Psychedelics & Neurostimulation for Brain Rewiring | Dr. Nolan Williams

1. 0:00 – 3:31

   Dr. Nolan Williams, Brain Stimulation & Depression Treatment

   1. AHAndrew Huberman0:00

      (Upbeat music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today, my guest is Dr. Nolan Williams. Dr. Williams is a medical doctor and professor of psychiatry and behavioral sciences at Stanford University School of Medicine. His laboratory and clinic focus on depression and other mood disorders. They focus specifically on the use of transcranial magnetic stimulation, which is a brain stimulation technique that can either activate or quiet specific brain circuits, as well as circuits within the body, in order to treat depression and other mood disorders. Other laboratories and clinics use TMS. What sets apart the work of Nolan Williams and colleagues is that they combine TMS with other treatments, and some of those treatments are among the more cutting edge that you've probably heard about these days, including ibogaine, psilocybin, MDMA, cannabis, DMT, and other drugs that, at this point in time, are experimental in terms of clinical trials, but that at least the preliminary data show hold great promise for the treatment of depression and other mood disorders. In the course of my discussion with Dr. Williams, we covered things such as the history of each of these drugs, how they came to be, and their current status in terms of their clinical use and legality. We also talk about their safety profiles, both in children and in adults, and we talk about what the future of psychedelic research and clinical use really looks like. For instance, we discuss how a number of laboratories and clinics are modifying psychedelics to remove some of their hallucinogenic properties while maintaining some of their antidepressant or anti-trauma properties. You'll also learn about some fascinating research in Dr. Williams' laboratory focus on ketamine, which is a drug that is increasingly being used to treat depression, and contrary to common belief, the effects of ketamine, in terms of relieving depression, may not actually arise from its dissociative effects. One thing that you'll find extraordinary about Dr. Williams is that not only does he have vast knowledge of the various treatments for depression, but that he and his laboratory are really combining these treatments in the most potent way, that is combining psychedelic treatments with brain-machine interface, or combining brain-machine interface with particular learning protocols, that is neuroplasticity protocols, which can directly change the brain in specific ways. So today, you're going to learn a tremendous amount about the neural circuitry underlying depression, as well as positive moods. You'll also learn about all the various drugs that I described, and you're really going to learn about the current status and future of the treatment of mood disorders. Today, you'll also learn about a number of ongoing studies in Dr. 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 Dr. Williams was, for me, one of the more stimulating and informative conversations I've ever had about psychedelics, which is simply to say that his breadth and depth of knowledge on that topic is incredible, and his breadth and depth of knowledge in terms of the underlying brain science and how it can all be combined with clinical applications is also extraordinary. I'm sure that by the end of today's episode, you're going to come away with a tremendous amount of knowledge about the clinical and non-clinical uses of those substances, and you're going to understand a lot more about how the healthy and diseased

2. 3:31 – 4:42

   Huberman Lab Premium

   1. AHAndrew Huberman3:31

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

3. 4:42 – 8:37

   InsideTracker, Eight Sleep, ROKA

   1. AHAndrew Huberman4:42

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

4. 8:37 – 9:16

   Momentous Supplements

   1. AHAndrew Huberman8:37

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

5. 9:16 – 15:11

   Depression, Risk Factors, Emergency Psychiatric Treatments

   1. AHAndrew Huberman9:16

      Thanks for joining today. I'm really excited to have this conversation. It's been a long time coming, and I have a lot of questions about different compounds, psychedelics in particular.

   2. NWNolan Williams9:27

      Yeah.

   3. AHAndrew Huberman9:27

      But before we get into that discussion, I want to ask you about depression, broadly speaking-

   4. NWNolan Williams9:33

      Sure.

   5. AHAndrew Huberman9:34

      ... intractable depression-

   6. NWNolan Williams9:35

      Mm-hmm.

   7. AHAndrew Huberman9:36

      ... 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.

   8. NWNolan Williams10:06

      Yeah, absolutely. So depression is, uh, a condition that, um, it has a lot of, a lot of, uh, manifestations. You know, so you can have kind of a, a depression that's primarily loss of interest. You can have folks who feel very anxious and they're kind of overactive. You can have people who don't have any anxiety at all and they're very underactive and they have low motivation to do anything. You know, so you have this huge range of symptoms that are in that umbrella of depression, and some of our work is to actually work with, with folks like Conor Glisten in Cornell and try to actually get, uh, biotypes based off of neuroimaging to see if we can kind of parse out the different depression kind of re- um, presentations in the, and see that clinically and also see that in the brain. Depression is, uh, the most disabling condition worldwide. Um, what's interesting about depression is it's both a risk factor, um, for other illnesses and it makes other medical and psychiatric illnesses worse, right? So recently, the American Heart Association added depression as the fourth, uh, major risk factor for coronary artery disease, right? So alongside the, the risk factors that we know, hypertension, high blood pressure, hyperlipidemia, high cholesterol, and, um, and diabetes, you know, high blood sugar, those three have been on the list for a long time, and depression en- de- you know, being added to the list as the fourth one. And, um, you know, really interesting, right? So in addition to taking medications to address those other three risk factors, we really have to be thinking about, um, how do you treat folks with depression to reduce their risk of having a heart attack in the future? And, you know, there's, some of that's being worked on now, but we don't have a complete solution to thinking about that at this time. And then the other thing that's interesting is once you have a heart attack and the indi- and, and the individuals end up having a heart attack...... the risk of having depression after the heart attack is higher than the normal population, right? And so, a lot of what we're doing in the lab actually is, um, is measuring kind of brain-heart connections. And we can actually, with transcranial magnetic stimulation, a form of brain stimulation, we can actually decelerate the heart rate. We can capture that heart rate deceleration, um, over the mood regulatory regions. And so actually a direct probe of that connection. So it's, it's, it's interesting. And so, you know, as you said a second ago, you know, it's a, it's a very disabling condition, moderate depression. It's about as disabling as, as having a heart attack, acutely having a heart attack. Severe depression is disabling as having cancer without treatment, you know, and, and dying from, from a cancer without treatment. And so, you know, it's, um, it's kind of underappreciated just how disabling depression is in that way. And I think, uh, important as stigma is consistently kind of being reduced over the years for mental illness, uh, for mental illnesses, then the idea that we can start really putting more funding and putting more focus at the federal level, you know, private foundation level, whatever it is, at a given university to, to thinking about, um, developing treatments. We've been very interested in a very particular, um, clinical set of problems around the, the most severe and the most high acuity, um, settings that, uh, folks with depression end up being in. And that's in, you know, emergency settings where they go into in-patient units. And, uh, you know, in the rest of medicine, if it's talking about heart attacks, if I start having chest pain right now and, um, and you bring me to a primary care doctor's office, they're going to have a certain number of tests and treatments, right? But very limited, because it's an out-patient, um, 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, um, invasive procedures to the heart, there are more tests and more treatments. In psychiatry, as we elevate the acuity of an individual, you go from being just depressed to being depressed and now thinking about ending your life, the number of treatments actually go down on average. I mean, in some scenarios they go up, but on average they go down and there are no tests, right? And so we've been very focused on that particular problem. Somebody that maybe was doing, you know, fairly okay with a pretty moderate depression, and then their depression gets worse, and then they end up in an emergency setting, and the, the field really hasn't developed a way of, um, you know, of consistently being able to treat that problem and folks end up getting the same standard oral antidepressants that they've been getting out-patient. And, and I came to this because I, you know, dual trained as a neurologist and psychiatrist. Went back and forth between neurology and psychiatry. Saw that in neurology we have all of these ways of treating acute brain-based problems, and really wanted to emulate that in psychiatry and find ways to develop and engineer new, you know, brain-based solutions.

