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Speaker A: 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 doctor Nolan Williams. Doctor 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 Doctor 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 antidepressant or anti trauma properties. You'll also learn about some fascinating research in doctor 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 Doctor Williams is that not only does he have vast knowledge of the various treatments for depression, but that he and his laboratory are really combining these treatments in the most 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 neural circuitry underlying depression as well as positive moods. You'll also learn about all the various drugs that I described, and you're really going to learn about the current status and future of the treatment of mood disorders. Today. You'll also learn about a number of ongoing studies in doctor Williams 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 Doctor 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. 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 element. Element is an electrolyte drink with everything you need and nothing you don't. That means plenty of salt, magnesium and potassium. The so called electrolytes, and no sugar, salt, magnesium and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electrolytes need to be present in the proper ratios. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. Element contains a science back to electrolyte ratio of 1000 milligrams. That's 1 gram of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes. And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, if you'd like to try element, you can go to drink element. That's lMnt.com Huberman to claim a free element sample pack with your purchase. Again, that's drinkelement lmnt.com dot Huberman Today's episode is also brought to us by waking up. Waking up is a meditation app that includes hundreds of meditation programs, mindfulness trainings, yoga Nidra sessions, and NSDR non sleep deep rest protocols. I started using the waking up app a few years ago because even though I've been doing regular meditation since my teens and I started doing yoga Nidra about a decade ago, my dad mentioned to me that he had found an app turned out to be the waking up app, which could teach you meditations of different durations and that had a lot of different types of meditations to place the brain and body into different states and that he liked it very much. So I gave the waking up app a try and I too found it to be extremely useful because sometimes I only have a few minutes to meditate, other times I have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain and body into lots of different kinds of states, depending on which meditation I do. I also love that the waking up app has lots of different types of yoga Nidra sessions. For those of you who don't know, yoga Nidra is a process of lying very still but keeping an active mind. It's very different than most meditations, and there's excellent scientific data to show that yoga nidra and something similar to it called non sleep deep rest, or NSDR, can greatly restore levels of cognitive and physical energy, even with just a short ten minute session. If you'd like to try the waking up app, you can go to wakingup.com huberman and access a free 30 day trial. Again, that's wakingup.com huberman to access a free 30 day trial. And now for my discussion with doctor Nolan Williams. Thanks for joining today. I'm really excited to have this conversation. It's been a long time coming and I have a lot of questions about different compounds, psychedelics in particular.

Speaker B: Yeah.

Speaker A: But before we get into that discussion, I wanna ask you about depression, broadly speaking.

Speaker B: Sure.

Speaker A: Intractable depression. How common depression is or isn't. I heard you say in a wonderful talk that you gave that depression is perhaps the most debilitating condition worldwide. And yet, in contrast to other medical conditions like cancer, we actually have a fairly limited number of tools to approach depression. And yet the number of tools and the potency of those tools is growing. So if you could educate us on depression? I would really appreciate it.

Speaker B: Yeah, absolutely. So depression is a condition that has a lot of manifestations. 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. 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, Liston and Cornell and try to actually get biotypes based off of neuroimaging to see if we can 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. Recently, the American Heart association added depression as the fourth major risk factor for coronary artery disease, alongside the risk factors that we know, hypertension, high blood pressure, hyperlipidemia, high cholesterol, and diabetes, high blood sugar. Those three have been on the list for a long time. And depression, and being added to the list is the fourth one. Really interesting. 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 their risk of having a heart attack in the future? And 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 end up having a heart attack. The risk of having depression after the heart attack is higher than the normal population. A lot of what we're doing in the lab actually is measuring brain heart connections. And we can actually, with transcranial magnetic stimulation, a form of brain stimulation, we can actually decelerate the heart rate. We can capture that heart rate deceleration over the mood regulatory regions. And so actually a direct probe of that connection. So it's interesting. And so, as you said a second ago, it's a very disabling condition. Moderate depression is about as disabling as having a heart attack, acutely having a heart attack. Severe depressions as disabling is having cancer without treatment and dying from a cancer without treatment. And so it's kind of underappreciated 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. Then the idea that we can start really putting more funding and putting more focus at the federal level, 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 emergency settings, where they go into inpatient units 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, 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. In some scenarios, they go up, but on average, they go down, and there are no tests. We've been very focused on that particular problem. Somebody that maybe was doing fairly okay with a pretty moderate depression, and then their depression gets worse, and then they end up in an emergency setting, and the field really hasn't developed a way of consistently being able to treat that problem. And folks end up getting the same standard oral antidepressants that they've been getting outpatient. And I came to this because I dual trained as a neurologist and psychiatrist, went back and forth between neurology and psychiatry, saw that in neurology, we have all these ways of treating acute brain based problems, and really wanted to emulate that in psychiatry and find ways to develop and engineer new brain based solutions.

Speaker A: There's a lot to unpack there. One thing that you said, 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.

Speaker B: Brain is it the first place where the stimulation goes is called the dorsolateral prefrontal cortex. It's the sense of control governor of the brain. And then what we know is that when you use a magnet, use what we call Faraday's law, this idea of using a magnetic pulse to induce an electrical current in electrically conducting substances, in this case, brain tissue, but not skull or scalp or any of that or hairdouse, 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 anterior cingulate in the insula and the amygdala, and ultimately the tract goes into something called the nucleus tractus solitarius, 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 cardiologists measure heart rate, and you stimulate over this left dorsolateral, you get a deceleration of the heart rate, and it's very time locked to the stimulation. So it's a two second train of stimulation. At 1 second, you see the deceleration. It goes down about ten beats per minute, and then it'll drift back up, and there's a break for 8 seconds on the stimulation, 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 ten beats per minute, every train. And so we know 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. It's our work. Other folks work, Martin Arns in Europe, the Netherlands work showing the same connections. I think it's been replicated like four or five times.

Speaker A: So you mentioned left dorsolateral prefrontal cortex. Anytime 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 the left dorsolateral prefrontal cortex would be connected to the heart in this way?

