Psychedelics & Neurostimulation for Brain Rewiring | Dr. Nolan Williams

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology 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 ibigan 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 Psych delic research and clinical use really looks like for instance we discuss how a number of Laboratories and Clinics are modifying psychedelics to remove some of their hallucinogenic properties while maintaining some of their anti-depressant or anti- truma 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's laboratory I should mention that they are recruiting subjects for these studies if you go to BSL which stands for brain stimulation laboratory so that's BS sl. 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 most stimulating and informative conversations I've ever had about psychedelics which is simply to say that his breadth and depth of knowledge on that topic is incredible and his breadth and depth of knowledge in terms of the underlying brain science and how it can all be combined with clinical applications is also extraordinary I'm sure that by the end of today's episode you're going to come away with a tremendous amount of knowledge about the clinical and non-clinical uses of those substances and you're going to understand a lot more about how the healthy and diseased brain work I'm pleased to announce that the hubman Lab podcast has now launched a premium channel I want to be very clear that 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tremendous benefit from them things like enhancing sleep and the depth of sleep or for enhancing focus and cognitive ability or for enhancing energy or adjusting hormone levels to Optimal range for you the huberman Lab podcast is now partnered with momentous supplements to find the supplements we discuss on the hubman Lab podcast you can go to live momentus spelled o us liv.com huberman and I should just mention that the library of those supplements is constantly expanding again that's liv.com huberman and now for my discussion with Dr 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 yeah but before we get into that discussion I want to ask you about depression broadly speaking sure 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 yeah absolutely so depression is a 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 hunor Liston and 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 um presentations in the and see that clinically and also see that in the brain depression is U 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 is the fourth uh major risk factor for coronary artery disease right so alongside the risk factors that we know hypertension high blood pressure hyper lipidemia high cholesterol and um and diabetes you know high blood sugar those three have been on the list for a long time and Depression end up 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 the risk of having a heart attack in the future and you know there's some of that's being worked on now but we don't have a complete solution to thinking about that at this time and then the other thing that's interesting is once you have a heart attack in the in the individuals end up having 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 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 as you said a second ago you know it's a it's a very disabling condition moderate depression is about as disabling as is having a heart attack acutely having a heart attack severe depressions is disabling is 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 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 folks with Depression end up being in and that's in you know emergency settings where they go into inpatient 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 outpatient 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 consistently being able to treat that problem and folks end up getting the same standard oral anti-depressants that they've been getting outpatient and and I came to this because a you know dual trained as a neurologist and psychiatrist went back and fourth 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 you know brain-based Solutions there's a lot to unpack there 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 but you described I believe uh a direct relationship between areas of the brain associated with emotion and heart rate yes and that makes perfect logical sense to me but I think um at the same time many people out there probably think of the relationship between the the heart and the mind as kind of woo or kind of a a soft biology but here you're talking about an actual physical connection yep between uh what area of the brain is it 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 and then 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 SC 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 dorsal lateral prefrontal and if you do that in the actual scanner which we can do you can see that that distributes down into the anterior singulate in the insula and the amydala and ultimately the tract goes into something called the nucleus tractus solitarius and ultimately into the Vagas nerve into the heart so the the heart uh very consistently seems to be the end organ of the dorsolateral prefrontal cortex if you measure heart rate in standard ways that cardiologist measure heart rate and you stimulate over this left do c lateral you get a deceleration of the heart rate and it's very time loock to the stimulation so it's a 2C train of stimulation at 1 second you see the deceleration it goes down about 10 beats per minute and then it'll drift back up there's a break for eight 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 10 beats per minute every train and so we know and 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 other folks work Martin arens and um in in Europe uh the Netherlands work showing the same connection so I think it's been rep replicated like four or five times so you mentioned left dorsal lateral prefrontal cortex anytime I hear about lateralization of function I get particularly curious yeah um because obviously we have two uh mirror symmetric sides of the brain 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 dorsal prefrontal cortex does this have anything to do with handedness right hand or left hand because we know right-handed 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 dorsal atal prefrontal cortex would be connected to the heart uh in this way yeah yeah I think so so left or Catal 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 uh 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 you put them on the human connecto uh 100 you know thousand patient map and you ask the question what they're all functionally connected to left dorsal lateral if you take lesions that cause Mania in individuals and you put those all on the human connecto map and ask what they're all the one common area they're all connected to it's the right dorsal lateral and so there seems to be a hemispheric you know uh you 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 anti-depressant you can um excite the right and that's antim manic in some studies and so this idea that there is this hemispheric balancing of mood is is quite interesting right 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 being a large collections of sequencing and mapping of genes they're proteomes of proteins of uh connectomes as U so-called connectomics of connections between neurons so the human connectone project is ongoing um and I find that incredible that within the connectone project they can identify these regularities of right versus left or Catal 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 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 more or less so what gives the these properties um to the right and left dors lateral 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 yeah it's a it's a great question and and you know it hasn't been worked out which your original question was around and I a lefthanded 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 because 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 is 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 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 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 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 you know part and parcel with uh with with uh anxiety um in my laboratory we've studied fear a bit in animals and in humans and we um often observe brachi cardio 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 uh think about or recognize but um given that stimulation of dorsolateral prefrontal Cortex slows the heart rate down and can alleviate depressive sympt 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 um does that help alleviate depression yeah that's a great question so the um I'll answer the second question first um so we know that um and their ongoing trial of this uh if you stimulate in the Vegas nerve um in an implanted Vegas nerve stimulator you can actually um you know have this the aparant um parts of the the Vegas um you project ultimately up to the dlpfc through the singulate through these anterior insula so that same that 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 in 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 a a 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 and what if I were somebody who did not have a stimulating electrode in my Vegas nerve and I was dealing with minor depression and I decided I wanted to take some other approach to slow my heart rate down via the Vegas for instance um exhale emphasized breathing or deliberately slow cadence breathing 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 dorsal lateral prefrontal cortex to achieve some of that alleviation absolutely yeah so there's there's a number of studies um implicating DP the dorsal lateral and uh and say you know meditation uh mindfulness that sort of thing and and they're small studies but but pretty welld 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 um than folks that that aren't you know if you're if you were an athlete 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 dorsal lateral prefrontal um physiology pre poost 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 and um and depression and you know studies are kind of Point towards it it's not not every study is is is you know um positive for this but um but quite a few studies say basically that low heart rate variability is uh associated with se you know moderate to severe depression um and that may be part of that mechanism of that heart brain uh risk 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 even mentioned Catatonia or somebody that just doesn't seem motivated or excited to do anything I think a Mania is elevated heart rate being excited on the other hand I realiz that anxiety which you know 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 um disorders to for lack of a better word and for what percentage of people that have depression does some approach to reducing heart rate work whether or not it's stimulation of the dorsal left dorsal lateral prefrontal cortex by way of transcranial magnetic stimulation or by taking a beta blocker or by stimulating the Vegas can we throw out a number a rough number does that help 30% 50% how Pro how long lasting is that that relief yeah and to be clear the um 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's than it appears to be itself you know Central to the mechanism the 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 you know 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 deer a it's not it's not a huge you know it's not a huge amount right so it only explains um a small percentage and so it's it's unlikely that simply dis you know simply reducing the heart rate and in fact you know for many years Propranolol and these sorts of drugs actually were implicating causing depression and so that that's been kind of debunked but it's 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 that area that is the mood regulatory area there's some parasympathetic cortical kind of process that's going on that gets in and and causes this to happen and it's you know it's independent a mood you can take a normal healthy um individual and you can do this and they're going to decelerate their heart rate I'm so glad you mentioned the parasympathetic nervous system which of course is the most people think of as the rest and digest or the kind of calming side of the autonomic nervous system as I'm hearing you say all this and in particular 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 um and when I think about the autonomic nervous system I like to think about as a seesaw of you know alertness and calmness and when you're sleep it's very a lot of calmness and when you're panicking it's a lot of alertness to the but that and I don't think this has ever been defined and when I teach the medical students at Stanford neur Anatomy I my wish is that someday I'll be able to explain what the hinge in that process would be right 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 that depression is sort of a lack of control over inner state so that when I'm stressed I can't get myself out of it 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 a quality meal these kinds of things yeah so this is perhaps the first time that I've ever um heard about a potential circuit for the hinge as I'm referring to it does that make any sense all absolutely okay I just want to make sure that I'm framing this correctly in my mind yeah absolutely and in some studies if you do the same identical stimulation on the right dorsal lateral you can get an acceleration you know just kind of further confirming this idea of lateralization right that that even it appears that even the prefrontal cor you know cortical uh areas seem to be lateralized in this in this way and I you know it's um it's less uh the right finding is is more variable depending upon the study the left's very consistent in this way um so uh so we've talked about Sharon's cranial magnetic stimulation for getting into these networks and and I also just want to take a brief tangent and say I because I've heard you say this before I think it's so vital what you're saying that it's really not about stimulation of areas it's or any specific brain area or vegus nerve being important per se it's really about a network a connection a series of connections I think that's really important for people to understand and is kind of new emerging theme really the the other thing that to me seems extremely important for us to consider is what ex 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 uh talk ourselves into a manic state or an excited state a positively excited state that doesn't qualify as Mania you know other areas of the brain I I think of they is responsible for perception or for for motor control but here we are in this mysterious frontal cortex area which people say executive function planning Etc 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 and here I spent my career you know in neuroscience and still I I still can't really understand what it's doing and maybe it's doing 50 things 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 doors Catal um is functionally connected with the Anor the dorsal anterior singulate uh with a lot of functional connectivity in high hypnotizes 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 or Catal prefrontal cortex than the part that seems to be important for regulating mood and so the left doors lateral seems to have connections that are locations specific within the overall kind of named Brain region that connect to various parts of the singulate and seem to regulate it right and so if you knock out the left or Catal prefrontal cortex and you have people do the Stroop task for instance which is a a task where you have it's a simple task 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 called a congruent and then the in congruent 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 so you have to suppress a response yeah yeah exactly and so um I'm sorry you do the 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 door Catal prefrontal port or either one you can actually knock out the ability to do that well and it'll take longer for people on the in congruent cards to uh to be able to name it and so they have a they have a kind of a time delay that's greater than they had before they got stimulated so that's a part of the 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 inhibitory way within the left dorsal lateral 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 Hypno iability 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 or Catal 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 the part of this of the dorsal lateral that seems to be lower in the you know kind of more lateral um and um and um inferior on the uh dlpfc and connected with this subgenual anterior singulate so the part of the Interior singlet that processes emotion 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 foundation 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 athletic greens.