Neuroscientist On How To Achieve A Calm State & Rewire An Anxious Brain | Nolan Williams

we basically live in a simulation that's created by our Biology one of the most troubling glitches in that Matrix is depression you're an intersection of something that I think is really important with transcranial magnetic stimulation and psychedelics what's happening what causes depression if you take somebody and you stress them in the scanner and you cause them to have this what they call social defeat stress right where you make them feel like they you know have this inability to control you know the external world this inability to this kind of sense or feeling of kind of social defeat in front of others that sort of thing then a certain brain region will go offline what brain region is called the left or cilateral prefrontal cortex so that's the region that's involved in control and perceptions of control control or perceptions of control yeah perceptions of control that brain region goes offline and you know the idea is that if you accumulate enough of that you're sending a signal into the system that basically trains a system like a memory to keep that system offline how are you knocking that out in the first place is that where we're using transcranial magnetic stimulation no so it's um it's essentially this idea that you know external stimuli you know feelings of loss of control feelings you know social humiliation whatever it is so you humiliate them while they're in the machine I don't I don't but there have been studies that uh the folks have done that right really use social defeat stressors and different through different tasks or watching videos you can make you can induce sadness and normal healthy controls so I could put you in the scanner and make you experience Sadness by playing like some of the you know most sadness inducing you know movies um that that people have ever seen so you can there are experimental ways of manipulating emotions even normal healthy controls you can do it in people with illness and you can accentuate it right you can make folks experience more symptoms even than their Baseline say depressive symptoms and those are ways of moving this network around and then understanding what it is so we've been doing that for a long time you know since the mid 90s one of my my mentor that developed the original transcranial magnetic stimulation approach was doing experiments in at the National Institute of Mental Health in the mid 90s and they were doing these sorts of emotional manipulation sadness induction sorts of manipulations and so you can take somebody who's not sad you can make them sad and then another brain region comes online that's called the sub-genial anterior cingulate so the left or lateral is kind of like right at the edge of your eyebrow go all the way up to you know in the natural hairline and that's about where that is the subgenial anterior cingulate is more in the kind of midline of the brain it's under the corpus callosum so it kind of sits um you know more kind of behind my two fingers here and that region will come online during sadness and you know in depressed individuals kind of stay online and so you know the the dynamic between those two brain regions normally is and it's this is a simplification this is more regions that are involved but you know the core of it is the left or scholateral clamps down on the subgenial anterior cingulate in the case of mood regulation there are other parts of the dorsolateral that'll clamp down on the in other parts of the cingulate for cognitive control like pure cognitive control but essentially those two brain networks those two brain regions within you know Associated brain Networks are involved in this this Dynamic of control and if your external environment is such that it essentially trains through kind of a essentially a memory process these systems to be pathologically in the case of dorsolateral turned down in the case is sub-genial turned up then it makes the individual much more likely to have a depressive episode and much more likely to stay in a depressive episode and so we know from many different you know kind of epidemic epidemiological studies that folks with early life trauma so they've had you know abuse you have physical abuse sexual emotional abuse as a kid they're much more likely to you know experience depression and have harder to treat depression we call treatment resistant depression right and so it's like those early life experiences wire and a certain risk within this network the good thing to kind of get to our you know your question earlier in our research is that we're able to with stimulation reverse that Dynamic and we're able to do it not just with depression but we can actually move around perceive control phenomenon in other parts of the dorsolateral cingulate combination so we've been able to there's a paper coming out soon where we were able to move around trade hypnotizability make people more likely to suggestion when you say move around you're saying increase by altering what brain regions or online or offline or active or inactive so interesting okay so I I really try to convey to people a very simple notion you are having a biological experience I've said a thousand times if there's going to be an Epitaph on My Grave I would want it to be that just a reminder to people that ultimately you exist inside of this simulation is a cool way to say it but your your brain one light never touches your brain and even if it did the portion of the Electoral magnetic spectrum that we perceive as like one millionth of what is actually there so the the thing that we think of as everything is this tiny tiny tiny tiny tiny fraction of what's actually there and so in confusing your perception for reality you don't realize how much your brain is basically communicating to you to say oh this thing is bad or this thing is good not necessarily objectively bad or good and for me the the big breakthrough in my my life came when I realized oh wow all everything that I'm worried about not being able to achieve in my life is comes down to brain plasticity can I get better yes or no if I can get better then it's just about applying as much energy as I can do we have limits of course and are all of our limits different yes but at least focusing on that and so getting into the brain science of how this actually worked ended up unlocking literally the rest of my life so when I try to explain to people and start Rich successful didn't have entrepreneur parents nothing I I started behind the eight ball as far as I'm concerned not look many people had it worse but I was not primed for the kind of success that I ended up having and when I look at why it really does trace back to the moment I decided to understand how the brain worked and that allowed me to start pulling whatever levers I could which you know 25 years ago when I really started thinking about this there weren't as many levers to pull on but now as we start looking at things like this it gets pretty interesting so one thing that I try to communicate to people is you be become what you repeat now I have a thesis on this that you as somebody who knows is far better than I want wherever I go wrong let me know your brain is just a caloric hog it it's just gobbling up resources from an evolutionary standpoint resources in the form of calories were very hard to come by so your brain was like all right look if you're gonna do anything a lot I'm gonna optimize that through a process called myelination and I'm going to wrap fatty tissue around the neurons that you fire in groups a lot and so those networks I think if I were going to use your language I would say circuits begin to form of these interconnected neurons where clusters whether it's depression-like symptoms oh you think this depressive thing a lot and so this brain region lights up this other one goes quiet I'm going to make that easier I'm going to almost make that your default and so because I have made the communication between those neurons Easier by myelinating them now that it just takes less caloric resources so now the state of being depression becomes the easiest calorically state for you to be in and that's how people end up just you repeat your way to Joy misery whatever yes totally and um you know there's a kind of an old Neuroscience saying what what uh fires together wires together which is essentially what you just said right and so the one caveat I think that I put in there is for a lot of folks you know especially the early life trauma folks it's it's less they're they're not in a place developmentally if they're a kid or their their cognitions are such that they even recognize that is that part of the problem they don't have a defense uh uh sort of thought-based defense mechanism to re contextualize sometimes they don't know what's what's abnormal and normal I mean if you're talking about a seven-year-old you know or a five-year-old it's hard right it's hard to have that level of context but yet they're exposed to these events that create perceptions of not having control that are probably you know in that setting accurate right if you're you know if you're if it's a kid experiencing some sort of abuse you know they don't have they don't have control you know and so that's why you know it kind of sets those some of those individuals up you know for future you know psychiatric illness some of those individuals have you know profound resilience you know and don't have that problem and we so there's been a big Focus to try to understand why some people are resilient they have these really bad early life you know trauma um experiences and then they go on to be okay even despite all of that others you know end up having you know a psychiatric diagnosis like depression what's cool I think and where you know we've really focused is this idea that just as you're pointing out that you can learn these things you know one way you know we can actually use neurostimulation techniques like non-invasive magnetic stimulation where people are awake and able to talk and watch television and all that stuff while this is going on and you can actually change you know the the brain you know connectivity in such a way where you could re-establish dominance of the right brain circuitry right you can turn on areas that you know maybe have spent you know that individual spent a long time you know kind of wired up in a certain way and you can change it so that they can actually clamp down um you know say the sadness region and have control over it and that's been what's been really striking for me as we've been doing a lot of these these experiments is that you know I have patients all the time say to me you know I I don't even understand how I'm able to do this right now because I've never been able to do it what's this whatever it is you know I had a um a patient who told me that she put her feet on the dashboard of the car every single time her significant other would drive her somewhere she was so afraid of getting in a car accident scream at him and be really anxious and really upset and like hated being in the car and a couple of days into our you know really rapid stimulation approach you know she knew that she was better because she was like she sat down in the car she started they started you know getting ready to go and then the significant others like you're not going to put your feet on the dashboard like this was like literally every time she get in the car and she's like I guess I don't need to whoa roll the window down and like let the wind come in you know what I mean so it's one of these things or you know patients who've come to me after you know receiving their their week of stimulation and they come in the next week and they say you know they told me before they started like all these psychotherapists told me I wasn't trying hard enough to do the Psychotherapy right and this weekend instead of like going to the beach or whatever you think they do now that they're feeling well they went and spent the weekend like reading the the cognitive behavioral therapy workbooks or the mindfulness workbooks or whatever and they're like yeah I just like whipped through it in two hours and did the whole workbook or whatever you know and you're like you know one like like how did you do that why did you do that you know and they're like because I I knew that I couldn't you know and it was something kind of