   9. AHAndrew Huberman15:09

      There's a lot to unpack there.

6. 15:11 – 17:51

   The Brain-Heart Connection, Vagus Nerve, Prefrontal Cortex

   1. AHAndrew Huberman15:11

      One thing that you said, um, is I'd like to focus on a bit more, because I think we hear that the brain and the heart are connected.

   2. NWNolan Williams15:18

      Mm-hmm.

   3. AHAndrew Huberman15:19

      But you described, I believe, uh, a direct relationship between areas of the brain associated with emotion-

   4. NWNolan Williams15:26

      Mm-hmm.

   5. AHAndrew Huberman15:26

      ... and heart rate.

   6. NWNolan Williams15:28

      Yes.

   7. AHAndrew Huberman15:28

      And that makes perfect logical sense to me. But I think, um, at the same time, many people out there probably think of the relationship between the, the heart and the mind as kind of woo or kind of a-

   8. NWNolan Williams15:42

      Mm-hmm.

   9. AHAndrew Huberman15:42

      ... a soft biology. But here you're talking about an actual physical connection-

   10. NWNolan Williams15:46

       Yep.

   11. AHAndrew Huberman15:46

       ... between, uh, what area of the brain is it ?

   12. NWNolan Williams15:49

       The, the, the, you know, the first place where the stimulation goes is called the dorsolateral prefrontal cortex. It's kind of the sense of control kind of governor of the brain.

   13. AHAndrew Huberman15:58

       Mm-hmm.

   14. NWNolan Williams15:58

       And then it'll, and then what we know is that when you use a magnet, use kind of what we call Faraday's Law, this idea of, um, using a magnetic pulse to induce, uh, an electrical current in electrically conducting substances, so in this case brain tissue, but not skull, or sca- scalp or any of that, or hair. You avoid all that, just the brain tissue. Then you have a direct depolarization of cortical neurons, you know, the surface of the brain's neurons in this dorsolateral prefrontal, and if you do that in the actual scanner, which we can do, you can see that that distributes down into the anterior cingulate, in the insula, in the amygdala, and ultimately the tract goes into something called the nucleus tractus solitarius, and ultimately into the vagus nerve into the heart. So the, the heart, uh, very consistently seems to be the end organ of the, uh, 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 one second you see the deceleration, it goes down about 10 beats per minute, and then it'll drift back up and there's a break for eight seconds on the stimulation. It drifts back up and the stimulation goes back in, and then the heart rate goes back down. So you see the heart rate just do this, 10 beats per minute every train. And so we know if you do that over visual cortex, you don't get that, or motor cortex, you don't get any of those findings. It's really specific to this kind of control region of the brain. And so, yeah, it seems to, you know, it's our work, other, uh, other folks' work, Marten Arens in, in, um, in, in Europe, uh, the Netherlands work showing the same connections. I think it's been rep- replicated like four or five times.

7. 17:51 – 22:34

   Right vs. Left Brain Hemispheres & Mood Balance, Connectome

   1. NWNolan Williams17:51

   2. AHAndrew Huberman17:51

      So you mentioned left dorsolateral prefrontal cortex. Any time I hear about lateralization of function, I get particularly curious.

   3. NWNolan Williams18:00

      Yeah.

   4. AHAndrew Huberman18:01

      Um, because obviously we...... have two, uh, mirror-symmetric sides of the brain.

   5. NWNolan Williams18:06

      Yup.

   6. AHAndrew Huberman18:07

      Um, there are, you know, rare exceptions to this, like the pineal and things of that sort, uh, that are only, there is only one pineal. Um, 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, um, a topic for another time. But, um, why do you think the left dorsolateral prefrontal cortex would be connected to the heart, uh, in this way?

   7. NWNolan Williams18:38

      Yeah. Yeah, I think, so, so left dorsolateral, um, uh, you know, is, is thought to be the, the side that when you excite it, when you kind of, um, 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, um, strokes in the brain that, um, that cause depression and you put them on the human connectome, uh, hundred, you know, 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, you know, uh, y- you know, balancing of mood, uh, 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, they're both antidepressant. You can, um, excite the right and that's anti-manic in some studies. And so this idea that there is this hemispheric balancing of mood is, is quite interesting, right?

   8. AHAndrew Huberman19:54

      It's incredibly interesting. And just so, um, people know, if, um, if you're curious what the connectome is, a connectome is a term that was built out of this notion of genomes, uh, being a large, uh, collections of sequencing and mapping of genes, they're proteomes of proteins of, uh, connectomes as, uh, so-called connectomics of connections between neurons. So the Human Connectome Project is ongoing, um, and I find that incredible that within the Connectome Project they can identify these regularities of right versus left dorsolateral prefrontal cortex. Especially since, um, I've looked at a fair number of brains, um, from humans, not, certainly not as many as you have, uh, 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, um, kind of an accelerator and a break, if you will-

   9. NWNolan Williams20:55

      Yeah. That's right.

   10. AHAndrew Huberman20:56

       ... on, um, 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, um, bits, the same parts list-

   11. NWNolan Williams21:07

       Yeah.

   12. AHAndrew Huberman21:07

       ... more or less. So what gives the, these properties, um, 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, um, hemispheric biases?

   13. NWNolan Williams21:22

       Yeah, that's a, that's a great question. And, you know, 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, right? And that, you know, unfortunately that study still hasn't been done at the level, 'cause that would be probably pretty helpful for teasing some of this out. But, you know, it's, it's, um, it's still, you know, it's still being sorted out, right? We, we know enough to know this phenomenon exists because we can use TMS as a probe and do this sort of, these sorts of manipulations. But, um, 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, uh, but it, you know, it's kind of empirically true in the sense that you can push and pull on those systems or in this, in the case of s- of strokes that folks have, and then you kind of get their brains and, and their brain images and look at where the strokes landed, those kind of causal bits of information point to this, this, um, asymmetry.

   14. AHAndrew Huberman22:33

       Interesting.

8. 22:34 – 33:02

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

   1. AHAndrew Huberman22:34

      Well, in that case, going with what we do know, that stimulation of dorsolateral prefrontal cortex slows the heart rate down-

   2. NWNolan Williams22:41

      Mm-hmm.

   3. AHAndrew Huberman22:41

      ... transiently, but it slows it down-

   4. NWNolan Williams22:43

      Yup.

