey help and talked about on another podcast, is this idea that in all those cases, the device itself is a physical layer content of a stimulation protocol that's their aiuto for a given condition in a given brain region.

And so in the case of depression, which we know the most about for with tms, we've been doing tms studies for depression for, you know, since eighteen named, five wrote in a clear rance in two thousand, two thousand, eight, two thousand and nine. And in that in that time frame, we were able to go from really knowing very little at all about how to do something like this to getting an fda clearance. In the way that I went down was that there were two groups studying um different components in in I H the first group was studying mood neuroanatomy on functional imaging.

That was kind of the first generation of functional imaging back then to pet scans, which you're kind of metabolic scans um and then expect scans. And the idea there was looking at activity and metabolic and preferences cortex and what they found in these can more crude scans is a just general hypotheses vy hypo metabolism. The other group, red stairs at the national institute for neurological diseases and stroke in I N S.

They were looking at using TM s, which had been around for ten years, and repetitively stimulating in motor cortex. What they found was, gosh, we can get a read out in throw a muscle movement amplats that's really reproductive across people. It's like univerSally reproducible.

And if we do certain stimulation approaches, they are biologically active to either increase excitability I either the motion and a set intensity goes up, the amount of ample to goes up, or in habitual d potentiate, IT goes down with other biological stimulation approaches than a third outcome, which is important, that is, in earth, IT doesn't do either. So you can stimulation approaches to do one, you know, increase activity, decrease activity, or or, or inert. And so what they found was, oh, we can cite certain brain regions.

And my mentor, my jorge said, had this kind of aha moment. We said, wow, there's under activity and preferences cortex in depression. And we can increase activity using this thing that we know.

We can increase activity, motor cortex. We just need to put IT in the left or salata preference core tex. And then they combined the two and started stimulating once a day, kind of very abbreviated fashion. In long behold, some of those depression patients resolved the depression.

And back then, and still today, you can go and as the psychiatry patients stay at the nations to the mill health and go through clintrials, try to get treated and their patients had been there for months and they are able to be discharged because mood was Better yeah and so this very crude approach where they are using rural measurements, where deal pfc. Was and they were stimulating with devices that you needed to physically dunk the coil and an ice bath. And with that, they still were able to, the kind of genius of this, amErica and others still be able to, to create A A purely engineer stimulation approach, which was cool about that, is that they kind of found two things, right? They found this one stimulation.

IT does have some entire press and effect is its limited. IT doesn't treat everybody, but does have some entire pressing effect in this bigger concept that a new modulation device is kind of like a pharmaceutical company for you, right? That in given individual a tms device or whatever the modulation device is able to generate to in create a stimulation approach that is specific to a given condition in specific to an individual.

And so the physical layer is just how you exert that similarly to how we make pharmacy ticals drugs and at pharmaceutical company. But the actual therapy itself is what you do, where you do IT. And so what we learned from, you know, another twenty thirty years of this is that you can modify the stimulation protocol in such a way you can create a whole new treatment and put IT through the same tms device, or think god you, an evolved version of IT, where you don't have to don IT nice and can actually really handle much more aggressive stimulation approaches.

And so in two thousand and five, a group polishin neuron, a paper demonstrating that if you, if you stimulate with the hip camp rythm through A T M S. Coil, you can excite the brain with memory rythm in at the last of an hour, so you can change coral, xie ling and the thun twitch for an hour, sending three minutes of excited tory or forty seconds. In the case of inhibitory ies stimulation that myself ics, they became rhythms so much more efficient than original T. M. S. approaches.

And so, you know, after that group tried to do IT this kind of six week schedule, and after that, you know, and while they were doing that, we decided, gosh, you know, this prom, I talked about the beginning of the show where you have this know this problem, that we 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 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 print about the space learning theory.

The idea for for the viewers is it's a simple psychological thing that we've also seen IT in hippo cample slice sort of physiology too, where if I am cramming for a test, what I do is I write out sixty note cards, and I read each one for a minute until I get to the first note carden again. And that's about an hour later, right? And we just, we just intuitively do this.

We all, we all, you automatically do that. And we intuit that because we know that what doesn't work is writing out one note card and looking at IT over and over again. Nobody ever does that, right? We we've all been in in grade school, medical school.

We have these big stacks and new cards. That space learning theory is the idea that you need to see about every hour to an hour and a half. And that optimizes learning.

If you take the same stimulation approach that i'm talking about, the status stimulation approach, and you take a hit, a cample slice of a mouse and you stimulate you, you enlarge some dangerous spines and you prime some. And then if you stimulate right after that, you don't get any change, is called in mass stimulation. But if you wait about an hour to an hour and a half, you get more dynamics, pines and large and more primed, which, by the way, also is what cademy does.

IT does that causes this injured spine and largest. And so you know, what we found was, is that the old way of doing tms, the idea of just doing IT once a day every day, five days a week for six weeks, didn't utilize the space learning through. It's like studying for a month to just a little bit once a day like you remember some of that stuff, but it's like not as pot as that week or 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 a way to do IT and day.

