Dr. Nolan Williams: Psychedelics & Neurostimulation for Brain Rewiring | Huberman Lab Podcast #93

Transcription for the video titled "Dr. Nolan Williams: Psychedelics & Neurostimulation for Brain Rewiring | Huberman Lab Podcast #93".


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Introduction And Guest Overview

Dr. Nolan Williams, Brain Stimulation & Depression Treatment (00:00)

Welcome to the Huberman Lab Podcast where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Nolan Williams. Dr. Williams is a medical doctor and professor of psychiatry and behavioral sciences at Stanford University School of Medicine. His laboratory and clinic focus on depression and other mood disorders. They focus specifically on the use of transcranial magnetic stimulation, which is a brain stimulation technique that can either activate or quiet specific brain circuits, as well as circuits within the body, in order to treat depression and other mood disorders. Other laboratories and clinics use TMS. What sets apart the work of Nolan 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 Ibogaine, psilocybin, MDMA, cannabis, DMT, 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 with Dr. Williams, we covered things such as the history of each of these drugs, how they came to be and their 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 psychedelic research and clinical use really looks like. For instance, we discuss how a number of laboratories and clinics are modifying psychedelics to remove some of their hallucinogenic properties while maintaining some of their anti-depressant or anti-trauma properties. You'll also learn about some fascinating research in Dr. Williams Laboratory focused on ketamine, which is a drug that is increasingly being used to treat depression. And contrary to common belief, the effects of ketamine in terms of relieving depression may not actually arise from its dissociative effects. One thing that you'll find extraordinary about Dr. 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 potent way, that is combining psychedelic 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 neurocircuitary 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. Williams's laboratory. I should mention that they are recruiting subjects for these studies. If you go to BSL, which stands for brain stimulation laboratory, so that's bsl.stanford.edu, 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 Dr. Williams was, for me, one of the more stimulating and informative conversations I've ever had about psychedelics, which is simply to say that his breadth and depth of knowledge on that topic is incredible, and his breadth and depth of knowledge in terms of the underlying brain science and how it 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 diseased brain work. I'm pleased to announce that the Huberman Lab Podcast has now launched a premium channel.

Sponsors And Key Topics Discussed

Huberman Lab Premium (03:31)

I want to be very clear that the Huberman Lab Podcast will continue to be released every Monday at zero cost to consumer, and there will be no change in the format of these podcasts. The premium channel is a response to the many questions we get about specific topics, and it will allow me to really drill deep into specific answers related to those topics. So once a month I'm going to host an Ask Me Anything, so-called AMA, where you can ask me anything about specific topics covered on the Huberman Lab Podcast, and I will answer those questions. Those, of course, will be recorded. There will also be other premium content available to premium subscribers, such as transcripts and short videos of new tools and unique tools for mental health, physical health, and performance. If you want to check out the premium channel, you can go to HubermanLab.com/premium. There's a $10 a month charge or $100 per year, and I should mention that a large portion of the proceeds from the Huberman Lab Premium channel will go to support scientific research that develops the very sorts of tools that we talk about on the Huberman Lab Podcast. The rest of the support for the Huberman Lab Podcast Premium channel will go to supporting the regular Huberman Lab Podcast. Again, that's HubermanLab.com/premium.

InsideTracker, Eight Sleep, ROKA (04:42)

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Inside Tracker. Inside Tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in getting regular blood work done. For the simple reason that many of the factors that impact your immediate and long-term health can only be analyzed with a quality blood test. One problem with a lot of DNA tests and blood tests, however, is you get data back about levels of metabolic factors, levels of hormones, etc., but you don't know what to do with that information. Inside Tracker makes interpreting your data and knowing what to do about it exceedingly easy. They have a personalized platform where you can go and you can see those levels of hormones, metabolic factors, lipids, etc., and they point to specific nutritional tools, behavioral tools, supplement-based tools, etc., that can help you bring those numbers into the ranges that are optimal for you. If you'd like to try Inside Tracker, you can go to insidetracker.com/huberman to get 20% off any of Inside Tracker's plans. Again, that's insidetracker.com/huberman to get 20% off. Today's episode is also brought to us by 8Sleep. 8Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. I started sleeping on an 8Sleep mattress cover a few months ago, and it is simply incredible. In fact, I don't even like traveling anymore because they don't have 8Sleep mattress covers in hotels and airbnbs. One of the reasons I love my 8Sleep mattress covers so much is that, as you may have heard before on this podcaster elsewhere, in order to fall and stay deeply asleep, you need your body temperature to drop by about 1 to 3 degrees. I tend to run warm at night, which makes it hard to sleep and sometimes wakes me up in the middle of the night. When you sleep on an 8Sleep mattress cover, you can program the temperature of that mattress cover for specific times in the early, middle, and late part of your night so that the mattress stays cool. As a consequence, you sleep very, very deeply. It also tracks your sleep, so it's paying attention to how many times you're moving, how deep your sleep is. It gives you a sleep score. All wonderful data to help you enhance your sleep, and of course sleep is the foundation of health, physical health, and performance, which makes an 8Sleep a terrific tool for enhancing your sleep, but all aspects of your life really. If you're interested in trying an 8Sleep mattress cover, you can go to 8sleep.com/huberman to check out the Pod3 cover, and you can save $150 at checkout. 8Sleep currently ships to the USA, to Canada, the UK, and select countries in the EU and Australia. Again, that's 8sleep.com/huberman to save $150 at checkout. Today's episode is also brought to us by ROCO. ROCO makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two All-American swimmers from Stanford, and everything about ROCO eyeglasses and sunglasses were designed with performance in mind. I've spent a lifetime working on the visual system, and I can tell you that your visual system has to contend with some pretty significant challenges in order to be able to see clearly as you move from one area to the next, for instance, when you go from a shady area to a bright area. ROCO understands this and have designed their sunglasses and eyeglasses accordingly, so you can see with crystal clarity. In addition, because they were initially designed for performance, things like running and biking, they're extremely lightweight, but they have a terrific aesthetic. So unlike a lot of eyeglasses and sunglasses that were designed for sports, they make you look like a cyborg. They have styles that make you look like a cyborg if you like those, but they also have styles that you'd be perfectly comfortable wearing to work or out to dinner, etc. They're really terrific glasses. I love mine because I can wear them anywhere, and I also use them when running and going out hiking, etc. If you'd like to try ROCO eyeglasses or sunglasses, you can go to ROCO. That's R-O-K-A dot com and enter the code Huberman to save 20% off your first order. Again, that's ROCO R-O-K-A dot com and enter the code Huberman at checkout.

Momentous Supplements (08:37)

On many episodes of the Huberman Lab podcast, we talk about supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them, things like enhancing sleep and the depth of sleep, or for enhancing focus and cognitive ability, or for enhancing energy or adjusting hormone levels to optimal range for you. The Huberman Lab podcast is now partnered with Momentus Supplements. To find the supplements we discuss on the Huberman Lab podcast, you can go to LiveMomentus spelled O U S, LiveMomentus dot com slash Huberman. I should just mention that the library of those supplements is constantly expanding. Again, that's LiveMomentus dot com slash Huberman. And now for my discussion with Dr. Nolan Williams.

Depression, Risk Factors, Emergency Psychiatric Treatments (09:16)

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, I 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 in the potency of those tools is growing. So if you could educate us on depression, I'd really appreciate it. Yeah, absolutely. So depression is a condition that it has 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 and they're kind of overactive. You can have people who don't have any anxiety at all and they're very underactive and they have low motivation to do anything. You know, 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 folks like Connor listed in Cornell and try to actually get biotypes based off of neuroimaging to see if we can kind of parse out the different depression kind of presentations and see that clinically and also see that in the brain. Depression is the most disabling condition worldwide. What's interesting about depression is it's both a risk factor for other illnesses and it makes other medical and psychiatric illnesses worse, right? So recently the American Heart Association added depression is the fourth major risk factor for coronary artery disease, right? So alongside the risk factors that we know, hypertension, high blood pressure, hyperlipidemia, high cholesterol and diabetes, you know, high blood sugar, those three have been on the list for a long time and depression and being added to the list is the fourth one. And you know, really interesting, right? So in addition to taking medications to address those other three risk factors, we really have to be thinking about 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's 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 a heart attack in the individuals and of 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 measuring kind of brain heart connections and we can actually with transcranial magnetic stimulation, a form of brain stimulation, we can actually decelerate the heart rate and capture that heart rate deceleration 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 a very disabling condition, moderate depressions about is disabling is having a heart attack, acutely having a heart attack. Severe depressions is disabling is having cancer without treatment, you know, and dying from a cancer without treatment. And so, you know, it's kind of under appreciated just how disabling depression is in that way. And I think important as stigma is consistently kind of being reduced over the years for mental illness, for mental illnesses, than the idea that we can start really putting more funding and putting more focus at the federal level, you know, private foundation level, whatever it is at a given university to thinking about developing treatments. We've been very interested in a very particular clinical set of problems around the most severe and the most high acuity settings that folks with depression end up being in. And that's in, you know, emergency settings where they go into inpatient units. And you know, and the rest of medicine, if it's talking about heart attacks, if I start having chest pain right now and you bring me to a primary care doctor's office, they're going to have a certain number of tests and treatments, right? But very limited because it's an outpatient facility. If you bring me to the emergency room after that, there are more tests and more treatments. If you put me in the ICU or in the cath lab where they do invasive procedures to the heart, there are more tests and more treatments. In psychiatry, as we elevate the acuity of an individual, you go from being just depressed to being depressed and now thinking about ending your life, the number of treatments actually go down on average. I mean, in some scenarios they go up, but on average they go down and there are no tests, right? And so we've been very focused on that particular problem. Somebody that maybe was doing fairly okay with a pretty moderate depression and then the depression gets worse. And then they end up in an emergency setting and the field really hasn't developed a way of, you know, consistently being able to treat that problem and folks end up getting the same standard oral antidepressants that they've been getting outpatient. And I came to this because, you know, dual trained as neurologists and psychiatrists and went back and forth between neurology and psychiatry, saw that in neurology we have all of these ways of treating acute brain-based problems and really wanted to emulate that in psychiatry and find ways to develop an engineer new, you know, brain-based solutions. There's a lot to unpack there.

The Brain-Heart Connection, Vagus Nerve, Prefrontal Cortex (15:11)

One thing that you said is I'd like to focus on a bit more because I think we hear that the brain and the heart are connected, but you described, I believe, 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 at the same time, many people out there probably think of the relationship between the heart and the mind as kind of woo or kind of a soft biology. But here you're talking about an actual physical connection between what area of the brain is it? The first place where the stimulation goes is called the dorsolateral prefrontal cortex. It's kind of the sense of control kind of governor of the brain. And then what we know is that when you use a magnet, use kind of what we call Faraday's law, this idea of using a magnetic pulse to induce an electrical current in electrically conducting substances. So in this case, brain tissue, but not skull or scalp or any of that or hair, you avoid all that, just the brain tissue. Then you have a direct depolarization of cortical neurons, the surface of the brain's neurons in this dorsolateral prefrontal. And if you do that in the actual scanner, which we can do, you can see that that distributes down into the enterosyngulate in the insula and the amygdala. And ultimately, the tract goes into something called the nucleus tractus solidarius and ultimately into the vagus nerve into the heart. So the heart very consistently seems to be the end organ of the dorsolateral prefrontal cortex. If you measure heart rate in standard ways that cardiology measures your heart rate and you stimulate over this left dorsolateral, you get a deceleration of the heart rate. It's very time-locked to the stimulation. So it's a two second train of stimulation. At one second, you see the deceleration. It goes down about 10 beats per minute and then it'll drift back up and there's a break, great seconds on the stimulation and drifts back up and the stimulation goes back in and then the heart rate goes back down. So you see the heart rate just do this 10 beats per minute every train. And so we know, and if you do that over visual cortex, you don't get that or motor cortex, you don't get any of those findings, it's really specific to this kind of control region of the brain. And so, yeah, it seems to, you know, it's our work. Other folks work, Martin Arnes in Europe. The Netherlands work showing the same connections. I think it's been replicated like four or five times.