Speaker B: Yeah. So left dorsolateral is thought to be the side that when you excite it, when you kind of do excitatory stimulation, potentiating sort of stimulation, that you can reduce depressive symptoms. And a guy by the name of Mike Fox at Harvard has demonstrated that if you have strokes in the brain that cause depression and you put them on the human connectome thousand 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 in 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 a hemispheric 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 antidepressant. You can excite the right, and that's antimanic in some studies. And so this idea that there is this hemispheric balancing of mood is quite interesting, right?

Speaker A: It's incredibly interesting. And just so people know, if you're curious, what the connectome is, connectome is a term that was built out of this notion of genomes being large collections of sequencing and mapping of genes. They're proteomes of proteins, of connectomes, those so called connectomics of connections between neurons. So the human connectome project is ongoing, and I find that incredible, that within the connectome project, they can identify these regularities of right versus left or solid prefrontal cortex, especially since I've looked at a fair number of brains from humans, 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? Dorsolateral 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?

Speaker B: 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. 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 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 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 brain images and look at where the strokes landed. Those kind of causal bits of information point to this, this asymmetry.

Speaker A: Interesting. Well, in that case, going with what we do know, that stimulation of dorsolateral prefrontal cortex slows the heart rate down transiently, but 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? Does it tell us anything fundamental about depression, that anxiety is inherent to depression? Faster heart rate is 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 I. 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?

Speaker B: Yeah, that's a great question. I'll answer the second question first. We know that there are ongoing trials of this. If you stimulate in the vagus nerve in an implanted vagus nerve stimulator, you can actually have this afferent parts of the vagus project, ultimately up to the DLPFC, through the cingulate, through these anterior insula. So that same, that obviously the same tract. Right. And you can stimulate there and alleviate depression, which seems very unusual. Right. You're stimulating a cranial nerve down in the neck, but if you can get up into the brain, you actually can improve depressive symptoms. And so more evidence that this is kind of a whole track and system. And if you stimulate in part of that system, it appears that you can improve mood.

Speaker A: 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 feed back to the dorsolateral prefrontal cortex to achieve some of that alleviation?

Speaker B: Absolutely, yeah. So there's a number of studies implicating DLP, the dorsal lateral, and say, meditation, mindfulness, that sort of thing. And they're small studies, but pretty well design 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. You go from being completely in total volition to having semi volition. You have thoughts that you really have a hard time controlling and that sort of thing. And 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. And the extreme form of that is catatonia, where people in a very severe form of depression get stuck motorically, and they obviously can't. They have no control or very limited control. And so 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. Maybe that's part of the process. I'm not aware of any studies specifically looking at dorsal lateral 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 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.

Speaker A: So 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. So lower heart rate might make somebody more depressed. You've mentioned catatonia or somebody that just doesn't seem motivated or excited to do anything. I think a mania is elevated heart rate. And being excited. On the other hand, I realized that anxiety, which brings about ideas, 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 left dorsolateral prefrontal cortex by way of transcranial magnetic stimulation, or by taking a beta blocker or by stimulating the vagus? Can we throw out a number, a rough number? Does that help? 30%, 50%? How long lasting is that relief?

Speaker B: 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. That heart rate variability piece may be, and there's some studies that link the two, but the actual deceleration seems to be much more of a marker that you're in the right system. But it 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. It's not a huge amount, so it only explains a small percentage. And so it's unlikely that simply reducing the heart rate, and in fact, for many years, propranolol 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. 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.

Speaker A: I'm so glad you mentioned the parasympathetic nervous system, which, of course, is 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 at the extremes that might be true, but rather it's something about the regulatory network, the ability to control your own nervous system to some extent. And when I think about the autonomic nervous system, I like to think about as a seesaw of alertness and calmness. And when you're asleep, it's 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 states, 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 get 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 it. Does that make.

Speaker B: Yeah, absolutely. Absolutely. Okay.

Speaker A: I just want to make sure that I'm framing this correctly in my mind.

Speaker B: Yeah, absolutely. And in some studies, if you do the same identical stimulation on the right dorsolateral, you can get an acceleration, you know, just kind of further confirming this idea of lateralization. Right. That even. It appears that even the prefrontal cortex, you know, cortical areas seem to be lateralized in this. In this way. And I. You know, it's. It's lessen. The right finding is more variable depending upon the study. The left is very consistent in this way.

Speaker A: We've talked about transcranial magnetic 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 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? 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 mania. Other areas of the brain I think of 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 spent my career in neuroscience, and I still can't really understand what it's doing. And maybe it's doing 50 things.

Speaker B: Yeah, no, it'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 Spiegel and I have been working on this, and he's found and published this ten years ago, that a different part of the left dorsolateral is functionally connected with the dorsal anterior cingulate, with a lot of functional connectivity in 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 dorsolateral prefrontal cortex than the part that seems to be important for regulating mood. And so the left dorsilateral 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 dorsolateral prefrontal cortex and you have people do the Stroop 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 reduced in the color blue, and you have to name. You have to say the word. You don't name the color.

Speaker A: You have to suppress a response.

Speaker B: Yeah, yeah, exactly. And so. I'm sorry, you name the color, and you see the word written in a different way. And so, basically, if you stimulate in a way that inhibits the left dorsolateral prefrontal cortex, or either one, you can actually knock out the ability to do that well, and it'll take longer for people on the incongruent cards to be able to name it. They have a time delay that's greater than they had before they got stimulated. 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 we were able to stimulate in an inhibitory way within the left dorsolateral prefrontal cortex that's involved with this cognitive control area, and we were able to knock that area out and increased 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 dorsolateral than, say, we do. And we do these very intensive stimulation approaches to treat severe depression, and we're able to get people out of depression with the part of the dorsal lateral. It seems to be lower in the more lateral and inferior on the DLPFC and connected with a subgenual anterior cingulate. So the part of the anterior cingulate that processes emotion.