And then what we also figured out is that people are underdogs ing T M. S. Because if you just keep going, after six weeks out to months, three, four, five, more and more people get Better. So we figured out it's not just one day ring of five times a Normal do, even if seven and a half months worth than five days using space learning .

theory to every hour.

every hour for ten hours, for five days, for five days. So it's a fifty blocks ts, ninety minutes of actual stimulation, but spread out through the day in the same way of learning, which is perfect for an impatient psychiatry.

Five days manage.

Yeah, you get stimulation. Nobody ever dropped out by the schedule. The folks they want to do this, want to do IT still do there nine minutes they'll get breakfast.

We'll do there nine minutes they will go see their therapist, whatever IT is. And so what we found um with this reorganization in in time of the stimulation dose. And then the third component is we do a resting state, functional connectivity scans on everybody.

And we have ways now, on the last five, ten years of picking out that specific sub general del p fc sub circuit that I was talking about earlier, that single D L pfc. We can pick that out every single one. You you want to come to lab, we can find your .

D L P .

fc band, and we can, we can find that spot in each person. Instead of finding the same spot on the skull, we find the same spot on the brain. And we can stimulate. We do that every hour on the hour.

What we found what we have found is that folks will will within one to five days in more cases than not, depending upon if you're looking at open label or in trials, more between sixty and ninety percent of the time, they will go into full on remission in this since they're totally Normal from a moods standpoint at the end of this. And legal 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 know, we have had four years of permission, years of permission and it's it's really that cramming of the test. It's really that idea that you're laying in that information of the exact orate, but in the the signals, 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 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 not taking out out of the hypo campus is hand your own hippo campus is hand. You're sending the same signal. The hippocampus Normally signals out. Now you're sending that signal into the preferences 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 when they can 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, like some people, you know, not everybody, but there is a subsection of people with accessory where they will say, I kind of feel no, or if gi side effects, so I can't, I can't, you know, I don't have the sexual interest that I used to have and that sort of thing, you know, not anything necessary. Ze, as I said earlier, life saving, you know, for a subsection of people, these things really work. But with this, what you see is that people don't talk about that stuff. And I think it's it's likely because you're tapping into that core circuitry and you're reversing IT. You're doing IT with a with a magnet that because it's a very profound electoral magnet, the same field drink as an immerse scanner is able to induce the current in the brain in this vocal targeted way without getting into the rest of the brain, without getting into the rest of the body at all, and just really kind of acting only on that circuitry that's involved.

Incredible IT is the same study still ongoing? And if people are interested in potentially being um uh patients or subjects in the study, uh can we provide them a portal link?

Absolutely yes. So we have um now that the treatment um my some my students whenever a company called magnetic ticals, they've been working on this. We've got nothing a clearance now and and now books can get IT through trials over the next couple of years because it's gonna some time for that company to kind of get up and running and get a you to get a device and get the whole thing set up nationally.

But well, that's all going on. There's still about a thousand patients that need to be recruiting across a bunch of different trials all over the country will take people from anywhere in the country. We also have. Partners in new york can send the ago and and soon to be south garland and other places where we can actually know. My lab can help to kind of let people know where to go, where you based off where are at in the us, and get them access to being able to a trial.

And what we've trying to do is make IT so that even if you get the you know fifty fifty chance, you're going to get the real deal or you're going to get the the non real deal. But what we have figured out as a way to let everyone have access um if they if they got the not real deal version, the kind of shame version of the fake version for the first part of the trial, there are other trials where they can have access to the real version. So essentially everybody eventually gets access to having the real version. And so that's been a big thing for me is I I want everybody that comes through one of our trials to be able to have access. I think it's important while while you know the companies doing what they are doing and what the labs s doing and kind of nationally what you know other partner labs you're doing.

well, I can show you you're going .

to get some interest.

Thank you and thank you so much uh, for taking us on this incredible voyage through the neurosis, lying, certain aspects of depression, the coverage of the different types of depression, the various they are reputed compounds, how they work with. Talk about a lot of things, saying you shared so much knowledge and even as I say that I I very much wanna have you back to talk about many other things as well that we didn't have time to cover.

But but I just really want to thank you for the work that you do. I know we are colleagues, but um you run an enormous laboratory IT enormous my but forty people is a big group, very big group. Plus here you're in the clinic. You also have a life a of your own outside of work and 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, of avoiding off and suicidal depression is just incredible work and incredible generosity. Just thank you so much.

Well, thank you. Mean, I mean, I you know, similarly, I want to thank you for what you do. And I I think I think that I ve got a lot of friends of focus that are out of the medical profession, friends of mine, one of my buddies who's a real estate agent, who works with this, who's a big, big fan, your show and I told a couple of people like that I was coming on and um and they were like super stuck like know we watch we watch every show and you know super excited to watch um mine and they said something very important to me that you know you make this this complicated a neuroscience of in brain body science, successive you know in in a way that that you have a gift to do and I think that that's so important to them in this show is doing so much to to help a science literacy and yeah appreciate you so well.

Thank you. I'm gratified and honed by your statement, and I look forward to more. Thank you. absolutely.

Thank you.

Thank you for joining me today for my disgusting with doctor nolan Williams, I hope you found our discussion about psychic delicate, another compound about trans cranial magnetic stimulation, and about the treatments for depression in general to be as stimulating as I did. If you would like to learn more about the work being done in doctor Williams laboratory, you can go to the brain stimulation laboratory website, which is bsl that stanford die du.

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