   5. AHAndrew Huberman22:43

      ... and seems to alleviate at least some symptoms of depression-

   6. NWNolan Williams22:45

      Mm-hmm.

   7. AHAndrew Huberman22:46

      ... leads me to the question of why would that be the case? Is it, does it tell us anything fundamental about depression, that, uh, anxiety is inherent to depression? I think a faster heart rate is, you know, part and parcel with, uh, with, with, uh, anxiety. Um, in my laboratory, we've studied fear a bit in animals-

   8. NWNolan Williams23:07

      Yeah.

   9. AHAndrew Huberman23:07

      ... and in humans, and we, um, often observe bradycardia where somebody or an animal is afraid of something and rather than the heart rate speeding up, it actually slows down.

   10. NWNolan Williams23:17

       Yeah.

   11. AHAndrew Huberman23:17

       Something that most people don't, uh, think about or recognize, uh, but, um, 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, this tells us about the basic architecture of depression-

   12. NWNolan Williams23:37

       Mm-hmm.

   13. AHAndrew Huberman23:37

       ... and its physiology at the level-

   14. NWNolan Williams23:39

       Yeah.

   15. AHAndrew Huberman23:40

       ... 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-

   16. NWNolan Williams23:47

       Mm-hmm.

   17. AHAndrew Huberman23:48

       ... um, does that help alleviate depression?

   18. NWNolan Williams23:50

       Yeah, no, that's a great question. So the, um, I'll answer the second question first. Um, so we know that, um, and there are ongoing trials of this, uh, if you stimulate on the vagus nerve, um, in an implanted vagus nerve stimulator, you can actually-... um, you know, have this, the afferent, um, parts of the, the vagus, um, project ultimately up to the DLPFC through the cingulate, through these anterior insula. So that same, uh, obviously the same tract, right? And you can, uh, stimulate there and alleviate depression, which seems very unusual, right? You're stimulating a cranial nerve down on the neck, but if you can get up into the brain, you actually can improve depressive symptoms. And so, you know, more evidence that this is, uh, a s- kind of a whole track and system. And, um, if you stimulate in part of that system, it appears that you can, uh, improve mood.

   19. AHAndrew Huberman24:44

       What if I were somebody who did not have a stimulating electrode in my vagus nerve and I, uh, was dealing with minor depression and I decided-

   20. NWNolan Williams24:52

       Yeah.

   21. AHAndrew Huberman24:52

       ... I wanted to take some other approach to slow my heart rate down-

   22. NWNolan Williams24:55

       Yeah.

   23. AHAndrew Huberman24:55

       ... via the vagus? For instance, um, exhale emphasized breathing-

   24. NWNolan Williams24:59

       Mm-hmm.

   25. AHAndrew Huberman24:59

       ... or deliberately slow cadence breathing-

   26. NWNolan Williams25:02

       Mm-hmm.

   27. AHAndrew Huberman25:03

       ... um, things of that sort. Is there any evidence that behavioral interventions of those kinds, um, 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?

   28. NWNolan Williams25:19

       Absolutely, yeah. So there's, there's a number of studies, um, implicating DLP- the dorsolateral and, uh, and say, you know, meditation, uh, mindfulness, that sort of thing, and, and they're small studies, but, but pretty well designed studies suggesting that behavioral interventions in mild depression actually work quite well. There seems to be a volitional threshold for depression, where at some point you, you start losing, it, you, you go from being completely in total volition to having kind of 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, right? Where people in a very severe form of depression get kind of stuck motorically, right? And they obviously can't... They have no control, and so, um, or, or very limited control. And so, you know, I think there's a threshold in which these sorts of interventions will work. Exercise seems to really be a good treatment for, for mild depression, and it may work through the mechanism you're describing, right? As, as we all know, you know, athletes hold a lower resting heart rate-

   29. AHAndrew Huberman26:34

       Mm-hmm.

   30. NWNolan Williams26:34

       ... um, than folks that, that aren't... You know, if you're, if you were an athlete and you had a lower resting heart rate, you stopped, you know, exercising and a couple years later, your resting heart rate, in many cases, goes up, right? And so maybe that's, um, maybe that's part of the process. I'm not aware of any studies specifically, um, looking at dorsolateral prefrontal, um, 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. Um, there, there's been a lot of work with heart rate variability-
9. 33:02 – 37:46

   Prefrontal Cortex & Cognitive Control, TMS

   1. AHAndrew Huberman33:02

      extremely important for us to consider is what ex- what are these lateral prefrontal cortices doing?

   2. NWNolan Williams33:11

      Mm-hmm.

   3. AHAndrew Huberman33:11

      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, uh, talk ourselves into a manic state or an excited state, a positively excited state that doesn't qualify as mania? Uh, you know, other areas of the brain I, I think of they, as responsible for perception or for, for motor control, but here we are in this mysterious frontal cortex area-

   4. NWNolan Williams33:42

      Yeah.

   5. AHAndrew Huberman33:42

      ... which people say executive function, planning-

   6. NWNolan Williams33:44

      Yeah.

   7. AHAndrew Huberman33:44

      ... et cetera. Are we talking about thoughts? Are we talking about structured thoughts or are we talking about dreamlike thoughts? What in the world is going on in the prefrontal cortex? (laughs)

   8. NWNolan Williams33:54

      Yeah. Yeah, no.

   9. AHAndrew Huberman33:55

      And here I've spent my career, you know, in neuroscience and I still, I, I still can't really understand what it's doing, and maybe it's doing 50 things.

   10. NWNolan Williams34:03

       Yeah, no, it's a great, it's a great question. So, you know, to... So one of the, one of the studies that, that we've been working on in addition to the depression work is actually trying to change trait hypnotizability. So, um, David Spiegel and I have been working on this and, um, you know, he's found and, uh, published this 10 years ago, that a different part of the left dorsolateral, um, is functionally connected with the anterior s- d- the dorsal anterior cingulate, uh, 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 dorsolateral 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, right? And so if you knock out the left dorsolateral prefrontal cortex and you have people do the Stroop task, for instance, which is a, a task where you have p- it's a simple task, you probably know this. You have people name the color of words. And so if I, if I look at a, what, you know, 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, uh, called a congruent. And then the incongruent is red in the color blue and you have to name, you have to say the, the word, you don't, um, name the color.

   11. AHAndrew Huberman35:42

       So you have to suppress a response.

   12. NWNolan Williams35:43

       Yeah. Yeah, exactly. And so, um... I'm sorry. You do the other, you, you name the color and you, you, and you see the word written, um, in a different way. And so basically, um, if you, 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, uh, to be able to name it. And so they have, uh, they have a, a kind of a time delay that's greater than they had before they got stimulated...... so that part of the, the prefrontal cortex that's different than the part of the prefrontal cortex that's involved in mood regulation. The nice thing about TMS is that you can go through and you can find these areas that are functionally defined through brain imaging, and you can perturb them and answer the question you're talking about, "How do I understand this part of the prefrontal cortex and its function, this part?" And so we were able to stimulate in- in an inhibitory way within the left dorsolateral prefrontal cortex that's involved with, you know, this sort of cognitive control, um, area, and we were able to knock that area out and, um, and increase trait hypnotizability. So people had, uh, greater, um, hypnotizability after they got active stimulation versus when they got sham. And so it suggests that that brain circuit is involved in the, uh, in the process of what hypno- you know, therapeutic hypnosis ends up being, but it's a very different region within the left dorsolateral than, say, we do when we do these very intensive, uh, stimulation approaches to treat severe depression and we're able to get people out of depression, um, you know, with a part of the s- of the dorsolateral that seems to be lower in the, you know, kind of more lateral, um, in d- um, and, um, inferior on the, uh, DLPFC and connected with the subgenual anterior cingulate, so the part of the anterior cingulate that processes emotion.