Speaker A: I'd like to take a quick break and acknowledge one of our sponsors, athletic greenshouse. Athletic greens, now called ag one, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking athletic greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking athletic greens, and the reason I still take athletic greens once or usually twice a day is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long term health. And those probiotics and athletic greens are optimal and vital for microbiotic health. In addition, athletic greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met and it tastes great. If you'd like to try athletic greens, you can go to athleticgreens.com huberman and they'll give you five free travel packs that make it really easy to mix up athletic greenshouse while you're on the road, in the car, on the plane, etcetera. And they'll give you a year's supply of vitamin D, three k, two. Again, that's athleticgreens.com Huberman to get the five free travel packs and the year's supply of vitamin D, three k two. Based on what you told us about the Stroop task and the role of the prefrontal cortex and Stroop task, to me, the Stroop task is a rule switching game. Yep, in one moment, the rule is you read whatever the word says and then you switch and 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.

Speaker B: Okay, that's right.

Speaker A: 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 people 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. 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 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, 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 dorsal hour 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, it feels like a lie if you feel like garbage, to say that it doesn't fit with the rule, it's like saying, that card is not red, that card is green, when your eyes tell you that it's red.

Speaker B: That's right.

Speaker A: And it seems like there's something about prefrontal cortex that, in principle, gives flexibility to rules based on what we know on the Stroop task. So, given its connectivity, can we assume that the talk therapy that occurs in a. The 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, that in re scripting that, that somehow it allows us to do a sort of stroop task on our beliefs, is that a tremendous leap? I'm just really trying to frame this in the context of 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, what are the algorithms that govern prefrontal cortex?

Speaker B: Yeah, absolutely. So, in a kind of standard cognitive behavioral therapy session, what the therapist is trying to do is identify those beliefs and. 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 had a lot of patients who've told me, like my therapist told me, that I wasn't trying hard enough in therapy, and I really am trying hard. But these are moderate, pretty severe, depressed patients. And as soon as we get them, well, with the TMS approaches, kind of rapid five day approach, and the next week, we come in and see them, and they'll say, you know, what I did all weekend is I looked at my therapy books, and now I can understand it. I actually see TMS as a way of having exogenous sorts of cognitive functions that in milder forms of depression, we can pull off with psychotherapy. This idea of being able to turn that prefrontal cortex on and have it govern these deeper regions in depression. The deeper regions govern the prefrontal cortex. They precede the prefrontal cortex, timing wise, and we've got some data in review now, wherever we're seeing that in depressed individuals that are responsive to our rapid TMS approach, we call Stanford accelerated intelligent neuromodulation therapy, or s and T or Saint. 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 temporally 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.

Speaker A: So you're not talking about, obviously physically moving these structures. You're talking about, in time, their activation. So in one case, it's like the coach telling the player what to do, and in the other case, like the player telling the coach what to do. And you restore order to the game.

Speaker B: Or order to the game. What it looks like is depression, to your point, is a bunch of spontaneous content that's semi volitional, that's being generated out of this conflict detection system. The cingulate that seems to sense conflict and feed that information gets 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 reinharden time, re regulate in time the left dorsolateral over the cingulate, the more of an antidepressant effect you have.

Speaker A: 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.

Speaker B: 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 buffing it up TMS is almost like exercise for the brain, right? You're kind of exercising this region over and over again with a physiologically relevant to signal and kind of turning that system on. And what's interesting, I think, really interesting for this show is to, we had a couple of folks, probably five or six folks, that have actually told me this, where if they remit early enough in the week, we have this very dense stimulation approach where we can stimulate people really rapidly over a five day block. 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. We're getting to a point where we can tell how long it's going to take, but we're not there yet. Every time somebody gets better at day one or two, at the beginning, when we first started doing this, we'd say, we're not sure. We think this is safe to keep going, but what do you want to do? Everybody was like, no, I want to keep going. By Wednesday, they're totally zeroed out on the depression scales, even better than most people walking around, really. No anxiety, no depression or anything. Thursday, the first guy that told me this, he came in and he said, you know, I was driving back to my hotel, and I decided to go to the beach. And I just sat there and I was totally present in the present moment for an hour. And he's like, I read about this in my mindfulness books, but I experienced it last night, and I've never experienced anything like this before. And I was like, hmm, that's interesting, but kind of wasn't sure. And then I didn't tell any, obviously, any more patients about that. And then about five over the last couple of years, when they remit early in the week, by the end of the week, they're going to the beach, and they're totally having what people describe as a pretty mindful, present moment sort of experience, which is really interesting. What that is, I don't have full on scientific data to tell you, but it's an interesting anecdote that, folks, when you push them through this point of feeling clinically well, that some people end up reporting this additional set of features.

Speaker A: You mentioned the cingulate and the anterior cingulate in particular, because now I feel like for the first time in my career, I have some sense of what prefrontal cortex might actually be doing besides providing a bumper for the rest of the brain. 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 and for the non neuroscientists out there, when I say mapped, if we were to put someone in a scanner and focus in on cingulate or put an electrode in there, what makes the neurons in there 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?

Speaker B: Yeah, so that Stroop task, those incongruent word color associations, the dorsal part of that, for obsessive compulsive disorder patients, certain kind of triggers. You'll see some of the neuroimaging studies will point to anterior cingulate. In the very crude psychosurgery world 50 years ago, the anterior cingulotomy was a way of treating obsessive compulsive disorder, because that area seems to be overactive. In people who are experiencing obsessive compulsive disorder, you can kind of walk. The cingulate wraps around this white matter tract like bundles that wraps around that. And so there's a part that's above that, around that, and below that. And depending upon how much of the conflict task has an emotional component, the more ventral and subgenual that activation is. So the dorsal part of the anterior cingulate seems to be kind of more of a pure cognitive, maybe obsessive compulsive disorder sort of area. Whereas when you start getting into mood sorts of triggers, like facial expression conflicts, where you're supposed to, there's an emotional stroop 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 stroop conflict. And that seems to be more peri. Genial 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 it's distributed. There are heart rate kind of components to it, autonomic components in there, too. There's something called akinetic mutism. I'm a board certified neuropsychiatrist, behavioral neurologist, and I've seen a lot of these, what we call zebra cases in neurology, where people have these unusual neurological presentations, and one of them is a kinetic mutism. If you have a glioma sitting in the inner hemispheric fissure and 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 cingulate works as well. It's like if it's not functioning, then people have a hard time connecting with reality. It seems to need to be constantly online to be able to interact with the exterior world.