Right vs. Left Brain Hemispheres & Mood Balance, Connectome (17:51)

So you mentioned left dorsolateral prefrontal cortex. Any time I hear about lateralization of function, I get particularly curious because obviously we have two mirror symmetric sides of the brain. There are rare exceptions to this, like the pineal and things of that sort that are only there is only one pineal. What is special about the left dorsolateral prefrontal cortex? Does this have anything to do with handedness, right hand or left hand? Because we know right hand and left handedness has a lot to do with lateralization of function for language. A topic for another time. But why do you think that left dorsolateral prefrontal cortex would be connected to the heart in this way? Yeah. Yeah, I think so left dorsolateral, you know, is thought to be the side that when you excited, when you kind of do excitatory stimulation, potentiating sort of stimulation that you can reduce depressive symptoms. And a guy by the way, Mike Fox at Harvard, it's demonstrated that if you have strokes in the brain that cause depression, you put them on the human connectome 100,000 patient map and you ask the question what they're all functionally connected to, left dorsolateral. If you take lesions that cause mania in individuals and you put those all on the human connectome map and ask what they're all, the one common area they're all connected to, it's the right dorsolateral and so there seems to be hemispheric, you know, you know, balancing of mood between these two brain regions. And we know this from an experimental standpoint too because you can take individuals with depression and you can excite the left or you can inhibit the right and they're both anti-depressant. You can excite the right and that's anti-manic in some studies. And so this idea that there is this hemispheric balancing of mood is quite interesting, right? It's incredibly interesting. And just so people know if you're curious what the connectome is, a connectome is a term that was built out of this notion of genomes being a large collections of sequencing and mapping of genes. They're proteomes of proteins of connectomes as so-called connectomics of connections between neurons. Even connectome project is ongoing and I find that incredible that within the connectome project they can identify these regularities of right versus left or solato prefrontal cortex especially since I've looked at a fair number of brains from humans, not certainly not as many as you have. And if you look at the architecture, the layers, the cell types and even the neurochemicals of which cells are expressing say dopamine or serotonin or receiving input from areas that make dopamine or serotonin, they don't look that different on the right and left side. And yet here we're talking about a kind of an accelerator and a break if you will on depression and mania using what, at least by my eye and I think other people's eye look to be basically the same set of bits, the same parts list, more or less. So what gives these properties to the right and left or solato prefrontal cortex? Is it the inputs they receive? Is this something that we learn during development or do you think that we come into the world with these hemispheric biases? Yeah, it's a great question. And it hasn't been worked out which your original question was around in a left handed individual which as you know 25% of those folks end up having a right brain dominance or 1% of right handed people have a right brain dominance if it's flipped. And that unfortunately that study still hasn't been done at the level because that would be probably pretty helpful for teasing some of this out. But it's still being sorted out. 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 gotten so interested in it that they've been able to get a mechanism of why that is. But it's kind of empirically true in the sense that you can push and pull on those systems or in the case 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 causal bits of information point to this asymmetry. Interesting.

Heart Rate & Depression, Behavioral Interventions, Transcranial Magnetic Stimulation (TMS) (22:34)

Well in that case going with what we do know that stimulation of dorsolateral prefrontal cortex slows the heart rate down transiently but it slows it down and seems to alleviate at least some symptoms of depression. Leads me to the question of why would that be the case? Is it, does it tell us anything fundamental about depression that anxiety is inherent to depression, I think of faster heart rate as part and parcel with anxiety. In my laboratory we've studied fear a bit in animals and in humans and we often observe brachycardia where somebody or an animal is afraid of something and rather than the heart rate speeding up it actually slows down something that most people don't think about or recognize. But given that stimulation of dorsolateral 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 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 were to have or find other ways to slow the heart rate down say with a beta blocker does that help alleviate depression? Yeah that's a great question. I'll answer the second question first. We know that in their ongoing trials of this if you stimulate in the vagus nerve and an implanted vagus nerve stimulator you can actually have this afferent parts of the vagus. You project ultimately up to the DLPFC through the cingulate through these anterior insula so that's obviously the same tract and you can stimulate there and alleviate depression which seems very unusual. You're stimulating a cranial nerve down on the neck but if you can get up into the brain you actually can improve depressive symptoms. More evidence that this is a whole track and system and if you stimulate in part of that system it appears that you can improve mood. What if I were somebody who did not have a stimulating electrode in my vagus nerve and I was dealing with minor depression and I decided I wanted to take some other approach to slow my heart rate down via the vagus. For instance, exhale emphasized breathing or deliberately slow cadence breathing. Things of that sort. Is there any evidence that behavioral interventions of those kinds can alleviate depression or some symptoms of depression and is there any evidence that it does indeed feedback to the dorsolateral prefrontal cortex to achieve some of that alleviation? Absolutely. Yeah. There's a number of studies implicating the dorsolateral and say meditation, mindfulness, that sort of thing and they're small studies but pretty well designed studies suggesting that behavioral interventions in mild depression actually work quite well. There seems to be a volitional threshold for depression where at some point you start losing it, you go from being completely in total volition to having kind of semi-volution. You have thoughts that you really have a hard time controlling and that sort of thing. When you go through that threshold at some point it gets harder and harder for those sorts of things to kind of kick in and work. In the extreme form of that is catatonia, right? More people in a very severe form of depression get kind of stuck motorically, right? They obviously can't. They have no control or very limited control. I think there's a threshold in which these sorts of interventions will work. Exercise seems to really be a good treatment for mild depression and it may work through the mechanism you're describing, right? We all know athletes hold a lower resting heart rate than folks that aren't. If you were an athlete, you had a lower resting heart rate, you stopped exercising and a couple of years later your resting heart rate in many cases goes up, right? Maybe that's part of the process. I'm not aware of any studies specifically looking at dorsolateral prefrontal physiology pre-post exercise but it would be a great study. I think that would be really helpful to understanding this especially if you had a correlation of changes and kind of lowering of say heart rate with mood improvements. There's been a lot of work with heart rate variability and depression and studies are kind of point towards it. Not every study is positive for this 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 heart brain risk. I'm both intrigued and a little bit perplexed by this relationship between heart rate and depression. On the face of it, I would think of depression as depressed. A lower heart rate might make somebody more depressed. You've even mentioned catatonia or somebody that just doesn't seem motivated or excited to do anything. I think of mania as elevated heart rate and being excited. On the other hand, I realized that anxiety which brings about ideas as elevated heart rate is also built into depression which brings me back to what you said earlier which is that when we say depression, are we really talking about four or five different disorders for lack of a better word and for what percentage of people that have depression does some approach to reducing heart rate work, whether or not it's stimulation of the dorsal lateral prefrontal cortex by way of transcranial/minal stimulation or by taking a beta blocker or by stimulating the vagus. Can we throw out a rough number? Does that help 30%, 50%? How long lasting is that relief? Yeah, and to be clear, the deceleration of the heart rate is in the moment when the stimulation is happening but it's not something that's necessarily maintained chronically. It's more of an indicator that you're in the right network more than it appears to be itself central to the mechanism. The heart rate variability piece may be and there's some studies that link the tube. 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 and the mood system just sit next to each other and the stimulation hits both. If you look at how much of the variance in the mood is explained by the heart rate deceleration, it's not a huge amount. It only explains a small percentage. It's unlikely that simply reducing the heart rate and in fact for many years, propanolol and these sorts of drugs actually were implicating causing depression and so that's been kind of debunked but it's unlikely that simply decelerating the heart rate is going to improve depression but what it does tell you is that if you're in that area that is the mood regulatory area, there's some parasympathetic cortical kind of process that's going on that gets in and causes this to happen and it's independent of mood. You can take a normal healthy individual and you can do this and they're going to decelerate their heart rate. I'm so glad you mentioned the parasympathetic nervous system which of course is the most people think of as the rest and digest or the calming side of the autonomic nervous system. As I'm hearing you say all of 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 with depression although I think streams that might be true but rather it's something about the regulatory network, the ability to control your own nervous system to some extent. When I think about the autonomic nervous system, I like to think about it as a seesaw of alertness and calmness and when you're asleep it's for a lot of calmness and when you're panicking it's a lot of alertness but that and I don't think this has ever been defined and when I teach the medical students at Stanford Neuroanatomy, my wish is that someday I'll be able to explain what the hinge in that process would be. Not the ends of the seesaw. We know what the sympathetic nervous system is and what it's to wake us up and make us panic or make us feel nicely alert and calm. We know what puts someone into sleep or a coma or makes them feel relaxed but what shifts from one side of the seesaw to the other and the tightness of that hinge seems to be what you're describing that depression is sort of a lack of control over inner state so that when I'm stressed I can't get myself out of it but when I'm feeling completely collapsed with exhaustion I can't get out of bed and motivated to do the very things that would help me get out of depression like a workout or social connection or eat a quality meal these kinds of things. So this is perhaps the first time that I've ever heard about a potential circuit for the hinge as I'm referring to. Does that make sense at all? Yeah, absolutely. I just want to make sure that I'm framing this correctly in my mind. Yeah, absolutely and in some studies if you do the same identical stimulation on the right door slatter we can get an acceleration. Just kind of further confirming this idea of lateralization, right? It appears that even the prefrontal cortical areas seem to be lateralized in this way and I, you know, it's less, the right finding is more variable depending upon the study the left is very consistent in this way. So we've talked about Schren's cranial mednetist stimulation for getting into these networks and I also just want to take a brief tangent and say, 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 vagus nerve being important per se. It's really about a network, a series of connections. I think that's really important for people to understand and is kind of a new emerging theme really. The other thing that to me seems extremely important for us to consider is what are these lateral prefrontal cortices doing?

Prefrontal Cortex & Cognitive Control, TMS (33:02)

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 talk ourselves into a manic state or an excited state, a positively excited state that doesn't qualify as many other areas of the brain? I think of they is responsible for perception or for motor control. But here we are in this mysterious frontal cortex area, which people say, executive function, planning, et cetera. Are we talking about thoughts? Are we talking about structured thoughts? Are we talking about dreamlike thoughts? What in the world is going on in the prefrontal cortex? And here I spend my career in neuroscience and I still can't really understand what it's doing and maybe it's doing 50 things. Yeah, that's a great question. So one of the studies that we've been working on in addition to the depression work is actually trying to change trait hypnotizability. So David Spiegl and I have been working on this. And he's found and published this 10 years ago that a different part of the left door slateral is functionally connected with the dorsal anterior cingulate with a lot of functional connectivity and high hypnotizables and not much in low hypnotizables. And that's a different kind of a different sub-region within this bigger brain region we call left door slateral prefrontal cortex than the part that seems to be important for regulating mood. And so the left door slateral seems to have connections that are location specific within the overall kind of named brain region that connect to various parts of the cingulate and seem to regulate it. And so if you knock out the left door slateral prefrontal cortex and you have people do the strup task for instance which is a task where you have, it's a simple task. You probably know this, you have people name the color of words. And so if I look at one of the cards that they'll show you, it'll have the word red in red and that's very easy and that's called a congruent. And then the incongruent is red in the color blue and you have to name, you have to say the word you don't name the color. So you have to suppress a response. Yeah, exactly. And so I'm sorry you do that, you name the color and you see the word written in a different way. And if you stimulate in a way that inhibits the left door slateral prefrontal cortex or either one, you can actually knock out the ability to do that well and it'll take longer for people in the incongruent cards to be able to name it. And so they have a kind of a time delay that's greater than they had before they got stimulated. So that's a part of the prefrontal cortex that's different than the part of the prefrontal cortex that's involved in mood regulation. The nice thing about TMS is that you can go through and you can find these areas that are 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 prefrontal cortex and its function, this part? And so we were able to stimulate in an inhibitory way within the left door slateral prefrontal cortex that's involved with this sort of cognitive control area and we were able to knock that area out and increase trait hypnotizability. So people had greater hypnotizability after they got active stimulation versus when they got sham. And so it suggests that that brain circuit is involved in the process of what therapeutic hypnosis ends up being. But it's a very different region within the left door slateral than say we do when we do these very intensive stimulation approaches to treat severe depression and we're able to get people out of depression. You know, with the part of the door slateral it seems to be lower in the kind of more lateral and inferior on the DLPFC and connected with this subgenual anterior cingulate. So the part of the anterior cingulate that processes emotion.