inherently not fully functioning in my brain now that it is I need to prove to myself that I could do it which I thought was really like important and kind of anecdotally I saw enough of that you know to where it was like pretty it's been pretty clear to me that turning these systems on restores folks ability to have kind of full volition and be able to do you know have real control through choice to your point and I think kind of at the experiential level that is what's you know kind of functionally wrong with depression you know is in in the more kind of moderate to severe states that control is lost you know there's there's too much kind of repetitive behavior-based stuff of avoidance of pain or fear or whatever it is you know whoa okay so uh this is very interesting one thing that I'm particularly um interested in right now is AI and I've seen some of the AI um basically neural feedback setups that are being developed as you were talking I was like I have a hunch that what we're going to find over time is that this is really patterns of firing in the brain more than like one region it's going to be a symphony of things like there there are times where you want you know the the anxiety region to be active and the control center to be low but you you want those to be appropriate to the given situation and if I had to guess uh over time with AI we'll be able to start matching just like thousands tens of hundreds of thousands of people in these devices seeing the different setups that they're in so we know oh you're trying to learn right now being in the stressed out State that's not going to be optimal for learning you need to get into this state now if it's like biofeedback so I used to have a really bad problem with my it's actually manifesting my scalenes but it was a mid-back problem which I never would have guessed once I had a biofeedback device that would beep at me when I was firing my mid-back I learned to control my mid-back and then I could solve my problem with my scalenes super weird so I have a feeling it's going to be similar like if you can learn to control a region of the brain which I love saying things like this in front of people who can tell me if I'm crazy uh but I can I can actually capture the sense of Joy or Elation in like little small bits just by thinking about it by knowing what it's like and so I can like put myself in that state I can't take myself from like I'm legitimately depressed oh my God I'm on cloud nine but I can grab these little moments consciously on purpose and so my hope is that if you have a device that is able to track your brain waves and you know what your target brainwave pattern is and you can sort of grab you can train yourself to be in a certain a learning state or a joyful state or whatever and one does that sound crazy yeah so that to me is could be obviously we'd need data but that could be really transformational absolutely no I think the the um the you know technology kind of device space within mental health and brain health it's just you know right that we're kind of scratching the surface I mean the tech that we've been developing to your point is both a location derivation that's in you know individualize the person using machine learning but then also it's um a pattern of stimulation that in that case sends a message of turn on stay on remember to stay on in that brain region you know and essentially mimicking the sort of learning that you do with say note cards right you write out 60 note cards and you look at it one every minute or something and you get back to the first one about an hour later so we call space learning theory you don't like just write one out and look at it 50 times and set it down right like people don't do that they have a stack of note cards stimulation can be the same way you stimulate you give a certain amount of time for the dendritic spines to enlarge and Prime and about an hour later you stimulate again it emulates that same exposure re-exposure thing that you see with being exposed to a piece of information on the note card and then about an hour later you get back to that first note card you see it again these are not different right it's that idea of being able to kind of lock those memories in but it's very simplistic right we don't all we kind of know is we can turn this system on or off and kind of send signals in timed patterns to really reinforce turning it on or reinforce turning it off but to your point like ideas around using machine learning AI to develop new parameter sets that send more sophisticated signals send like a you know Morse code from the from the stimulation operator into the brain that's giving actual information um you know is going to be important and then to your point also learning how to pick this stuff up and have behavioral techniques to reinforce it before you have to get to a place where you're putting dense amounts of stimulation to the brain and we're calling it a diagnosis right like I think we're only doing that because we're not good at picking it up early enough and doing more preventative stuff so things get to some you know moment where people are not doing well and they're in high risk situation and then we you know and then we kind of you know jump in and treat them with these you know Technologies but my hope is that we figure out a way to kind of move it back to your point find less less and less invasive things that can train the brain in a way that you don't you kind of never get there or whatever you know but you know but that's the Hope yeah man if that ends up working out that'll that'll be transformative so I'm uh I am both terrified of AI and probably unreasonably optimistic uh I yeah I there's patterns patterns everything is patterns and if we can learn some of those patterns and can can lock into those patterns in a way that becomes useful I think this really gets interesting I think you were just talking about this but I wouldn't have known to pick up on it except for the fact that I've done a lot of research on you but um you were talking about Morse code like actually being able to play back into the brain and one thing I've heard you talk about is that we can and I don't know the method by which you do this but you can basically record biological patterns for a given State play that back to the brain in some way through uh frequency frequencies and the brain's like oh I know what to do with that frequency pattern tell me about that because it if what you're saying is that a lack of control and you may hate me putting these words in your mouth but if if a lack of control is depression that that the when you put somebody in the state where they feel they have no control it is the setup that leads you to sort of negatively interpret the world uh then being able to memorize the playback of the opposite of that lay it over the brain pull you out of that into a new region uh would be phenomenal yeah and that's yeah you you know you basically yeah you basically have it so I think we had a paper that came out in the proceedings the National Academy of Science like a month ago one of my um Superstar um was a postdoc and a in a research fellow within Psychiatry residency he's faculty now so he's already kind of moving up the food chain but um Anish Mitra and so he spent 10 years um looking at this phenomenon of in you know brain connectivity is reflected in the fluctuations of the of the blood within a given brain region and so that's reflective of electrical activity it's a surrogate of electrical activity that we can measure really easily with with MRI and so you know he was able to find that in brain regions that are connected where we kind of average over how the fluctuations you know um occur within time within that brain region that there's actually a subtle offset between a connected brain region suggesting causality so if this area is slightly in front of this area it's likely that this area is signaling to this area right and so what he found was that cingulate area and that dorsolateral area you know have a temporal offset from each other and in normal non-depressed individuals essentially everyone um the left or scholateral that control region is temporarily in front of the cingulate in depression some in this case 70 percent of the sample the cingulate was in front of the dorsolateral anterior insulin in the individuals that responded to our stimulation approach essentially all of them had this flip the people that didn't respond none of them had the flip and on the post scan it flipped back to normal on the people it had the abnormality BM begin with and had the clinically relevant change in their symptomatology and so what we call the other kind of interesting thing is what we call depression is probably a you know a combination of multiple things right and we saw this 100 years ago with with idiopathic Parkinson's disease what we think about is you know true to form Parkinson's right there's actually a bunch of other things that look like Parkinson's and you know historically they're all lumped together Lewy Body uh dementia Progressive super nuclear palsy um you know idiopathic Parkinson's disease you know other things all lumped together and then over time we figured out how to separate them based off of you know techniques of in this case you know being able to do kind of postmortem studies of people but you know in the case of depression I think we're going to use non-invasive biological techniques to say okay this group has this particular signaling abnormality in this group has something else you know and trying to kind of separate that out but at least in a sub-population of people to your point it's this flipping of the signal and so the kind of sadness region and areas around it are signaling to the the control region probably having dominance over it you're out there making a million decisions every single day and each pointless choice you have to make like what color socks to wear or what jacket to put on is just another distraction from the game-changing decisions that you should be focusing on Save the brain power and the hassle of choosing what shoes you wear with vessel vessi's shoes are made with a patented knit material that is both waterproof and breathable keeping your feet cool in the summer and warm in the winter and dry no matter what check out all of Bessie Styles at vesi.com impact and use code impact for 15 off your order simplify your life with Bessie yeah man perception is everything so going back to why we have such an epidemic of depression and why um kovid really kicked it off is this so out of control yeah so that makes sense to me in terms of why covid would exacerbate it I I have a broader Theory that I would love for you to dismantle and help make me smarter that I would have thought was true leading into covid and that is um Lisa Feldman Barrett is she at Stanford do you know she wrote a book called how emotions are made I don't remember now where she's from but um she talks about how the emotions we have we perceive as coming from our thoughts but in reality it's a Confluence of thoughts the body largely the gut and then the brain sort of going back and forth in this communication you sort of never know which started the whole conversation but they're going back and forth and the Brain will ultimately create a narrative about why you feel the way that you feel and having spent a lot of time looking at nutrition I think a lot about nutrition obviously the impact that that has on the gut than if the gut is involved in Emotion in communicating with the brain I was looking at the modern world going okay our diets are just absolute tragedies we no longer have to exercise to survive so now exercise becomes completely optional Modern Life especially with social media is pushing people into isolation even if you're around people you're emotionally distant you're emotionally isolated and so you start putting all of that together and everything just deranges just enough that um especially if you're already predisposed of this because of childhood trauma now you're just you're way out of whack but only some of that I would liken to control like Diet that's to me sort of a bodily communication that's microbes that are sort of derailing or you may also and this part I don't I don't have I don't even have another person that has said something along these lines that makes me think this but when I think about mitochondria mitochondrial