10. 37:46 – 39:00

    AG1 (Athletic Greens)

    1. NWNolan Williams37:46

    2. AHAndrew Huberman37:46

       I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic Greens, now called AG1, 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, uh, 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 in 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 Greens while you're on the road, in the car, on the plane, et cetera, and they'll give you a year's supply of vitamin D3 K2. Again, that's athleticgreens.com/huberman to get the five free travel packs and the year's supply of vitamin

11. 39:00 – 45:49

    Belief/Identity “Rules”, Re-scripting, TMS & Talk Therapy

    1. AHAndrew Huberman39:00

       D3 K2. Based on what you told us about the Stroop task and the role of the prefrontal cortex in the Stroop task, to me the Stroop task is a rule switching game.

    2. NWNolan Williams39:09

       Yep, for sure.

    3. AHAndrew Huberman39:09

       You're saying in one moment, the, the rule is you read whatever the word says, and then th- then you switch, and then you say the rule now is you tell me what color the word is written in, and you suppress whatever it is the word says.

    4. NWNolan Williams39:23

       Yeah, that's right.

    5. AHAndrew Huberman39:23

       Okay? Okay. A rule in some sense is a, uh, like that is a- a transiently adopted belief system.

    6. NWNolan Williams39:30

       Yep.

    7. AHAndrew Huberman39:31

       So I could imagine that in depression, which has all sorts of backstory to it-

    8. NWNolan Williams39:36

       Mm-hmm.

    9. AHAndrew Huberman39:36

       ... um, that of course, the psychiatrist or psychologist or friend can pull on that thread. Like for instance, somebody might believe that they are bad-

    10. NWNolan Williams39:44

        Yep.

    11. AHAndrew Huberman39:44

        ... um, or that they don't deserve love. I'm trying to bring this into the typical language that people talk about.

    12. NWNolan Williams39:49

        Yeah. Yeah, absolutely.

    13. AHAndrew Huberman39:50

        Or that they will never succeed-

    14. NWNolan Williams39:51

        Yep.

    15. AHAndrew Huberman39:52

        ... 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-

    16. NWNolan Williams40:00

        Yeah, that's right. That's right.

    17. AHAndrew Huberman40:00

        ... at some level. It's, they're rules that are more pervasive over time, unfortunately. But I could imagine that if the PFC is also contains some sort of maps or algorithms related to rules of emotionality or self-representation, or things that we've heard, I think there must be data out there that's saying that, you know, whatever h- we heard in middle school when someone made fun of us, we can remember that. 'Cause I can remember things that people said-

    18. NWNolan Williams40:24

        Yeah.

    19. AHAndrew Huberman40:24

        ... um, about a jacket I wore one day or something-

    20. NWNolan Williams40:27

        Yeah.

    21. AHAndrew Huberman40:27

        ... in the fourth grade. C- crazy. I didn't even like the jacket. Um, now I think it was kind of cool.

    22. NWNolan Williams40:32

        (laughs)

    23. AHAndrew Huberman40:32

        But anyway, the, the point being that we have an intense memory for these things-

    24. NWNolan Williams40:36

        Yeah, totally.

    25. AHAndrew Huberman40:36

        ... to set up a sort of rule or a question, like maybe I don't really know how to dress, for instance.

    26. NWNolan Williams40:42

        Yeah.

    27. AHAndrew Huberman40:42

        Maybe that's why I always wear the same black shirt.

    28. NWNolan Williams40:44

        (laughs)

    29. AHAndrew Huberman40:44

        But in all seriousness, it seems like the, the dorsolateral prefrontal cortex is in this amazing position to access rules, which-

    30. NWNolan Williams40:52

        Mm-hmm.
12. 45:49 – 48:36

    Dorsolateral Prefrontal Cortex, TMS & Depression Treatment

    1. AHAndrew Huberman45:50

       Can we therefore say in, in crude terms that the dorsolateral prefrontal cortex really is the governor of how we interpret physiological signals and spontaneous thoughts?

    2. NWNolan Williams46:02

       It is, it, it places a lens that the rest of the brain sees things through. And, and you can, you can do these experiments where you, you can put a normal, healthy control person in the, in the scanner and you can make them feel like they have a loss of control, and then you can see that region come offline, right? So you experimentally manipulate the system and so kind of buffing it up, um, it's like almost, TMS is almost like exercise for the brain, right? You're, you're kind of exercising this region over and over again with a physiologically relevant signal and kind of turning that system on. And what's interesting, uh, we're, I think really interesting for, for this show is to, you know, we had a couple of folks, um, you know, 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, they get better on day one, we still give them the other four days because it's in the protocol to do that and we can't ... We're, we're getting to a point where we can tell how long it- it's gonna take, but we're not there yet. And so, you know, every time somebody gets better at day one or two, at the beginning when we first started doing this we'd say, "You know, we're not sure, you know, we think this is safe to keep going, but, you know, what do you want to do?" And everybody was like, "No, I want to keep going." And so, you know, they're by Wednesday they're like totally zeroed down on the depression scales, you know, even better than most people walking around, like really no anxiety, no, no depression or anything. By Thursday, the first guy that, 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, and then I didn't tell any, you know, obviously any more patients about that, and then about five over the last couple of years when they get- they remit early in the week, by the end of the week they're like going to the beach and they're like totally having a, what people describe as a pretty mindful-... present moment sort of experience, which is really interesting, you know, what that is. I mean, I don't have p- full on scientific data to tell you, but it, it's just, it's a, it's an interesting anecdote, right, that, that folks, when you push them through this point of, of feeling kind of clinically well, that some people end up reporting this additional set of features, so.

    3. AHAndrew Huberman48:35

       Y- yeah, you mentioned the

13. 48:36 – 54:27

    Cingulate Cortex & Emotion, Dissociation & Catatonia

    1. AHAndrew Huberman48:36

       cingulate and the anterior cingulate in particular. Um, because now I feel like for the first time in my career, I have some sense of what prefrontal cortex might actually be doing (laughs) um, besides providing a bumper for the, for the rest of the, the brain. Um, is th- the cingulate, it seems, is a, is a more primitive structure in the sense that it's, um, it's under the, ideally it's under the regulation of this top down control from prefrontal cortex.

    2. NWNolan Williams49:02

       Mm-hmm. Yeah.