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 Etc and they'll give you a year supply of vitamin D3 K2 again that's athletic greens.com huberman to get the five free travel packs and the year supply of vitamin D3 K2 based on what you told us about the stoop task and the role of the prefrontal cortex and stoop task to me the sto task is a rule switching Game Y you're saying in one moment the the rule is you read whatever the word says and then then you switch and then you say the rule now is you tell me what color the word is written in and you suppress whatever it is the word says okay that's right okay a rule in some sense is a uh like that is a a transient adopted belief system y so I could imagine that in depression which has all sorts of backstory to it 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 um 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 stro 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 that saying that you know whatever we heard in middle school when someone made fun of us we can remember that cuz I can remember things that people said um about a jacket I wore one day or something the fourth grade crazy I didn't even like the jacket um now I think it was kind of cool but anyway the point being that we have an intense memory for these things to 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 the dorsal ow prefrontal cortex is in this amazing position to access rules which are beliefs and beliefs are rules and then for moments or longer to those rules and so for somebody who's depressed to just simply look themselves in the mirror and say you are great you are fantastic that's it feels like a lie if you feel like garbage to say that it 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 that it's red and that's right and it seems like there's something about prefrontal cortex that that in principle gives flexibility to rules based on what we know about the stoop task so so given its connectivity can we assume that the talk therapy that occurs in a the psychiatrist office or with a friend or through journaling out something um because we do know that reporting things about trauma are 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 rescripting that that somehow it allows us to do a sort of Stroop task on our beliefs is that is that a tremendous leap I'm just really trying to frame this in the context of what what I and most people think of as depression yeah totally um because the network components are vitally important but I I guess what I'm trying to figure out is like what are the what are the the algorithms that govern prefrontal cortex yeah absolutely so in a in a kind of standard cognitive behavioral therapy session right what what um the therapist is trying to do is identify those beliefs and um and you know kind of determine how how fixed they are you know if they're flexible as you're saying and then um and then help folks to find another explanation for them and to uh and to kind of reintegrate that potential other explanation into their their memory system right um where where I think TMS is really interesting actually we had a lot of patients who've told me like my my therapist told me that I wasn't trying hard enough in therapy and um you know and I I really am trying hard but these are you know moderate pretty severe depressed patients and as soon as we get them well with with the TMS approaches you know kind of Rapid you know 5-day approach and the next week we come in and see them and they'll say you know what I did all weekend is I looked at my therapy books and now I can understand it and so you know I actually see TMS is a way of having kind of exogenous sorts of cognitive functions that in milder forms of depression we we can pull off with Psychotherapy you know this idea of being able to kind of turn that prefrontal cortex on and have it govern these deeper regions in depression the deeper regions govern the prefrontal cortex they they precede the prefrontal cortex timing wise and we've got some data in review now we we're seeing that in depressed individuals that are responsive to our rapid TMS approach we call Stanford accelerated intelligent neurom modulation therapy or S&T or Saint if you look at the Brain before people get this they will they will have a temporal delay where the singulate 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 singulate with effective treatment we can flip the timing of things so the dorsal lateral is in front of the anterior singulate just like in a normal person so you're not talking about obviously physically moving these structures talking about in time their Activation so in one case it's like the coach telling the player what to do and in other like a player telling the coach what to do and you you restore order to the game you restore order to the game and and and what it looks like is dep depression to your point is a bunch of kind of spontaneous content that's semi volitional that's being kind of generated out of this conflict um detection system the singulate that seems to to uh to sense conflict and kind of feed that information gets overactive in depression and um and then in depression it looks like the left doors lateral 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 we just exogenously do the same sort of thing we restore the governance of the left dors Sal lateral over the singulate area and that is correlated with treatment Improvement so the degree in which you can re time re-regulate in time the left doors Catal over the singulate the more of an anti-depressant effect you have can we therefore say in in crude terms that the dorsal lateral prefrontal C Tex really is the governor of how we interpret physiological signals and spontaneous thoughts 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 can experimentally manipulate the system and so kind of buffing it up I 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 I think really interesting for for this show is to you we had a couple of folks um You 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 rapid over a 5day 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 we can't we're we're getting to a point where we can tell how long it's going to take but we're not there yet and so you know every time somebody gets better at day one or two at the beginning when we first started doing this we'd say you know we're not sure you know we think this is safe to keep going but you know what do you want to do and everybody was like no I want to keep going and so you know they're by Wednesday they're like totally zero down 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 hm 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 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 you mentioned the singulate and the anterior singulate 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 um besides providing a bumper for the for the rest of the the brain um is the singulate it seems is 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 but what's mapped in the singul in and for the non- neuroscientists out there when we say mapped if if we were to put someone in a scanner and focus in on singulate or put an electrode in there what what makes the neurons in their 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 singulate what does the singulate like yeah yeah so so that stoop task those in congruent word color associations the the dorsal part of that um for obsessive compulsive disorder patients certain you know certain kind of triggers you'll you'll see some some of the neur Imaging studies will point to to anterior singulate 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 because that area seems to be overactive in people who are experiencing obsessive compulsive disorder you can kind of walk the singulate wraps around you know this white matter track like bundles it wraps around that and so there's a part that's above that around that and below that and depending upon how emotion how much of the 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 singular 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 they 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 that seems to be more perig genual subgenual areas right so you can kind of you can trigger the singulate based off the level of emotional veilance 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 autonomic components in there too there's something called a kinetic mutism you you know I'm a a board certified neuros psychiatrist beh behavioral neurologist and I've seen you know a lot of these what we call zebra cases in neurology where people have you know these unus usual neurological presentations and one of them is a a kinetic mutism and so you have a Goma sitting in the inner hemispheric Fisher and H kind of having um pressure on the singulate 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 singulate 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 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 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 as a dissociative State um do you see that in depression and I mean we're we're speculating here as to whether or not that involves a singulate but what you're saying has holds a lot of salience um for me and thinking about this example 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 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 some of the work that he's been working on is around posterior singulate and and the capacity to dissociate but yeah you know with our stimulation approach to to dlpfc Dorsal anterior singulate one of the subscales that moved the most was the dissociative subscale for for hypnotizability so even a normal individual um you know you see that that change in in uh in that kind of experience of dissociation I am highly hypnotizable D David hypnotized me a number of times in fact we have a clip of that on our cuber live Channel I I've always um well always starting my early teens I started exploring hypnos I'm extremely hypnotizable and um self hypnosis or assisted hypnosis um I don't know that I ever go into associative States uh I'll try and avoid um forcing you into running a clinical session right now but uh to assess anything like that but this brings about something really um interesting I think which which is I'm aware that some of the more popular emerging treatments for depression include things like ketamine Y which is a dissocia of anesthetic is that right yep and yet and my assumption is that as a dissociative anesthetic that it leads to dissociative States where people can sort of third person themselves and be some feel somewhat distanced from their emotions yes I've also been hearing that there are emerging treatments psilocybin being one of them but some other treatments uh MDMA Etc that we'll parse each of these in in detail that lead to the exact opposite State during the effect of the drug which is a highly engaged um emotionality and heart rate and sense of self yeah and can also lead to relief of depression now whether or not this again reflects that depression has many conditions as opposed to just one or whether or not somehow tickling uh or in some cases pushing really hard on the opposite ends of the the scale really matter I am absolutely fascinated and again also perplexed by this why would it be that a drug that induces dissociative States and a drug taken separately that induces hyper associative States would lead to relief of the same condition yeah no that's a great question yeah so for um for ketamine you know the the level of of dissociation appears to be correlated with the the therapeutic effect it appears to be um necessary but not sufficient to produce an anti-depressant 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 T typically tend to have less um less potent anti-depressant effects from ketamine we did a study a couple of years ago it was really interesting so we we gave folks Naltrexone which is an opiate um antagonist a mu and Capa opiate receptor antagonist and we we we gave F the same individuals a pill of that or a pill of placebo and they had no idea which one they were getting was this low dose nxone 50 milligrams so it's pretty high dose okay yeah and so we we gave a typical ketamine therapeutic dose and then we gave 50 milligrams of nxone uh or Placebo and then in the same individuals we we gave two you know two infusions one with each of those conditions and and if they had an anti-depressant effect we waited until they relapsed then we gave them the other condition and then we look to see what um what effect of blocking the opioid receptor um what effect would you see on the anti-depressant 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 nxone because nxone 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 in MDA receptor antagonism and glutamate effects and so if it's just that the glutamate part is um is the part driving the anti-depressant effect you shouldn't have any difference in the anti-depressant effect between the two conditions if however the anti-depressant effect is primarily is the the opioid properties of ketamine are are necessary for the anti-depressant effect then you should have a loss of anti-depressant effect during the ketamine plus nxone 