AG1 (Athletic Greens) (37:46)

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Belief/Identity “Rules”, Re-scripting, TMS & Talk Therapy (39:00)

You're saying in one moment the rule is you read whatever the word says and then you switch and then you say the rule now is you tell me what color the word is written in and you suppress whatever it is the word says. Okay. That's right. Okay. A rule in some sense is like that is a transiently adopted belief system. So I could imagine that in depression which has all sorts of backstory to it that of course the psychiatrist or psychologist or friend can pull on that thread. Like for instance 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 we'll talk about or that they will never succeed or that even if they keep succeeding it's just going to get harder and harder and it will never feel good. These are sort of rules like the Stroop task. That's right. At some level. They're rules that are more pervasive over time unfortunately. But I could imagine that if the PFC is also contains some sort of maps or algorithms related to rules of emotionality or self representation or things that we've heard I think there must be data out there that's saying that whatever 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. Now I think it was kind of cool. But anyway the point being that we have an intense memory for these things is set up a sort of rule or a question like maybe I don't really know how to dress for instance. Maybe that's why I always wear the same black shirt. But in all seriousness it seems like the Doris et al prefrontal cortex is in this amazing position to access rules which are beliefs and beliefs are rules and then for moments or longer to switch those rules. And so for somebody who's depressed to just simply look themselves in the mirror and say you are great you are fantastic that's 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 read that card is green when your eyes tell you that it's read. And it seems like there's something about prefrontal cortex that in principle gives flexibility to rules based on what we know in this group task. So given its connectivity can we assume that the talk therapy that occurs in a psychiatrist's office or with a friend or through journaling out something because we do know that reporting things about trauma or difficult circumstances or the rules that we contain and tend to hide inside of us about how we feel miserable about ourselves or anything really. But in re-scripting that that somehow it allows us to do a sort of strip task on our beliefs is that is that a tremendous leap. I'm just really trying to frame this in the context of what what I and most people think of as depression. Yeah totally. Because the network components are vitally important but I guess what I'm trying to figure out is like what are the what are the algorithms that govern prefrontal cortex. Yeah absolutely. Kind of standard cognitive behavioral therapy session right what the therapist is just trying to do is identify those beliefs and kind of determine how fixed they are, if they're flexible as you're saying and then help folks to find another explanation for them and to kind of reintegrate that potential other explanation into their memory system right. Where I think TMS is really interesting actually we have a lot of patients who've told me like my therapist told me that I wasn't trying hard enough in therapy and you know and I really am trying hard but these are you know moderate to pretty severe depressed patients. And as soon as we get them well with the TMS approach is you know kind of rapid you know a five day approach and the next week we come in and see them and they'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 prefrontal cortex on and have it govern these deeper regions and depression the deeper regions govern the prefrontal cortex they precede the prefrontal cortex timing wise we've got some data in review now or we're seeing that in depressed individuals that are responsive to our rapid TMS approach we call Stanford Accelerated Intelligent Neremodulation Therapy or S&T or S&T. If you look at the brain before people get this they will have a temporal delay where the cingulate is in front of the DLPFC and in people that are normal healthy controls no depression the dorsolateral prefrontal cortex is temporarily in front of the anterior cingulate with effective treatment we can flip the timing of things so the dorsolateral is in front of the anterior cingulate just like in a normal person. So you're not talking about obviously physically moving these structures talking about in time the time they're activation so in one case it's like the coach telling the player what to do and it's like a player telling the coach what to do and you restore order to the game and what it looks like is depression to your point is a bunch of kind of spontaneous content that's semi-volitional that's being kind of generated out of this conflict detection system the cingulate seems to sense conflict and kind of feed that information it's overactive in depression and then in depression it looks like the left dorsolateral does not sufficiently clamp down on it and what therapy appears to do is to kind of restore that what we see with TMS over that region is that we just exogenously do the same sort of thing we restore the governance of the left dorsolateral over the cingulate area and that is correlated with treatment improvement so the degree in which you can re time re regulate in time the left dorsolateral over the cingulate the more of an antidepressant effect you have.

Dorsolateral Prefrontal Cortex, TMS & Depression Treatment (45:49)

Can we therefore say in crude terms that the dorsolateral prefrontal 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 you can do these experiments where you can put a normal healthy control person 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. So you can experimentally manipulate the system and so kind of buffing it up it's like almost TMS is almost like exercise for the brain right you're kind of exercising this region over and over again with a physiologically relevant signal and kind of turning that system on and what's interesting I think really interesting for this show is to you know we had a couple of folks you know probably five or six folks that have actually told me this where if they were met early enough in the week we have this very dense stimulation 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 if they get better on day one we still give them the other four days because it's in the protocol to do that and we can't. We're getting to a point where we can tell how long it's going to take but we're not there yet and so you know every time somebody gets better at day one or two at the beginning when we first started doing this we'd say you know we're 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 you know they're by Wednesday they're like totally zero down the depression scales you know even better than most people walking around like really no anxiety no depression or anything by Thursday the first guy that told me this he came in and he said you know I was driving back to my hotel and I decided to go to the beach and I just sat there and I was totally present in the present moment for an hour and he's like I read about this in my mindfulness books but I experienced it last night and I'm never experienced anything like this before and I was like hmm that's interesting but kind of wasn't sure and then and then I didn't tell any you know obviously any more patients about that and then about five over the last couple of years when they get they were mid early in the week by the end of the week they're like going to the beach and they're like totally having what people describe is a pretty mindful present moment sort of experience which is really interesting you know what that is I mean I don't have full on scientific data to tell you but it's just it's an interesting anecdote right that folks when you push them through this point of feeling kind of clinically well that some people end up reporting the seditional set of features so yeah you mentioned the singular and the enter singular in particular because now I feel like for the first time in my career I have some sense of what prefrontal cortex would actually be doing besides providing a bumper for the rest of the brain is the cingulate 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 prefrontal cortex but what's mapped in the cingulate in the ends for the non-neuro scientists out there when I say mapped if we were to put someone

Cingulate Cortex & Emotion, Dissociation & Catatonia (48:36)

in a scanner and focus in on cingulate or put an electrode in there what makes the neurons in their fire what sorts of things in the body and in the mind and out in the world light up for lack of a better phrase the cingulate what does the cingulate like yeah yeah so so that strip task those incongruent word color associations the the dorsal part of that for obsessive compulsive disorder patients certain you know certain kind of triggers you'll you'll see some some of their imaging studies will point to to enter your cingulate in the kind of very crude psychosurgery world 50 years ago the entire singularity was a way of treating obsessive compulsive disorder right because that area seems to be overactive in people who are experiencing obsessive compulsive disorder you can kind of walk the cingulate wraps around you know this white matter track like bundles it wraps around that and so there's a part that's above that around that and below that and depending upon how emotion how much of the the conflict task has an emotional component the more ventral and subgenual that that activation is so the dorsal part of the anti-resingulate seems to be kind of more of a pure cognitive maybe obsessive compulsive disorder sort of area whereas you start getting into mood sorts of triggers like facial expression conflicts where you're supposed to you know there's an emotional strip task where you show the word happy and then you have a face of a person that looks mad then that's another way of having the same sort of strip conflict that seems to be more periginual subgenual areas right so you can kind of you can trigger the cingulate based off the level of emotional valence from none down to a lot and that seems to be how the how it's distributed there are you know heart rate kind of components to it autonomic components in there too there's something called a kinetic mutism you know I'm a board certified neuropsychiatrist behavioral neurologist and I've seen you know a lot of these what we call zebra cases in neurology where people have you know these unusual neurological presentations and one of them is a kinetic mutism so you have a glioma sitting in the inter hemispheric fissure and kind of having pressure on the cingulate 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 cingulate works as well right it's it's like if it's 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 know online to be able to interact with the exterior world is it involved in some of the dissociative states that sometimes people who are very stressed or or depressed experience you said catatonia being an extreme one but I know someone for instance that when they get really stressed and it can even be if someone yells at them or someone's angry even if someone's angry with them or they perceive someone's angry with them there's a developmental backstory to why they likely feel this way they sort of just kind of can't this is a high high functioning individual normally and they just sort of can't function they can't complete simple things like email or groceries or things for a short while it's it's almost like a catatonia and they refer to as a dissociative state do you see that in depression and I mean we're we're speculating here as to whether or not that ball is a cingulate but what you're saying it holds a lot of salience for me in thinking about this example yeah yeah there's um so you see you see catatonia is an extreme outcome of depression and of um and sometimes it gets a friendie and other illnesses um dissociation is an extreme outcome or even some cases a less extreme outcome of PTSD and trauma and um you know and it's also a phenomenon that happens naturally in some people that are highly hypnotizable and so if you asked David Spiegel I'd say that um you know some of the work that he's been working on is around posterior cingulate and the uh capacity to dissociate but yeah you know with our stimulation approach to to dlpfc dorcel anterior cingulate one of the subscales that moved the most was the dissociative subscale for for hypnotizability so even a normal individual um you know you see that that change and in uh in that kind of experience of dissociation I am highly hypnotizable oh yeah David hypnotized me a number of times if we have a clip of that on our human life channel I I've always um well always it was starting my early teens I started exploring hypnosis I am extremely hypnotizable and um self hypnosis or assisted hypnosis um I don't know that I ever go into dissociative states uh I'll try and avoid um forcing you into running a clinical session right now but uh 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 ketamine which is a dissociative anesthetic is that right yep and yet and my assumption is that as a dissociative anesthetic that it leads to dissociative states where people can sort of third person

Psychedelics And Depression Treatment

Ketamine, the Opioid System & Depression; Psychedelic Experience or Biology? (54:27)

themselves and be somewhat distanced from their emotions yes I've also been hearing that there are emerging treatments psilocybin being one of them but some other treatments uh MDMA etc that will parse each of these in in detail that lead to the exact opposite state during the effect of the drug which is a highly engaged um emotionality and heart rate and sense of self yeah and can also lead to relief of depression now whether or not this again reflects that depression is many conditions as opposed to just one or whether or not somehow tickling uh or in some cases pushing really hard on the opposite ends of the the scale really matter I am absolutely fascinated and again also perplexed by this why would it be that a drug that induces dissociative states and a drug taken separately that induces hyper associative states would lead to relief of the same condition yeah that's a great question yeah so for um for ketamine you know the the level of dissociation appears to be correlated with the theroputic effect it appears to be um necessary but not sufficient to produce an antidepressant effect and so um folks that that don't have any any psychological change um from the ketamine or or don't experience any dissociation typically tend to have less um less potent anti-depressant effects from ketamine we did a study a couple of years ago it was really interesting so we we gave folks uh naltrexone which is an opiate um antagonist mu and capo opiate receptor antagonist and we we gave folk the same individuals a pill of that or a pill of placebo and they had no idea which one they were getting was this low dose naltrexone 50 milligrams so it's pretty high dose okay yeah and so we we gave a typical ketamine therapeutic dose then we gave 50 milligrams of naltrexone or placebo and then in the same individuals we we gave two you know two infusions one with each of those conditions and and if they had an antidepressant effect we waited until they relapsed then we gave them the other condition and then we looked to see what um what effect of blocking the opioid receptor um what effect would you see on the antidepressant effect of blocking the opioid receptor with the idea that if ketamine works the way that a lot of researchers at the time thought that it you know completely worked in which is the glutamate system then you would have um no effect of naltrexone because naltrexone just interacts with the opiate system it doesn't do anything with any other systems ketamine has a lot of effects over you know it has opiate clear opiate effects um in mice in various ways of looking at that um and an mda receptor antagonism and glutamate of effects and so if it's just that the glutamate part is um is the part driving the antidepressant effect you shouldn't have any difference in the antidepressant effect between the two conditions if however the antidepressant effect is primarily is the the opioid properties of ketamine are necessary for the antidepressant effect then you should have a loss of antidepressant effect during the ketamine plus naltrexone condition that you observed in the ketamine plus placebo condition and what we what we saw was that there was a dramatic blockade of the antidepressant effect when naltrexone was present in this yeah in the people that had a had an antidepressant um effect with ketamine plus um placebo alone and um and then some friends of mine did a tms study with pain and they stimulated over the left or slateral prefrontal cortex and they gave naloxibinaloxone which works basically the same way as naltrexone and they were able to block the anti-pain effects of tms with a opiate blocker so this idea that another kind of convergent point right this idea that the opioid receptor may have a role in mood regulation what's also interesting is if you look at people that are getting a total knee operation very painful operation right um you know total knee replacement and you you age sex you know everything match the individuals that are going through that but you have a group of people that don't have depression and a group of people that do have depression the presence of depression triples the the oral uh opioid 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 transiently it seems to have a pro an antidepressant effect chronically it seems to have a very pro-depressant effect it 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 the the ketamine trial is that we didn't see any effect on the dissociation and so the dissociation was the same each time so the psychological effect of the what we call the trip or the the kind of dissociative effect where people are having a psychological phenomenon from ketamine that was identical both times and so it it kind of um it also challenged this idea that the psychological experience of the psychedelic effect may be all that's necessary to produce an effect and that the pharmacology doesn't matter as long as you can achieve that state and so you know we think we pretty clearly debunked that idea that the underlying pharmacology 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 you know essentially the psychological effect and still have a drug that works to to treat the the under the illness that you're trying to target and you know a lot of there was a mouse study out this week where they had an LSD analog and they were able to see some some animal level data to suggest that could be true but but until we figure that out in humans it's 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 and really understand what's what's doing what it's so critical and it's so critical to the other conversation that we'll surely get to which is the progression of psychedelics from illicit illegal 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 u.s. but just to make sure that people are getting this and how crucial this is what we're really talking about here is the fact that you know somebody takes a multi-gram dose of psilocybin or somebody takes MDMA or they take ketamine and they experience relief from their trauma their depression their addiction or any number of the other things that indeed those compounds have been shown to be useful for in certain contexts clinically supported etc. There's this gravitational pull to the idea that oh it was the hallucinations it was the dissociative state it was the feeling of connectedness and what we're really saying is that while 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 mu opioid receptor a lot of your experiments with naltrexone or a change in the underlying neuromodulation that had anywhere from nothing to something to do with the real shift and I know there's a group up at UC Davis that published a paper in nature about a year ago also looking at these are is a chemistry lab essentially modifying psychedelics to remove the hallucinogenic properties the mood altering properties and actually seeing some pretty impressive effects in shifts in mood after the drug wears off and I know this this gets people upset when they hear it a lot of people this gets a lot of people upset really yeah because people think oh no it's the it's the intense 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 liken it in my mind to you know it's like somebody it's 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 of connect the the experience of the of the actual birth to the connection when in fact there that's true it turns out but there are a bunch of other things happening too that are simply that's simply the reflection of the fact that you're holding a child and the pheromonal effects etc so anyway I think it's very important that these different variables be figured out along those lines I want to make sure that before we dive a bit deeper into ketamine and psilocybin um that we do touch on a really important topic that has been in the press a lot lately which is SSRI selective serotonin reuptake inhibitors because we can't really have a discussion about depression without talking about SSRI's and then I want to circle back to ketamine and psilocybin it seems that um there are now data in which that essentially state that there's no direct link between serotonin levels and depression although I my understanding