dysfunction if there's any sort I mean there has to be signaling of some kind so it's like where are we picking up on that signaling is that also part of the body telling us that there's a problem and if your diet's off you're gonna feel in the gut and in the mitochondria so do you think any of that played into pre-covet and then kova just exacerbates it with control or is depression really just you feel out of control that's the pattern and when you have it you're in real trouble um I mean and that gets back to the you know the statement I said earlier around you know there are probably multiple things that kind of get lumped into depression right not everyone you know some people kind of are in an over control phenomenon you know so it's not everybody necessarily has this um has a kind of a perceived loss control necessarily right and that may be more of a problem of us being a kind of lumpers instead of Splitters on the diagnosis but to your question I mean it what's hard about um understanding any psychiatric condition is that you need to establish some level of causality right it's the reason why psychiatrists over here neurology is over here is because in neurology you know the the game is where's the lesion you know and in Psychiatry historically there is no lesion right there's no kind of lesion that we can pick up on on standard Imaging methodologies that are employed because the dysfunction just isn't tied to a lesion well it's electrical you know effectively so what we think about as a lesion really ends up being you know in the case of that paper I talked about earlier flipping of the signaling directionality it functions kind of like illusion so if you take people that have depression from a stroke and you look at you know you look at where all those Strokes fell on a common brain Atlas like functional Atlas um you know Mike Fox and others um at Harvard found that um you know brain lesions that are functionally connected to that same control region are um you know are associated with depression and and brain lesions that don't follow within a network that's connected to that control region don't have to you know those individuals on so if you saw if I had a stroke and you looked at it you would determine by the region of the brain that I had the stroke and whether I'm now at higher risk for a stroke related depression or not yeah so they I think they're doing those prospectively now but in a retrospective way at a group level you can put all those lesions in the brain and the vast majority of them would if you had depression from stroke would be functionally connected to that same control region and so you know it looks like a lot of what we think about as depression ends up being you know that sort of a problem but but to your point right it's it's a complicated it's a complicated thing right if you you know if you stimulate on the vagus nerve um in the you know in the neck um you can you know produce signals up into the brain and treat depression right and there's a huge medicare-funded study going on right now to start paying for something like that where you actually stimulate a cranial nerve you know that that also you know propagates down to the gut propagates to the heart you know and if you stimulate and go up it'll um you know it'll affect those same core brain regions to to your point the brain and the gut and the heart are all you know you know well interconnected and so you know causal mapping and understanding of some of the questions that you're talking about is exactly kind of the way to do it you know and you can actually it's not a hypothesis you can actually test it right because you can you can cause interruptions or you can accentuate signals in any of those spots and then see how it changes the mood you can do the same thing with functional you with neurostimulation either invasive or non-invasive you can look at the same sort of thing with lesions like stroke lesions and with all of that information we've been able to develop maps that tell us kind of what is connected to what and what systems are signaling but it's still really early days I mean I tell people this is like 1950s 1960s Cardiology you know it's it's not you know developed at the level where where there are 10 texts you know 10 chapters I'm sorry 10 volumes of a of a textbook you know like in cardiology where you see a rhythm on an EKG and you know exactly what it is what's causing it you know what it's called that whole thing like Psychiatry is very far away from that that reality but there's definite roads in the last 10 years to where we're headed in that direction there's a clear signal I think that we're we're gonna go there and that we're going to be able to map it out and to your point earlier about the you know where AI I think is really useful is that this is such a complicated you know process and it's so much more complex than just simply what's going on measurements in the heart but it's these complex Dynamics between the heart and the gut and the brain that it's going to take you know a lot of kind of dense data collection to really also understand at the behavioral level what's going on um you know I think covet exacerbated kind of a cultural you know problem that we're having around being separated being you know you know being on Facebook instead of seeing somebody in person that whole piece of things which also contributes to to depressed mood and then it kind of take away the control Factor take away the ability to to see people in person wearing masks being at home you know being kind of stuck at home for a period of time or whatever it is and uh I think that sense of control goes goes further and further down you know we think about depression like we think about you know how many fingers you have on your hand or something but it's actually on a it's on a gradient you know we just draw a line and say this is like the syndrome that is depression and below this it's normal but if you look at it like the scales that we use for what's normal people could be you know reasonably symptomatic you know at the high range of that you know so they'll still somebody can be what we call in remission or you know no depression and still have 10 points on a 60 point scale right and and I'd argue that actually like like most people aren't a zero you know most I'm not or not yeah I mean we see we see people I mean it was funny the other day one of one of the patients running for it through our trial um you know my wife works with me at Stanford too and she's a psychiatrist and runs a lot of the clinical operation and so cinemat you know one of the other guys that's working with me sent a message and said this patient's a zero and then like the conversation was oh how great would it be to be a zero because nobody as zero means you slept eight hours last night you fell asleep immediately you slept all through the night you woke up rested you're completely not anxious you're you're completely optimistic in a good mood and you you got up without any problem and you got going and you know so it's it's it's hard to you know when you get down to it I think a lot more people even than the percentages that we think about that are in true to form depressive episodes or having some you know kind of mild symptoms and you know the the number of those people that um you know a number of people that were experiencing those mild symptoms I think in covid probably went up too we don't track that but I think that would be my suspicion as well what's interesting and kind of you know one of my theories I think will happen in the future is just like with blood pressure and cholesterol and all these other things where we say oh this is the bad number and then we're gonna We shift it oh and we're now we're going to be more conservative this is actually the bad number and you need to have your LDL even lower or you need to have your blood pressure even lower or whatever it is I think that we're going to get to a place as we get better at this um tracking it and treating it that you know the number of what's acceptable what's normal or whatever may move a little bit too because I think that somebody on a 10 points on a 60 point scale that's that's probably not ideal either right you know I was gonna say I haven't been a zero since I was like nine yeah so yeah getting to a zero would be amazing in fact I have struggled pretty profoundly with anxiety uh part of why I came up with the thesis around diet was that was the Big Fix for me it didn't take me to a zero though I would say it it alleviated my symptoms by 70 it took it from completely unmanageable what the hell is going on in my life this is really a problem too okay back to you know where I've been since I was a little kid where I would say I'm probably more prone to anxiety than the average person but um from uh I don't need to take medication or anything like that so um that is the thought of being at a zero is like somebody saying that I could be a superhero so that would when I was researching you I was like yo transcranial magnetic stimulation is something I would very much like to try I want to do your five-day process I don't know how hard that is if that's like I can just roll up and we zap me or like yeah but that that would be crazy because I've told my wife when I'm when I'm anxious I feel like I'm mortal and when my anxiety is at a zero I truly feel like a superhero and it and it does happen every now and then I'll be just in a perfect zone of comfort where I'm supremely confident in my abilities and something the stakes are really low you know and it's like okay yeah this this is how I want to feel all the time and the fact that I almost never feel like that it's it's been sort of the Holy Grail of what I've been chasing since I started researching the brain and it's interesting because I never put my finger on control before but that really would be a very easy way to recontextualize what brain plasticity allowed me to believe in is that I controlled my future my future wasn't controlled by my current level of intellect which was my big struggle I didn't think I was smart enough to do the things I wanted to do and once I realized oh wait I can get better then it was like okay now I felt in control and I didn't conceive of it that way I just felt like there's something I can do but that's really really fascinating okay so keeping it um very tangible for people for a minute so covet hits people are getting isolated they are freaked out about what the future feels like they definitely feel completely out of control did you have a or do you have a best practices for people in hard times like that to avoid sliding into depression Yeah It's Tricky I mean I I think um you know the kind of standard answer there right would be that folks if they had a therapist to go and you know chat with a therapist about what's going on how how does how do we make therapy work for us is this cognitive behavioral therapy talk therapy yeah I think that's for all like a lot of the digital Therapeutics work that that folks have been trying to you know because therapists are hard to get there's you know many times you're paying out of pocket they're expensive in the you know the Bay Area I'm sure in La it's the same thing like it's you know it's a complicated process to get a hold of a therapist so trying to figure out ways to scale that through digital means makes a lot of sense you know there hasn't been a whole lot of preventative work that's been done in Psychiatry um you know it's mostly been you have you now have this diagnosis now we're going to start doing something I don't think that's the fault of any one um I don't think that's the fault of the field or anything it's just like it's hard enough to treat it when it gets to this point but I'd argue actually it may be better to um to you know try to intervene earlier we try to do this study with orthopedic surgery at Stanford it was just very hard to to coordinate and kind of figure out how to do it um you know with all everything else that was going on but people had motor vehicle accidents broke their leg or broke their hip or whatever they have this huge conversion rate to PTSD and depression later whoa yeah why PTSD they just went through a traumatic event with a car accident and they thought they may have died they may die you know in that that moment that they were you know head-to-head Collision or whatever it is you know and