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 anti-depressant effect when elone was present in yeah in the people that had a had an anti-depressant 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 do lateral prefrontal cortex and they gave noox IV nxone which works basically the same way as nxone 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 it's also interesting is if you look at people that are getting a total knee operation very painful operation right um you know total knee replacement and you you age sex you know everything match the individuals that are going through that but you have a group of people that don't have depression and a group of people that do have depression the presence of depression triples the the oral uh opioid dose by day four that's required that's required to to cover the pain but what may be happening is it's not just treating physical pain maybe treating emotional pain as well right at least transiently it seems to have a pro an anti-depressant effect chronically it seems to have a very Pro depressant effect and can make people treatment resistant but you know it's it's an interesting phenomenon but yeah the opioid system seems to be pretty pretty involved but what's interesting there with the the 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 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 elicity legal 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 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 shown to be useful for in certain contexts clinically supported Etc there's this like 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 Allah your experiments with nxone or a change in the underlying neuromodulation that had anywhere from nothing to something to do with the real shift yeah and I know there's a group up at UC Davis that published a paper in nature about a year ago also looking at um these are is a chemistry lab essentially modifying psychedelics to remove this the hallucinogenic properties the mood altering properties and actually seeing some pretty impressive effects in shifts in mood after the drug wears off and I know this this gets people upset when they hear it a lot of this gets a lot of people upset really because people think oh no it's the it's the intense experience that matters but um in fact uh that may not be the case at all in fact it's so powerful for people that sometimes I liken it in my mind to you know it's like somebody it's like the birth of a new child and it's such an incredible experience and then people feel so much connection and they sort of connect the the experience of the of the ual birth to the connection when in fact there that's true it turns out but there are a bunch of other things happening too that are that's simply the reflection of the fact that you're holding a child and the fonal effects Etc so anyway I I think it's very important that these different um variables be uh figured out 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 a really important topic that has been in the press a lot lately which is SSR selective serotonin reuptake Inhibitors because we can't really have a discussion about depression without talking about ssris and then I want to Circle back to um ketamine and psilocybin it seems that um there are now data 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 obsess 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 what's going on with ssris in your patients and in other other people as well yeah that the um yes the the experiment that I described a bit ago around the n trexon and and ketamine was the first time I'm aware of where we were able to essentially eliminate an an anti-depressants effect by using a second drug as an kind of a blockade and it highlights a bigger issue right the issue that we haven't had a good way of really understanding how these drugs work and so it's the difference I think a lot of the the controversy there is that um it's been difficult I think for folks um to see that something can in one hand work and on the other hand we don't know know how it works right um and so um ssris clearly work um you know many many meta analyses kind of proving that out right that that in a subpopulation of individuals they achieve great benefit from depression uh you know for depression uh for obsessive compulsive disorder for generalized anxiety disorder Panic you know all 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 U 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 derive neurotrophic Factor get upregulated with chronic um oral anti-depressant use and and so that's that's kind of the idea is that um is that these things work but what's powerful and I think what the author of this paper was extremely controversial P paper were were u 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 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 experience and Psychotherapy kind of going in and correcting or helping you to figure out or and you know show you being able to see or people hear you so that you can eventually come to the conclusion of certain cognitions that aren't helping you right and there's a huge you know there's a huge importance there but there's a history where you know things like the 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 you know for a long time 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 of average American out there right is that it's telling it's sending a message of there's something missing with me whether it be my experiences I had no control of over when I was a child or um a chemical in my brain what I think is really powerful with with TMS um you know really powerful TMS and a level even powerful the Psychedelic story is it saying something different you know TMS works and there's no serotonin coming in or out of the brain right and we're we're doing a rapid form of TMS that works in 1 to 5 days there's no there's it's very unlikely that there's some long-term kind of upregulation of Serotonin that's driving that so our work actually kind of pushes back on this serotonin hyp hypothesis as being kind of the center of depression because it says look we're not giving anybody any serotonin we're simply turning these brain regions on and we're focused on the circuitry and that's Psychiatry 3.0 it's not just like neuromodulation neuromodulation is a really nice you know use case for Psychiatry 3.0 because it's a a way to focally and directly perturb brain regions and whatever modality you're using but you know there are a lot of a lot of groups that are actually doing neuroimaging before and after and they're able to see circuit level changes for something like psilocybin or ketamine long after the drug is gone right suggesting in those same brain regions converge so the subgenual default mode network connection that we see is changing with our our our St um Stanford neurom modulation therapy technique it's 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 re-calibrate instead of I have something missing or I 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 with some of the Psychedelic work that we've done where people are actually in normal levels of mood for sustained periods of time or within five days within five or less days and in the case of the psychedelics within a few days right so we can get people out of these States they're totally well there's no drug in their system at that point in the case of psychedelics it was never a drug in their system in the case of of TMS and it and it just tells us 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 athm 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 then I think what's what's empowering and what a lot of patients have told me is they say you know I've gotten dep you know some people will relapse and need more stimulation or need more psychedelics 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 re aieve it and I can't and and I I don't fear that I'm chronically broken I don't fear that the chemical imbalance is still imbalanced I don't fear that these things that I couldn't control in my childhood you know are going to be there and drive this problem forever and I think that's that's what's so powerful about this the sense of control the sense of control the sense of they're not doing the stimulation themselves they're not administering the drug in these trials themselves they probably never will these will probably be Medical Treatments but they are choosing to do it and in that sense they are in control yeah I have a a good friend 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 um 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 do psilocybin clinical 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 cliche statement of the Timothy L era um also you know right there that's a stoop task of sorts it's it's a it's a synesthesia it's a combining of perceptions but it's it's sort of stoop task is in that it's a new set of rules for the same stuff yeah right and um people do many people do report improvements in uh 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 uh you and I were talking about earlier um they will report for instance a a new way of seeing the old problem that's 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 and then the second question is um what is it about psilocybin and related molecules in terms of their neurochemistry in terms of the ways they disrupt thinking and feeling Etc during the session that allow this uh novel rule consideration phenomenon yeah so the first question I think it's an it's an it's an EV evolutionary neurobiology answer right I think that at the individual person level you know it doesn't make a whole lot of sense that when we're really stressed out some of us want to eat more right at the individual person level because it's like that's not particularly that good for my health in the long term but if you think about it like you know in some 500 years ago a thousand years ago if I'm highly stressed out it's most likely that I'm about to not have food at some point and I should eat a bunch of food that is high fat high sugar high carb food to put on weight for that you know next phase where in this stress I may be in battle and I don't have food and I have enough fuel on board right and so we we end up being a 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 that you know they hear some loud noise and all of a sudden they're behind a car or behind a you know I've heard of folks you know jump and run behind a trash can or whatever in the middle of San Francisco when they hear a loud noise but if you put them back in the battlefield highly adaptive that's highly adaptive right and so I think what what the what's interesting is that um we in the absence of using substances like psychedelics end up having these very persistent memories that are attached to negatively valanced emotion predominantly um as you were saying earlier the jacket and and Elementary School we you know I had various things like that for me too right you you you remember these things um and uh and we we hold on to those things from I think an evolutionary neurobiology standpoint but what seems to for whatever reason kind of alleviate that are these um are these substance is some new like MDMA some that have been around for thousands of years like psilocybin and used um in in kind of sacramental 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 we're treating folks with Navy Seals and data is still being you know being analyzed but the anecdotes that we're getting right are folks are coming back and they're saying 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 ear upregulation of brain derived neurotrophic factor in the case of ibigan G 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 reconsolidate a memory uh when we bring it back up we always Rec consol but reconsolidating 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 is 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 a placebo for a psilocybin journey is is hard to imagine we've got you know we've been thinking about this and maybe that ketaman study that I talkinging about earlier if we could give people n treone and ketamine maybe that's a good you know uh a good sort of placebo condition right because we know that we can block any of the actual anti-depressant effects Kine they can still have an experience you know so that's one way of doing it but thinking about ways to do that really kind of proving this out and that's been um yeah I think that's been been kind of central to the way I've been been thinking about this but yeah I think there's the work that's been done so far the first Sil cybin trial um the first MDMA trial was published in nature medicine recently um and what do those generally say I mean that that that that they are effective for a number of people after one session two sessions what's what's sort of the general Contour let's let's uh start with psilocybin and MDMA 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 stand assumed levels of PTSD Improvement that you can observe in individuals um with this level of PTSD right so what we call the effect size which is essentially like a a a measure a coin 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 size is there you know approach effect sizes things that are pretty effective like ant acids for or heartburn right and you see that with with um with MDMA treatment so does that mean that um for people that have trauma who do a and again we're talking about in a clinical setting they they take one or two doses of of MDM I think the standard Maps dose is 150 to 775 milligrams again doing this with a physician ETC control clinical trial legal um yep exactly they do it once or twice and broadly speaking what percentage of people who had trauma report feeling significant relief from their tra trauma afterward it's about two-thirds of people had a had um a clinically significant uh change in their PTSD that's impressive which is impressive right and how how long lasting was that I mean these trials were ended pretty recently so it 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 um psilocybin um you know that contrast it with ketamine which only on average lasts about a week and a half for a single infusion so it's a much shorter so they have to get repeated infusions of ketamine every 10 days or so yeah or forever for some people or they end up getting like like like a bunch of doses for a couple of weeks and then for some people that seems to last a while um you know that's where I think I think the the psilocybin story for depression and the um and the MDMA story for PTSD seemed more interesting to me so for psilocybin what is the um rough percentages on and this would be relief not from trauma but from depression yeah yeah exactly so it's you know in open label studies it's closer to like half to two-thirds of people end up getting better depending upon their level of treatment resistance in the in the blinded trials it was more like a third or so of people you know experienced um relief and and this is you know this is a press release of of the data you know and so it hasn't uh to my knowledge it hasn't been published yet and so you I'm looking forward to say the full paper on that