Speaker A: Is it involved in some of the dissociative states that sometimes people who are very stressed 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 almost like a catatonia, and they refer to as a dissociative state. Do you see that in depression? And, I mean, we're speculating here as to whether or not that involves a singulate, but what you're saying holds a lot of salience for me in thinking about this example.

Speaker B: Yeah. Yeah, there's. So you see catatonia as an extreme outcome of depression and of sometimes schizophrenia and other illnesses. Dissociation is an extreme outcome, or even some cases a less extreme outcome of PTSD and trauma. And it's also a phenomenon that happens naturally in some people that are highly hypnotizable. And so if you asked David Spiegel, he'd say that some of the work that he's been working on is around posterior cingulate and the capacity to dissociate. But, yeah, with our stimulation approach to DLPFC, dorsal anterior cingulate, one of the subscales that moved the most was the dissociative subscale for hypnotizability. So even in a normal individual, you see that change in that kind of experience of dissociation.

Speaker A: I am highly hypnotizable. David's hypnotized me a number of times. In fact, we have a clip of that on our Huberman lab clips channel. I've always, always started my early teens, I started exploring hypnosis. I'm extremely hypnotizable. And self hypnosis or assisted hypnosis, I don't know that I ever go into dissociative states. I'll try and avoid forcing you into running a clinical session right now to assess anything like that. But this brings about something really 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?

Speaker B: Yep.

Speaker A: And my assumption is that as a dissociative anesthetic, that it leads to dissociative states where people can sort of third person themselves and feel somewhat distanced from their emotions. I've also been hearing that there are emerging treatments, psilocybin being one of them, but some other treatments, MDMA, et cetera, that we'll parse each of these in detail, that lead to the exact opposite state during the effect of the drug, which is a highly engaged emotionality and heart rate and sense of self.

Speaker B: Yeah.

Speaker A: 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 or in some cases pushing really hard on the opposite ends of 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?

Speaker B: Yeah, that's a great question. Yeah. So for ketamine, the level of dissociation appears to be correlated with the therapeutic effect. It appears to be necessary but not sufficient to produce an antidepressant effect. And so, folks that don't have any psychological change from the ketamine or don't experience need dissociation, typically tend to have less potent antidepressant effects from ketamine. We did a study a couple of years ago. It was really interesting. So we gave folks naltrexone, which is an opiate antagonist, mu and Kappa opiate receptor antagonist, and we gave the same individuals a pill of that or a pill of placebo, and they had no idea which one they were getting.

Speaker A: Was this low dose in altrexone, 50 milligrams.

Speaker B: So it's pretty high dose, yeah. And so we gave a typical ketamine therapeutic dose, and then we gave 50 milligrams of naltrexone or placebo. And then in the same individuals, we gave two infusions, one with each of those conditions. And if they had an antidepressant effect, we waited until they relapsed, and then we gave them the other condition. And then we looked to see what effect of blocking the opioid receptor. 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 completely worked in, which is the glutamate system, then you would have 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. It has clear opiate effects in mice and various ways of looking at that and NMDA receptor antagonism and glutamate effects. If it's just that the glutamate part 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, 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 saw was that there was a dramatic blockade of the antidepressant effect when naltrexone was present in the people that had an antidepressant effect with ketamine plus placebo alone. And then some friends of mine did a TMS study with pain, and they stimulated over the left dorsilateral prefrontal cortex, and they gave naloxone iv naloxone which works basically the same way as naltrexone. And they were able to block the anti pain effects of TMS with an opiate blocker. So this idea that another kind of convergent point, 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, a very painful operation, total knee replacement, and you age, sex, 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 oral opioid dose by day four.

Speaker A: That's required.

Speaker B: That's required 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 an antidepressant effect. Chronically it seems to have a very pro depressing effect. It can make people treatment resistant. But it's an interesting phenomenon. But yeah, the opioid system seems to be pretty involved. But what's interesting there with the, that 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 what we call the trip or the kind of dissociative effect where people are having a psychological phenomenon from ketamine that was identical both times. And so 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 we think we pretty clearly debunked that idea that the underlying pharmacology and the state seem to be important. We don't know for sure if you can, and a lot of people are working on this, if you can take out essentially the psychological effect and still have a drug that works to treat the illness that you're trying to target. There was a mouse study out this week where they had an LSD analog and they were able to see some animal level data to suggest that could be true. But until we figure that out in humans, it's to be determined. But it is curious being able to use experimental manipulations to try to separate some of these phenomenon apart and really understand what's doing what.

Speaker A: 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 presumably at some point either decriminalized or legal drugs, which has not yet happened, at least not in the US. Um, but just to make sure that people are getting this, um, and how crucial this is, what we're really talking about here is the fact that, you know, if somebody takes a multigram dose of psilocybin, or somebody takes, um, 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, et cetera. 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 la your experiments with naltrexone or a change in the underlying neuromodulation that had anywhere from nothing to something to do with the real shift. 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 gets people upset when they hear it. This gets a lot of people upset, really? Because people think, oh, no, it's the intense experience that matters, but, in fact, 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, 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 as they sort of connect the. The experience of the actual birth to the connection, when in fact, that's true, it turns out, but there are a bunch of other things happening, too. That's simply the reflection of the fact that you're holding a child and the pheromonal effects, etcetera. 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, 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 there are now data that essentially state that there's no direct link between serotonin levels and depression, although my understanding is that the SSRI's are powerfully effective for certain forms of 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? What's going on with SSRI's in your patients and in other, other people as well?