SSRIs, Serotonin & Depression; Childhood, Chemical Imbalance or Circuit? (01:03:42)

is that the SSRI's are powerfully effective for certain forms of obsession obsessive compulsive 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 SSRI's are they useful are they not useful um what's that what's going on with SSRI's your patients and and other other people as well yeah the um yes the experiment that I described a bit ago around the naltrexone and and ketamine is the first time I'm aware of where we were able to essentially eliminate an an antidepressant's effect by using a second drug as in kind of a blockade and it 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 controversy there is that um it's been difficult I think for folks um to see that something can in one hand work and in the other hand we don't know how it works right um and so um SSRI's clearly work um you know many many meta-analyses kind of proving that out right that that in a subpopulation of individuals they achieve great benefit from depression uh you know for depression uh for obsessive compulsive disorder for generalizing anxiety sort of panic you know all these things you can see uh an improvement in those symptoms with what we call SSRI's or selective serotonin reuptake inhibitors 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 uh between two neurons um for a while and allowing for more serotonin to kind of be there the issue um 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 plasti brain plasticity effects right we know that things like brain-derived neurotrophic factor get up regulated with chronic oral antidepressant use and and so that's that's kind of the idea is that um is that these things work but what's powerful and I think what the authors of this paper was extremely controversial paper were were in part trying to say was that there's not a there's not a deficit of serotonin you're not born with uh what people call a chemical imbalance and psychiatry is known this is not actually new information anybody you know it's it's kind of a rehashing of a bunch of information we've known for a while now but in the lay press it's kind of hit in a way that it didn't seem to grab attention um before with previous publications but this idea that this chemical imbalance idea is wrong um I really I really think that part's important because I think that um you know for a while I think psychiatry you know what I'll call psychiatry 1.0 right this kind of idea of Freud and psychotherapy and its and its origins um it was a lot around you know the your family and those experiences and psychotherapy kind of going in and correcting or helping you to figure out or and you know show you being able to see or people hear you so that you can eventually come to the conclusion of certain cognitions that aren't helping you right and there's a huge you know there's a huge importance there but there's a history where you know things like the schizophrenic mother and all that you know that was a concept at some point right and so we've transitioned from that to to the you know for a long time the chemical imbalance which I'll call psychiatry 2.0 you know this idea that there's something chemically missing and um and 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 you know kind of um kind of a person I mean kind of average American out there right is that it's telling it's sending a message of there's something missing with me whether it be my experiences I had no control of over when I was a child or um a chemical in my brain what I think is really powerful with with TMS um you know really powerful TMS and a level even powerful the psychedelic story is it saying something different you know TMS works and there's no serotonin coming in or out of the brain right and we're doing a rapid form of TMS that works in one to five days there's no there's it's very unlikely that there's some long-term kind of up regulation of serotonin that's driving that so our work actually kind of pushes back on this serotonin 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 circuitry and that's psychiatry 3.0 it's not just like neuromodulation neuromodulations are really nice you know use case for psychiatry 3.0 because it's a way to vocally and directly 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 neuroimaging before and after and they're able to see circuit level changes for something like psilocybin or ketamine long after the drug is gone right suggesting in those same brain regions converge so the sub-genual default mode network connection that we see is changing with our stan stamford neuromodulation therapy technique at that same set of brain regions that ketamine and psilocybin seem 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 electrophysiology and it's basically kind of recalibrating a circuit that is recalibratable instead of I have something missing or have some set of experiences early in life that are that are going to forever trap me in these psychiatric diagnoses and so it kind of challenges that idea and I think that's what's so powerful about psychiatry 3.0 this idea of focusing on the circuit because it gets us into thinking about psychiatry and psychiatric illnesses is something that are recoverable people can get better people you know we've seen with our tms techniques we've seen it with some of the psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time or within five days within five or less days and in the case of the psychedelics within a few days right so we can get people out of these states they're totally well there's no drug in their system at that point in the case of psychedelics it was never a drug in their system in the case of of tms and it just tells us that that it's it's it's fixable it's just like the heart it's just like you know it's just like any rhythm in the heart it's just like you know these these other illnesses that it's like a broken leg we can go in and do something and we can get somebody better than i think what's what's empowering and what a lot of patients have told me as they say you know i've gotten to you know some people will relapse and need more stimulation or need more psychedelics or whatever it is but they'll tell me i i've relapsed and i'm depressed again but i'll 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 reachieve it and i can't and i i don't fear that i'm chronically broken i don't fear that the chemical imbalance is still imbalanced i don't fear that these things that i couldn't control in my childhood you know are going to be there and drive this problem forever and i think that's that's what's so powerful about this the sense of control the sense of control the sense of they're not doing the stimulation themselves they're not administering the drug in these trials themselves they probably never will these will probably be medical treatments but they are choosing to do it and in that sense they are in control yeah i have a good friend i won't out him for for reasons they'll become clear in a moment who was quite obese um and lost a lot of weight and was really proud of himself and then because we could say he sort of relapsed 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 relapsed it was very clear he had essentially relapsed to the previous set of eating behaviors and lack of exercise behaviors and has now brought himself back again um and it it just resonates uh with your story that you know once somebody understands they can do it because they've been there before this this idea again of of considering new rules that that there's um and and that brings me to this question about psychedelics and and the frankly the altered thinking and perception that occurs in in high dose psilocybin clinical sessions um it seems that the disordered thinking even though it could be random right uh hearing hearing colors and and seeing sounds is always

Memories & “Rule” Creation; Psilocybin & “Rule” Resolution (01:13:58)

the you know kind of cliche statement of the timothy leery area um also you know right there that's a strup task of sorts it's a it's a synesthesia it's a combining of perceptions but it's a it's sort of strup task-ish in that it's a new set of rules for the same stuff yeah right and um people do many people do report improvements in trauma related symptomology and depression as i understand it for my read of the clinical trials after taking psilocybin because during those sessions something comes to mind spontaneously as you and i were talking about earlier um they will report for instance a new way of seeing the old problem that's right the old problem could be the voice that they're no good they'll never nothing will ever work out or could be even more subtle than that 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 um uh don't serve us well that's one question and then the second question is um what is it about psilocybin and related molecules in terms of their neurochemistry in terms of the ways they disrupt thinking and feeling etc during the session that allow this uh novel rule consideration phenomena yeah so the first question i think it's an it's 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're really stressed out some of us want to eat more right at the individual person level because it's like that's not particularly that good for my health in the long term but if you think about it like you know in some 500 years ago a thousand years ago if i'm highly stressed out it's most likely that i'm about to not have food at some point and i should eat a bunch of food that is high fat high sugar high carb food to put on weight for that you know next phase where in this 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 uh you know 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 say let's say ptsd right a lot of a lot of veterans come back and they experience these ptsd symptoms and they're not at all useful back home right you know that you know uh they hear some loud noise and all of a sudden they're behind a car or they're behind a you know i've heard of folks you know jump and run behind a trash can or whatever in the middle of san francisco when they hear a loud noise but if you put them back in the battlefield you're highly 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 psychedelics end up having these very persistent memories that are attached to negatively valenced emotion predominantly um as you were saying earlier the jacket and in elementary school we you know i had various things like that for me too right you you remember these things um and uh and we we hold on to those things from i think an evolutionary neurobiology standpoint but what seems to for whatever reason kind of alleviate that are these um are these substances some new like mdma some that have been around for thousands of years like psilocybin and used in kind of sacramental and as a sacrament in uh in traditions um seem to have a therapeutic effect it seems to be pretty long lasting for these 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 we're treating folks with navy seals and data still being you know being analyzed but the anecdotes that we're getting right or folks are coming back and they're saying i finally that's finally gone right this kind of these set of PTSD symptoms are finally gone and so this idea that for whatever reason going into what's probably a highly plastic state like we were talking about earlier up regulation of brain deriving or trophic factor in the case of ibogaine glial deriving or trophic factor this highly plastic state and um the ability to re you know kind of re-experience memories and then as you know you know we we always re-consolidate a memory when we bring it back up we always re-consolidate but re-consolidate it in that state for whatever reason um may drive um drive a therapeutic effect um and um you know the the the jury's still out there's a I'm a I would say that I'm I'm kind of a I'm an agnostic to what tool I'm using kind of guy like I'm my business is to find treatments that help people and so I'm much more like pragmatic about it you know if if this sort of thing which has a lot of cultural baggage um but if this sort of thing ultimately ends up being therapeutic if we can design trials that convince me and others that it is then we should absolutely use it you know and uh and if it doesn't then um then then we clearly shouldn't use it right um and I think that's a big that's a big question the field's gonna have to work out we have a hard time blinding these trials because the placebo condition is not easy to pull off right a placebo for a psilocybin journey is is hard to imagine we've got you know we've been thinking about this and maybe that ketamine study that I was talking about earlier if we could give people naltrexone and ketamine maybe that's a good you know uh a good sort of placebo condition right because we know that we can block any of the actual antidepressant effects of ketamine they still have an experience you know so that's one way of doing it but thinking about ways to do that and really kind of proving this out and that's been um yeah I think that's been been kind of central to the way I've been been thinking about this but yeah I think there's the work that's been done so far the first psilocybin trial um the first MDMA trial is published in Asia medicine recently um and what do those generally say I mean the that that that they are effective for a number of people after one session two sessions yeah what's what's sort of the general contour let's let's uh start with psilocybin and MDMA yeah so MDMA appears to and and um you know one to a few MDMA sessions have a an anti-PTSD effect that seems to be you know outside of the kind of standard assumed levels of PTSD improvement that you can observe in individuals with this level of PTSD right

MDMA & Post-Traumatic Stress Disorder (PTSD) Treatment, Psilocybin & Depression Treatment (01:21:00)

so what we call the effect size which is essentially like a a a measure a cone's D effect size the measure that allows for you to compare different treatments to each other for different conditions that are you know agnostic to what the actual illness is you know um the effect size is there uh you know approach effect sizes the things that are pretty effective like antacids for heartburn right and you see that with with um with MDMA treatment so does that mean that um for people that have trauma who do a and again we're talking about in a clinical setting they they take a one or two doses of of MDMA I think the standard MAPS dose is 150 to 175 milligrams again doing this with a physician etc control clinical trial legal um yeah exactly they do it once or twice and broadly speaking what percentage of people who had trauma report feeling significant relief from their trauma trauma afterward it's about two-thirds of people had a had um a clinically significant uh change in their PTSD that's impressive which is impressive right and how how long lasting was that I mean this trials were ended pretty recently so it appears the last for a while in the earlier trials where they followed people out it seemed to last for kind of in the years range for some people and so it's you know it's pretty it's pretty compelling um psilocybin um you know that in contrast that with ketamine which only on average lasts about a week and a half for a single infusion so it's a much shorter so they have to get repeated infusions of ketamine every 10 days or so yeah wherever for some people or they end up getting like like like a bunch of doses for a couple of weeks and then for some people that seems the last a while um you know that's where I think I think the psilocybin story for depression and the um in the MDMA story for PTSD seem more interesting to me so for psilocybin what is the um rough percentages on and this would be relief not from trauma but from depression yeah yeah exactly so it's you know an open label studies it's closer to like half to two-thirds of people end up getting better depending upon their level of treatment resistance in the in the blinded trials it was more like a third or so of people you know experienced um relief and this is you know this is a press release of the data you know and so it hasn't uh to my knowledge it hasn't been published yet and so I'm looking forward to seeing the full paper on that one but but it you know separated from from placebo and looks you know looks pretty pretty good as well it looks like it's um you know the first of two trials that need to be done to get this thing um approved for treatment resistant depression and so um so that stuff looks looks good in terms of MDMA um for many years it was reported