so they have these traumatic experiences and it's an opportunity to try to prevent to your point you know could you use brain stimulation to try to get in there and prevent this you know future um symptomatic event from happening um you know there's been some work we know that heart heart attacks myocardial infarctions you you know you have this post Mi depression risk you know and so there's been some work there trying to think about ssris and okay so hold on it do you think that that's happening because of the brain Heart Like physical connection so it's not a psychological thing if I'm terrified I had a heart attack this is Yo there's a real physiological connection between these two and they are communicating that something is bad and that leads to the depression yeah I mean that that'd be my suspicion like is that is that um counterintuitive for the field or is that like yeah everybody assumes that to be true um you know we've done some work on this there were a couple other people that have done work in this were actually like the stimulation approach that we're using you can decelerate the heart rate so we know actually that it's a direct connection because you decelerate the heart rate by starting at the brain yeah whoa so you stimulate here and you can very reproducibly drop the heart rate I we are mimicking a condition of all as well yeah so if you turn this system on it's involved in the parasympathetic control of the heart you kind of drop the heart rate right so you end up having a reduction of heart rate by toning up control which makes some level of sense because that's our parasympathetic system is set up to where you know we're perceiving that everything's okay and you know we're able to you know digest our food and have a lower heart rate you know and you know and counterbalanced by the sympathetic system which is this kind of fight or flight process right and so um so yeah so you can you can decelerate the heart rate from the brain um it's mechanistically I think there's been some work on this um you know as far as trying to understand exactly why that happens but it definitely happens I mean people that have heart attacks um have a much higher risk of post heart attack depression depression is now one of the four leading risk factors for having a heart attack I'm sorry why I mean it's just that two-way communication yeah I mean we don't know enough for me to be able to being depressed increases your risk of heart attack yes as much as diabetes is it ramping your heart rate over time or because I always think of a heart attack as being about an occlusion like blood has been blocked by physical blockage so is the in fact this is we're going to fractal here very fast uh there's two things now that are tied in my mind I'll let you tell me how we're going to tease them out so uh the fact that depression increases your risk of heart attack but that I assume heart attack has a physical reason for happening and is not purely psychological but maybe you're going to tell me this well I mean I don't think anything's you know we this kind of brain mind dualism thing it's like we've divorced these things that aren't really divorced conceptually you know Freud kind of started that process but it's not actually you know they're not actually separated right and so what what we feel and those negative emotions and all of that um or just play to your point playing playing out in brain networks that are ultimately connected to the heart we know if we can if we can slow the heart rate down by turning this region up they're connected so whatever if if this isn't sending it signaling down to the heart then this the heart's not receiving a signal that it normally receives in Wellness now why from from the Vegas into the heart and the coronary is why that happens we don't know but it definitely happens there's something called takasubo's cardiomopathy so that's another interesting I was going to say that yeah you know about this yeah never heard of this in my life I don't even I don't even know what you just said yeah so it's it's um it's this Japanese word I it and it's uh I think it's like um I I don't remember the translation I feel like it's like some sort of basket or something but um but essentially it's a ballooning of the heart and so it can happen um from a stroke in the brain in the same same connected brain regions it can also it's also called the broken heart disease it can happen with an intense emotional experience yeah so when you say it's ballooning is it adding muscle fiber to the heart like the heart kind of dilates and they go into heart failure so you have to like do all sorts of heart failure Maneuvers dilates meaning the empty space grows larger yeah you have a cardiomyopathy yeah you have this you know problem with your heart pumping and you can actually get that just from a a what we would sort of colloquially call a broken heart yeah I mean it's extremely rare like for listeners like like it's a very unlikely event you know it doesn't happen very often but if you there was a study that came out a couple of years ago that I think 85 or 90 of the people that had it had a pre-existing psychiatric diagnosis right and then they had some you know somebody died or something like that a major life stressor and then all of a sudden they ended up you know on the cardiac unit with takasubos and so yes you can have physical things that happen in the Heart from things that are happening in your brain and the idea that somehow the a psychiatric illness is less real just like that's like a fiction right like it's just as real right it you you wouldn't be able to have a post-stroke depression if it wasn't just as wired in as having a post-stroke hemiparesis where you can't move your arm it's just that they're they're more complex systems right and there's a level of semi volitionality to it right like I'm depressed but in certain circumstances I can house is on fire I can run out of the house even if I feel like I can't really move or do much you know in the extreme case of Catatonia you can't but most people depression you know can can amount enough you know energy to be able to leave a burning building or something like that and they're kind of back to their their base State and so I think folks you you know it's it's very wired in it's very biological it's just as I think just as biological as many other things that we think about as like purely biological it's just a matter of really Discovery and understanding and coming up with tools so that's what we've been focused on is just like how do we build how do we build tools and I'm a very agnostic tool Builder I I really don't care like what the social perception of the tool is I really don't care what you know um which is what we got a psychedelics you know study ketamine do nerve stimulation like if if it's safe for the patient and it's acceptable for the patient and it's something that I would suggest to my mother brother spouse then um you know and the risk benefit is right um Do no harm and all those things right then we'll look at it you know we don't have any um we don't have any kind of off limits because I have some conceptual problem with something you know um and so I think that's that's been very useful and it's given us the ability to ask a lot of interesting questions um because we're willing to go into these spaces that um you know not not so many people are willing to go in within the mental health kind of research space so yeah I'm I am incredibly uh eager to pursue that path and figure out um what theory LED you to psychedelics but first there's another thing that feels related to the um the emotional trauma creating heart trauma connection that I wanted to talk about which is what you call Psychiatry 3.0 so this idea that um in fact if you don't mind walk people through Psychiatry one two and now 3.0 um yeah definitely and this is uh a concept you know not just for me buddy of mine Jonathan downers been talking about this as well it's a it's a concept of um you know we've basically had three major epochs within Psychiatry and kind of modern modern Psychiatry with you know Freud Ford um the first one being that the problem is inherently a Content problem content of your thoughts yeah and Psychotherapy effectively is you know the ability to you know to introduce different ways of looking at the information or different frame points of view or framing of it or introducing new relationships in the case of the their patient therapist relationship where the dynamic changes so the person can have insights you know that's that's basically Psychiatry one 1.0 the kind of transition between 1.0 which is psychotherapy focused in 2.0 which is you know psychopharmacology focused there was a major kind of historical issue there and there were two camps you know there were the analysts psychotherapists and there was psychopharmacol psychopharmacologists and that happened over you know the 50s 60s 70s even into you know into the 80s and some of this still extends in today and this is going to be ssris and things like that yeah you know like Thorazine the early antipsychotics that took the schizophrenic patient out of long-term care so there's a big Exodus of patience um you know early monoamine oxidase Inhibitors and tricyclic drugs that were the precursors to ssris those drugs really you know kind of um Jarred the idea that it was totally content because if you can just take a pill and then all of a sudden to kind of your point the person has a total change in perspective how could that be if it's a Content problem um and then what I would say Psychiatry 3.0 kind of circuit-based thinking about you know mental illness aligns it with neurology neurosurgery you know in all of those Specialties into kind of a common circuit language you know I can have I'm trained as a psychiatrist and neurologist but you know kind of I can have a psychiatric Dialogue on the circuit level with and you know fellow neurologist or a neurosurgeon then you're speaking the same language and we've never really been there we haven't been there since pre-fraud you know with the kind of discussion around what the problem is with a patient with psychiatric illness with epilepsy whatever and so what's useful about Psychiatry 3.0 is that it it Embraces the first two right because it takes the first two into account and says okay if you're Psychotherapy or if you're drug moves this circuit then and you know our stimulation moves the circuit we can have a um what we what we would call a modality independent kind of predictive biomarker right something like this or you know area that changes or however you want to think about it and so it's more about the end product of the kind of biological change and that as a tool maker and as somebody who thinks a lot about making you know building tools and building measurements so those tools you know it makes you very agnostic like how do we figure out what what the problem is and then how do we move the problem circuitry around such that we understand we can even further confirm it and then it's just a simple thing of does this move that circuit you know and it gets us out of all these theories and stuff which I'm less inclined to you know necessarily be thinking about you know I'm much more just trying to figure this out and I think that's what um that's what Psychiatry 3.0 effectively is is the ability to develop a circuit-based understanding and then develop new treatments based off of circuit measures and then then think about the existing treatments based off of those same circuit measures and really get us away from the you know the negative Framing and Psychiatry 1.0 was the framing of the schizophrenogenic mother you know this whole idea that somehow you're parenting a lot of schizophrenia you know that person's parent LED them to develop schizophrenia which has been totally debunked right interesting so what was that original Theory yeah no there's a you know kind of over controlling mother you know and and all that sort of thing and then all of a sudden this patient had you know had schizophrenia and all and a lot of do you think there's anything in the wives tale of that that it's uh early trauma you feel out of control because the mother's controlling you so It ultimately it ends up being a circuit thing because my my next question in understanding the circuits is is the circuit the manifestation of another root cause or is the