one but but it you know separated from from Placebo and looks you know looks pretty pretty good as well it looks like it's um you know the first of two trials that need to be done to get this thing um approved for treatment resistant depression and so um so that stuff looks looks good in terms of MDMA um for many years it was reported uh in the popular press and there was a paper publish 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 in in injected these monkeys because with not MDMA but with methamphetamine which is known to be neurotoxic so it was kind of a public admittance of oops or big like really big screw up so oops um but never a retraction and then never really a a publicly acknowledged um correction in the in the popular press so it seems that in the appropriate dosage range and with these one or two sessions my assumption and this again is an assumption um tell me if I'm right or wrong here is that MDMA is not neurotoxic for serotinergic neurons at appropriate Doses and with appropriate sourcing Etc so um it was an interesting study that um I think the guy's name is is Halper uh last name's Halper at um not Casey Halper not different different I think Joshua Halper I'm blanking on his first name but but um Casey hel was a guest on this podcast um and is a former colleague of ours at Stanford who unfortunately we lost to University of Pennsylvania and maybe someday we'll we'll bring him back yeah that's right so this this individual um you know received some NIH funding to actually Nida you know National Institute for drug abuse funding to um to explore uh individuals um of the Mormon faith in Utah who um who partake in only MDMA so um the way this works is that uh MDMA um happened kind of after a lot of the religious documents were were uh developed and so MDMA isn't on the prohibited drug list the ban substance ban substance list I have some good friends who are LDS I do I do as well um you know just a kind of set of facts you know and so um so these these folks um only use MDMA but they don't they're not you know the problem with with some people using drugs they're poly substance users right so you can't you can't say it's the MDMA if they've also taken other psychedelics and they've taken opiates and they've taken cocaine and you have this picture where you can't really tease out that problem but but with this right it was just individuals that were part of the Mormon faith and so they they were um kind of purists in the sense they only used MDMA and he confirmed all of that and um and it was a a brilliant study right because then he was able to go in and look at their cognitive profiles versus individuals of you know the same geography the same Faith all of that that happened to not take uh MDMA and found there were no neurocognitive uh differences so it it does that mean that it was not damaging it was not damaging it it's hard to know because to really do this study well you'd have to track these folks down before they ever took MDMA and do a pre-post and compare to people that didn't but you know this is about as good of a study as you can do uh in given the you know given the situation to be able to check this out um additionally when I was back in Charleston and working at the Medical University of South Carolina I one of my mentors um there Dr Wagner um was a nurse olist at MUSC and he was also the the neuropsychologist for the early MDMA trials and so he did all the neurocognitive batteries for individuals pre poost and similarly did not see any changes in neurocognitive profiles in a negative way and so you know there's there's data from experimental patients receiving this there's data from people that are chronic users you know who only take MDMA um and that that combination of of uh of data suggests that um there's no there's certainly uh no apparent risk in the kind of one to two to three dose range um it's it's probably unlikely that at least you know modest dose exposure over a lifetime doesn't appear to have a a profound neurocognitive um damaging effect yeah interesting yeah I know that um sourcing is key and we're here we're talking about clinical trials where Purity is assured um and you know years ago when so-called Raves were really popular maybe they're still popular never been been to one so I wouldn't know um if they're happening or not that's how um in the no I am but um it was clear that you know testing for Purity was important because that sometimes the drugs um are made such that there are contaminants like methamphetamine which we know is highly neurotoxic I think that one reason why people think that MDMA might be neurotoxic is the the uh reported um drop in energy or sort of feeling fatigued for a few days afterward I spoke to a physician colleague of ours who said that that uh very likely has something to do with the surgeon prolactin that arrives subsequent to the big dopamine surge that occurs in um in MDMA and I mention that because I know a number of people um talk about serotonin depletion after taking MDMA he has 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 Etc that eventually also wears off does that make sense to you as a physician yeah it makes sense I mean you know the difference between say MDMA and and psilocybin is that MDMA is kind of an amphetamine of sorts right so it has it has effects in dopamine and the uh in cybin you know pretty pretty neutral and you know 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 and that makes I haven't heard that story but that makes sense to me too since you mentioned siloc cybin let's talk a little bit about the neurochemistry of psilocybin as a serotonergic agent my understanding is it um operates on these uh is it the 5ht serotonin 2C receptor 2A excuse me 2A and and uh 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 um that there is increased con uh activation of lateral connection sort of broader areas of the brain being co-active than would normally occur maybe that explains some of the synesthesias you know seeing sounds and and hearing colors and the as the trivial example but rule breaking um within the mind um but then I've also heard um that perhaps it's lack of gating of sensory input so normally if I'm looking at something I'm not thinking about the sensation in my right toe unless it's irrelevant but if I'm thinking about the sensation in my right toe I'm generally not thinking about the truck around the corner so we have these attentional spotlights but that somehow it creates a more um it adds spotlights degates the thalamus degates the thalamus right through the reticular thalamic structure so um what is the evidence that any of that is true and are there other phenomena is there involvement of dorsolateral prefrontal Cortex that we aware of and what I'm really headed here in a few minutes is um you know is there a place for combining directed stimulation of the brain with psychedelics so that the effects of Serotonin could be um primarily within the structures that you know from your work to be relevant to to depression so what so but to simplify at first what's going on when one takes psilocybin and um why is it interesting in light of depression yeah definitely so um you David nut and Robin carard Harris's work around neuroimaging psychedelics they're kind of the some of the first folks to do that work and um you know and to their great surprise they thought there was going to be an increase in activity on psychedelics and what they found is the opposite right there's kind of a an overall decrease in the level of activity in the brain um with psychedelics but they they've also looked at connectivity and there's this kind of small world you know large World connectivity that you you think about and so you know small world meaning there's a lot there's kind of a much more kind of focused kind of cortical function or you know subcortical function or whatever it is and uh and what you see is a difference in that um in that level of Engagement of of brain regions the connectivity kind Global connectivity to your point kind of increases and so you know it's it's it's interesting you know I think to to kind of have a convergent theory on this it's still you know to be determined there's still a lot of work I think that needs to be done but um but it's certainly um suggestive that there's pretty profound changes in um in brain activity and brain connectivity after and what we found to be really interesting is the the anti-depressant effects of psilocybin have a particular um connectivity change that we also see with our our TMS approaches right and it's this connectivity between the subgenual anterior singulate and the default mode Network and so when we do this effective Stanford neurom modulation therapy stimulation we see a downregulation the connectivity between the negatively valanced mood state in the case of depressed individual in the self- representation of the brain and you see that same connectivity change occur post psilocybin you know suggesting there's a convergent mechanism and it makes sense right you've kind of got an overc connected negatively valanced system conflict system that's kind of you know kind of attached onto the self- representation and people feel stuck right and then when you when you do whatever you do that's effective it it un it unpairs those two systems I want to ask you about this phenomenon I've heard about during psilocybin Journeys I heard about this from um Dr Matthew Johnson who's running a lot of the clinical trials at John's Hopkins and uh 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 and is under the 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 actually gave an example of a patient who thought that um I think it was a she could move into the painting in the wall and obviously that wasn't true in the real world although it was true in her mind so they prevented her from doing that but that letting go that some how um untethering from the autonomic arousal that's occurring is important um which brings us back to this idea or me back to this idea of a like a seesaw where sort of letting go of the hinge just sort of you your heart rate's going up like Just Go With It in trust you know your heart rate's going down Just Go With It in trust you're thinking about uh something very powerful and depressing related to your childhood you're just supposed to go there without fear you're thinking about what's possible in terms of could happen so anyway you get the the picture can we think of that as as just the willingness to um do a million different variations on the the emotional Stroop task you know you will entertain the full full array of rules within your head and consider them or is there something more to it you know and again we're we're in the the outer margins of of understanding here but what are your thoughts on on this notion of letting go such a key variable for relief from depression during the Psychedelic Journey yeah so I'll I'll talk a little bit about something called exposure and response prevention therapy that that's a typical kind of gold standard treatment for OCD and it help to kind of you know help help this a little bit U conceptually and so what that really is it's a Letting Go therapy and so you know uh exposure response prevention the idea is that you have to expose the individual to something that that you know some something that triggers an obsession that they then want to do whatever the compulsion is right and so I'll give you you know my first exposure and response prevention patient when I was a resident um he was very concerned about um leaving the lights on this car and um and so what we did is we went out and we turned the lights on in his car and locked his door so his lights were on and he was super worried this going kill his battery um and we went and we spent an hour talking about things and we went back out to his car and his battery was fine and his lights were on and he cranked the car and we did it maybe one other time and then all of a sudden that was gone right and that's the idea is that you know you're essentially exposing and you want to do it at levels that are from an anxiety standpoint tolerable but exposing the person to something and then letting them see that that exposure ends up being fine right it ends up not causing the thing that they're that they end up being worried about um and so you know in some sense being in the Psychedelic State and we are all we are all taught at a level to to retain some level of control you know people have more or less of that but we're all effectively retaining some level of control we all wake up in the morning and put clothes on to go into society we all try to say you know most people try to say the right things they don't try to do things that are outside of cultural norms when they're in conversation and so we're we're constantly at some level controlling the situation that we're in and so it's you know it's not it makes a lot of sense that in that state part of the therapeutic effect that may be linked to the neural circuitry is this idea of Letting Go and essentially letting the system you know the network configuration maybe whatever it is um assume a state that you've essentially been fighting the whole time the same way that my OCD patient was fighting this uh 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 at some level letting go there meaning letting us just turn the lights on and him not do anything or letting go meaning in the Psychedelic State you're just letting go of whatever it is you're holding on to negatively balanced think thoughts about yourself in the in the um you know setting of having depression or you know reexperiencing a trauma um you know memory and allowing that to just happen and reeing it again through a Different Light um you know feels the same in the sense that that's allowing for whatever is going on with these psychedelic states to do whatever they do it's fascinating um you said exposure response therapy is the traditional name exposure response prevention prevention therapy done outside of this the Psychedelic Journey it's done outside the Psychedelic Journey but that idea of Letting Go is is you know present in both of those you know psychother kind of straight up totally sober non psychedelic non anything psycho manualized Psychotherapy that we know works really well for OCD and then you know in that psychedelic State and so people have done studies with with psilocybin and now there's some studies with MDMA trying to look at um you treating OCD um you know with the same sort of idea of letting go right and how do you how do you have an OCD patient kind of let go maybe even letting go of not washing their hands anymore you know kind of accepting the idea they're not going to get germs on their hands or whatever it is you know and so it's kind of part of that part and parcel that same sort of thinking when I was in college I developed a compulsive Superstition I'm not afraid to admit this I um somehow developed a knock on wood Superstition and I would uh I was actually kind of ashamed by of it because it rationally made no sense I'm I don't consider myself a superstitious person never was a superstitious kid you know I'd step on the sidewalk cracks i' C I'd