Speaker B: Yeah. That experiment that I described a bit ago around the naltrexone and ketamine is the first time I'm aware of where we were able to essentially eliminate an antidepressants effect by using a second drug as a blockade. And it highlights a bigger issue. 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 it's been difficult, I think, for folks to see that something can, on one hand, work, and on the other hand, we don't know how it works. SSRI's clearly work many, many meta analyses, proving that out of that, in a subpopulation of individuals, they achieve great benefit from depression, for depression, for obsessive compulsive disorder, for generalized anxiety disorder, panic, all these things. You can see 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 blocking the reuptake of serotonin and leaving the serotonin in this, in between two neurons for a while and allowing for more serotonin to kind of be there. The issue is that they don't work immediately, so they don't work the same day you start taking them. And that suggests that probably it's nothing. Exactly the serotonin being in there that's directly driving it, that it's much more likely that it may have, some say, brain plasticity effects. We know that things like brain derived neurotrophic factor get upregulated with chronic oral antidepressant use. That's the idea, is that these things work. But what's powerful. And I think what the authors of this paper was extremely controversial paper, were in part trying to say was that there's not a deficit of serotonin. You're not born with what people call a chemical imbalance. And psychiatry has known this. This is not actually new information to anybody. It's kind of a rehashing of a bunch of information we've known for a while now. But in the lay press, it's kind of hit in a way that it didn't seem to grab attention before with previous publications. But this idea that this chemical imbalance idea is wrong, I really think that part's important, because I think that for a while, I think psychiatry, what I'll call psychiatry 1.0, this idea of Freud and psychotherapy and its origins, it was a lot around your family and those experiences in psychotherapy kind of going in and correcting or helping you to figure out or 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. There's a huge importance there. But there's a history where things like the schizophrenogenic mother and all of that, that was a concept at some point. And so we've transitioned from that to, for a long time, the chemical imbalance, which I'll call psychiatry 2.0, this idea that there's something chemically missing. And I think that the trouble there for a patient who's nothing, a physician, who's not someone who's, you know, who's steeped in these sorts of ideas, who's more of a person, 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 over when I was a child or a chemical in my brain, what I think is really powerful with TMS, really powerful TMS and a lovely, even powerful. The psychedelic story is it's saying something different. 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. It's very unlikely that there's some long term upregulation of serotonin that's driving that. Our work actually kind of pushes back on this serotonin hypothesis as being kind of the center of depression, because it says, look, we're not giving anybody any serotonin. We're simply turning these brain regions on, and we're focused on the circuitry, and that's psychiatry 3.0. It's not just like neuromodulation. Neuromodulation is a really nice use case for psychiatry 3.0 because it's a way to focally and directly perturb brain regions in whatever modality you're using. But there are 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, suggesting in those same brain regions converge the subgenual default mode network connection that we see is changing with our Stanford neuromodulation therapy technique. It's that same set of brain regions that ketamine and psilocybin seem to act on, these connections between brain networks that seem to shift. And so it refocuses the story on something that's highly correctable, and it's basically electrophysiology, and it's basically kind of recalibrating a circuit that is recalibratable instead of, I have something missing, or I have some set of experiences early in life 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. We've seen with our TMS techniques, we've seen it with some of the psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time within five days, within five or less days. And in the case of the psychedelics, within a few days, 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 it's fixable. It's just like the heart. It's just like an arrhythmia in the heart. It's just like these other illnesses that it's like a broken leg. We can go in and do something, and we can get somebody better. Then I think what's empowering and what a lot of patients have told me is they say, I've gotten to, some people will relapse and need more stimulation or need more psychedelics or whatever it is, but they'll tell me 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 improves, it gets better, I will be able to re achieve it. I don't fear that I'm chronically broken. I don't fear that the chemical imbalance is still imbalanced. I don't fear I. That these things that I couldn't control in my childhood are going to be there and drive this problem forever. And I think that's what's so powerful about this.

Speaker A: The sense of control.

Speaker B: The sense of control, the sense of they're not doing the stimulation themselves, they're not administering the drug in these trials themselves, and 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.

Speaker A: I have a good friend. I won't out him, for reasons that'll become clear in a moment, who was quite obese and lost a lot of weight and was really proud of himself. And then I guess we could say he sort of relapsed, in a sense. Not all the way, 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. And it just resonates with your story that once somebody understands, they can do it because they've been there before. This idea, again, of considering new rules. And that brings me to this question about psychedelics and frankly, the altered thinking and perception that occurs to in high dose psilocybin clinical sessions. It seems that the disordered thinking, even though it could be random, right. Hearing colors and seeing sounds is always the kind of cliche statement of the Timothy Leary area. Also right there, that's a stroop task of sorts. It's a synesthesia, it's a combining of perceptions, but it's sort of task ish in that it's a new set of rules for the same stuff. Right? And people do, many people do report improvements in trauma related symptomology and depression, as I understand it from my read of the clinical trials after taking psilocybin, because during those sessions, something comes to mind spontaneously, as you and I were talking about earlier, they will report, for instance, a new way of seeing the old problem. And the old problem could be the voice that they're no good, nothing will ever work out or could be even more subtle than that. So that raises two questions. One is about the basic functioning of the human brain, which is, why do you think the brain would ever hold on to rules that don't serve us? Well, that's one question. And then the second question is, what is it about psilocybin related molecules in terms of their neurochemistry, in terms of the ways they disrupt thinking and feeling, et cetera, during the session that allow this novel rule consideration phenomenon?

Speaker B: Yeah. So the first question, I think it's an evolutionary neurobiology answer, right? At the individual person level, 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, 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 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 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, let's say, PTSD. A lot of veterans come back and they experience these PTSD symptoms at all useful back home, right? They hear some loud noise, and all of a sudden they're behind a car, or they're behind. I've heard of folks 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, highly adaptive. That's highly adaptive. I think what's interesting is that we, in the absence of using substances like psychedelics, end up having these very persistent memories that are attached to negatively valence emotion. Predominantly, as you were saying earlier, the jacket in elementary school, I had various things like that. For me, too. Right? You remember these things, and we hold onto those things from, I think, an evolutionary neurobiology standpoint. But what seems to, for whatever reason, kind of alleviate that are these substances, some new, like MDMA, some that have been around for thousands of years, like psilocybin and used in kind of sacramental as a sacrament in traditions, seem to have a therapeutic effect that seems to be pretty long lasting for these phenomenon. And so it's just curious, right? It's curious that in the absence of that, these things will keep going on and on, but in the presence of that exposure, then all of a sudden, you see a resolution of the problem. And we have some work now, we're treating folks with Navy SeaLs, and data is still being analyzed, but the anecdotes that we're getting are folks are coming back, and they're saying it's finally gone. 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, upregulation of brain derived neurotrophic factor, in the case of ibogaine, glial derived neurotrophic factor, this highly plastic state, and the ability to re experience memories. And then, as you know, we always reconsolidate a memory. When we bring it back up, we always reconsider. But reconsolidating it in that state, for whatever reason, may drive a therapeutic effect. And the jury is still out. I would say that I'm kind of agnostic to what tool I'm using. Kind of guy like, my business is to find treatments that help people. And so I'm much more pragmatic about it. If this sort of thing, which has a lot of cultural baggage, but if this sort of thing ultimately ends up being therapeutic, if we can design trials that convince me and others that it is, then we should absolutely use it. And if it doesn't, then we clearly shouldn't use it. And I think 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.