    3. AHAndrew Huberman49:03

       But what's mapped in the cingulate? And, and s- for the non-neuroscientists out there, when I say mapped, if, if we were to put someone in a scanner and focus in on cingulate or put an electrode in there, what, what makes the neurons in there fire? What, what sorts of things in the body and in the mind and out in the world, uh, light up, for lack of a better phrase, the cingulate? What does the cingulate like?

    4. NWNolan Williams49:23

       Yeah. Yeah, so, so that Stroop task, those incongruent word color associations, the, the dorsal part of that, um, for obsessive compulsive disorder patients, certain, you know, certain kind of triggers you'll s- you'll see. Some, some of the neuroimaging studies will point to, to anterior cingulate. Uh, in the kind of very crude psychosurgery world 50 years ago, the anterior cingulotomy was a way of treating, um, obsessive compulsive disorder, right? 'Cause that area seems to be overactive in people who are experiencing obsessive compulsive disorder. You can kind of walk d- The cingulate wraps around, you know, this white matter track, like bundles, so it wraps around that. And so there's a part that's above that, around that, and below that. And depending upon how emot- how much of the, um, the conflict task has an emotional component, the more, um, ventral and subgenual that, um, that activation is. So the dorsal part of the anterior cingulate seems to be kind of more of a pure cognitive, maybe, um, obsessive compulsive disorder sort of area, whereas when you start getting into mood sorts of triggers, like facial expression, um, conflicts where you're supposed to... That, you know, there's an emotional Stroop task where you show the word happy and then you have a face of, of a person that looks mad, then that's another way of having the same sort of Stroop conflict, and that seems to be more perigenual, subgenual areas, right? So you can kind of, you can trigger the cingulate based off of the level of emotional valence from none down to a lot. And, uh, and that seems to be how the, how it's distributed. There are, you know, heart rate kind of components to it and autonomic components in there too. There's something called akinetic mutism. You know, you know, I'm a, I'm a board certified neuropsychiatrist, behav- behavioral neurologist and have seen, you know, a lot of these what we call zebra cases in neurology, where people have, you know, these unusual neurological presentations, and one of 'em is a- akinetic mutism. And so if you have a glioma sitting in the inner hemispheric fissure and ha- kind of having, um, 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, and so that tells you something about how the, how the cingulate works as well, right? It's, it's like if it's, um, if it's not functioning, then people have a hard time kind of connecting with reality. It seems to need to be constantly on, you know, online to be able to interact with the exterior world.

    5. AHAndrew Huberman52:05

       Is it involved in some of the dissociative states that sometimes people who are very stressed or, or depressed experience? You said catatonia being an extreme one. But, um, I know someone, for instance, that when they get really stressed, and it can even be if someone, um, yells at them or someone'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-

    6. NWNolan Williams52:28

       Mm-hmm.

    7. AHAndrew Huberman52:28

       ... they likely feel this way. Um, they sort of just kind of can't... This is a high, high functioning individual normally, and they, they just sort of can't function. They can't complete simple things like email or, or groceries or things for, for a short while. It's, it's almost like a catatonia, and they refer to it as a dissociative state. Um, do you see that in depression? And, uh, I mean, we're, we're speculating here as to whether or not that involves the cingulate.

    8. NWNolan Williams52:55

       Yeah.

    9. AHAndrew Huberman52:55

       But what you're saying has a, holds a lot of salience, um, for me in thinking about this example.

    10. NWNolan Williams52:59

        Yeah, yeah. There's, um ... So you see, you see catatonia as an extreme outcome of depression and of, um, and sometimes schizophrenia and other illnesses. Um, dissociation is an extreme outcome, or even some cases, a less extreme outcome of PTSD and, and trauma.

    11. AHAndrew Huberman53:16

        Mm-hmm.

    12. NWNolan Williams53:16

        And, um, you know, and it's also a phenomenon that happens naturally in some people that are highly hypnotizable. And so if you ask David Spiegel, he'd say that, um, you know, some of the work that he's been working on is around posterior cingulate and, and the, uh, capacity to dissociate. But yeah, you know, w- with our stimulation approach to, to DLPFC, dorsal anterior cingulate, one of the subscales that moved the most was the dissociative subscale for, for hypnotizability. So even in a normal individual, um, you know, you see that, that change in, in, uh, in that kind of experience of dissociation.

    13. AHAndrew Huberman53:54

        I am highly hypnotizable.

    14. NWNolan Williams53:56

        Oh, yeah?

    15. AHAndrew Huberman53:56

        David, David's hypnotized me a number of times.

    16. NWNolan Williams53:58

        Oh, nice.

    17. AHAndrew Huberman53:58

        In fact, we have a clip of that on our Huberman Lab clips channel.

    18. NWNolan Williams54:01

        Oh, that's good.

    19. AHAndrew Huberman54:01

        I, I've always, um, well, always, starting at my early teens I started exploring hypnose. I am extremely hypnotizable, and, um, self-hypnosis or assisted hypnosis-Um, I don't know that I ever go into (laughs) dissociative states. Uh, I'll try and avoid, um, f- forcing you into d- running a clinical session right now but, uh, to assess anything like that. But this brings about something really, um, interesting, I think, which is,

14. 54:27 – 1:03:42

    Ketamine, the Opioid System & Depression; Psychedelic Experience or Biology?

    1. AHAndrew Huberman54:27

       I'm aware that some of the more popular emerging treatments for depression include things like ketamine.

    2. NWNolan Williams54:34

       Yup.

    3. AHAndrew Huberman54:34

       Which is a dissociative anesthetic, is that right?

    4. NWNolan Williams54:37

       Yup. Yup.

    5. AHAndrew Huberman54:38

       And yet... And my assumption is that as a dissociative anesthetic that it leads to dissociative states-

    6. NWNolan Williams54:44

       Yup.

    7. AHAndrew Huberman54:44

       ... where people can sort of third person themselves-

    8. NWNolan Williams54:46

       Yup.

    9. AHAndrew Huberman54:46

       ... and be su- feel somewhat distanced from their emotions.

    10. NWNolan Williams54:50

        Yes.

    11. AHAndrew Huberman54:51

        I've also been hearing that there are emerging treatments, psilocybin being one of them, but some other treatments, uh, MDMA, et cetera, that we'll parse each of these in, in detail, that lead to the exact opposite state during the effect of the drug, which is e- a highly engaged, um, emotionality and heart rate and sense of self.

    12. NWNolan Williams55:13

        Yeah.

    13. AHAndrew Huberman55:14

        And can also lead to relief of depression. Now whether or not this, again, reflects that depression is many conditions as opposed to just one, or whether or not somehow tickling, uh, or in some cases pushing really hard on the opposite ends of the, the scale really matter, I am absolutely fascinated and, again, also perplexed by this. Why would it be that a drug that induces dissociative states and a drug taken separately that induces r- hyper-associative states would lead to relief of the same condition?

    14. NWNolan Williams55:45

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

    15. AHAndrew Huberman56:34

        Was this low dose naltrexone?

    16. NWNolan Williams56:35

        50 milligrams, so it's pretty high dose.

    17. AHAndrew Huberman56:37

        Okay.