walk under ladders you know even try to walk under a ladder um even though I don't suggest it um but somehow I picked this thing up and um and I used to sneak it at times I told my girlfriend at the time I had it in hopes that that would prevent me from doing it um and it's It's tricky sometimes it actually comes back where I think gosh I didn't say you know knock on wood I didn't knock on wood I hope that doesn't actually happen and it's and it's quote unquote crazy right but I crazy in the sense that it makes no sense rationally why the events would be linked and yet I think a lot of people out there do have in internal superstitions um maybe by talking about it now it'll it'll go away I just clearly I just need to challenge it um you know it's uh anyway I mention it because I um I consider myself you know generally rational person but um it's interesting how these motor patterns um get get activated and and this notional 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 jump the car but in my case I I need to think about what the ultimate fear is yeah and you know I I think uh I think a lot of people so there's it's interesting if you look at say the OCD scale or the depression scale or whatever we don't Define normal as zero we Define normal as some number range Above So zero to in the case of the Montgomery asberg depression rating scale one of the depression scales we use 10 right that's the normal noral range and so people can have some sadness and still be considered normal in the case of the OCD scale it's about the same tin right where we say it's kind of starts to be you know AB you know mildly abnormal or something and I always you know i' always tell the medical students look my friends that are surf instructors they're more like a zero on the ybg people that are professionals you know they're they're they're nonzero but you're it's still within the normal range and and especially you know in the in the case that you're talking about it doesn't sound like it got in your way it doesn't sound I mean you're obviously highly successful tenur professor at Stanford and do all the the great things that you do um and so it's it's very much kind of within the normal range and ex I think totally um totally assume that a lot of people have have these sorts of things and as long I think something as a psychiatric diagnosis when it severely impairs your ability to function and that's when we kind of cross that threshold but know I think that I think that a lot of people and it's great that you're bringing this up I mean it's very anti- stigmatizing that you're bringing 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 the reality is is a psychiatrist I talk to a lot of patients a lot of people that are you know family members you know um 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 we're just all we're all just kind of more predisposed not to talk about it but I think it's important to talk about it because I think that when we start all talking about it then we realize that we're all kind of in this together in a way and that we're and then some folks that you know have you know have to knock a hundred times we call that OCD or you know and they have all you know germ they're worried about germs and all these other things we call that OCD and then in that circumstance you know they need treatment right but but it is really on just like blood sugar just like blood pressure it's on a range you know and it's not just these discret diagnoses you have them or you don't it's good to know I actually feel some relief just hearing this because I am slightly I wouldn't say ashamed ier embarrassed by it but I I I offer it as a you know that you know it it is what it is as they say um and it certainly doesn't seem to hinder hinder my um my life much knock on wood um so if we could talk a bit about ibaan I I'm I don't know much about ibaan although anytime I hear the you know a I ne you know lidocaine iag I think of an anesthetic um uh and going to the dentist which is an unpleasant experience for me generally um what's what is ibigan um does this have anything to do with uh the so-called toad um you know people talk about smoking frog skin toad skin um what is it used for clinically is it legal in the US in ter as a clinical tool um who's using it and for what purposes if you could educate me on Iain I truly know nothing about it except I think I know how to spell it correct yeah that's fair yeah so so ibugan is a um is one of the alkaloids that you can extract from a um an iboga tree root bark that's um typically growing in the compan the in the country of gaban Africa so gaban is one of the West African countries kind of middle um of Africa the on the west coast and um and gaban is um has a a group of of folks um you know called the buti um it's a religious kind of sacramental group that sacramentally uses um iboga root bark as part of of that the sacrament um and they uh they've been using iboga root bark for a very long time um and it's it's you know part of the tradition there's a whole um there's a whole set of of kind of ceremony around it um if you're interested in this there's a book called breaking open the head by uh Daniel pinchbeck that goes goes through and talks about this um this whole process but essentially um the gabanes have been using this for a long time and um and it's a it's a kind of an atypical psychedelic it's not it's not a psychedelic that we normally think about with psilocybin and LSD where there are visual perceptual changes right so if you if you take psoc psilocybin or LSD what you what you experience is you experience these kind of visual um perceptual differences in the external world right and on enough LSD or Sol cybin an individual can actually perceive something visually in the external world that isn't there as we talked about earlier um ibigan doesn't do that ibigan does something different it it's kind of like have you ever seen Minority Report with you know the movie with Tom Cruz I think 15 or 20 years ago or something so it dates us a little bit but um it was this it was this movie where he would be able to go and see these kind of pre- crimes and he had this big you know this big screen where he could look at scenes from from time and like kind of go through that scene and see it and so what what individuals taking iigame 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 an ATT detached empathy and being able to see this as almost a third party even though they were there but they're able to see it you know as a third party so claudo nanho a psychiatrist from Argentina you know described this a lot of books that that he wrote and I think the 80s and 90s around this and so you know ibag again's been around for a long time Howard lotof American guy that brought it over from um from Africa he was a poly substance user used every drug you know on you know that he get his hands on took ibigan including a lot of other psychedelics by the way took ibigan and then never did another drug again supposedly because he had such a profound ibaan experience ibigan is in no way a recreational substance it's not a recreational substance if you want it to be a recreational substance because you're essentially having this what they call a Life review they also call it 10 years of psycho therapy in a night so these are the terminology that people talk about the issue how long does it last is it truly one night it's 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 it's definitely the longest acting psychedelic substance I know of and um and so people people you know will take this and they'll they'll have this re-evaluation of the a given memory and then as we were talking about earlier reconsolidate that memory again and then it seems to have you know an effect of of that reconsolidation process and so you know about five four or five years ago I was tapped by Rob Robert Minka one of the um you know senior neuroscientists we both know in the University he says well there's a you know there's an unnamed donor that's very interested in um in funding uh a group you know a scientific kind of open label study of um of the Navy Seals that have been going down to Mexico and taking uh ibigan and and also 5mt which I'll talk about in a second um to treat PTSD you know they claimed have traumatic brain injury um depression you know that whole constellation of symptoms you know and as as it was described to me um by various people that had done this by their spouses and and whatnot um you know John we'll just say John JN couldn't screw a light into a light like a light bulb into a light fixture right they just they were just so debilitated they couldn't do kind of simple tasks what we call activities of daily living and they were coming back and having these really dramatic improvements in uh in you know all aspects of of life and so you know we have over the last couple of years been able to um to do this first inhuman kind of full neurobiological clinical neuro cognitive evaluation of what iban is doing in this case in in Special Operations Special Forces individuals former Navy Seals former Army Rangers that that kind of crew of folks and look at the pre-post changes that we um that their experience to be able to totally quantitate all of that and so we've been able to capture all the clinical scales you know depression scales PTSD scales all that standard stuff neurocognitive batteries so how does your executive function work specifically how does your verbal memory all that and then neuroimaging and EEG so this will be the first human study of ioan for those and the reason why is because ibigan is kind of the both seemingly the most potent and most um and and mo seemingly to me at least most powerful um psychedelic but the 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 and reduce the risk quite a bit and that's what we we all did but um but but that's why people haven't really studied it as much um and it's it isn't as uh in addition there's like no nobody goes to a rave on IBU game there's no Recreation at all with this it's not fun it's people say that it's relieving but it's hard work right because yeah you're re you're reexamining things and um you know and so then so then we we we see these folks after and I I'll tell you you know we have't fully analyze the data yet but I'll tell you that you know from from what my folks are telling me it's pretty dramatic you know people come back and they're doing um they're doing a lot better they're doing a lot better and um nobody I'll knock on what nobody's had any sort of uh cardiac issue at all um in you know in the cohort that we've studied and um and they look a lot better and they feel a lot better too and uh and they describe these experien of being able to go back through and you know um soldiers experienced something called moral injury right where they maybe they accidentally blew something up and it had a kid in it or something like that you know you know if they're in Afghanistan or Iraq maybe you know child died on accident or maybe maybe a you know a civilian died or whatever it was right and they and they suffer these moral injuries as part of the job it's almost one of the kind of you know vocational risks they come back and say that they've they've they've um forgiven themselves you know which is which is huge right and and part of that is being able to see themsel in a different light and having empathy finally for themsel and being able to kind of have that experience of of forgiving and so so very cool the the study um you know what was happening was they were taking Ian and then taking something called 5mo DMT people call the Toad it's the Sonoran um River toad I think it's like you you can find these in Mexico find them in Ariz Iona um in in the back of the the the toad um produces something called 5 Meo DMT which is a um you know flavor of DMT that produces a particular psychedelic effect also used um as a Sacrament is it a dimethyl tryptamine is that it is it is a five U Meo dimethyl tryptamine so it's a kind of dimethyl tryptamine with with a kind of addition to it the the deal there is um that it lasts longer than traditional DMT you know it's like 20 minutes to 5 or three or whatever kind of thing and um and so then so these guys were taking IA and then they would take the 5o DMT after we had to kind of divorce those two things to be able to do the study and just understand what Iain was doing and they go back down a month later and they'll do the 5mo DMT so two completely separate sessions two two completely separate sessions and one quick question about Iva game before a bit more on 5mo DMT um is the Iain Journey guided or the person just closes their eyes and they just start falling into the back catalog of memories they have um a bunch of Preparatory sessions and then they have a bunch of sessions after that they kind of um they're able to kind of rehash things um during there's a sitter that sits there and kind of sits with them um and and and helps them out but it's not it's pretty the phenomenon of the drug seems to drive a lot of this right um and so a lot of it ends up being what we call supportive Psychotherapy you're just kind of being there and you know maybe you're holding the person's hand maybe you're just saying I'm here maybe whatever it is but you're making sure they know you're around but you're not really there's not really an interaction per se and then the whole kind of goal there is just to get to get folks to kind of go back through and reexamine these memories and ultimately look look like they re um reconsolidate them and um you know it's very interesting I mean there's a there's this kind of Tim as you said earlier Timothy L kind of sociocultural construct that ends up being overlaid over psychedelics and what I think is that if you rid yourself of all of those preconceived notions of what it is and isn't and the counterculture movement all that stuff that neither of us were ever involved in neither of us are ever partake in you know is is kind of straight scientists looking at this right if you can kind of rid yourself of all those social cultural constructions and then reexamine this these if we just discovered these today we would say that these sorts of drugs are a huge breakthrough in Psychiatry because they allow for us to do a lot of the sorts of things we've been thinking about with with ssris with psychotherapy but kind of combined right Psychotherapy plus plus drugs in a in a substance that kind of allows you to reexamine these things and so it's it's interesting it'll you know there's a lot to do to try to figure out if that's true you you know and and I can say that as it stands right now we don't know if it's that statement is true right there's a lot more work that needs to happen for that statement to be proven to be true but the hypothesis is if it is true then it's very likely that this will be seen as a breakthrough because it allows you to do these sorts of things that you can't do with normal waking consciousness but also why we have to really think about this and you know these drugs can't be recreational drugs they really shouldn't be recreational drugs right they're really too powerful to be used in the context of recreation