Speaker A: Obviously, a placebo for a psilocybin journey is hard to imagine.

Speaker B: 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 placebo condition, because we know that we can block any of the actual antidepressant effects academy they still haven't experienced. That's one way of doing it. But thinking about ways to do that and really proving this out. Yeah, I think that's been kind of central to the way I've been thinking about this. But, yeah, I think there's the work that's been done so far. The first psilocybin trial, the first MDMA trial was published in Nature Medicine recently.

Speaker A: And what do those generally say? I mean, that they are effective for a number of people after one session, two sessions. What's sort of the general contour? Let's start with psilocybin and MDMA.

Speaker B: Yeah. So MDMA appears to, in one to a few MDMA sessions, have an anti PTSD effect that seems to be outside of the kind of standard assumed levels of PTSD improvement that you can observe in individuals with this level of PTSD. So what we call the effect size, which is essentially like a Cohen's d effect size, is a measure that allows for you to compare and different treatments to each other for different conditions that are agnostic to what the actual illness is. The effect sizes there approach effect sizes things that are pretty effective, like antacids for heartburn. And you see that with MDMA treatment.

Speaker A: So does that mean that for people that have trauma who do a. And again, we're talking about in a clinical setting, they take one or two doses of. Of MDM. I think the standard maps dose is 150 to 175 milligrams. Again, doing this with a physician, et cetera, controlled clinical trial. Legal.

Speaker B: Yep, exactly.

Speaker A: They do it once or twice. And broadly speaking, what percentage of people who had trauma report feeling significant relief from their trauma afterward?

Speaker B: It's about two thirds of people had a clinically significant change in their PTSD.

Speaker A: It's impressive.

Speaker B: Which is impressive. Right.

Speaker A: And how long lasting was that? I mean, these trials were ended pretty.

Speaker B: Recently, so it appears to last for a while. In the earlier trials, where they followed people out, it seemed to last for kind of in the years range for some people. And so it's, you know, it's pretty. It's pretty compelling. Psilocybin, you know, 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.

Speaker A: So they have to get repeated infusions of ketamine every ten days or so.

Speaker B: Yeah, forever for some people. Or they end up getting like a bunch of doses for a couple of weeks, and then for some people, that seems to last a while. That's where I think the psilocybin story for depression and the MDMA story for PTSD seemed more interesting to me.

Speaker A: So for psilocybin, what is the rough percentages? And this would be relief not from trauma, but from depression.

Speaker B: Yeah, yeah, exactly. So it's 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 blinded trials, it was more like a third or so of people experienced relief. And this is a press release of the data, and so it hasn't. To my knowledge, it hasn't been published yet. I'm looking forward to seeing the full paper on that one, but it separated from placebo and looks pretty good as well. It looks like it's the first of two trials that need to be done to get this thing approved for treatment resistant depression. So that stuff looks good in terms of MDMA.

Speaker A: For many years, it was reported 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 from the same group that essentially admitted that the first time around, they had injected these monkeys 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, but never a retraction, and then never really a publicly acknowledged correction in the popular press. So it seems that in the appropriate dosage range, and with these one or two sessions, my assumption, and this again, is an assumption, 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, etcetera.

Speaker B: There's an interesting study that I think the guy's name is Halpern. Last name's Halpern.

Speaker A: Not Casey Halpern.

Speaker B: I think Joshua Halpern. I'm blank on his first name.

Speaker A: Casey Halpern was a guest on this podcast and is a former colleague of ours at Stanford, who, unfortunately, we lost to University of Pennsylvania, and maybe someday we'll bring him back.

Speaker B: Yeah, that's right. So this individual received some NIH funding to, actually, Nidae National Institute for Drug Abuse funding to explore individuals of the Mormon faith in Utah who partake in only MDMA. So the way this works is that MDMA happened kind of after a lot of the religious documents were developed. And so MDMA isn't on the prohibited.

Speaker A: Drug list, the banned substance above.

Speaker B: Banned substance list.

Speaker A: I have some good friends who are lds.

Speaker B: Yeah, great people. I do as well, just to kind of set a facts. And so these folks only use MDMA, but they don't. They're not the problem with some people using drugs. They're poly substance users, right? So 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. Have this picture where you can't really tease out that problem. But with this, it was just individuals that were part of the mormon faith, and so they were kind of purists in the sense they only used MDMA. And he confirmed all of that. And it was a brilliant study. Right. Because then he was able to go in and look at their cognitive profiles versus individuals of the same geography, the same faith, all of that, that happened to not take MDMA and found there were no neurocognitive differences.

Speaker A: So does that mean that it was not damaging?

Speaker B: It was not damaging. 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 this is about as good of a study as you can do, given the situation to be able to check this out. Additionally, when I was back in Charleston and working at the medical University of South Carolina, one of my mentors there, Doctor Wagner, was a neuropsychologist at MUSC. He was also the neuropsychologist for the early MDMA trials. He did all the neurocognitive batteries for individuals pre post and similarly did not see any changes in neurocognitive profiles in a negative way. There's data from experimental patients receiving this. There's data from people that are chronic users who only take MDMA. And that combination of data suggests that there's certainly no apparent risk in the one to two to three dose range. And it's probably unlikely that at least modest dose exposure over a lifetime doesn't appear to have a profound neurocognitive damaging effect.