Is MDMA Neurotoxic?, Drug Purity, Dopamine Surges, Post-MDMA Prolactin (01:24:12)

in the popular press and there was a paper published in science that MDMA was neurotoxic that it would kill serotonin neurons this was what 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 injected these monkeys because of the with not MDMA but with methamphetamine which is known to be neurotoxic so it was kind of a public admittance of oops or big like really big screw-up so oops um but never a retraction and then never really a publicly acknowledged 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 this is again as an assumption um tell me if i'm right or wrong here is that MDMA is not neurotoxic for serotonergic neurons at appropriate doses and with appropriate sourcing etc so um it was an interesting study that um i think guys name is Halpern uh last name is Halpern it um not kc Halper not kc a different different i think Joshua Halpern i'm playing on his first name but but um kc Halpern was a guest on this podcast um and as a former colleague of ours at stanford who unfortunately we lost to university of pennsylvania and maybe someday we'll we'll bring him back yeah that's right so this this individual um you know received some NIH funding to actually NIDA you know national institute for drug abuse funding to um to explore uh individuals um of the mormon faith in utah who um who partake in only mdma so um the way this works is that um MDMA um happened kind of after a lot of the religious documents were were developed and so MDMA isn't on the prohibited drug list the banned substance above banned substance list i have some good friends who are LDS yeah great great boy i do i do i do as well um you know just to kind of set a fact you know and so um so these these folks um only use MDMA but they don't they're not you know the problem of with some people using drugs they're poly substance users right so you can't you can't say it's the MDMA if they've also taken other psychedelics and they've taken opiates and they've taken cocaine and you have this picture where you can't really tease out that problem but but with this right it was just individuals that were part of the mormon faith and so they they were um kind of purists in the sense they only used MDMA and he confirmed all of that and um and it was a brilliant study right because then he was able to go in and look at their cognitive profiles versus individuals of you know of the same geography the same faith all of that that happened to not take uh MDMA and found there were no neurocognitive uh differences so it does that mean that it it was not damaging it was not damaging it it's hard to know because to really do this study well you'd have to track these folks down before they ever took MDMA and do a pre-post and compare to people that didn't but you know this is about as good of a study as you can do uh in given the you know given the situation to be able to check this out um additionally when i was back in Charleston and working in the medical university of south carolina i one of my mentors um there dr wagner um was a neuropsychologist at immunosine he was also the the neuropsychologist for the early mdma trials and so he did all the neurocognitive batteries for individuals pre-post and similarly did not see any changes in neurocognitive 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 are chronic users you know who only take MDMA um and that that combination of uh of data suggests that there's no there's certainly no apparent risk in the kind of one to two to three dose range um it's it's probably unlikely that at least you know uh modest dose exposure over a lifetime doesn't appear to have a a profound neurocognitive damaging effect yeah interesting yeah i know that um sourcing is key and we're here we're talking about clinical trials where purity is assured um and you know years ago when so-called raves were really popular maybe they're still popular never been one been to one so i don't know if they're happening or not that's how um in the know 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 methamphetamine which we know is highly neurotoxic i think that one reason why people i think that MDMA might be neurotoxic is the the uh reported um drop in energy or sort of feeling fatigued for a few days afterward i spoke to a physician colleague of ours who said that that uh very likely has something to do with the surgeon prolactin that arrives subsequent to the big dopamine surge that occurs in um in MDMA and i mention that because i know a number of people um talk about serotonin depletion after taking MDMA he has in mind that while that could be true it's likely that anytime somebody takes something or does something where there's a huge lift in dopamine that there's very likely a huge compensatory increase in prolactin that follows in prolactin has a kind of sedative effect numbing effect on mood and libido etc that eventually also wears off does that make sense to you as a physician yeah it makes sense i mean you know the difference between say MDMA and and psilocybin is that MDMA is kind of an amphetamine of sorts right so it has it has effects in dopamine and the uh in psilocybin's you know pretty pretty neutral and you know maybe a little bit of dopamine effects but kind of much more of a serotoninergic focused drug and so yeah i think you're going to see kind of a different profile after and and that makes i haven't heard that story but that makes sense to me too since you mentioned psilocybin let's talk a little bit about the neurochemistry of psilocybin as a serotoninergic agent my understanding is it operates on these uh is it the five ht serotonin two c receptor two a excuse me two a and and receptors and that i've seen a bunch of different reports in terms

Psilocybin, Brain Connectivity & Depression Treatment (01:30:38)

of what it's 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 are for instance and tell me again if these are right or wrong um that there is increased conic activation of lateral connection sort of broader areas of the brain being co-active then would normally occur maybe that explains some of the synesthesia's you know seeing sounds and hearing colors and that as the trivial example but rule breaking um within the mind um but then i've also heard um that perhaps it's 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 irrelevant but if i'm thinking about the sensation in my right toe i'm generally not thinking about the truck around the corner so we have these attentional spotlights but that somehow it creates a more um it adds spotlights uh it degates the thalamus right through the reticular thalamic structure so um what is the evidence that any of that is true and are there other phenomena is their involvement of dorsolato prefrontal cortex that we are aware of and what i'm really headed here in a few minutes is um you know is there a place for combining directed stimulation of the brain with psychedelics 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 what so but to simplify at first what's going on when one takes psilocybin and um why is it interesting in light of depression yeah definitely so um you know David Nutt and Robin Carran Harris's work around neuroimaging psychedelics are kind of the first folks to do that work and um you know into their great surprise they thought there was going to be an increase in activity on psychedelics and what they found is the opposite right there's kind of an overall decrease in the level of activity in the brain um with psychedelics but they they have also looked at connectivity and there's this kind of small world you know large world connectivity that you think about and so you know small world meaning there's a lot there's kind of a much more kind of focused kind of cortical function or you know sub-cortical function or whatever it is and uh and what you see is a difference in that um in that level of engagement of brain regions so the connectivity kind of global connectivity to your point kind of increases and so you know it's it's interesting you know I think to kind of have a convergent theory on this it's still you know to be determined there's still a lot of work I think that needs to be done but um but it's certainly um suggestive that there's pretty profound changes in um in brain activity and brain connectivity after and what we've found to be really interesting is the the anti-depressant effects of psilocybin have a particular um connectivity change that we also see with our our tms approaches right and it's this connectivity between the sub-genual anterior cingulate and the default mode network and so when we do this effective stamford neuromodulation therapy stimulation we see a down regulation the connectivity between the negatively valenced mood state in the case of depressed individuals in the self-representation of the brain and you see that same connectivity change occur post psilocybin you know suggesting there's a convergent mechanism and it makes sense right you've kind of got an over connected negatively valenced system conflict system that's kind of you know kind of attached on to the self-representation and people feel stuck right and then when you when you do whatever you do that's effective it it un and unpairs those two systems i want to ask you about this phenomenon i've heard about during psilocybin journeys i heard about this from um dr matthew johnson who's running a lot of the clinical trials at uh john's hopkins and uh has been a guest on this podcast he

Various Approaches To Mental Health Disorders And Their Clinical Uses

Exposure Response Prevention: “Letting Go” & Depression Treatment (01:34:53)

said that there's something seems to be important about the patient who's depressed or who's and is under the influence of psilocybin or the patient who's trying to get a over smoking or an eating disorder who's taking psilocybin and is in the clinic that there's something important to this notion of letting go that people will feel as if their thoughts and their feelings and maybe even their body aren't under their control and that the clinician's job under those circumstances is of course to make sure that they're physically safe so they don't jump out a window or try to actually give an example of a patient who thought that um i think it was a she could move into the painting in the wall and obviously that wasn't true in the real world although it was true in her mind so they prevented her from doing that but that letting go that somehow um untettering from the autonomic arousal that's occurring is important um which brings us back to this idea or me back to this idea of of a like a seesaw where sort of letting go of the hinge and just sort of your heart rates going up let just go with it and trust you know your heart rate's going down just go with it and trust you're thinking about uh something very powerful and depressing related to your childhood you're just supposed to go there without fear you're thinking about what's possible in terms of what could happen so anyway you get the the picture can we think of that as just the willingness to um do a million different variations on the the emotional strip task you know you will entertain the full full array of rules within your head and consider them whereas there's something more to it you know and again we're we're in the the outer margins of understanding here but what are your thoughts on on this notion of letting go as such a key variable for relief from depression during the psychedelic journey yeah so i'll i'll talk a little bit about something called exposure and response prevention therapy that that's a typical kind of gold standard treatment for OCD and i'll help to kind of you know help help this a little bit uh conceptually and so what that really is is it's a letting go therapy and so you know exposure response prevention the idea is that you have to expose the individual to something that you know some something that triggers an obsession that they then want to do whatever the compulsion is right and so i'll give you you know my first exposure and response prevention patient when i was a resident um he was very concerned about um leaving the lights on this car and um and so what we did is we went out and we turned the lights on in his car and locked his door so his lights were on and he was super worried this kind of kills battery um and 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 on and he cranked the car and we did it maybe one other time and then all of a 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 to something and then letting them see that that exposure ends up being fine right it ends up not causing the thing that they're that they end up being worried about um and so you know in some sense being in the psychedelic state and we are all we're all taught at a level to to retain some level of control you know people have more or less of that but we're all effectively retaining some level of control we all wake up in the morning and put clothes on to go into society we all try to say you know most people try to say the right things they don't try to do things that are outside of cultural norms when they're in conversation and so we're constantly at some level controlling the situation that we're in and so it's you know it's not it makes a lot of sense that in that state part of the therapeutic effect that may be linked to the neural circuitry is this idea of letting go and essentially letting the system you know the network configuration maybe whatever it is um assume a state that you've 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 50 times before he would go and do whatever he needed to do and in some level letting go there meaning letting us just turn the lights on and him not do anything or letting go meaning in the psychedelic state you're just letting go of whatever it is you're holding on to negatively balanced think thoughts about yourself and the in the you know setting of having depression or you know re-experiencing a trauma you know memory and allowing that to just happen and re seeing it again through a different light you know it feels the same in the sense that that's allowing for whatever is going on with these psychedelic states to do whatever they do fascinating um you said exposure response therapy is the traditional name exposure response prevention prevention therapy done outside of this the psychedelic journey it's done outside the psychedelic journey but that idea of letting go is is you know present in both of those you know psychotherap kind of straight up totally sober non psychedelic non anything psychomaniualized that psychotherapy that we know works really well for OCD and then you know in that psychedelic state and so people have done studies with with psilocybin and now there's some studies of MDMA trying to look at um you're treating OCD um you know with the same sort of idea of letting go right and and how do you how do you have an OCD patient kind of let go maybe even letting go of not washing their hands anymore you know kind of accepting the idea they're not going to get germs in their hands or whatever it is you know and so it's kind of part of that part and parcel that same sort of thinking when I was in college I developed a compulsive superstition I'm not afraid to admit this I I'm somehow developed a knock on wood superstition and I would uh I was actually kind of ashamed by uh of it because it rationally made no sense I'm not I don't consider myself a superstitious person

Normal Spectrums for Mental Health Disorders (01:41:23)

never was a superstitious kid you know I'd step on the sidewalk cracks I'd cat I'd walk under ladders you know I even try to walk under a ladder um even though I don't suggest it 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 that I had it in hopes that that would prevent me from doing it um and it's tricky sometimes it actually comes back but I think gosh I didn't say you know knock on wood I didn't knock on wood I hope that doesn't actually happen and it's and it's quote unquote crazy right but I crazy in the sense that it makes no sense rationally why the events would be linked and yet I think a lot of people out there do have in internal superstitions um maybe by talking about it now it'll it'll go away I just see clearly I just need to challenge it um you know it's uh anyway I mentioned because I um I consider myself you know generally rational person but um it's interesting how these motor patterns um get get activated and and this notion of letting go because I don't actually know what consequence I fear and the fear as I was hearing an example you gave you know the fear of 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 of a deal you jumped the car and that's right but in my case I need to think about what the ultimate fear is yeah and you know I think uh I think a lot of people so there's it's interesting if you look at say the OCD scale or the depression scale or whatever we don't define normal as zero we define normal as some number range above so zero to in the case of the Montgomery Asper depression rating scale one of the depression scales we use 10 right that's the normal range and so people can have some sadness and still be considered normal in the case of the OCD scale it's about the same 10 right where we say it's kind of starts to be you know ab you know mildly abnormal or something and I always you know I always tell the medical students look my friends that are surf instructors they're more like a zero on the YBOG people that are professionals you know they're they're non-zero but you're still within the normal range and especially you know in the in the case that you're talking about it doesn't sound like it got in your way it doesn't sound I mean you're obviously highly successful tenured professor at Stanford and do all the great things that you do and so it's it's very much kind of within the normal range and it's I think totally totally assumed that a lot of people have have these sorts of things and as long I think something is a psychiatric diagnosis when it severely impairs your ability to function and that's when we kind of cross that threshold but you know I think that I think that a lot of people and it's great that you're bringing this up I mean it's very anti-stigmatizing that you're bringing up right because I think a lot of people hold that stuff in and they don't want to talk about it because they're worried that somebody else may think something but the reality is is a psychiatrist I talked to a lot of patients a lot of people that are you know family members you know folks that are just going through a death 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 predisposed 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 realize that we're all kind of in this together in a way and that we're and then some folks that you know have you know have to knock a hundred times we call that OCD and you know and they have all you know germ they're worried about germs and all these other things we call that OCD and then in that circumstance you know they need treatment right but but it is really on just like blood sugar just like blood pressure it's on a range you know and 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 because I am slightly I would say a