because they can put you into these states and in the this generation of psychedelic researchers are really clear about that you know I think the 60s folks were not clear about that and they they felt like there was a this whole kind of cultural thing that was going on there but I think this cohort of individuals really understands that in order to really make this happen we have to understand that if you need a prescription for an SSRI which doesn't change your Consciousness a whole lot and we we're very worried about that and the doctor has to evaluate you for that every week that the idea that some of these substances would would go outside of of very strict medical supervision is uh is kind of properous actually it's kind of it's kind of a dumb moment I think for for all of medicine to say look we've you know if we're going to do this right we've got to do it in such a way that's so protected that's so safe that we make sure people know these things are not recreational and they're really for the pure purposes of of really powerfully changing um cognition for a while and letting people have these what seem to be you know relatively therapeutic States I think it's great that you're doing this study and along the lines of the sort of the early iterations of psychedelics and the counterculture of the 60s and 7s some of which took place like one floor of the Cuckoo's Nest I think is actually based on um the menow park VA which is you know in our neighborhood of Stanford um and things are quite a bit different now I know um you and I have spent some time with the operators and former operators at an event on last Veterans Day in fact um the so-called veterans solutions group that's um pioneering a lot of these psychedelic treatments for former special operators and current special operators and what's interesting to me about that is in contrast to the counterculture movement of the 60s and 70s um that room was filled with people that are very much of a structure the military right so it's no longer um considered leftwing right-wing anti-military pro-military here this isn't just but one group of people who's exploring psychedelics as a treatment for trauma and PTSD and other other things and of course you also have other domains of society looking at this and in fact there were it was really interesting because they were both um farle and far right politicians at at that event up on stage together talking about um in kind of lighter terms heart medicine but also talking about neurobiology and talk it was just fascinating from a from the perspective of somebody who's trying to learn about this stuff that psychedelic therapies no longer sit within the anti-establishment realm it's it's both it's it's it's independent of all that um certainly when people in the military are adopting it as a potential treatment again still under exploration but also under exploration at universities like Stanford and Johns Hopkins and UCSF and University College London and on and on um along the lines of tree barks and Toad skins um tell me about Iowaska um and as a plant uh you know it's intriguing um and is it a Ser Pro serotonergic um drug like psilocybin um and is it uh useful for the same sorts of conditions that we've talked about um thus far and if you could um perhaps tell me a little bit also about the um Brazilian prisoners study yeah yeah definitely iasa is another psychedelic it's used as a Sacrament um in um in Brazil and um in Peru and Ecuador and Colombia so a lot of the South American countries and um and what they do is they combine two plants together with where one plant of the two plant combination would effectively do nothing but the two plant combination together is capable of producing um producing this very profound psychedelic effect and what's really kind of curious is that there're as I understand at 10 to 20,000 plant species in the Amazon and somehow somebody tried them all combined these two plants together in certain proportionality in cooked this for five 10 hours to the point where you cook out the dimethyl tryptamine out of one of the plants and cook out the reversible monoamine oxidase inhibitor out of the other plant it's such a way that the reversible monoamine oxidase inhibitor prevents the the GI breakdown of the dimethyl tryptamine in such a way that it's then allowed to cross the bloodb brain barrier and get into the brain and if you didn't add the reversible mono me oxidase inhibitor plant derived into this combination then it would never cross the brain if you put people on a standard Psychiatry prescribed mono amune oxidase inhibitor that wasn't reversible you you'd throw them in serotonin syndrome right so this kind of like sweet spot that somehow iasa practitioners have found being able to get DMT into the brain from an oral source with this combination of am monoamine oxidase inhibitor is curious um and so that that substance has been explored as an anti-depressant agent and some Studies have looked at that it also seems to be very safe there um there's a there's a psychiatrist down at um UCLA Harbor who's done a lot of work with this where um where he's looked at children even that have been exposed to of small doses of iasa is is kind of a Sacrament within Amazonian tribes and found no neurocognitive effects no neurocognitive effects in adults and um and so it appears to be safe it's part of it's kind of part and brought into various religions including kind of merged with Catholicism in South America which is kind of very interesting and so you know in some sects of Catholicism in Brazil it's used as Sacrament during religious um ceremonies and so it became interesting to Brazilian researchers as to whether or not they could affect recidivism rates for prisoners in Brazilian prisons right so they gave half of the prisoners um you know some sort of inert substance and half of the prisoners a um aasa session and the the uh recidivism rate or the return to prison rate in the iasa exposed individuals was statistically significantly lower than the recidivism rate in in the uh in the control group suggesting that um you know whatever is going on there seems to have an effect on whatever drives criminal Behavior whatever criminal behavior that happened to be and I don't have the the details on the exact nature of the crime um you know no I am also in no way saying that we should just be giving psychedelics to to to folks in prison and all of that I think that that that that is a very edgy thing to do and probably not something that anybody should try but but it does it does kind of bring up this this curious question of of what is it about that that would drive people to um to change those behaviors and and why why do people make those behavioral decisions and and a lot of times if you look at prisons in the United States you know you say people say this what's the biggest mental health facility in the in the United States it's a prison yeah there's a a lot to unpack there for sure uh you know the homeless issue the prison issue um it does lead to something that I heard recently which is related to all this which is um cannabis um you know we hear a lot nowadays about uh people will say well it's safer than alcohol and we did an episode on alcohol that at least by my read of the literature um indeed alcohol does seem to be um quite bad for our health Beyond I think it's pretty clear that not drinking is better for your health than drinking at all and here I'm not trying to tell people what to do but that those are what the data say and forget the studies on red wine you'd have to drink so much red wine to get enough Resveratrol it's not even clear Resveratrol does anything useful anyway etc etc nonetheless cannabis is now available in a lot of very high potency forms people are vaping cannabis um people are smoking cannabis I certainly am not saying that cannabis is bad for people necessarily although I think children I would like hope that their brain development would be be completed first you know get to age 25 I know that sounds late um for a lot of people but um the THC obviously Taps into some um endogenous systems of of of OC cannaboid systems and is powerful and I've seen this uh this report that was in uh Lance at Psychiatry this last year that said that early use of potent cannabis meaning age 14 to 20 or so can potentially lead to an exacerbation of psychosis later in life and I actually put this out on social media and it sort of exploded um I didn't expect it to people were saying well that's not causal and obviously it's not causal um because people say well maybe people with psychotic Tendencies are seeking out cannabis although that's sort of a weak argument in in the sense that there's a at least a four times um 4X increase in these uh psychotic episodes for people later in life but what are your thoughts about cannabis because I do want to acknowledge that it does have medical benefits for certain things a pain chemotherapy um so by no means trying to to knock on cannabis in its appropriate medicinal use but what what should we think about cannabis in terms of this finding that it can exacerbate a psychosis in certain individuals yeah so I think you know there's this kind there's a couple of things right so cannabis is is multiple you know cannaboids right TC CBD CBN sativas and you know indicas yeah there's a lot there to unpack there's a there's a lot of there's but there are two there are two main you know kind of chemicals you think about and kind of how things are are are um are essentially bred right and so you know there's a lot of cannabis it's really bred to be very high very potent THC and there's a lot and there's cannabis where the THC is bred completely out so there's stories um you know from from Colorado right this this um strain of of cannabis that's THC free there's no THC at all and it's all CBD and they uh it's called Charlotte's Web um and a bunch of uh kids parents one kid and then kind of a string of parents after that moved to Colorado when cannabis was legal because legalized because CBD is anti-epileptic so CBD is also antis psychotic and so there have been a number of studies that if you give CBD at high doses it's antis psychotic in schizophrenic established schizophrenic patients the issue is that we've bred CBD out of marijuana selectively over time we've gotten very good at figuring out how to do that right conversely THC is pro psychotic and proepileptic right and so when you talk about is cannabis cause psychosis or does cannabis treat psychosis it appears to be more related to the proportions of CBD to T C than it does to the kind of idea of cannabis so for me there's a there's a and I have no stock in this or anything like that but there's a company called GW Pharmaceuticals and I haven't looked into them in a while but they um they they have a lot of clinical trials for something called draes syndrome which is a seizure disorder where kids seiz a whole lot Linux gasto syndrome which is a seizure disorder kids are seizing 300 times a day both of these are like kids are seizing so much they they're basically in a seizure or in the postal phase constantly and and they've failed everything they failed barbituates they failed bromides which we we just don't use anymore except in these cases because of the side effects and they'll give kids CBD and I think CBD is pretty safe drug compared to bromide right and so this idea that that CBD in a kid is actually safe it's it's it's a cannaboid but it's CBD and it's safe right and so that to me is is totally fine also giving CBD is an adjunctive treatment for for schizophrenia there have been some positive trials and negative trials in that but there seems to be no negative side effects it seems to reduce some of the metabolic syndrome issues in in uh folks with schizophrenia who are having side effects from the primary antis psychotic the the converse is there's clearly cases where people that are taking very high doses of THC become psychotic they get put into the psychiatric unit nothing happens other than they they kind of get the THC out of their system and then they resolve their psychosis right and so that that and you know a handful of people who have had you know seizures related to to high doses of THC and Syncopy and all sorts of things and so this idea that THC high doses of THC can be Pro psychotic is also not taking a shot at people that think that cannabis overall is a good thing it's just it it's just is what it is and the kind of pure if you I think if you zoom back and you say you're a true naturalist you're thinking about natural medicines in the world you should think well probably marijuana was balanced THC CBD at some point and then we just we humans messed with it right and and that most likely that was probably okay at some level and then we pushed it one way or another and what I mean by okay is in a 45-year-old it's okay kind of thing now what I think is going on with the with the kids with the teenagers is you've got prefrontal maturation right and then you're exposing them to a whole lot of high THC load and um while it's unclear if it's if it's cause or effect it's certainly in the picture and if I were a parent I wouldn't want my 16-year-old smoking marijuana if I were a parent and my 30-year-old otherwise healthy um totally fine you know whatever Banker lawyer kid decided to try marijuana for the first time I wouldn't scold them about it right so I think it's it's kind of a different thing right I would never want my up to 25 year-old just like you're saying before prefrontal maturation I would never want my kid to be exposed at all but it looks like accept in you know susceptible individuals that are susceptible to drug induced psychosis it looks like you know it's a it's a relatively safe thing past prefrontal maturation you know again I can't I'm not going to comment of cause and effect but but I would say that you know it doesn't if you're a parent it doesn't make much sense right it might you know you want to you never know what's ultimately going to hurt your kid I mean you know my wife's PR we were talking about this earlier my wife's pregnant now she she kind of avoids everything right rightfully so right this idea that we just we want to be careful when our children's brain are developing and I think that's really what you were saying and I think actually important the bigger question you asked which is relative risks of drugs is an interesting one so David nut published in I think it was in the Lancet I'll have to look it up but I think in the Lancet an article about relative drug risks for the person and for society and this was like he was on the the the UK's like British um drug uh policy group where essentially what he showed was if you took if you look at societal risk plus personal risk and you combine those two you know what drug is The Most Dangerous Drug in the world I'm gonna guess it's alcohol it's alcohol right behind heroin and cocaine and and somewhere in the middle is marijuana and right on the tail end on the other on the exact other end of this silos cybin is caffeine usually doesn't make the list I I it may have been on list it was if it was it was probably pretty close to psilocybin but somewhere in the middle was