Speaker A: Interesting. Yeah, I know that sourcing is key. And here we're talking about clinical trials where purity is assured. And years ago, when so called raves were really popular, maybe they're still popular. Never been to one, so neither wouldn't know if they're happening or not. That's how in the know I am. But it was clear that testing for purity was important because sometimes the drugs are made such that there are contaminants like methamphetamine, which we know is highly neurotoxic. I think that one reason why people think that MDMA might be neurotoxic is the reported drop in energy or feeling fatigued for a few days afterward. I spoke to a physician colleague of ours who said that that very likely has something to do with the surge in prolactin that arrives subsequent to the big dopamine surge that occurs in MDMA. And I mention that because I know a number of people talk about serotonin depletion after taking MDMA. He has it 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. And prolactin has a kind of sedative effect, numbing effect on mood and libido, et cetera, that eventually also wears off. Does that make sense to you as a physician?

Speaker B: Yeah, it makes sense. I mean, the difference between, say, MDMA and psilocybin is that MDMA is kind of an amphetamine of sorts, right? So it has effects in dopamine, and the psilocybin is pretty neutral and maybe a little bit of dopamine effects, but kind of much more of a serotonergic focused drug. And so, yeah, I think you're going to see kind of a different profile after. And that makes. I haven't heard that story, but that makes sense to me, too.

Speaker A: Since you mentioned psilocybin, let's talk a little bit about the neurochemistry of psilocybin as a serotonergic agent. My understanding is it operates on these. Is it the five ht, serotonin, two C receptors, two a, two a. Excuse me, two a and receptors. And that I've seen a bunch of different reports in terms 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, that there is increased activation of lateral connection, sort of broader areas of the brain being coactive than would normally occur. Maybe that explains some of the synesthesias, seeing sounds and hearing colors, as the trivial example, rule breaking within the mind. But then I've also heard 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. It adds spotlights.

Speaker B: Yeah.

Speaker A: De Gates. The thalamus, right through the reticular thalamic structure. So, what is the evidence that any of that is true, and are there other phenomena? Is there involvement of dorsolateral prefrontal cortex that we are aware of? And where I'm really headed here in a few minutes? Is there a place for combining directed stimulation of the brain with psychedelics so that the effects of serotonin could be primarily within the structures that you know from your work to be relevant to depression? But to simplify it first, what's going on when one takes psilocybin, and why is it interesting in light of depression?

Speaker B: Yeah, definitely. So, David Nutt and Robin Carhart Harris's work around neuroimaging psychedelics, they were some of the first folks to do that work. And to their great surprise, they thought there was going to be an increase in activity on psychedelics. And what they found is the opposite. There's an overall decrease in the level of activity in the brain with psychedelics, but they've also looked at connectivity, and there's this kind of small world, large world connectivity that you think about, and so small world, meaning there's a much more focused cortical function or subcortical function or whatever it is. And what you see is a difference in that level of engagement of brain regions. The connectivity, kind of global connectivity, to your point, kind of increases. And so it's interesting, I think, to kind of have a convergent theory on this. It's still to be determined. There's still a lot of work, I think, that needs to be done. But it's certainly suggestive that there's pretty profound changes in brain activity and brain connectivity after. And what we found to be really interesting is that the antidepressant effects of psilocybin have a particular connectivity change that we also see with our TMS approaches. It's this connectivity between the subgenual anterior cingulate and the default mode network. When we do this effective Stanford neuromodulation therapy stimulation, we see a downregulation, the connectivity between the negatively valence 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, suggesting there's a convergent mechanism. And it makes sense, right. You've kind of got an over connected, negatively valence system conflict system that's kind of attached onto the self representation and people feel stuck. Right. And then when you do whatever you do that's effective, it unpairs those two systems.

Speaker A: I want to ask you about this phenomenon I've heard about during psilocybin journeys. I heard about this from doctor Matthew Johnson, who's running a lot of the clinical trials at Johns Hopkins and has been a guest on this podcast. He said that there's something seems to be important about the patient who's depressed or who's under the influence of psilocybin, or the patient who's trying to get 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, that they don't jump out a window or try to actually give an example of a patient who thought that. 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 untethering from the autonomic arousal that's occurring is important. Which brings us back to this idea, or me back to this idea of a see saw where you're sort of letting go of the hinge. Just sort of. Your heart rate's going up. Like, just go with it in trust your heart rate's going down, just go with it in trust. You're thinking about 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 picture. Can we think of that as just the willingness to do a million different variations on the emotional stroop task? You will entertain the full array of rules within your head and consider them. Or is there something more to it? And again, we're in the outer margins of understanding here, but what are your thoughts on this notion of letting go as such a key variable for relief from depression during the psychedelic journey?

Speaker B: Yeah, so I'll talk a little bit about something called exposure and response prevention therapy. That's a typical kind of gold standard treatment for OCD. And I'll help to kind of help this a little bit conceptually. And so what that really is, it's a letting go therapy. And so exposure and response prevention, the idea is that you have to expose the individual to something that, you know, something that triggers an obsession that they then want to do whatever the compulsion is, right? And so I'll give you my first exposure and response prevention patient. When I was a resident, he was very concerned about leaving the lights on in his car. 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 that it's going to kill his battery. And we went and we spent an hour talking about things and we went back out to his cardinal 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'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 end up being worried about. And so in some sense being in the psychedelic state and we're all taught at a level to retain some level of control. 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. 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 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, the network configuration, maybe whatever it is, 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 onto negatively valence thoughts about yourself in the setting of having depression or re experiencing a trauma memory and allowing that to just happen and seeing it again through a different light, it feels the same in the sense that that's allowing for whatever's going on with these psychedelic states to do whatever they do.

Speaker A: Fascinating. You said it's exposure response therapy is the traditional name. Exposure response, prevention, prevention therapy done outside of the psychedelic journey.

Speaker B: It's done outside the psychedelic journey. But that idea of letting go is present in both of those, you know, psychotherapy, kind of straight up, totally sober, non psychedelic, non anything, psycho manualized psychotherapy that we know works really well for OCD and then in that psychedelic state. And so people have done studies with psilocybin and now there's some studies with MDMA trying to look at treating OCD with the same sort of idea of letting go. Right. And how do you have an OCD patient kind of let go, maybe even letting go of not washing their hands anymore, kind of accepting the idea they're not going to get germs on their hands or whatever it is. And so it's kind of part of that, part and parcel that same sort of thinking.