circuit the root cause and I couldn't do anything to influence it because I can influence it from the outside so it seems like if I can fix it from the outside I can probably break it oh yeah from the outside and certainly if you let me control diet and things like that I can probably really do some damage so I'm curious I get it that it isn't just mom is what made me this but is there some element of what they're groping for is that person with a mom that was that unhinged they're probably this cascading set of problems that are relatively predictable yeah I mean you know that particular idea has been debunked you know the the next thing I was going to say was this you know chemical imbalance kind of idea which has essentially been debunked the idea that or wait I think we shouldn't blow past that because even for me that stops me so you're saying Psychiatry 2.0 uh this is a serotonin imbalance false we've it's it's not a it's not a problem where there isn't you know the messaging history Berkeley has been there isn't enough your brain is faulty because there isn't enough of external transmitter in place and then therefore you need this drug and it's not really you know there's no evidence of that right um and so we've known yeah so but to plant a flag which I'd love you to speak to uh ssris selective serotonin reuptake inhibitor they work they do some percentage of people but it isn't because of the way that it's balancing your serotonin is that the yeah so the idea I mean what we think is really going on there because it you know as you know it takes kind of a while for it to work a month two months whatever is that it's actually upregulating plasticity to your point right and specifically bdnf yeah and so for people that don't know do you have brain derived neurotrophic Factor yeah so it's just like a brain you know kind of growth promoting Factor right and so you know it's probably more like that or more like it's having an interaction with some of the you know kind of dendritic spines that sort of thing much less about acutely up regulating serotonin because if it if it worked like that then it would work in a day or two days or three days right it actually takes time for it to work because there's something else um more complex going on and you know the the problem at a fundamental level is you put a drug in your body that upregulates also to your point earlier GI serotonin like gut serotonin and all that we don't have conclusive human studies saying this is how this works for ssris we've done that with ketamine right where you know my lab in collaboration with Alan chatsburg and Boris Heifetz at Stanford um then to my knowledge the only study that's totally blocked an antidepressant effect and that was with ketamine where we were able to use a Opia blocker and actually block the antidepressant effects totally of ketamine with with co-administration of an opiate blocker when you give somebody that same person ketamine with with a placebo pill they have a they have a perfectly good you know remission from ketamine so what I'm drawing from that is that ketamine is not working at the disassociative level it's working at the opiate level it's the opiate level is necessary it may not be sufficient but it's necessary you know and those people had the same amount of dissociation when they had the Naltrexone so it's that's not sufficient the Naltrexone being the thing that blocked the opiate yeah that is very interesting yeah but to get back to the SSRI thing you know I think that the big messaging there which I think you know the field is known for a long time but I think optically there's been over the last couple of years a real intent to walk back from is that there's some missing thing in your brain that the the Pharma is somehow gonna you know that these ssris or whatever it is are gonna replace then I'd argue that the neurostimulation work that we're doing even further accentuates that if depression as a serotonin problem in that way stimulation shouldn't be the answer right you don't it'd only be replacement of of you know um neurotransmitters that are lacking or whatever right it's this idea that it's really a circuit problem and that's kind of what Psychiatry 3.0 gets into now stimulation of circuits releases neurotransmitters so it's not it's not divorced from that idea it's just much more complicated than that idea but also empowering because it doesn't seem like you need any of that stuff in your system to get better you can get better without any of it in your system it really it's just really about engaging the brain circuitry that's involved so yeah I think you know each each era kind of debunked the last era and re-contextualized the last era to understand it more but it's not kicking any treatments out to your point as to surprise have saved lots of lives they're you know you introduced an SSRI into a country in the suicide rates go down you know so we know that that those drugs you know do um you know do have an effect the issue ultimately ends up being that not everybody responds to them what we call treatment resistance or hard to treat depression or whatever term you want to use and in those individuals those are the individuals that we study we don't study treatment naive people those are do you have any sense of what the treatment resistant people have in common yeah that's part of what we're trying to figure out now some of that flipping of the signal that I was talking about earlier is one potential how easy it is to flip the signal for them oh just the fact that it's flipped you know we don't know we know in a highly treatment resistant population that most of them had it but going back and looking actually at the broader treatment naive depressive population understand that um you know to understand it you know in the context of people that are treatment resistant versus treatment responding with a given oral antidepressant you know um you know Leanne Williams and others have been trying to look at that as it relates to kind of earlier stage treatments and how to do predictions with brain brain circuitry but it's you know it's a it's a very hard problem to solve because we're we don't know how the treatments work and we you know or at least the oral antidepressants we don't fully know how they work and we don't fully know in a given individual what the brain's circuitry differences are and so you're you're kind of you have two variables that aren't well controlled and so that's why we've focused primarily on things like stimulation where you can say okay I'm stimulating here I I know this isn't going into the rest of my brain I know it isn't going into my body I'm just stimulating here then I'm trying to figure out what's different about the people that get well from just stimulating here versus the people that don't get well it controls a lot more of it so that you can derive some sort of answers in humans in mice we have a lot of really cool science around that but you know Translating that it's been hard you know as far as drug effects and all that so man one thing I'd be very curious to see people look at would be bdnf and specifically bdnf and recidivism so as you're talking about it one of the things that if somebody came to me and they said hey I'm depressed the first thing I'm going to say is get your diet and under control meaning basically don't need sugar Whole Foods and then exercise now exercise I never really knew I have no idea why it works but certainly exercise spikes beat ANF I've heard bdnf referred to as Miracle Grow for the brain and if what this is and the reason I I would love to see it looked at with recidivism so let's say somebody does your five-day protocol so for people that haven't sort of put it together yet you have transcranial magnetic stimulation you put a device in the head that zaps them basically gets the circuits to go in the right order again so we're doing that but then my question is at the end of the five days what do the people have in common where that lasts for a long time and what do the people have in common where that falls off really fast now I have no idea but this at least would be testable is what are the either the bdnf response rate to the treatment or the Baseline levels of bdnf like are they bdnf super producers low they're probably low already or they wouldn't be in the study if my hypothesis is correct but then as we test them we can see like of that population like which like pumps that harder which lower and then if the people that were in the the responder bdnf group meaning they they create more of it if they had a longer shelf life of efficacy of the protocol then it's like oh maybe there's something there right that's really interesting that would certainly explain because it's my understanding I could be wrong about this but it's my understanding that uh exercise has a higher efficacy rate than ssris is that true um you'd have to look I'd have to look at the study I mean I think that there's definitely um in mild kind of mild even maybe moderate depression there's good evidence that exercise is very effective you know aerobic exercise more than weightlifting um to I haven't seen you know there haven't been any studies at scale you know there's it's usually like single site studies sort of thing and they're comparing like a standard treatment versus um you know one exercise regimen I'm not aware of multiple different you may have this study at your fingertips but multiple different exercise regiment regimens versus say a standard treatment like an oral um antidepressants I don't have it at my fingertips but that is a very worthy thing to look into I'd be super curious to see what that is the other thing about exercise so this goes into your Psychiatry 1.0 2.0 3.0 so if content is part of the problem it just it's not sufficient to explain the phenomena uh if I were if I really wanted someone to feel good about themselves like I literally just had a woman come to me she was really upset she had just had she got scammed basically and lost I don't know if everything but lost a lot and was at a dark place in her career also got scammed and so she was just like really down on herself yeah and I was like look if I had just lost everything the fir this is so weird I'm putting things together in real time thank you very much uh what what I said there is if I lost everything the first thing I would do is start working out because when you work out you realize you have complete control yeah over your body over what you eat over the way you look how you feel which again man you really put something together for me uh so that is interesting so working out will make you feel better about yourself one because you'll just start improving two you have control and that sense of like I can do the right things and I can end up in a better situation I can change the way I look which hey people can I'm agnostic like like you're agnostic about what the tool ends up being I I'm agnostic as to why looking good makes people feel better but it does so you can whine and cry that people shouldn't want their ass to look great in jeans but it is super motivating for humans um man that's interesting I will be very curious to see what comes of all that there was some studies where they Botox gilbeller right here this muscle here and uh treat depression because they can't scowl yeah I mean well I mean that's that's one idea right is that if you you know there's some feedback kind of where the more you smile the better you feel you know that sort of thing and if you can block kind of frown muscles Maybe you know and these things are you know kind of wired all the way back um into emotion circuitry so it it makes some sense that um you know that intervening even in those places would make sense to have a mood improving effect but still kind of grounded in this idea of it being ultimately seeable within the brain circuitry you know that idea of the expression you wear on your face controlling your emotions is one of the things that got me to start saying to myself at first you're having a biological experience was um my I I work a lot and this was also true when I was younger and my wife and I were just married and we would inevitably get in arguments on Saturday it was like the only day that we had to spend together yeah and so I I am slow to anger but once I get angry it's not as true anymore but it used to be once I got angry I would stay angry for a very