ketamine somewhere in the middle was was was um amphetamine somewhere in the you know a little closer to cocy I think was MDMA you know but but if it's it's this combined personal you know kind of world risk of these things and so alcohol makes it because there's a huge amount of personal risk and there's a huge amount of societal risk right drunk drivers kill x amount of kid you know people in the world fight sexual assaults all that yeah and then all the cancer and all that stuff and so it it beats out cocaine it beats out heroin it beats out all of these things and and yet um and yet we don't we don't as a culture for whatever reason we don't as a culture see it as a drug and that's the part that really baffles me you know and they serve it I mean this is no knock on Stanford at all of course I wouldn't do that this is every institution I've been to they serve alcohol at the graduate student events that's right you know they serve alcohol they we they do a happy hour I've never been a drinker I can take it or leave it so and I realize that some people they really enjoy alcohol you know um my former partner I mean she just was in that you know 10% or so of people who would have a glass of wine and just feel great and the second one feel great I I just want to take a nap after I I have a bit of alcohol so it never does much for me I always feel poisoned I feel lucky in that sense but it's it's unbelievable that it is so prevalent and it's it's just it's baked into the medical even Medical Institution they they'll pop a bottle of champagne to celebrate the opening of a hospital that's right that's right it's pretty crazy yeah no you're absolutely right you know I think I think what's going to happen but this is me you know looking at the crystal ball a little bit but I think what's going to happen is what happened with doctors and smoking so if you look at the 50s and 60s right there're all these pictures of doctors smoking cigarettes you know with patient are you know psychiatrist doing Psychotherapy and smoking a cigarette with the patient sitting on the couch you know surgeons smoking a cigarette in between cases they all these pictures of that right and now all of a sudden smoking's totally banned I think it's totally banned from most of Stanford campus my suspicion is as you're suggesting right you know this is everywhere and it's all kind of ubiquitous at some critical point some Tipping Point everybody's going to realize that just like with smoking we've got a red Hospital systems and universities of alcohol and at some point in 50 years it's my view that we'll look at back at these these scenarios that you're talking about and and be like you know what we uh we were foolish about this we I can't believe that we we gave people alcohol on the way you know when they graduated from whatever you know and I think we'll have a different take on it but it's going to take it's going to take a longer time I think I think people did a really good job tying smoking to lung cancer and it's like very a very simplistic story smoking lung cancer you know now you know as you know alcohol increases the risk of a lot of different cancers not so clear which one I mean there's like you know the kind of oral like the throat tongue cancer that's one breast cancer yeah breast cancer you know and so it's it's kind of it's a harder story to tell you know and I think that's why and everybody you know and then there's this whole it's you know my mom says this it's like I drank my glass of wine because my doctor told me it was heart healthy and we were talking about this and I try to no no no but but Dr so and so said it's heart healthy and so it ends up being this thing where like she's drinking alcohol because she thinks that it's it's good for her heart and um you know and it's it's hard I've had those conversations with her it's hard to untie that and I think that um yeah some point we're going to hit some some threshold moment and it'll be interesting if we really look at the data and really look at what's safe and not safe from purely from this analysis it kind of It kind of points to the right direction it's really interesting and also say nothing of poor judgment under the influence of alcohol I mean I I would venture that if we were to remove alcohol from University campuses watch watch the students are going to Lobby against me if I say this but if you were to remove alcohol from campuses I mean just think about the the what I suspect would be the Improvement in good decision making oh and and um that would occur or you know I've got stories from graduate school and it it it was very different you know 10 years ago there was a lot more alcohol consumption again that was never my thing but I know people who made really bad decisions yeah um in any case um there's a whole landscape there emerging I think you got your finger right on the pulse of it I I want to touch on something slightly different than what we've been talking about but definitely related to depression and this again is one of these intriguing but perplexing things which is that sleep deprivation yeah can improve symptoms of depression and yet I'm imp personally very familiar with the fact that if I don't sleep well for one night or don't sleep at all in fact I do have an ability to function pretty well the next day I'll do this non-sleep deep rest practice that I blab a lot about on the hubman Lab podcast which for me is tremendously restorative but I like a good night sleep I think everybody understands now thanks to the great work of Matthew Walker and others that really gotten out into the world saying look the foundation of mental health physical health and high performance if that's your thing being a functional human being is to try and get enough quality deep sleep at least 80% of the nights of your life if you can that's that's something to focus on just like good nutrition good just like exercise and social connection Etc so sleep deprivation we know can Imp in particular I think rapid eye movement components of sleep deprivation can improve the symptoms of depression and yet um being sleep deprived can also really disregulated our control of the autonomic system I noticed on night two or night three of poor sleep if I'm going through a stressful phase and that's happening all of a sudden my heart rate is chronically elevated my thought patterns become really disrupted I can't then exercise do I my decision- making is thrown off my emotionality is more lab out the hinge as we referring to it earlier feels Less in control uh under my control and maybe I wonder sometimes if I enter that state that you referred to earlier where the dorat prefrontal cortex is no longer leading the singulate but the singulate is now in charge the players are in charge of the coach yeah um not a good situation so I know you've done some work on sleep deprivation and light and effects um please tell us about that and please tell us about this triple therapy is that yeah yeah so friend of mine Greg Salem one another one of the professors at Stanford um was very interested in sleep he did a bunch of bunch of training in sleep before you went to medical school and um and got very interested in this idea that as you're saying if you sleep deprive somebody um One Night in just kind of an isolated single night at the at the end of that sleep deprivation they will have an anti-depressant effect but as soon as they fall asleep they lose it so if it's a depressed individual you can get them to be less depressed acutely soon as they fall asleep they wake up 8 hours later then they come they come back into the same level of depression and so the idea was that you needed to do some sort of circadian reset and that part of what part of what depression is is that it's a disregulated circadian system and so mentors of Mind say if you can just get the sleep better that's half the battle of dealing with depression because so many people have insomnia around depression and have a whole host of types of insomnia fall having a hard time falling asleep waking up in the middle of the night and waking up early are all symptoms of depression and so what this does is it sleep deprives the individual and then there's a certain calculation of shifting their phase and simultaneously exposing them to Bright Lights so that's the triple the phase shift the sleep deprivation and the bright light to try to get their circadian rhythm essentially the the theory is reentrained and so um you know in the in the trials that we've done and other trials um prior to ours and and and after you know it looked like there was a pretty pretty profound anti-depressant effect from this triple therap this triple therapy that seemed to be durable meaning durability is this term we use to say that not only can you get kind of Point Relief but that the relief ends up you know lasting what's important to know about this is like you shouldn't do this at home for sure this what you would need to do this with a professional because it's complicated it's not just one thing and it in sleep deprivation while it seems to be anti-depressant it's pro- anxiety so if you take a highly anxious person that's not depressed and you sleep deprive them they get profoundly anxious and so that's the other thing that that you have to really realize is that this is like everything else that I've talked about today all things that you you have to do under medical supervision but but curious right and and I think you know the question that always comes up is why isn't this used more and I think the reason is that there's not really a mechanism for or you know ultimately in in medicine as sad as it is you have to have a code to do a thing there has to be a code associated with a treatment and it's hard to figure out how to make a code for this and so I think that's part of it and so if if there's a way and somebody's got to kind of take that baton on that but if there's a way to make a code for this um you know I think you could you could actually you know turn it into something that was more widely widely utilized and you know dream up ways of how to how to integrate AI passive sensing all that stuff to really make that work um but I think that would be that would be the the idea that would be the trajectory I'd see so yeah yeah having a billable to Insurance code is is fundamental and a lot of listeners of this podcast I I think have a background in engineering science and we will put a link to that uh manuscript that talks about the triple therapy because here we're talking about one night sleep deprivation some timed light exposure to the eyes and and then shifting in the circadian clock things Central to the themes of this the podcast that come up often um I think for the typical person can we say uh that trying to get a regular light dark cycle and sleep Rhythm would be beneficial for overall mood regulation yeah I think for for the typical person um you know really really kind of re-regulating your sleep and and trying to get you know a good night sleep in which you fall asleep stay asleep wake up in a set time every morning is going to be pretty crucial um you know in mild depression I think that one has a lot of control over that as we were talking about earlier I think when you you hit some threshold in depression where things become kind of semi volitional and it's harder to kind of will yourself into that um there are therapies like um you know there there's a CBT for insomnia for instance where you can do cognitive behavioral therapy to help with insomnia sometimes people and I'm not I'm No Sleep expert that kind of pass this to Greg to fully talk about this but but um but some of what goes on that people with kind of milder insomnia experience is like blue light out of their computer and things like that that they so you can use like blue light blockers to to it tricks your your brain as you know better than me it tricks your brain to think that it's still light outside and so people will they'll have insomnia because their brain still thinks that it's light outside and then people will um you know the kind of strict CBT for sleep um you know uh therapists will say there are only two things that you should do in your bed and if you're under a certain age and and whatnot it's really one thing that you should do in your bed which is to sleep and um and and be with your partner uh right so those are those are kind of the two um the two things that you should do in a bedroom and that's really the only things that you should do in a bedroom if you're having sleep problems you shouldn't watch TV in a bedroom you shouldn't eat in the bedroom you shouldn't you know hang out keep the phone out of the bedroom keep the phone out of theed bedroom yeah yeah um we should get Greg Salem on the podcast we the I'll just mention for people that want to regulate their sleep we have a a sleep toolkit that's available as a downloadable PDF at huberman lab.com just go to the menu and a lot of the things in that toolkit are based on work from Stanford sleep Laboratories including Jamie zeiters and other lab um not aimed at depression specifically um listen uh Nolan Dr Williams uh this has been an amazing uh Voyage Through the circuitry of autonomic control this landscape of the prefrontal cortex is uh I find incredibly fascinating and I I just I'm going to start off by saying please do come back again and teach us more about that and your TMS work I before we wrap however I do want to give you the opportunity to talk about the saint study yeah is it Saint or Saints plural yeah it's Saint so so um Saint or what're we're calling it S&T now um saint has you know the intent was not to to to kind of connect it to religion but uh but we may have um accidentally done so and so we we abbreviated it to S&T for the for the subsequent trials which was initially Stanford accelerated intelligent neurom modulation therapy or now we're calling Stanford neurom modulation therapy but it's um the idea there which is a cool idea is that TMS um is a device that delivers um the delivers a treatment and the treatment is the protocol and the protocol is the stimulation parameter set in a specific brain region for a specific condition and so what's cool about neuromodulation whether it be trans cranial magnetic stimulation or trans cranial direct current stimulation or deep brain stimulation like what Casey hurn talked about you know um on another podcast is this idea that in all those cases the device self is a physical layer conduit of a stimulation protocol that's therapeutic for a given condition in a given brain region and so in the case of depression which we know the most about for with TMS we've been doing TMS studies for depression for you know since 1995 right in a clearance in 2000 um 2008 2009 and in that um in that time frame we were able to go from really knowing very little at all all about how to do something like this to getting an FDA clearance and and the way that it went down was that there were two groups studying um different components at NIH the first group was studying mood neuroanatomy on functional Imaging that was kind of the first generation of functional Imaging back then so pet scans um which are kind of metabolic scans um and