Ibogaine & “Life Review”; PTSD, Depression & Clinical Trials (01:45:35)

shame is there of embarrassed by but I offer it as a you know that you know it is what it is as they say and certainly doesn't seem to hinder my my life much knock on wood so if we could talk a bit about Ibogaine I don't know much about Ibogaine although anytime I hear the you know AINE you know Lydocaine Ibogaine I think of an anesthetic and going to the dentist which is an unpleasant experience for me generally what's what is Ibogaine does this and have anything to do with the so-called toad you know people talk about smoking frog skin and toad skin what is it used for clinically is it legal in the US in terms of a clinical tool who's using it and for what purposes if you could educate me on Ibogaine I truly know nothing about it except I think I know how to spell it correctly yeah that's fair so so Ibogaine is a is one of the alkaloids that you can extract from a iboga tree root bark that's typically growing in the company in the country of Gabon Africa so Gabon is one of the west African countries kind of middle of Africa on the west coast and and Gabon is has a group of folks you know called the Boiti it's a religious kind of sacramental group that sacramentally uses Iboga root bark is part of that's this the sacrament and they they've been using Iboga root bark for a very long time and it's you know part of the tradition there's a whole there's a whole set of of kind of ceremony around it if you're interested in this there's a book called Breaking Open the Head by Daniel Pinchbeck that goes goes through and talks about this this whole process but essentially the Gabon is I've been using this for a long time and and it's a it's a kind of an atypical psychedelic it's not it's not a psychedelic that we normally think about with psilocybin and LSD where there are visual perceptual changes right so if you if you take psilocybin psilocybin or LSD what you what you experience is you experience this kind of visual perceptual differences in the external world right and on enough LSD or psilocybin an individual can actually perceive something visually in the external world that isn't there as we talked about earlier Ibogaine doesn't do that Ibogaine does something different it it's kind of like if you ever seen Minority Report with you know the movie with Tom Cruise I think 15 or 20 years ago or something so it dates us a little bit but it was this it was this movie where he would be able to go and see these kind of pre-crimes and he had this big you know 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 Ibogaine will say is that open eyes they don't see anything but closed eyes they'll go back through and re-experience earlier life memories and they will be able to experience it from a place of empathy not only for themselves but from others and come to 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 a third party so Claudio Naranho a psychiatrist from Argentina you know described this a lot of books that that he wrote and I think in the 80s and 90s around this and so you know Ibogaine's been around for a long time Howard Lotsoff American guy that brought it over from from Africa he was a poly substance user used every drug you know you know that he had his hands on took Ibogaine and including a lot of other psychedelics by the way took Ibogaine and then never did another drug again supposedly because he had such a profound Ibogaine experience Ibogaine is in no way a recreational 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 10 years of psychotherapy in a 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 you redo or anything go sometimes depending upon how fast you metabolize it sometimes 24 sometimes 36 hours sometimes it can be shorter but it is a long time wow it's a very long time so it's it's definitely the longest acting psychedelic substance I know of and and so people people you will take this and they'll have this reevaluation of a given memory and then is we were talking earlier to reconsolidate that memory again and then it seems to have you know an effect of of that re-consolidation process and so you know about five four five years ago I was tapped by Rob Robert Molinka one of the you know senior neuroscientists we both know in the university he says well there's a you know there's an unnamed donor that's very interested in um in funding a group you know a scientific kind of open label study of of these navy seals that have been going down to Mexico and taking Ibogaine and and also and at 5m EODMT which I'll talk about in a second to treat PTSD you know the claim to have traumatic brain injury depression you know that whole constellation of symptoms you know and as it was described to me by various people who had done this by their spouses and and whatnot you know John will just say John John couldn't screw a light into a light light a light bulb into a light fixture right they just they were just so debilitated they couldn't do in a simple tasks what we call activities of daily living and they were coming back and having these really traumatic improvements in uh in you know all aspects of of life and so you know we have over the last couple of years been able to um to do this first inhuman kind of full neurobiological clinical neurocognitive evaluation of what Ibogaine is doing in this case in in uh special operations special forces individuals former navy seals for me army rangers that that kind of crew folks and look at the pre-post changes that we um that their experience to be able to totally quantitate all of that and so we've been able to capture all the clinical scales you know depression scales PTSD scales all that standard stuff neurocognitive batteries so how does your executive function work specifically how does your verbal memory all of that and then neuroimaging and EEG so this will be the first human study of Ibogaine for those and the reason why is because Ibogaine's kind of the both seemingly the most potent and most and seemingly to me at least most powerful um psychedelic but the the one that has the most risk to because it has a cardiac effect it seems to be that you can screen people out that have risk off of their electrocardiogram and reduce the risk quite a bit and that's what we all did but but but that's why people haven't really studied it as much and it's it isn't as uh in addition there's no right nobody goes to rave on Ibogaine there's no recreation at all with it it's not fun it's people say that it's relieving but it's hard work right because yeah you're re you're re-examining things and um you know and so then so then we we see these folks after and i'll tell you you know we haven't fully analyzed the data yet but i'll tell you that you know from from what my folks you're telling me it's pretty dramatic you know people come back and they're doing um they're doing a lot better they're doing a lot better and um nobody i'm not gonna would nobody's had any sort of cardiac issue at all um in you know in the cohort that we've studied and um and they look a lot better and they feel a lot better too and uh and they describe these experiences of being able to go back through and you know um soldiers experience something called moral injury right where they maybe they accidentally blew something up and had a kid in it or something like that you know you know if they're in afghanistan or iraq maybe a you know child died on accident or maybe maybe you know a civilian died or whatever it was right and then they suffer these moral injuries as part of the job and it's almost one of the kind of you know vocational risks they come back and say that they've they've um forgiven themselves you know which is which is huge right and then in part of that is being able to see themselves in a different light and having empathy finally for themselves and being able to kind of have that experience of of forgiving and so so very cool the the study um you know what was happening was they were taking abigene and then taking something called five emeodm t people call the toad it's the sennoran um a river toad i think it's like you can you find these in mexico find them in arizona um in in the back of the the toad um produces something old five emeodm t which is a um you know flavor of dm t that produces a particular psychedelic effect also used as a sacrament is a dimethyl tryptamine is that it is it is a five um emeodimethyl tryptamine so it's a kind of dimethyl tryptamine with with a kind of addition to it the the deal there is um that it lasts longer than traditional dm t you know it's like 20 minutes at five three or whatever kind of thing and um and so then so these guys were taken abigene and then they would take the five emeodm t after we had to kind of divorce those two things be able to do the study and just understand what abigene was doing and they go back down a month later and they'll do the five emeodm t so two completely separate sessions two two completely separate sessions and one quick question about abigene before a bit more on five emeodm t um is the abigene journey guided or the person just closes their eyes and they just start falling into the back catalog of memories they have um a bunch of preparatory sessions and then they have a bunch of sessions after that they kind of um they're able to kind of rehash things um during there's a sitter that sits there and kind of sits with them um and and helps them out but it's not it's pretty the phenomenon of the drug seems to drive a lot of this right um and so a lot of it ends up being what we call supportive psychotherapy just kind of being there and you know maybe you're holding the person's hand maybe you're just saying i'm here maybe whatever it is but you're making sure they know you're around but you're not really there's not really an interaction per se and then the whole kind of goal there is just to get to get folks to kind of go back through and reexamine these memories and ultimately look look like they re um re-consolidate them and um you know it's very interesting i mean there's a there's this kind of tim

Clinical Use of Psychedelics (01:57:16)

as you said earlier timothy leery kind of socio-cultural construct that ends up being overlaid over psychedelics and what i think is that if you rid yourself of all of those preconceived notions of what it is and isn't and the counterculture movement all that stuff that neither of us were ever involved in neither of us are ever partaken you know it's kind of straight scientists looking at this right if you can kind of rid yourself of all those socio-cultural constructions and then re-examine this these if we just discovered these today we would say that these sorts of drugs are a huge breakthrough in psychiatry because they allow for us to do a lot of the sorts of things we've been thinking about with with SSRIs with psychotherapy but kind of combined right psychotherapy plus plus drugs in a in a substance that kind of allows you to re-examine these things and so it's it's interesting it'll you know there's a lot to do to try to figure out if that's true you know and and i can say that as it stands right now we don't know if it's that statement is true right there's a lot more work that needs to happen for that statement to be proven to be true but the hypothesis is if it is true then it's very likely that this will be seen as a breakthrough because it allows you to do these sorts of things that you can't do with normal waking consciousness but also why we have to really think about this and you know these drugs can't be recreational drugs they really shouldn't be recreational drugs right they're really too powerful to be used in the context of recreation because they can put you into these states and in the this generation of psychedelic researchers are really clear about that you know i think the 60s folks were not clear about that and they they felt like there was a whole kind of cultural thing that was going on there but i think this cohort of individuals really understands that in order to really make this happen we have to understand that if you need a prescription for an ssri which doesn't change your consciousness a whole lot and we 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 of very strict medical supervision is uh it's kind of preposterous actually it's kind of it's kind of a dumb moment i think for for all of medicine to say look we've you know if we're gonna do this right we've got to do it such a way that's so protected that's so safe that we make sure people know these things are not recreational and they're really for the pure purposes of of really powerfully changing cognition for a while and letting people have these what seem to be you know relatively therapeutic states i think it's great that you're doing this study and along the lines of the sort of the early iterations of psychedelics and the counter-culture of the 60s and 70s some of which took place like one floor of the cuckoo's nest i think is actually based on the menlo park v.a which is you 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 at an event and last veteran's day in fact um the so-called veteran solutions group that's um pioneering a lot of these psychedelic treatments for former special operators and current special operators and what's interesting to me about that is in contrast to the counter-culture movement of the 60s and 70s 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 isn't just but one group of people who's exploring psychedelics as a treatment for trauma and PTSD and other other things and of course you also have other domains of society looking at this and in fact there were but it was really interesting because they were both um far left and far right politicians at that event up on stage together talking about um in kind of lighter terms heart medicine but also talking about neurobiology and talking it was just fascinating from a from the perspective of somebody who's trying to learn about this stuff that psychedelic therapies no longer sit within the anti-establishment realm it's it's both it's it's independent of all that um certainly when people in the military are adopting it as a potential treatment again still under exploration but also under exploration at universities like Stanford and Johns Hopkins and UCSF and University College London and on and on um along the lines of tree barks and toad skins um tell me about ayahuasca um and as a plant uh you know it's intriguing um

Ayahuasca, Brazilian Prisoner Study (02:01:59)

and is it a pro-serotonergic um drug like psilocybin um and is it useful for the same sorts of conditions that we've talked about um thus far and if you could um perhaps tell me a little bit also about the um Brazilian prisoner study yeah yeah definitely ayahuasca is another psychedelic it's used as a sacrament um in um in Brazil and um in Peru and Ecuador and Colombia so a lot of the South American countries and um 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 psychedelic effect and what's really kind of curious is that they're as I understand it 10 to 20 000 plant species in the Amazon and somehow somebody try them all combined these two plants together and certain proportionality and cook this for five 10 hours to the point where you cook out the dimethyl tryptamine out of one of the plants and cook out the reversible monomine oxidase inhibitor out of the other plant it's such a way that the reversible monomine oxidase inhibitor prevents the the GI breakdown of the dimethyl tryptamine 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 monomine oxidase inhibitor plant derived into this combination then it would never cross the brain if you put people on a standard psychiatry prescribed monomine oxidase inhibitor that wasn't reversible you'd you'd throw them into serotonin syndrome right so this kind of like sweet spot that somehow ayahuasca practitioners have found of being able to get dm t and the brain from an oral source with this combination of a monomine oxidase inhibitor it's curious and so that that substance has been explored as an antidepressant agent and some studies have looked at that it also seems to be very safe there um there was a there's a psychiatrist down at ucla harbor who's done a lot of work with this where um where he's looked at children even that have been exposed just kind of small doses of ayahuasca is is kind of a sacrament within amazonian tribes and found no neurocognitive effects no neurocognitive effects in adults and um and so it appears to be safe it's part of it's kind of part and brought into various religions including kind of merged with Catholicism in South America which is kind of very interesting and so you know in some sex of Catholicism in Brazil it's used as a sacrament during religious ceremonies and so it became interesting to Brazilian researchers as to whether or not they could affect recidivism rates for prisoners in Brazilian prisons right so they gave half of the prisoners um you know some sort of inert substance and half of the prisoners a ayahuasca session and the the recidivism rate or the return to prison rate in the ayahuasca exposed individuals was statistically significantly lower than the recidivism rate in the uh 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 note I am also in no way saying that we should be giving psychedelics to to folks in prison and all of that I think that that that is a very edgy thing to do and probably not something that anybody should try but but it does it does kind of bring up this this curious question of of what is it about that that would drive people to to change those behaviors and and why why do people make those behavioral decisions and in a lot of times if you look at prisons in the United States you know you set people say this what's the biggest mental health facility in the in the United States it's a prism yeah there's a lot to unpack there for sure uh you know the homeless issue the prison issue um it does lead to something that I heard recently which is related to all this which is um