long time so I ended up writing this note and giving it to my wife and I said the next time I get mad just read me this letter and in the letter I said hey me it's me there there there's no ulterior motive here you know that if you stay mad all day you're gonna regret this you've never once stayed mad and been like I'm so glad I was mad all day uh so what I want you to do right now is laugh out loud because you know that if you force yourself to because it's from that study where they put a pencil in your mouth and you bite down and it sort of forces you into this faux smile yeah and I would not be surprised if there's a replication crisis around that but laughing for sure will change your neurochemistry and so I did it she only had to read me the letter once because when I burst into laughter I it changed my neurochemistry so rapidly partly because I just felt ridiculous but in an amusing way and it changed my neurochemistry so fast and so profoundly that I was like oh my God now at the time what I said to myself is you're just a neurochemical processing plant now maybe I'm just a circuitry or circuit board and you know I'm turning on the right circuits but that was like whoa that little thing has had such a big impact on my marriage that realizing how by manipulating my face I can make myself feel differently that's just weird to me but it's so useful yeah I mean I think that yeah we're this reverberating system on itself right and if you can impact some aspect of it then you can change the system and so it makes a lot of sense that yeah those are essentially um you know psychotherapeutic techniques in in many ways you know like a CBT sort of technique so yeah that's awesome now when you're not on camera do you have a secret hypothesis about how this all adds up from a root cause perspective like what is all of this I know you need data and I know you don't nobody knows right now but do you have a sort of mental map in your brain that you know will probably get debunked over time but that anchors you to what you look at next one of the most provocative papers that's come out over the last you know couple of years as it relates to thinking about psychiatric illness and serotonin and that whole story is this um this paper that came out of UC Davis a couple of months ago in science where they they showed that in um if you were to kind of agonize the five eight the intracellular 5-ht2a receptors um where the neurons you're able to produce changes in dendritic spine um and producing dendritic spine enlargement um but you know they weren't able to see that with extracellular 5-ht2a receptors we think about these as serotonin receptors but the problem with that kind of conceptualization of them is that serotonin doesn't cross through the cell membrane so it doesn't seem to get into The 5ht2a receptors that are intracellular and agonize them because they're not lipophilic enough and so the substances that do cross that are lipophilic and seemingly agonize these intracellular receptors the only ones that seem to be responsible for producing these dendritic spine enlargements that we think are probably linked to antidepressant effects are psychedelic compounds you know and folks have over time theorized although this is completely unproven um that the brain actually has its own endogenous at least dimethyltryptamine production I've heard that right and um there have been a number of animal human studies and epilepsy patients and CSF and all this stuff trying to trying to look at that none of it's been particularly conclusive but it's interesting right why would you have a receptor that we were thinking about as a serotonin receptor in a place that's inaccessible to serotonin and you end up you know is that is that like a vestigial receptor right like our appendix or tonsils or whatever it's just vestigial and it's not you know nothing endogenously activates it which is probably the least provocative thing to think about if that science paper replicates and that's a real that's a real you know consistent finding um if if we endogenously make DMT that's kind of wild right you know because it's a schedule on substance like it's something that that we you know that U.S government officials have blocked us from getting you know from a plant but if the brain makes it it kind of turns that whole thing on its head don't we also make opioids and cannabinoids yeah so certainly the they have a long history of blocking things that we already make in the body yeah that's fair uh okay that's super interesting so I'm gonna put it in my words so there is potentially a receptor in the brain that is designed for psychedelics at least some subset of what we think of as psychedelics it's yeah I mean it's yeah and that would be the third idea is that it's there because of some exogenous use yeah it's definitely I wasn't even thinking about that so that from an evolutionary standpoint is possible that we pass through a period where use was common enough that the brain evolved to use it for lack of a better word yeah that would be the third idea and and you know the the number two and number three obviously very provocative but it's not really explainable that this is It's not and can we see have has there been any study done where we give people a psychedelic and then look at if it's binding to those receptors yeah that was part of what the UC Davis folks were doing so they see it it is happening yeah yeah and and um you know only dendritic spines do grow as a result yep yeah and and you can get it if you make if you kind of um so the experiment that was interesting that they did was they also you know used chemical agents to make the cell membrane more permeable something that you couldn't do with a human brain because it would be problematic but for the purposes of of of understanding this at the cellular level they were able to make you know the cell membrane more permeable so that serotonin can get through and then if serotonin can actually get through that it does agonize that receptor and it does also do that and change the dendritic spines but it's one of these things where that's probably not what's actually going on and you you know uh normally because it's not actually permeable and so that it draws up these other questions of is this effectively a you know a receptor that that receives um you know input from other non-serotonin sources and um yeah you know I I think um figuring that out is going to be very if that's true figuring out why that is is going to be really Central to understanding a lot of kind of socio-cultural um reasons for mental illness why they're there what it is why that receptor is in that particular place I mean it's it just opens up a whole whole host of questions that that we definitely don't have any answers to okay so did people uh start deciding that there must be DMT endogenously produced because they saw these receptors and knew that it would fit in no that's this is way before it was theories about why people have these near-death experiences or these kind of phenomenon and around death and so we have never been able to uh validate that there have been studies you know CSF studies in humans and various animal studies um but it's it's not well established right um Rick straussman who's a psychiatrist and he was at University of New Mexico did all this work with the Mt in the 90s and early 2000s published a book on it trying to understand what DMT is and you know in his book he theorizes about endogenous DMT and the fact that you know the idea that it may may be present um but yeah hasn't been enough work to kind of conclusively establish it and there hasn't really been a real reason to do it before this UC Davis paper because it was like yeah that may be there but like you know there's it's not like there's a lock without a key and now all of a sudden it's like oh there may be a locker key you know there may be a door that you can only get to in a certain way and it's and it's um you know I think it's it's a pretty pretty important question to answer if that really if a couple more Labs can replicate this and show that that's the case then it's going to be important to understand that because that means something inherent about ultimately about how our brain plasticity works right you know and and curious right if you did have endogenous DMT when does endogenous DMT get released you know does it people think it's released during these near-death experiences does it get released during sleep does it get released during High you know High exertion exercise you know where you hit these kind of flow States you know I mean these are all the sort of questions you know that uh that we have no answers for but are just kind of interesting you know um yeah all right so I want to talk about treatment treatment resistant depression and um psychedelics so I I have never done I I've micro dose psilocybin I noticed effectively nothing and then as I pushed it pushed it a little bit it started to feel a little bit like I was drunk but like yeah uh so I've never done a macro dose where I expected something to happen yeah but nonetheless when somebody comes to me and is like yo I've been struggling with this for a long time like I'm really scared I'm going to take my own life one of the things that obviously go get therapy immediately do not pass go I'm not the guy to talk to yeah but as by way of making a checklist to run by your therapist here are things that I would say um try all the things that we know work and if none of that works then I would I personally in my own life would not consider myself to have tried everything until I had tried I'd start with MDMA which I know is outside of um technically being a psychedelic but it's just from uh my my whole theory around it's the context it's your frame of reference it's the simulation is glitching and it's a way to rapidly reorient the simulation everything is good and to revisit whatever problem you're having through that lens of like everything's good I love everyone I'm hopeful uh if that also didn't work then I would move on to like more traditional psychedelics I'm curious and I only say that because I've read enough headlines I haven't really gone into the studies but I've read enough headlines no there's it seems like there's really something there obviously warrants further exploration but really seems to be that treatment resistant depression seems to yield in a very substantive number of cases to psychedelics um obviously you gave us a little bit of a forerunner there with DMT and the possible key to the lock of The receptors in our brain but what what is coming out of that research where do we think that goes why does it seem to work and how often does it work yeah that's a great question so you know is that the Psychedelic science um conference in Denver a couple of weeks ago I was at the 2013 one um really telling anybody I was going to the 2013 one but I was able to tell everybody I went to the 2023 one so things have changed quite a bit in the last decade around this topic um and you know a lot more data right we know a lot more about what what these things can do MDMA seems to be a very profound um you know anti-trauma sort of substance um PTSD that sort of thing there's been one positive trial that was in nature medicine a couple of I guess a year or two back uh one of my best friends who's um in my wedding was um you know one of the investigators in that paper and they did a great job on that work there's another there's another positive study that's going to come out soon and people expect FDA to weigh in on this um soon and they actually released the guidance for doing studies in psychedelics during the the last day of the conference ironically psilocybin has been studied to your point in both major depression it's not necessarily treatment resistant and in individuals the true to form treatment resistant depression the major depression data Robin Card Harris had some of that went into New England Journal there's another um paper that is going to arise from um Chuck razon and that group um and uh he's he's holding that data close to his chest so we we get the sense that it's good but but haven't seen it um and that's in more non-treatment resistant major depression where you see higher you know response for Mission rates and the compass um the compass trial that was the treatment resistant trial the data was good it was um you know it wasn't