then spec scans and the idea there was looking at activity and Metabolism in prefrontal cortex and what they found in these kind of more crude scans is a just general hypoactivity hypo metabolism the other group right upstairs at the National Institute for neurological diseases and stroke in inds they were looking at using TMS which had been around for 10 years and rep repetitively stimulating in motor cortex what they found was gosh we can get a readout in thumb um muscle movement amplitude that's really reproducible across people it's like you know universally reproducible and if we do certain stimulation approaches they are biologically active to either increase excitability I.E the thumb motion and a set intensity goes up the amount of amplitude goes up or inhibitory dep potentiating it goes down with other biological stimulation approaches then a third outcome which is important that it's inert it doesn't do either so you can have stimulation approaches that do one you know increase activity decrease activity or you know or are inert and so what they found was oh we can excite certain brain regions and my mentor Mark George said had this kind of aha moment where he said wow there's underactivity in prefrontal cortex and depression and we can increase activity using this thing that we know we can increase activity in motor cortex we just need to put it in the left or Catal prefrontal cortex and then they combined the two and started stimulating once a day in this kind of very abbreviated fashion and lo and behold some of those depression patients resolved their depression and back then and still today you can go and as a psychiatric patient stay at the National Institute of Mental Health and go through clinical trials to try to get treated and there were P patients who had been there for months and they were able to be discharged because their mood was better yeah and so this very crude approach where they were using ruler measurements or where dlpfc was and they were stimulating with devices that you needed to physically dunk the coil in an ice bath and with that they still were able to the kind of Genius of this Mark and others still be able to to create a a a purely engineered stimulation approach what's what's cool about that is that that they they kind of found two things right they found this one stimulation protocol that does have some anti-depressant effect it's it's limited it doesn't treat everybody it does have some anti-depressant effect and this bigger concept that a neuromodulation device is kind of like a pharmaceutical company for you right that in a given individual a TMS device or whatever neurom modulation device is able to generate to to you can create a stimulation approach that is specific to a given condition and specific to an individual and so the physical layer is just how you exert that similarly to how we make pharmaceutical drugs in a pharmaceutical company but the actual therapy itself is what you do where you do it and so what we learned from you know another 20 30 years of this is that you can modify the stimulation protocol in such a way where you can create a whole new treatment and put it through the same TMS device or thank God an evolved version of it where you don't have to dunk it nice baths and and it can actually really handle much more aggressive stimulation approaches and so in 2005 um a group published a neuron a paper demonstrating that if you if you stimulate with the hipocampal rhythms through a TMS coil you can excite the brain with memory rhythms and it'll last an hour so you can change cortical excitability in this thumb twitch for an hour sending 3 minutes of excitatory or 40 seconds in the case of inhibitory stimulation that mimics The hample rhythms so much more efficient than the original TMS approach approaches and so you know after that group tried to do it in this kind of six we schedule and after that you know and while they were doing that we decided gosh you know this problem I talked about at the beginning of the show where you have these you know this problem that we we don't have a treatment for people who are in these high Acuity psychiatric emergency States right this idea that we're going to engineer a treatment where we can reorganize the stimulation approach in time to be much more efficient by utilizing something called space learning theory and so you you probably know about the space learning theory the idea for the for the viewers is it's a simple psychological thing but we've also seen it in hippocampal slice sort of physiology too where if I'm cramming for a test what I do is I write out 60 note cards and I read each one for a minute until I get to the first note Cardon again and that's about an hour later right and we just we just intuitively do this we all we all all you know automatically do that and we we we Intuit it that because we know that what doesn't work is writing out one note card and looking at it over and over again nobody ever does that right you you know we we've all been in in graduate school medical school and we have these big stacks of note cards that space learning theory it's this idea that you need to see it about every hour to an hour and a half and that optimizes learning if you take the same stimulation approach that I'm talking about this Theta birth stimulation approach and you take a hippoc cample slice of a Mouse and you stimulate you you enlarge some dendritic spines and you prime some and then if you stimulate right after that you don't get any change it's called in Mass stimulation but if you wait about an hour to an hour and a half you get more dendritic spines enlarged and more primed which by the way also is what ketamine does it does it causes this dendritic spine enlargement and so you know what we found was is that the old way of doing TMS this idea of just doing it once a day day every day 5 days a week for six weeks didn't utilize the space learning theory it's like studying for a month or two just a little bit once a day like you remember some of that stuff but it's like not as potent as that week where you're kind of cramming right and what we realized is that if we could reorganize the stimulation in times that we took the whole six week course we actually figured out a way to do it in a day and then what we also figured out is that people were underdosing TMS because if you just keep going after 6 weeks out to month three four five more and more people got better so we figured out it's not just one day we're going to get five times the normal dose we're going have seven and a half months worth in five days using space learning theory so every hour every hour for 10 hours for five days for five days so it's a 50h hour Block it's 90 minutes of actual stimulation but spread out through the day in the same way of learning which is perfect for an impatient psychiatric unit right five days is manageable yeah you can get stimulation no nobody's ever dropped out by the schedule um they they they you know folks that want to do this want to do it so they'll do their 9 Minutes they'll go get breakfast they'll do their 9 Minutes they'll go see their therapist or whatever it is and so what we found um with this reorganization in in time of the stimulation dose and then the third component is we do resting state functional connectivity scans on everybody and we have ways now in the last 5 to 10 years of picking out that specific subgenual dlpfc subcircuit that I was talking about earlier that singulate dlpfc we can pick that out in every single one if you if you want to come to the lab we can we can find your dlpfc subgenual it's even more robust thanate too just while we're in there yeah if you want to we can we can move around your hypnotizability um and we can we can find that spot in each person and instead of finding the same spot on the skull we find the same spot on the brain and we can stimulate we do that every hour on the hour what we found what we've found is that folks will um will within one to five days you know in in more cases than not and depending upon if you're looking at this open label or in Trials somewhere between 60 and 90% of the time they will go into fullon remission in the sense they're totally normal from a mood standpoint at the End of This and like I said with variable dur durability so that's the part we have to figure out now about dosing and how to keep people well but for some people you know we've had four years of remission you know a year of remission and it's it's it's really that cramming of the test it's really that idea that you're laying in that information in the exact right spot and the the signal is a simple signal but it's a profound one which is turn on stay on remember to stay on you know that idea that you're you're sending this memory signal into the brain and you're doing it in such a way that you're telling the system you're kind of taking it out of the hippoc campus's hand your own hippoc campus's hand and you're sending the same signal the hippocampus normally signals out now you're sending that signal into the prefrontal cortex and kind of utilizing the brain's own communication style to get it to get out of the state and what's very cool about this is that um is that people when they when they kind of exit out of that they end up um they end up saying they don't have any any side effects from it and they feel back to normal like some people you know not everybody but there's a subsection of people that with with ssris where they'll say I kind of feel numb or I have gi side effects or I can't I can't you know I don't have the sexual interest that I used to have and that sort of thing you know not anything gets esized as I said earlier life-saving you know for a subsection of people these things really work but with this what you see is that people don't talk about any of that stuff and I think it's it's likely because you're tapping into that core circuitry and you're reversing it and you're doing it with a with a magnet that because it's a very profound electromagnet it's the same field strength as an MRI scanner it's able to induce a current in the brain in this focal targeted way without getting into the rest of the brain without getting into the rest of the body at all and just really kind of acting only on that circuitry that's involved incredible is the saint study still ongoing and if people are interested in potentially being um uh patients or subjects in the study uh can we provide them a portal link abs absolutely yeah so we have um now the the treatment um my some of my students went over to a company called Magnus medical um and they've been working on this they've got an FDA clearance now and um and now folks can get it through trials over the next couple of years because it's going to take some time for that company to to kind of get up and running and and get a um you know get a get a device and get the whole thing set up uh nationally but while that's all going on there's still about a th patients that need to be recruited across a bunch of different trials all over the country we'll take people from anywhere in the country we also have Partners in New York and San Diego and and other and soon to be South Carolina and other places where we can actually kind of you know my lab can help to kind of let people know where to go where they you know based off of where they're at in the US and get them access to being able to be in a trial and what we've tried to do is make it so that even if you get the you know 50/50 chance you're going to get the real deal or get the the the non-real deal but what we have figured out is a way to let everyone have access um if they if they got the not real deal version the kind of sham version or the fake version for the first part of the trial there are other trials where they can have access to the real version so essentially everybody eventually gets access to having the real version and so that's been a big thing for me is I I want everybody that comes through one of our trials to be able to have access I think think it's important while um while you know the companies doing what they're doing and what the labs doing and kind of nationally what you know other partner labs are doing well I can assure you you're gonna get some interest uh happy to happy to have it yeah thank you and listen thank you so much uh for taking us on this incredible Voyage Through the neuros circuitry underlying certain aspects of depression the coverage of the different types of depression the various uh therapeutic compounds how they work with we've um talked about a lot of things today and you you've shared so much knowledge and even as I say that I um I very much want to have you back to talk about many other things as well that we didn't have time to cover but also just really want to thank you for the work that you do I know we are colleagues but um you run an enormous laboratory enormous in my book 40 uh people is a is a big group uh very big group plus you're you're in the clinic you also have a a life uh of your own outside of work and to take the time to sit down with us and share all this knowledge that really is in service to mental health and and human feeling better and in fact avoiding often suicidal depression it's just incredible work and incredible generosity and just thank you so much oh thank you man I mean I I you know similarly I want to thank you for for what you're doing I mean I think I think that what you you know I've got a lot of friends uh folks that are not in the medical profession friends of mine uh you know one of my buddies who's a real estate agent who works with us uh who's a big big fan of your show and uh you know I told a couple people like that I was was coming on and um and they were like super stoked they're like we you know we watch we watch every show and um you know super excited to to to watch um mine and they they said something very important to me that you know you make this this complicated neuroscience and and kind of you know brain body science accessible you know in in a way that that few have a gift to do and I think that that's so so important and um and this show is doing so much to to help with science literacy and uh yeah appreciate you so well thank you I'm I'm gratified and honored uh by your statement and um I look forward to more thank you absolutely thank you thank you for joining me today for my discussion with Dr Nolan Williams I hope you found our discussion about psychedelics and other compounds about transcranial magnetic stimulation and about the treatments for depression in general to be a stimulating as I did if you'd like to learn more about the work being done in Dr Williams laboratory you can go to the brain stimulation laboratory website which is BS l. stanford.edu and there you have the opportunity to apply to be in one of the clinical trials for depression or other studies as well if you like to support the work being done in Dr Williams laboratory for the treatment of depression and other psychiatric disorders if you're learning from and are enjoying the hubman Lab podcast please subscribe to our YouTube channel that's a terrific zeroc cost way to support us in addition 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