    18. NWNolan Williams56:38

        Yeah, and so we, we gave a, a typical ketamine therapeutic dose and then we gave 50 milligrams of naltrexone, uh, or a placebo, and then in the same individuals we, we gave two in- you know, two infusions, one with each of those conditions, and, and if they had an antidepressant effect we waited until they relapsed, then we gave them the other condition. And then we looked to see what, um, what effect of blocking the opioid receptor, um, w- what effect would you see on the antidepressant effect of blocking the opioid receptor, with the idea that if ketamine works the way that a lot of researchers at the time thought that it, you know, completely worked in, which is the glutamate system, then you would have, um, no effect of naltrexone. 'Cause naltrexone just interacts with the opiate system, it doesn't do anything with any other systems. Ketamine has a lot of effects over... You know, it has opi- clear opiate effects, um, in mice and various ways of looking at that, um, and NMDA receptor antagonism and glutamate effe- effects. And so if it's just that the glutamate part is, um, is the part driving the antidepressant effect, you shouldn't have any difference in the antidepressant effect between the two conditions. If, however, the antidepressant effect is primarily... Is the, the opioid properties of ketamine are necessary for the antidepressant effect, then you should have a loss of antidepressant effect during the ketamine plus naltrexone condition that you observed in the ketamine plus placebo condition. And what we, what we saw was that there was a dramatic blockade of the antidepressant effect when naltrexone was present in this-

    19. AHAndrew Huberman58:18

        Interesting.

    20. NWNolan Williams58:18

        Yeah. In the people that had a, had an antidepressant, um, effect with ketamine plus, um, placebo alone. And, um, and then some friends of mine did a TMS study with pain and they stimulated over the left dorsolateral prefrontal cortex and they gave nalox- IV naloxone, which works basically the same way as naltrexone, and they were able to block the anti-pain effects of TMS with a opiate blocker. So this idea that another kind of convergent point, right? This idea that the opioid receptor may have a role in mood regulation. What's also interesting is if you look at people that are getting a total knee operation, a very painful operation, right? Um, you know, t- total knee replacement and you, you age, sex, you know, everything match the individuals that are going through that but you have a group of people that don't have depression and a group of people that do have depression, the presence of depression triples the, the oral, uh, opioid dose by day four. Right?

    21. AHAndrew Huberman59:19

        That's required.

    22. NWNolan Williams59:20

        That's required to, to cover the pain, but what may be happening is it's not just treating physical pain, maybe treating emotional pain as well, right? At least transiently it seems to have a pro- an antidepressant effect. Chronically it seems to have a very pro-depressant effect. It can make people treatment resistant. But, you know, it's, it's an interesting phenomenon. But yeah, the opioid system seems to be pretty, pretty involved. But what's interesting there with the, with the ketamine trial is that we didn't see any effect on the dissociation. And so the dissociation was the same each time. So the psychological effect of the, what we call the trip or the, the kind of dissociative effect where people are having a psychological phenomenon from ketamine, that was identical both times. And so it, it kind of, um... It also challenged this idea that the psychological experience of the psychedelic effect may be all that's necessary to produce an effect and that the pharmacology doesn't matter as long as you can achieve that state. And so, you know, we think we pretty clearly debunked that idea, that the underlying pharmacology and the state-... um, you know, seem to be important. We don't know for sure if you can... and a lot of people are working on this, if you can take out, you know, essentially the psychological effect and still have a drug that works to- to treat the- the under- the illness that you're trying to target. And, you know, a lot of... There was a mouse study out this week where- where they had an LSD analog and they were able to see some- some, uh, animal level data to suggest that could be true. But- but until we figure that out in humans, it's- it's kind of to be determined. But it is- it is curious, right, being able to kind of use experimental manipulations to try to separate, you know, some of these phenomenon apart and really understand what's- what's doing what.

    23. AHAndrew Huberman1:01:13

        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, um, validated and- and presumably at some point either decriminalized or legal drugs, which has not yet happened, at least not in the US. Um, but just to make sure that people are, uh, 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 multi-gram 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, like, gravitational pull to the idea that, "Oh, it was the hallucinations."

    24. NWNolan Williams1:02:05

        Yeah.

    25. AHAndrew Huberman1:02:06

        "It was the dissociative state."

    26. NWNolan Williams1:02:07

        Yeah.

    27. AHAndrew Huberman1:02:08

        "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 n- nothing to something to do with the real shift.

    28. NWNolan Williams1:02:36

        Yeah.

    29. AHAndrew Huberman1:02:36

        And I know there's a group up at UC Davis that published a paper in Nature, uh, uh, about a year ago also looking at, um... These are, it's a chemistry lab essentially modifying psychedelics to remove the s- the hallucinogenic properties-

    30. NWNolan Williams1:02:51

        Yeah.
15. 1:03:42 – 1:13:58

    SSRIs, Serotonin & Depression; Childhood, Chemical Imbalance or Circuit?

    1. AHAndrew Huberman1:03:42

       uh, figured out. Uh, along those lines, I- I want to make sure that before we dive a bit deeper into ketamine and psilocybin, um, that we do touch on, uh, a really important topic that has been in the m- press a lot lately which is SSRIs, selective serotonin-

    2. NWNolan Williams1:03:58

       Yeah.

    3. AHAndrew Huberman1:03:58

       ... reuptake inhibitors, because we can't really have a discussion about depression without talking about SSRIs-

    4. NWNolan Williams1:04:02

       Yeah.

    5. AHAndrew Huberman1:04:02

       ... and then I want to circle back to, um, ketamine and psilocybin. It seems that, um, there are now data in wh- that essentially say, state that there's no direct link between serotonin levels and depression. Although I... My understanding is that the SSRIs are powerfully effective for certain forms of obsessive- 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 SSRIs? Are they useful? Are they not useful? Um, what's the- what's going on with SSRIs in your patients-

    6. NWNolan Williams1:04:41

       Yeah.

    7. AHAndrew Huberman1:04:42

       ... and- and in other- other people as well?