as profound as what we were able to see with a less treatment resistant folks but you know about a third of people had benefit from it that was clinically relevant um and what dose were they giving people like is this a full-blown hallucination or it was all the benefit really was only observed in like the full full dose right like the with the 25 milligram dose which is 25 milligrams of pure psilocybin the active ingredient and magic mushrooms when you think about or psilocybin mushrooms or however you want to talk about it if you think about actually you know ingesting the mushrooms themselves you're talking about grams of mushrooms you know there's a certain conversion factor of grams of mushrooms to actual psilocybin the problem you know with the grams of mushroom thing is that the depending upon if you're getting mushrooms from this place or that place or this person or that person or whatever it is the mushrooms end up being different concentrations of psilocybin compared to like you know how much which is why I'm you know I'm pretty supportive of the kind of medicalization of this because I especially for treating diagnoses I think it's important if you've got somebody that's to your point suicidally depressed I want to if I'm going to give them something that has psilocybin and I want to know actually how much psilocybin they really are getting because the 10 milligram Group which is still not a trivial that's over a micro dose that you know that's you're feeling that didn't experience the same clinical benefit as the 25 milligram Group which is pretty heavy are we at heroic dose at that point you know I I will I don't use that term medically but that is what the that is what others would call a heroic dose a 25 10 would be um a dose that you're having you know a psychoactive drug effect one which was another dose in that study is essentially a micro dose to those nothing there not that much for the 10 clinically relevant effect about a 30 people for the 25. suggesting that you have to have this full experience um you know I you know I've I I don't have like a I'm agnostic to all these are all tools I think they're all going to be used for different things um going to skipping neuroma you know especially the stuff that we've been doing with accelerated TMS skipping that and going on to psilocybin is tricky and um and I always kind of bring people through stem first because the risk benefit profile and the like prep take it's it's functionally just boring right the prep to get somebody on board to do that and to for them to be psychologically ready to do that is so low I mean I tell people if if your doctor thinks that your treatment is boring and you think your treatment is boring that's great because that boring from the standpoint of what's going on not the outcome because that means that it's low risk right and you know TMS and what we call Saint this accelerated stimulation approach these are incredibly high risk benefit profile sorts of things where there's a theoretical risk of seizure we've never actually even seen it with a stimulation approach um that's it headache in some people it's Tylenol responsive and the benefit can be huge the problem with psilocybin isn't the people that got better you know their people get better they get better and it was good if you look at the adverse event list in that study that New England Journal study there was a decently high risk of emergence of more suicidal ideation or suicidal ideation particularly the individuals that didn't get better and it's not necessarily from the drug it's from this phenomenon of disappointment and hopelessness it's interesting right so this thing that's supposed to be like the thing didn't work for me and now I'm really despondent yeah and you and that's not even specific to psilocybin I'm not arguing that psilocybin caused that I'm arguing that there's just a general risk in those sort of scenarios where you see that sometimes we see that with people that go through brain surgery for depression like really really worst of the worst though there's experimental brain surgery sorts of moves where you can put stimulators into the head people that don't respond to that have a suicide risk we've seen that um and then you know folks who the you know on the S ketamine product kind of FDA product description post study there were a number of suicides once people were pulled off of s ketamine which is really interesting to get back to the kind of thing once you get pulled off so not while you're on it but if you stop is that a withdrawal thing or just the depression comes racing back uh you know certain certain individuals would not love it if I said that but I I think that you know that's an open question right um you know because it's during the During the period after um after it comes off board but I think it's this overall question of like you know kind of mitigating risk you know we we see this less when there are stimulation or you know not much at all within with a non-invasive neural stimulation bit and I think it's because people don't have to prep themselves to do it it doesn't feel like such a risk it doesn't feel like such a you know to take a psilocybin trip as a depressed individual that's never done it before which is really who they're looking for 50 year old 60 year old person they've gone through their whole life and avoided this and now they're taking this and they may have even had a bad experience with it and then they're still depressed that's not a you know it's a tough thing but how do you how do you prepare yourself for it uh psychologists still try to you know we'll do some work to prep folks for for therapy or just explanation of what the trip is going to be like and how to handle it if it gets scary yeah I mean in some ways that's therapy too right in the sense that you're you know supportive Psychotherapy or however you want to think about it but yeah I mean psycho education that sort of thing you're trying to get the person to be ready to win they go into this mental space and then they end up um you know feeling uh quite a bit different and in some ways kind of out of control right and then the kind of control comes back online when the trip is over you know what I mean and so that's that's I think and then you know processing insights you know psychedelics produce a lot of insights you know so processing insights processing you know um the positive and the negative you know and for some people with all those disclaimers for some people this is incredibly transformative right they come out of these experiences and they feel like they're a different person you know from like uh how how I'm approaching you know my significant other my friends you know they get out of the maybe the Mental Health crisis or their depression or whatever it is but you know we know that there's even lasting personality changes that happen you know if you give psilocybin to normal healthy control individuals they'll routinely rate it as one of the top five most important like a full-blown trip one of the top five most important um experiences in their lives up there with their wedding and their kids being born you know and that's that's saying something right that's pretty hard to pull off a lot of people and into life where they're able to process their imminent death you know so the tools are these tools are a little trickier than I think the stem tools are they have the ability to produce broader effects because you're it's not just about affecting the illness now you're affecting an entire like perceptual to your point kind of perception of how the world works you know what we've been working on is um is a psychedelic that's a less known psychedelic called ibogaine its issue has been historically that's um has quite a bit of cardiac risk you know and so um kind of one in 300 you know serious cardiac risk right um that those numbers come from individuals that have received ibogaine for the purpose of detox from usually end-stage heroin addiction so it's people who have probably had a heart infection before and all that sort of thing um so I get connected with a group back in 2018 um you know vets which is Amber Marcus Capone veterans exploring Treatment Solutions for this case TBI and ptsda depression and so that so Marcus actually went down to Mexico after a buddy went down to Mexico and took IBN his PTSD and traumatic brain injury symptoms got better and Marcus his traumatic brain injury symptoms got better um what does that tell us well in addition to being a brainer derived neurotrophic Factor up regulator IBN is a glial derived trophic Factor up regulator what does that mean it has you know that one has a role in regulating dopamine neuron health and other things so it's a broader kind of neurotrophic factor um up regular than just what we see with psychedelics and what we see with ssris if there are at least two apparently um growth factors that you can have in the brain are there only two are there a whole bunch more like what is that those are the main ones that people think about as far as like regulating the kind of standard you know serotonin receptor you know serotonin neuron dopamine neuron um and in glial derived neurotrophic factor in particular yeah that's been a harder one to move bdnf moves with a lot of different things and so um you know if you take a mouse and you give you get the mouse addicted to cocaine and you give it IBN it'll stop being addicted to cocaine if you give um direct injections of gdnf into dopamine neurons you have the same outcome it's really interesting right so that one that you know kind of effective IBN may be unique so yeah so we've been running this trial it'll come out and press and um six eight weeks from now um it's looking like human trials with ibogaine yep tell me more yeah yeah so we partnered so it's it has been very difficult to do this in the US historically because of the cardiac risk so we we kind of um constructed this study where in Stanford IRB agreed to this study which is amazing of them where we actually evaluated people at Stanford sent them down to Mexico so they were kind of already headed to Mexico signed up to do this through vets then they came to see us and they went down to Mexico received the IBN came back reevaluated them evaluated them in a month so we did the first neuroimaging study of ibogaine um effects first EEG study of ibogain effects blood full neurocognitive batteries um and it's an interesting phenomenon there's been about a thousand Navy Seals and Army Rangers and Special Forces guys that have gone down and taken this African root Park extract got it you can reboot your life your health even your career anything you want all you need is discipline I can teach you the tactics that I learned while growing a billion dollar business that will allow you to see your goals through whether you want better health stronger relationships a more successful career any of that is possible with the mindset and business programs in Impact Theory University join the thousands of students who have already accomplished amazing things tap now for a free trial and get started today I began is extracted from the iboga tree that's native tikkaban and surrounding um you know African countries and the the gabonese um group that that has kind of used this um as a Sacrament is the buity and they've been using this for Millennia and so um yeah it was kind of long story that led up to it there's a movie that a documentary that I was in Premiere at Tribeca about a month ago called of of light night um Lucy Walker um described you know kind of went through and described this history of the last kind of 50 to 60 years of trying to get get this studied in the U.S um but yeah we you know it's been there's been a difficulty in um in studying it in the US and so we partnered to do it those results are kind of pending and I can talk about that at a later date um there's been a lot of interest um you know kind of in the addiction treatment community in in Kentucky Kentucky interestingly ended up being the first state to to have a lot of interest in this they have money from some of the opiate lawsuits and and settlement money for for a lot of the you know the um the opiate oxycodone you know cotton codone problems they have um you know I think like 800 million dollars and they're trying whoa and so they're trying to they they're trying to earmark like um 42 million or so um towards