Cannabis: THC, CBD & Psychosis, Clinical Uses (02:06:55)

cannabis you know we hear a lot nowadays about uh people will say well it's safer than 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 beyond being I think uh and it's pretty clear that not drinking is better for your health than drinking at all and here I'm not trying to tell people what to do but 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 for a sveratrol it's not even clear with sveratrol it doesn't anything useful anyway etc etc nonetheless cannabis is now available in a lot of very high potency form people are vaping cannabis um people are smoking cannabis I certainly am not saying that cannabis is bad for people necessarily although I think children I would like hope that their brain development would be completed first you know get to age 25 I know that sounds late um for a lot of people but um the THC obviously taps into some um endogenous systems of of uh and the cannabinoid systems and it is powerful and I've seen this uh this report that was in uh Lancet psychiatry this last year that said that early use of potent cannabis meaning age 14 to 20 or so can potentially lead to an exacerbation of psychosis later in life and I actually put this out on social media and it sort of exploded um I didn't expect it to people were saying well that's not causal and obviously it's not causal um because people say well maybe people with uh psychotic tendencies are seeking out cannabis although that's sort of a weak argument in in the sense that there's a at least a four times um you know 4x increase in these uh psychotic episodes for people later in life but what are your thoughts about cannabis because I do want to acknowledge that it does have medical benefits for certain things yep a pain chemotherapy um so my no means trying to to knock on cannabis in its appropriate medicinal use but what what should we think about cannabis in terms of this finding that can exacerbate a psychosis in certain individuals yeah so I think you know there's this cut there's a couple of things right so cannabis is is multiple you know cannabinoids right THC CBD CBN sativas and you know indicas it gets that yeah there's a lot there to unpack yeah there's a lot of there's but there are two there are two main you know kind of chemicals you think about and kind of how things are or are essentially bred right and so you know there's a lot of cannabis it's really bred to be very high very potent THC and there's a lot and there's cannabis where the THC's bred completely out so there's stories um you know from from Colorado right this this strain of of cannabis that's THC free there's no THC at all and it's all CBD and they uh it's called Charlotte's web and a bunch of kids parents one kid and then kind of a string of parents after that moved to Colorado when cannabis was legal because legalized because CBD is anti-epileptic so CBD is also anti-psychotic and so there've been a number of studies that if you give CBD at high doses it's anti-psychotic and schizophrenic established schizophrenic patients the issue is that we've bred CBD out of marijuana selectively over time we've gotten very good at figuring out how to do that right conversely THC is pro-psychotic and pro-epileptic right and so when you talk about is cannabis caused psychosis or does cannabis treat psychosis it appears to be more related to the proportions of CBD to THC than it does to the kind of idea of cannabis so for me there's a there's a kind of no stockness or anything like that but there's a company called GW Pharmaceuticals and I haven't looked into them in a while but they um they they have a lot of clinical trials for something called dreveze syndrome which is a seizure disorder or kids sees a whole lot Linux Gasto syndrome which is a seizure disorder kids are seizing 300 times a day both of these are like kids are seizing so much they they're basically in a seizure or in the post-ictal phase constantly and and they've failed everything they've failed barbituates they failed bromides which we don't use anymore except into these cases because of the side effects and they'll give kids CBD and I think CBD is a pretty safe drug comparative bromide right and so this idea that that CBD in a kid is actually safe it's a it's a cannabinoid but it's CBD and it's safe right and so that to me is totally fine also giving CBD is an adjunct of treatment for for schizophrenia there've been some positive trials and negative trials in that but there seems to be no negative side effects it seems to reduce some of the metabolic syndrome issues and in uh folks with schizophrenia who are having side effects from the primary antipsychotic the the converse is there's clearly cases where people that are taking very high doses of THC become psychotic they get put into the psychiatric unit nothing happens out of me they kind of get the THC out of their system and then they resolve their psychosis right and so that that and you know a handful of people who have had you know seizures related to high doses of THC and syncopede and all sorts of things and so this idea that THC high doses of THC can be propsychotic is also not taking a shot at people that think that cannabis overall is a good thing it's just it just is what it is and the kind of pure if you I think if you zoom back and you say you're a true naturalist you're thinking about natural medicines in the world you should think well probably marijuana was balanced THC CBD at some point and then we just we humans messed with it right and and that most likely that was probably okay it's some level and then we pushed it one way or another and what I mean by okay is in a 45 year old it's okay kind of thing now what I think is going on with the the kids with the teenagers is you've got prefrontal maturation right and then you're exposing them to a whole lot of high THC load and while it's unclear if it's if it's cause or effect it's certainly in the picture and if I were a parent I wouldn't want my 16 year old smoking marijuana if I were a parent in my 30 year old otherwise healthy totally fine 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 it's kind of a different thing right I would never want my up to 25 year old just like you're saying before prefrontal maturation I've never want my kid to be exposed at all but it looks like except in you know susceptible individuals that are susceptible to drug induced psychosis it looks like you know it's a it's a relatively safe thing past prefrontal maturation you know again I can't I'm not going to comment of cause and effect but I but I would say that you know it doesn't if you're a parent it doesn't make much sense right it might you know you want to you never know what's ultimately going to hurt your kid I mean you know my wife's probably we're talking about this earlier my wife's pregnant now she kind of avoids everything right and rightfully so right this idea that we just we want to be careful when our children's brains are developing and I think that's really what you were saying and I think actually important the bigger question that you asked which is relative risks of drugs is an interesting one so David Nott published in I think he was in the Lancet I'll have to look it up I think in the Lancet an article about relative drug risks for the person and for society and this was like he was on the the the uk's like British drug policy group where essentially what he showed was if you took if you look at societal risk plus personal risk

Depression Treatment Techniques And Studies

Personal Relative Drug Risk & Alcohol (02:14:52)

and you combine those two you know what drug is the most dangerous drug in the world I'm gonna guess it's alcohol alcohol right behind heroin and cocaine and did it and somewhere in the middle is marijuana and right on the tail end on the other on the exact other end of this psilocybin is caffeine it did that usually doesn't make the list I may have been on the list it was it was probably pretty close to psilocybin but somewhere in the middle was ketamine somewhere in the middle was was amphetamine somewhere in the you know a little closer to psilocybin I think it was MDMA 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's a huge amount of personal risk and there's a huge amount of societal risk right drunk drivers kill x amount of kit you know people in the world fight sexual assault all that all that yeah and then all the cancer and all that stuff and so it beats out cocaine it beats out heroin it beats out all of these things and and yet um yet we don't we don't as a culture for whatever reason we don't as a culture see it as 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 of course I wouldn't do that this is at every institution I've been to they serve alcohol at the graduate student events that's right they serve alcohol they we they do a happy hour I've never been a drinker I can take it or leave it so and I realize that some people they really enjoy alcohol yeah you know um my former partner I mean she just was in that you know 10 percent or so people who have a glass of wine and just feel great and the second one feel great I just want to take a nap after I I have a bit of alcohol so it never does much for me I always feel poisoned I feel lucky in that sense but it's it's unbelievable that it is so prevalent and it's just it's baked into the medical even medical institutions they they'll pop a bottle of champagne to celebrate the opening of a hospital that's right that's right that's pretty crazy yeah no you're absolutely right you know I think I think what's going to happen but this is me you know looking at crystal ball a little bit but I think what's going to happen is what happened with doctors and smoking so if you look at the 50s and 60s right there are all these pictures of doctors smoking cigarettes and you know with patients or you know psychiatrists doing psychotherapy and smoking a cigarette with the patients sitting on the couch you know surgeons smoking a cigarette in between cases there are all these pictures of that right and now all of a sudden smoking is totally banned 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 ubiquitous it's some critical point some tipping point everybody's going to realize that just like with smoking we've got a rid hospital systems and universities of alcohol and at some point in 50 years it's my view that we'll look it back at these these scenarios that you're talking about and and be like you know what we uh we were foolish about this we I can't believe that we we gave people alcohol on the way you know when they graduated from whatever you know and I think we'll have a different take on it but it's going to take it's going to take a longer time I think I think people did a really good job of tying smoking to lung cancer and it's like very a very simplistic story smoking lung cancer you know now you know as you know alcohol increases the risk of a lot of different cancers not so clear which one I mean there's like you know the kind of oral like the throat tongue cancer that's one breast cancer yeah breast cancer you know and so it's it's kind of just it's a harder story to tell you know and I think that's why and everybody you know and then there's this whole it's you know my mom says this is like I drink my glass of wine because my doctor told me it was heart healthy and we were talking about this and I try to no no but but doctor so-and-so said it's heart healthy and so it ends up being this thing where like she's drinking alcohol because she thinks that it's it's good for her heart and you know it and it's it's hard I've had those conversations with her it's hard to untie that and I think that yeah at some point we're going to hit some some threshold moment and it'll 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 kind of it kind of points to the right direction it's really interesting and also saying nothing poor judgment under the influence of alcohol I mean I I would venture that if we were to remove alcohol from university campuses watch watch the students are going to lobby against me if I say this but if you were to remove alcohol from campuses I mean just think about the the what I suspect would be the improvement in good decision making and that would occur or you know I I've got stories from graduate school and put in it it was very different you know 10 years ago there was a lot more alcohol consumption again that was never my thing but I know people who made really bad decisions yeah in any case there's a whole landscape there emerging I think you've got your finger right on the pulse of it 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 yeah can improve symptoms of depression and yet I'm personally 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-sleep deep-rest practice that I

Circadian Reset for Depression, Sleep Deprivation, Light (02:20:42)

blab a lot about on the Huberman Lab podcast which for me is tremendously restorative but I like a good night's sleep I think everybody understands now thanks to the great work of Matthew Walker and others that have really gotten out 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 80 percent of the nights of your life if you can that's that's something to focus on just like good nutrition just like exercise and social connection etc so sleep deprivation we know can in particular I think rapid eye movement components of sleep deprivation can improve the symptoms of depression and yet being sleep deprived can also really dysregulate our control of the autonomic system I notice on night two or night three of course sleep if I'm going through a stressful phase and that's happening all of a sudden my heart rate is chronically elevated my thought patterns become really disrupted I can't then exercise do that I can my decision making is thrown off my emotionality is more laid about the hinge as we referring to it earlier feels less in control under my control and maybe I wonder sometimes if I enter that state that you refer to earlier where the Dorsalato prefrontal cortex is no longer leading the singular but the singular is now in charge the players are in charge of the coach yeah not a good situation so I know you've done some work on sleep deprivation and light and effects please tell us about that and please tell us about this triple therapy yeah yeah so friend of mine Greg Salem one another one of the professors at Stanford is very interested in sleep he did a bunch of bunch of training in sleep before he went to medical school and and got very interested in this idea that as you're saying if you sleep deprived somebody one night in just kind of an isolated single night if the at the end of that sleep deprivation they will have an antidepressant effect but as soon as they fall asleep they lose it so if it's a depressed individual you can get them to be less depressed acutely as soon as they fall asleep they wake up eight hours later then they come they come back into the same level of depression and so the idea is that you needed to do some sort of circadian reset and that part of what part of what depression is is that it's a dysregulated circadian system and so mentors of mine say if you can just get the sleep better that's half the battle of dealing with depression because so many people have insomnia around depression and have a whole host of types of insomnia having a hard time falling asleep waking up in the middle of night and waking up earlier all symptoms of depression and so what this does is it sleep deprives the individual and then there's a certain calculation of shifting their phase and simultaneously exposing them to bright lights so that's the triple the phase shift the sleep deprivation in the bright light to try to get their circadian rhythm essentially the theory is re-entrained and so you know in the in the trials that we've done and other trials prior to ours and after you know it looked like there was a pretty pretty profound anti-depressant effect from this triple therapy this triple therapy that seemed to be durable meaning durability is this term we use to say that not only can you get kind of point relief but that the relief ends up you know lasting what's important to know about this is like you shouldn't do this at home for sure this what you would need to do this with a professional because it's complicated it's not just one thing and it in sleep deprivation while it seems to be antidepressant it's pro-anxiety so if you take a highly anxious person that's not depressed and you sleep deprived then they get profoundly anxious and so that's the other thing that you have to really realize is that this is like everything else that i've talked about today all things that you you have to do under medical supervision but but curious right and and i think you know the question always comes up is why isn't this used more and i think the reason is that there's not really a mechanism for you know ultimately 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's a way and somebody's got to kind of take that baton on that but if there's a way to make a code for this um you know i think you could you could actually you know turn it into something that was more widely widely utilized and you know we probably dream up ways of how to how to integrate AI passive sensing all that stuff to really make that work but i think that would be that would be the the idea that would be the trajectory i'd see so yeah yeah having a billable to insurance code is it's 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's sleep deprivation some time to light exposure to the eyes and and then shifting in the circadian clock things central to the themes of this podcast that come up often um i think for the typical person can we say uh that trying to get a regular light dark cycle at sleep rhythm would be beneficial for overall mood regulation yeah i think for for the typical person um you know really really kind of re-regulating your sleep and and trying to get you know a good night sleep in which you fall asleep stay asleep wake up in a set time every morning is going to be pretty crucial 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 threshold and depression where things become kind of semi-volutional it's harder to kind of will yourself into that um there are therapies like um you know there's a cbt for insomnia for instance where you can do cognitive behavioral therapy to help with insomnia sometimes people and i'm not i'm no sleep expert that kind of pass this to greg to fully talk about this but but um but some of what goes on that people with kind of milder insomnia experiences like blue light out of their computer and things like that that they so you can use like blue light blockers to to it tricks your your brain is you know better than me it tricks your brain to think that it's still light outside and so people will still have insomnia because their brain still thinks that it's light outside and then people will um you know the kind of strip cbt for sleep um you know uh therapists will say there are only two things that you should do in your bed and if you're under a certain age and and whatnot it's really one thing that you should do in your bed which is to sleep and um and be with your partner uh right and 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 tv in a bedroom shouldn't eating a bedroom shouldn't you know hang out phone out of the bedroom keep the phone out of the bedroom yeah yeah um we should get greg seilam on the podcast we the i'll just mention for people that want to regulate their sleep we have a uh sleep toolkit that's available as a downloadable pdf at hubramelab.com just go to the menu and a lot of the things in that toolkit are based on work from stanford sleep laboratories including james eicers and others lab i'm not aimed at depression specifically um listen uh nolan dr williams uh this has been an amazing uh voyage through the circuitry of autonomic control this landscape of the prefrontal