    8. NWNolan Williams1:04:44

       Yeah. The- the, um, yeah. So the- the experiment that I described a bit ago around the naltrexone and- and ketamine is the first time I'm aware of where we were able to essentially eliminate an- an antidepressant's effect by using a second drug as an- kind of a blockade. And- and it highlights a bigger issue, right? The issue that we haven't had a good way of really understanding how these drugs work. And so it's the difference... I think a lot of the- the controversy there is that, um, it's been difficult, I think, for folks, um, to see that something can on one hand work and on the other hand we don't know how it works, right? Um, and so, um, SSRIs clearly work. Um, you know, many, many mo- uh, meta analyses kind of proving that out, right? That- that in a subpopulation of individuals they achieve great benefit from depression, uh, you know, for depression, uh, for obsessive compulsive disorder, for generalized anxiety disorder, panic, you know, all of these things you can see a- an improvement in those symptoms, um, with what we call SSRIs or selective serotonin reuptake inhibitors. The issue there is that these selective serotonin reuptake inhibitors end up, um, blocking the- the reuptake of serotonin and leaving the- the serotonin, you know, in this, um, in this kind of in between, uh, between two neurons, um, for a while and allowing for more serotonin to kind of be there. The issue, um, is that they don't- they don't work immediately, right? So they don't work like the same day you start taking them and that- that suggests that probably it's not exactly the serotonin being in there that's directly driving it, that it's much more likely that it may have some say plastic- brain plasticity effects, right? We know that things like brain-derived neurotrophic factor-... get up regulated with chronic, um, oral antidepressant use. And, and so that's, that's kind of the ideas that, um, is that these things work. But what's powerful, and I think what the authors of this paper, it was an extremely controversial pat- paper were, were, um, in part trying to say, was that there's not a, there's not a deficit of serotonin. You're not born with, uh, what people call a chemical imbalance. And psychiatry has known this. This is not actually new information. Anybody, you know, it's, it's kind of a rehashing of a bunch of information we've known for a while now, but in the lay press, it's kind of hit in a way that it didn't seem to, to grab attention, um, before with previous publications. But this idea that this chemical imbalance idea is wrong. Um, I, I really, I really think that part's important because I think that, um, you know, for a while, I think psychiatry, you know, what I'll call psychiatry 1.0, right? This kind of idea of Freud and, and psychotherapy and its, and its origins. Um, it was a lot around, you know, the, your family and those experiences and psychotherapy kind of going in and correcting or helping you to figure out, or, and l- you know, show you being able to see or people hear you so that you can eventually come to the conclusion of certain cognitions that aren't helping you, right? And there's a huge, you know, there's a huge importance there, but there's a history where, you know, things like the schizophrenogenic mother and all of that, you know, that was a concept at some point, right? And so we've transitioned from that to, to the ch- you know, for a long time, the chemical imbalance, which I'll call psychiatry 2.0. You know, this idea that there's something chemically missing. And, um, and, and I, I think that the trouble there for a patient who's not a physician, who's not someone who's, you know, um, who's, who's steeped in these sorts of ideas, who's, you know, more of, you know, kind of, um, kind of a person, a, a kind of average American out there, right? Is that it's telling, it's sending a message of there's something missing with me. Whether it be my experiences I had no control of, over when I was a child or, um, a chemical in my brain. What I think is really powerful with, with TMS, um, you know, really powerful with TMS and a lovely even powerful with the psychedelic story, is it's saying something different. You know, TMS works and there's no serotonin coming in or out of the brain, right? (laughs) And we're, we're doing a rapid form of TMS that works in one to five days. So there's no, there's... It's very unlikely that there's some long term kind of upregulation of serotonin that's driving that. So our work actually kind of pushes back on this serotonin hypo- hypothesis as being kind of the center of depression because it says, "Look, we're not giving anybody any serotonin. We're simply turning these brain regions on and we're focused on the circuitry." And that's psychiatry 3.0. It's not just like neuromodulation. Neuromodulation is a really nice, you know, use case for psychiatry 3.0 'cause it's so, a way to focally and directly perturb brain regions in, in whatever modality you're using. But, you know, there are a lot of, a lot of groups that are actually doing neuroimaging before and after, and they're able to see circuit level changes for something like psilocybin or ketamine long after the drug is gone, right? Suggesting... And those same brain regions converge to the subgenual default mode network connection that we see is changing with our, our, our stan- um, Stanford neuromodulation therapy technique. At that same set of brain regions that, that ketamine and, uh, psilocybin seem to act on, act on these connections between brain networks that seem to shift. And so it refocuses the story on something that's highly correctable and it's, it's basically electrophysiology and it's basically kind of recalibrating a circuit that is recalibratable instead of, "I have something missing or have some phenom- some set of experiences early in life that are, um, that are going to forever trap me in these, these psychiatric diagnoses." And so it kind of challenges that idea. And I think that's what's so powerful about psychiatry 3.0, um, this idea of focusing on the circuit because it gets us, gets us into thinking about psychiatry and psychiatric illnesses as something that are recoverable. People can get better. People, you know, we've seen with our TMS techniques, we've seen it with some of the psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time or- Within five days. ... within five or less days. And in the case of, of the psychedelics, within a few days, right? So we can get people out of these states. They're totally well. There's no drug in their system at that point, in the case of psychedelics. It was never a drug in their system in the case of, of TMS. And it, and it just tells us that, that it's, it's, it's fixable. It's, it's just like the heart. It's just like, you know, it's just like an arrhythmia in the heart. It's just like, you know, these, these other illnesses that it's like a broken leg. We can go in and do something and we can get somebody better. And I think what's, what's empowering and what a lot of patients have told me is they say, you know, "I've gotten depr-" You know, some people will relapse and need more stimulation or need more psychedelics or whatever it is, but they'll tell me, "I, I've relapsed and I'm depressed again, but I'll never think about killing myself again because I know that if I go get stimulated again, it, it improves, it gets better. It, it, it will, I will be able to reachieve it and I can't... And I, and I, I don't fear that I'm chronically broken. I don't fear that the chemical imbalance is still imbalanced. I don't fear that these things that I couldn't control in my childhood."... you know, are going to be there and drive this problem forever, and I think that's- that's what's so powerful about this.

    9. AHAndrew Huberman1:12:53

       The sense of control.

    10. NWNolan Williams1:12:54

        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.

    11. AHAndrew Huberman1:13:08

        Yeah, I have a- a good friend, uh, I won't out him for- for reasons that will become clear in a moment, who, um, was quite obese, um, 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- not- not all the way, but- but far along. But his tone around it was very different. He knew he had accomplished what his goal once before. He was disappointed in himself, but he knew exactly why he had relapsed. It was very clear. He had essentially relapsed to the previous set of eating behaviors and lack of exercise behaviors and has now brought himself back again. Um, and it- it just resonates, uh, with your story that, you know, once somebody understands they can do it because they've been there before, this- this idea again of- of considering new rules, that- that there's-

    12. NWNolan Williams1:13:56

        Yeah.

    13. AHAndrew Huberman1:13:57

        ... um,

16. 1:13:58 – 1:21:00

    Memories & “Rule” Creation; Psilocybin & “Rule” Resolution

    1. AHAndrew Huberman1:13:58

       and- and that brings me to this, uh, question about psychedelics and- and the, frankly, the altered thinking and perception that occurs in- in high dose psilocybin

    2. NWNolan Williams1:14:08

       Yeah.

    3. AHAndrew Huberman1:14:08

       ... uh, clinical, uh, sessions. Um, it seems that the disordered thinking, even though it could, uh, be random, right? Uh, hearing- hearing colors and- and seeing sounds is always the, you know, kind of cliché statement of the Timothy Leary area.

    4. NWNolan Williams1:14:22

       Yeah.

    5. AHAndrew Huberman1:14:22

       Um, also, you know, right there, that's a Stroop task of sorts.

    6. NWNolan Williams1:14:26

       Yeah.

    7. AHAndrew Huberman1:14:27

       It's a- it's a- it's a synesthesia, it's a combining-

    8. NWNolan Williams1:14:29

       Yes.