Speaker A: When I was in college, I developed a compulsive superstition. I'm not afraid to admit this. I somehow developed a knock on wood superstition. And I would have. I was actually kind of ashamed of it because it rationally made no sense. I don't consider myself a superstitious person. Never was a superstitious kid. I'd step on the sidewalk cracks. I'd walk under ladders. I'd probably even try to walk under a ladder, even though I don't suggest it. But somehow I picked this thing up 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. And it's tricky. Sometimes it actually comes back where I think, gosh, I didn't say knock on wood. I didn't knock on wood. I hope that doesn't actually happen. And it's quote unquote crazy, 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 internal superstitions. Maybe by talking about it now, it'll go away. Clearly. I just need to challenge it. You know, it's, uh. Anyway, I mentioned because I, um, I consider myself, you know, a generally rational person, but, um, it's interesting how these motor patterns, um, get. Get activated and this notion of letting go because I don't actually know what consequence I fear. And the fear as I was hearing the 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 jump the car. But in my case, I need to think about what the ultimate fear is.

Speaker B: Yeah. And I think a lot of people, 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 Asperg depression rating scale, one of the depression scales, we use ten, right? That's the normal range. People can have some sadness and still be considered normal. In the case of the OCD scale, it's about the same ten, right, where we say it's kind of starts to be mildly abnormal or something. And I'd always tell the medical students, look, my friends that are surf instructors, they're more like a zero on the Weibach people that are professionals. They're non zero. But it's still within the normal range, especially in the case that you're talking about. It doesn't sound like it got in your way. It doesn't sound. You're obviously highly successful, tenured professor at Stanford and do all the great things that you do. And so it's very much kind of within the normal range. And I think totally assumed that a lot of people have these sorts of things. And 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 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 bring it 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, as a psychiatrist, I talked to a lot of patients, a lot of people that are 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 have to knock 100 times, we call that OCD, and they have all germ. They're worried about germs and all these other things. We call that OCD, and then in that circumstance, they need treatment. But it is really just like blood sugar, just like blood pressure. It's on a range. And it's not just these discrete diagnoses. You have them or you don't.

Speaker A: It's good to know. I actually feel some relief just hearing this, because I am slightly, I wouldn't say ashamed. I was sort of embarrassed by it, but I offer it as a, you know, it is what it is, as they say, and it certainly doesn't seem to hinder 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 aine lidocaine ibogaine, I think of an anesthetic and going to the dentist, which is an unpleasant experience for me, generally. What is ibogaine? Does this have anything to do with the so called toad? People talk about smoking frog skin, toad skin. What is it used for clinically? Is it legal in the US as 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 correct.

Speaker B: Yeah, that's fair. So ibogaine is one of the alkaloids that you can extract from iboga tree root bark that's typically growing 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 Gabon has a group of folks called the bwiti. It's a religious, sacramental group that sacramentally uses iboga root. Bark is part of the sacrament, and they've been using iboga root bark for a very long time, and it's part of the tradition. There's a whole set of ceremony around it. If you're interested in this, there's a book called breaking open the head by Daniel Pinchbeck that goes through and talks about this whole process. But essentially, the Gabonese have been using this for a long time, and it's a. It's kind of an atypical psychedelic. It's not a psychedelic that we normally think about with psilocybin and LSD, where there are visual perceptual changes, right? So if you take psilocybin, psilocybin or LSD, what you experience is you experience these 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's kind of like, have 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 movie where he would be able to go and see these kind of pre crimes, and he had 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 individuals taking ibogaine will say is that open eyes, they don't see anything but closed eyes. They'll go back through and re experience earlier life memories, and they will be able to experience it from a place of empathy not only for themselves but from others and kind of 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 as a third party. So Claudio Naranjo, a psychiatrist from Argentina, described this. A lot of books that he wrote, I think, the eighties and nineties around this. And so Ibogaine's been around for a long time. Howard Lotsoff, american guy that brought it over from Africa, he was a polysubstance user, used every drug 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. Its not a recreational substance if you want it to be a recreational substance because youre essentially having this, what they call a life review. They also call it ten years of psychotherapy in a night. So these are the terminology that people talk about.

Speaker A: How long does it last? Is it truly one night?

Speaker B: It's usually, you know, it can go depending upon if you get redosed 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 definitely the longest acting psychedelic substance I know of. And so people will take this and they'll have this reevaluation of a given memory. And then, as we were talking about earlier, reconsolidate that memory again. And then it seems to have an effect of that reconsolidation process. And so about four or five years ago, I was tapped by Robert Malinka, one of the senior neuroscientists we both know in the university. He says, well, there's a. There's an unnamed donor that's very interested in funding a scientific, open label study of these Navy SEals that have been going down to Mexico and taking ibogaine, and also five MeO DMT, which I'll talk about in a second, to treat PTSD. They claim to have traumatic brain injury, depression, that whole constellation of symptoms. And as it was described to me by various people that had done this by their spouses and whatnot, John. We'll just say, John, John couldn't screw a light bulb into a light fixture. They were just so debilitated. They couldn't do simple tasks, what we call activities of daily living. And they were coming back and having these really dramatic improvements in all aspects of life. And so we have, over the last couple of years, been able to do this first in human kind of full neurobiological, clinical, neurocognitive evaluation of what ibogaine is doing, in this case, in special operations, special forces individuals, former Navy SEALs, former army Rangers, that kind of crew of folks. And look at the pre post changes that we. 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 is both seemingly the most potent and most seemingly, to me at least, most powerful psychedelic, but the one that has the most risk, too, because it has a cardiac effect. It seems to be that you can screen people out that have risk off of their electrocardiogram and reduce the risk quite a bit, and that's what we all did, but that's why people haven't really studied it as much, and it isn't as, in addition, there's. Nobody goes to rave on ibogaine. There's no recreation at all with it.