Stanford Neuromodulation Therapy (SNT) Study (02:28:43)

cortex is uh i find incredibly fascinating and i i just want 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 saint study yeah um is it saint or saint's plural yeah it's saint so so um saint or what we're we're calling an snt now um saint has you know the intent was not to to kind of connect it to religion but uh but we may have um accidentally done so and so we we abbreviated it to snt for the for the subsequent trials which was initially stanford accelerated intelligent neuromodulation therapy or now we're calling stanford neuromodulation therapy but it's um the idea there which is a cool idea is that tms um is a device that delivers um that delivers a treatment and the treatment is the protocol and the protocol is the stimulation parameter set in a specific brain region for a specific condition and so what's cool about neuromodulation whether it be transcranial magnetic stimulation or transcranial direct current stimulation or deep brain stimulation like what kasey hoppern talked about you know um on another podcast is this idea that in all of those cases the device itself is a physical layer conduit of a stimulation protocol that's therapeutic 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 1995 right in the clearance in 2000 um 2008 2009 and in that um 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 and in the way that it went down was that there were two groups studying different components at NIH the first group was studying mood neuro anatomy on functional imaging that was kind of the first generation of functional imaging back then so pet scans which are kind of metabolic scans um and then specced scans and the idea there was looking at activity and metabolism in prefrontal cortex and what they found in these kind of more crude scans is a just general hypoactivity hypo metabolism the other group right upstairs at the National Institute for Neurological Diseases and Stroke in INDS they were looking at using tms which had been around for 10 years and rep repetitively stimulating in motor cortex and what they found was gosh we can get a readout and thumb muscle movement amplitude that's really reproducible across people it's like you know universally reproducible and if we do certain stimulation approaches they are biologically active to either increase excitability i.e. the thumb motion and a set intensity goes up the amount of amplitude goes up or inhibitory depotensiating it goes down with other biological stimulation approaches then a third outcome which is important that it's inert it doesn't do either so you can have stimulation approaches that do one you know increase activity decrease activity or you know or are inert and so what they found was oh we can excite certain brain regions then my mentor Mark George said had this kind of aha moment where he said wow there's underactivity in prefrontal cortex and depression and we can increase activity using this thing that we know we can increase activity in motor cortex we just need to put it in the left or a solateral prefrontal cortex and then they combined the two and started stimulating once a day in this kind of very abbreviated fashion and lo and behold some of those depression patients resolved their depression and back then and still today you can go and as a psychiatric patient stay at the international institute of mental health and go through clinical trials to try to get treated and there were patients who'd been there for months and they were able to be discharged because the mood was better yeah and so it was just a very crude approach where they were using ruler measurements or a dlpfc was and they were stimulating with devices that you needed to physically dunk the coil in an ice bath and with that they still were able to the kind of genius of this mark and others there still be able to to create a a purely engineered stimulation approach what's cool about that is that they they kind of found two things right they found this one stimulation protocol it does have some antidepressant effect it's limited it doesn't treat everybody it does have some antidepressant effect and this bigger concept that a neuromodulation device is kind of like a pharmaceutical company for you right that in the given individual a tms device or whatever neuromodulation device is able to generate to you can create a stimulation approach that is specific to a given condition and specific to an individual and so the physical layer is just how you exert that similarly to how we make pharmaceutical drugs in a pharmaceutical company but the actual therapy itself is what you do where you do it and so what we learned from you know another 20

Space Learning Theory & TMS Stimulation (02:34:25)

30 years of this is that you can modify the stimulation protocol in such a way where you can create a whole new treatment and put it through the same tms device or thank god an evolved version of it where you don't have to dunk it nice baths and you and they can actually really handle much more aggressive stimulation approaches and so in 2005 a group published a neuron a paper demonstrating that if you if you stimulate with the hippocampal rhythms through a tms coil you can excite the brain with memory rhythms and it'll last an hour so you can change cortical excitability in this thumb twitch for an hour sending three minutes of excitatory or 40 seconds the case of inhibitory stimulation that mimics the hippocampal rhythms so much more efficient the original tms approaches and so you know after that group tried to do it in this kind of six-week schedule and after that you know and while they were doing that we decided gosh you know this problem i talked about at the beginning of the show where you have these you know this problem that we we don't have a treatment for people who are in these high acuity psychiatric emergency states right this idea that we're going to engineer a treatment where we can reorganize the stimulation approach in time to be much more efficient by utilizing something called space learning theory and so you probably know about the space learning theory is the idea for the for the viewers is it's a simple psychological thing but we've also seen it in hippocampal slice sort of physiology too where if i'm cramming for a test what i do is i write out 60 note cards and i read each one for a minute until i get to the first note card and again and that's about an hour later right and we just we just intuitively do this we all we all you know automatically do that and we 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 you know you know we've all been in in grad school medical school and we have these big stacks of note cards that's space learning theory it's this idea that you need to see it about every hour to an hour and a half and that optimizes learning if you take the same stimulation approach that i'm talking about this data versus stimulation approach and you take a hippocampal slice of a mouse and you stimulate you you enlarge some dendritic spines and you prime some and then if you stimulate right after that you don't get any change it's called in mass stimulation but if you wait about an hour to an hour and a half you get more dendritic spines enlarged and more primed which by the way also is what ketamine does it it does it causes this dendritic spine enlargement and so you know what we found was is that the old way of doing tms this idea of just doing it once a day every day five days a week for six weeks didn't utilize the space learning theory it's like studying for a month or two just a little bit once a day like you remember some of that stuff but it's like not as potent as that week where you're kind of cramming right and what we realized is that if we could reorganize the stimulation in times that we took the whole six-week course we actually figured out a way to do it in a day and then what we also figured out is that people were under dosing tms because if you just keep going after six weeks out to month three four five more and more people got better so we figured out it's not just one day we're gonna give five times the normal dose we're in seven and a half months worth and five days using space learning theory so every hour every hour for ten hours for five days for five days so it's a 50 hour block it's 90 minutes of actual stimulation but spread out through the day in the same way of learning which is perfect for an inpatient psychiatric unit right five days is manageable yeah then you can get stimulation nobody's ever dropped out by the schedule um they they're you know folks that want to do this want to do it so they'll do their nine minutes they'll go get breakfast they'll do their nine minutes they'll go see their therapist or whatever it is and so what we found um with this reorganization and in time of the stimulation dose and then the third component is we do resting state functional connectivity scans on everybody and we have ways now in the last five to ten years of picking out that specific sub-genual dlpfc sub-circuit that i was talking about earlier that singlet dlpfc we can pick that out in every single one if you want to come to lab we can we can find your dlpfc sub-genual it's even more robust than non-stimulate too just while we're in there yeah if you want to we can we can move around your hypnotizability um 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've found is that folks will um will within one to five days you know in in more cases than not and depending upon if you're looking at this open label or in trials somewhere between 60 and 90 percent of the time they will go into full-on remission in the sense they're totally normal from a mood standpoint at the end of this and like i said with variable durability so that's the part we have to figure out now about dosing and how to keep people well but for some people you know we've had four years of remission you know a year of remission and it's it's really that cramming of the test it's really that idea that you're laying in that information in the exact right spot and the the signal is a simple signal but it's a profound one which is turn on stay on remember to stay on you know that idea that you're you're sending this memory signal into the brain and you're doing it in such a way that you're telling the system you're kind of taking it out of the hippocampus's hand your own hippocampus's hand is you're sending the same signal the hippocampus normally signals out now you're sending that signal into the prefrontal cortex and kind of utilizing the brain's own communication style to get it to get out of the state and what's very cool about this is that is that people when they when they kind of exit out of that they end up they end up saying they don't have any any side effects from it and they feel back to normal like some people you know not everybody but there's a subsection of people that with with SSRIs where they'll say I kind of feel numb or I have GI side effects or 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 gets SSRIs 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 any of that stuff and I think it's it's likely because you're tapping into that core circuitry and you're reversing it and you're doing it with a with a magnet that because it's a very profound electromagnet it's the same field strength as an MRI scanner it's able to induce a current in the brain in this focal 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 is the same study still ongoing and if people are interested in potentially being patients or subjects in the study can we provide them a portal link? Absolutely yeah so we have now the the treatment some my students went over to a company called Magnus Medical and they've been working on this they've got an FDA clearance now and now folks can get it through trials over the next couple of years because it's going to take some time for that company to kind of get up and running and and get a you know get a device and get the whole thing set up nationally but while that's all going on there's still about a thousand patients that need to be recruited across a bunch of different trials all over the country we'll take people from anywhere in the country we also have partners in New York and San Diego and and other and soon to be South Carolina and other places where we can actually kind of you know my lab can help to kind of let people know where to go where they you know based off of where they're at in the US and get them access to being able to be in a trial and what we've tried to do is make it so that even if you get the you know 50/50 chance you're going to get the real deal or you're going to get the the the non-real deal but what we have figured out is a way to let everyone have access if they if they got the not real deal version the kind of sham version or 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 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 company's doing what they're doing and what the lab's doing and kind of nationally what you know other partner labs are doing well I can assure you're going to get some interest happy to happy to have it yeah thank you and listen thank you so much for taking us on this incredible voyage through the neurocircuitary underlying certain aspects of depression the coverage of the different types of depression the various therapeutic compounds how they work we've talked about a lot of things and you you've shared so much knowledge and even as I say that I I very much want to have you back to talk about many other things as well that we didn't have time to cover but I also just really want to thank you for the work that you do I know we are colleagues but you run an enormous laboratory enormous in my about 40 people is a big group very big group plus you're you're in the clinic you also have a life 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 avoiding often suicidal depression it's just incredible work and an incredible generosity and just thank you so much well thank you man I mean I you know similarly I want to thank you for for what you're doing I mean I think I think that what you know I've got a lot of friends folks that are not in medical profession new friends of mine you know one of my buddies who's a real estate agent who works with us it was a big big fan of your show and you know I told a couple people like that I was coming on and and they were like super stoked they're like we you know we watch we watch every show and you know super excited to to to watch mine and they said something very important to me that you know you make this this complicated neuroscience and kind of brain body science accessible you know and in a way that that few have a gift to do and I think that that's so important and and this show is doing so much to to help with science literacy and yeah appreciate you so well thank you I'm I'm gratified and honored by your statement and I look forward to more thank you absolutely thank you thank you for joining me today for my discussion with Dr. Nolan Williams I hope you found our discussion about psychedelics and other compounds about transcranial magnetic stimulation and about the treatments for depression in general to be as stimulating as I did if you'd like to learn more about the work being done in Dr. Williams laboratory you can go to the brain stimulation laboratory website which is bsl.stanford.edu and there you have the opportunity to apply to be in one of the clinical trials for depression or other studies as

Closing Remarks And Social Media

Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Huberman Lab Premium, Neural Network Newsletter, Social Media (02:45:35)

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