    9. AHAndrew Huberman1:14:29

       ... of perceptions, but it's- it's sort of Stroop task-ish in that it's a new set of rules for the same stuff.

    10. NWNolan Williams1:14:36

        Yeah.

    11. AHAndrew Huberman1:14:36

        Right?

    12. NWNolan Williams1:14:36

        Yeah.

    13. AHAndrew Huberman1:14:36

        And, um, people do... Many people do report improvements in, uh, trauma-related symptomatology and depression, as I understand it-

    14. NWNolan Williams1:14:45

        Yeah.

    15. AHAndrew Huberman1:14:45

        ... from my read of the clinical trials after taking psilocybin because during those sessions, something comes to mind spontaneously, as, uh, you and I were talking about earlier. Um, they will report, for instance, uh, a new way of seeing the old problem.

    16. NWNolan Williams1:15:00

        That's right.

    17. AHAndrew Huberman1:15:01

        And the old problem could be the voice that they're no good. They'll never... Nothing will ever work out, or could be even more subtle than that. So, um, that raises two questions. One is about the basic functioning of the human brain, um, which is, why do you think, um, the brain would ever hold on to rules that, um, uh, don't serve us well? That's one question.

    18. NWNolan Williams1:15:23

        Yeah, that's

    19. NANarrator1:15:23

        one.

    20. AHAndrew Huberman1:15:23

        And then the second question is, um, what is it about psilocybin and related molecules w- in terms of their neurochemistry, in terms of the ways they disrupt thinking and feeling, et cetera, during the session that allow this, uh, novel rule consideration phenomenon?

    21. NWNolan Williams1:15:44

        Yeah. So the first question, I think it's an- it's an- it's an eveler- evolutionary neurobiology answer, right? I think that at the individual person level, you know, it doesn't make a whole lot of sense that when we're really stressed out, some of us want to eat more, right? At the individual person level, 'cause it's like that's not particularly that good for my health in the long term. But if you think about it like, you know, in some 500 years ago, 1,000 years ago, if I'm highly stressed out, it's most likely that I'm about to not have food at some point and I should eat a bunch of food that is high fat, high sugar, high carb food to put on weight for that, you know, next phase where in this stress I may be a- in battle and I don't have food and I have enough fuel on board, right? And so we- we end up being, uh, you know, we end up being a result of- of probably a lot of biology that's not that useful in the modern era. And I think in the brain for- for, say, let's say PTSD, right? A lot of- a lot of veterans come back and they experience these PTSD symptoms and they're not at all useful back home, right? You know, they're, you know, uh, they hear some loud noise and all of a sudden they're behind a car or they're behind a, you know, I- I've heard of folks, you know, jump and run behind a trash can or whatever in the middle of San Francisco when they hear a loud noise. But if you put them back in the battlefield, yeah, they-

    22. AHAndrew Huberman1:17:07

        Highly adaptive.

    23. NWNolan Williams1:17:07

        That's highly adaptive, right? And so I think what- what the- what's interesting is that, um, we, in the absence of using substances like psychedelics, end up having these very persistent memories that are attached to negatively valenced emotion predominantly. Um, as you were saying earlier, the jacket in- in elementary school. We, you know, uh, I had various things like that for me, too, right? You- you- you remember these things. Um, and, uh, and we- we hold onto those things from an, I think, an evolutionary neurobiology standpoint, but what seems to, for whatever reason, kind of alleviate that are these, um, are these substances. Some new, like MDMA, some that have been around for thousands of years, like psilocybin and used, um, in- in kind of sacramental, sa- in- in a, as a sacrament in, uh, in traditions, um, seem to have a therapeutic effect that seems to be pretty long-lasting for these phenomenon. And so it's- it's just curious, right? It's curious that- that in the absence of that, these things will keep going on and on, but in the presence of that exposure, then all of a sudden you see a resolution of the problem. And we have some work now where we're treating folks with... Navy Seals, and the data's still being, you know, being analyzed, but the anecdotes that we're getting, right? Are... Folks are coming back and they're saying, "It finally... It's finally gone," right? This kind of, these set of PTSD symptoms are finally gone. And so this idea that for whatever reason-... going into what's probably a highly plastic state, like we were talking about earlier, up-regulation of brain-derived neurotrophic factor in the case of ibogaine, glial-derived neurotrophic factor, this highly plastic state and, um, the ability to re- you know, kind of re-experience memories and then as you know, you know, we, we, we always re-consolidate a memory, uh, when we bring it back up. We always re-consoli- but re-consolidating it in that state, for whatever reason, um, may drive, um, drive a therapeutic effect. Um, and, um, you know, the, the, the, the jury's still out. There's a, I'm a, I would say that I'm, I'm kind of a, I'm an agnostic to what tool I'm using kind of guy. Like, I'm, my business is to find treatments that help people, and so I'm much more like pragmatic about it. You know, if, if this sort of thing, which, um, has a lot of cultural baggage, um, but if this sort of thing ultimately ends up being therapeutic, if we can design trials that convince me and others that it is, then we should absolutely use it, you know? And, uh, and if it doesn't, then, um, then, then we clearly shouldn't use it, right? Um, and I think that's a big, that's a big question the field's going to have to work out. We have a hard time blinding these trials because the placebo condition is not easy to, to pull off, obviously.

    24. AHAndrew Huberman1:20:14

        Right. Uh, uh, a placebo for a psilocybin journey is, is hard to imagine.

    25. NWNolan Williams1:20:20

        We've got, you know, we've been thinking about this, and maybe that ketamine study that I was talking about earlier, if we could give people naltrexone and ketamine, maybe that's a good, you know, uh, a good sort of placebo condition, right? 'Cause we know that we can block any of the actual antidepressant effects of ketamine, they can still have an experience, you know? And so that's one way of doing it. But thinking about ways to do that and really kind of proving this out, and that's been, um, yeah, I think that's been, been kind of central to the way I've been, been thinking about this. But yeah, I think there's, the, the work that's been done so far, the first psilocybin trial, um, the first MDMA trial is published in Nature Medicine recently, um-

    26. AHAndrew Huberman1:20:59

        And what

17. 1:21:00 – 1:24:12

    MDMA & Post-Traumatic Stress Disorder (PTSD) Treatment, Psilocybin & Depression Treatment

    1. AHAndrew Huberman1:21:00

       do those generally say? I mean, the, that they, that they are effective for a number-

    2. NWNolan Williams1:21:04

       Yeah.

    3. AHAndrew Huberman1:21:04

       ... of people after one session, two sessions?

    4. NWNolan Williams1:21:06

       Yeah.

    5. AHAndrew Huberman1:21:06

       But what's, what's sort of the general contour of... Let's, let's, uh, start with psilocybin and MDMA.

    6. NWNolan Williams1:21:11

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

    7. AHAndrew Huberman1:21:59

       So does that mean that, um, for people that have trauma who do a, and again, we're talking about in a clinical setting, they ta- they take a, one or two doses of, of MDMA. I think the standard maps dose is 150 to 775 milligrams.

Episode duration: 2:48:55