ibogaine um research and so they um proposed to do this um so I was I was actually testifying in Kentucky um earlier this week uh in front of a the opiate commission about this and so and so they um one guy in particular Brian Hubbard in that in the Attorney General's office you know put this up as like an idea for dealing with Kentucky's opiate um crisis and what did they want to know is it effective in helping people get uh unaddicted yeah that's what it's actually been no like what it's been more established to do and so that you know this exploration of the veterans is a new application and we you know we've explored kind of those effects we've known for some time that it's a profound addiction interrupter of that Mouse study I was talking about earlier like for you know 30 years we've had case reports but it's been very hard to study it in the U.S because of the regulatory concerns around the heart and because of you know concerns of studying psychedelics historically so we're probably at a moment now where that shifting but um but yeah you know uh I think Hunter Biden in his documentary um took ibogaine and then describes it um there have been a number of other celebrities and and folks like that that um have taken ibogaine in very kind of variable levels of Optics kind of society you know at a societal level of you know knowing this but their clinics that operate in countries where this is legal including it's legal in Australia New Zealand but you know countries where this is legal where people will go and receive IBO game treatment for you know hard to treat addiction and so and the numbers are really really good for addiction Interruption so it's just been this issue of how do you how do you deal with the heart problem you know we've we've taken this kind of stance of co-administration of cardiac risk reduction drugs so you can kind of prophylax against potential heart problems before even ibogains on board and then you know concurrently with the IBN with the idea that you could you know risk reduce and you know we didn't observe any symptomatic cardiac problems during our trial which is great but yeah it's it's it's interesting you know this is we're at this precipice of really looking at these really interesting substances and ones that are really really I would say technologically advanced compared to the drugs that man has made when you say they're technologically advanced what do you mean that they're because one question that that I have based on some of the things you're saying is is it the profundity of the experience from a psychedelic or is it the glial uh brain growth factor I forget the exact letters there we go um yeah because if I can inject it right into the site the the glial derived neurotropic Factor if I can inject that right into the dopamine receptor was that it um sure but then that indicates that it may not be the profundity of the experience it's actually creating it going back to ssris and it's not that it's building up in your system it's that there's potentially that it's just causing you to um secrete more bdnf and that's really what's going on um what where does the data point that we need to look I get there's we don't have the conclusive anything yet but what does the data suggest is the next thing to look at yeah um so the the ways that people are trying to deal with this is by um modifying the molecule to take off the trip the problem with that idea is that it's a different drug you know I mean everybody wants to think it's the same drug but it's effectively a different drug when you do that now it could be a totally effective drug and if they modify the molecule if they modify the drug and then it still works just as well without the trip then you can make the argument that the trip isn't necessary if it doesn't work as well then you're it's kind of unclear right um you know the other way to do it which is a way that we're exploring is can you put drug and just in specific brain regions without putting in other brain regions now injecting directly after surgery and there's all this problems with that but there's a guy uh Rock a Ron that I'm working with at Stanford who's developed a tech where he can package drug into a nanoparticle cage so you can inject the drug sitting in these kind of cages and then you they just like eventually urinate it out or whatever and you never the drug never does anything because it's been bound into this cage the whole time but if you use ultrasound as a form of stimulation because you can use a focused form of ultrasound just like the diagnostic ultrasound but you can focus it to a point if you focus it to a point I'm going to say you know area of blood flow in the brain you know vessels carrying the drug it will warp the cage and let the drug out for a second but only in the specific region of the brain that you hit it with Wow right that is clever yeah and and what's cool about that is it allows you to ask the question of necessary and specific and all that so we're gonna release ketamine into the cingulate um into a singular into the anterior cingulate so same idea cage it up yeah hit it when it hits this part of the brain and see what happens yeah and we're looking at pain changes because pain is like um really nicely you know measured in the sense that you can have an acute you know anti-pain effect um whereas like the you know the longer term you know depression effects or whatever it's a little bit harder to to kind of measure that so if we're going to measure pain first and then the you know so that's the primary question can we reduce pain but relatedly do they have any sort of you know dissociation from the ketamine you know and start to be able to use you know specific drug release to do mapping experiments and you can do that with any psychedelic ketamine and so is this is putting the drug in this brain region um sufficient to produce all the therapeutic effects without causing the psychological effects or do you just get a piece of it suggesting that you and then you put you find you know this one contributes 30 33 this one contributes 33 this one contributes 33 to the total you put it in all three of those regions if you if you do have the psychological effect that maybe you can't divorce them if you don't have it um then you can you know and so that's another way of dealing with it but it's it's a really hard question and it's going to take 10 years to figure out that question I think you know in the short term you know my thing is pragmatics and just having tools and all that and so just trying to just try to test it with this with a trip knowing that it makes it a lot harder to you know to scale that you know because you have to have a lot more you know therapeutic involvement and all of that to be able to deal with a lot of the content what people say with ibogaine is that they um they have this Life review actually about 80 percent of people experience um a Life review on IBN and what that is is an autobiographical replaying of past emotionally relevant memories some of which aren't even really known to be relevant they just end up being critical moments the things you wouldn't expect pop up yeah which makes this really interesting and gets back to your question about high tech and so you know this is a drug that marches you through all the emotionally relevant parts of your life you have an intuition you're seeing this as a third party you have an intuition of what you thought and felt at that moment you have an intuition with the other person or people felt or thought of that moment you have a re-evaluation of that total situation and then a reconsolidation because every time you bring up a memory you reconsolidate it as you know and this drug for 30 hours marches you through all of these Jesus and at the end of it people say they've completely sorted you know all of that content and they're now in a place where they've they kind of have approached it in a totally different way so um with ibogaine specifically are has anybody put words to what the the vibe of the recontextualization is so like MDMA it makes you feel like you love yeah it's everyone actually but from what I've heard I began like they say it's it's hard it's work it's hard it's work yeah what does that mean exactly so no matter what sort of emotional thing you're you're looking at it's just I no longer feel emotionally charged about it and so now from a neutral perspective I'm going to reconsolidate it with a neutral sense it's a neutral stance but it can be very emotionally it can be very emotion inducing because you're not pro Tom in this whoa that's weird right and so so I I am sort of standing outside myself and I'm perfectly willing to say you were an [ __ ] in that moment yeah so like it's okay but you need to recognize where to file that appropriately yeah so your example earlier about the note to yourself when you're arguing with your wife on Saturdays that that almost is kind of the similar sort of idea right is that in some ways you you emulated that you were able to kind of see that you're going to do this your wife's gonna have this feeling and if you just give her this note then you know and so it's like that right it's like this idea that that you're you're able to go into that and you may even and I'm making this up you know you may even go into that and be like man I shouldn't even have been mad about that I you know the only reason why she's saying any of that is because of this other thing that I did or you know or whatever right or some other scenario but it's like you're able to see that you're also able to kind of Intuit the other person's perspective and I mean who knows how any of this works in a way that like they can then their kind of reasoning is contextualized for you and then you have this moment for some people and why it can be hard so you have to face the hard reality that the way that to your point the perception of the map of reality that you're operating on wasn't the territory at all right and that the way that you are seeing that event go down was totally through a lens that was the sort of kind of perceptual disturbances that we see the world through and and then operating off of that information that was inherently flawed right and and it seems to allow for folks to kind of re-evaluate all of that and and with that establish greater control and choice because you're you you kind of have a better calibration of the world like you know this idea of the map is in the territory like the closer your map is to the territory the more inherent control you have because you have a better sense of if I walk this way there is going to be land or there's going to be water or whatever you know and I think for a lot of us part of what goes wrong is my map is off enough to where I thought you know I was driving my car on the road the beach or whatever you know you know as a metaphor right and uh and I think that we do that all the time with our own perceptions of what's going on with reality and the people that we're interacting with and so it seems like if you at if you hear all the anecdotes it seems like what it does is it really gives you a better calibration and that but that calibration is inherently hard because you have to face the the truth that you were wrong whereas I think with MDMA it's much more to your point it's much more of like just a pure loving acceptance that your map isn't right but it's okay and in some ways both of those are highly useful and therapeutic right like you you kind of have to hold both of those that like my map is wrong and I have to face it at some point but I also have to love myself and accept myself for having a miscalibrated map because it's probably due to something that happened in my childhood that shifted my ability to see it or something that happened in my whatever like some trauma that I experienced in my early adulthood or whatever it is you know right like that's that's inherently like the the empathy the empathic part and I think you have to have both of those but but yeah that's definitely what that's definitely what the IB game seems to do is it seems to kind of write a bunch of views and take you down a journey and um it's it's pretty fascinating that it ends up being these Elite Fighters right which in in retrospect makes total sense why they'd be really in droves going down there because they're not worried about a one in 300 I mean it's it's not really probably one in 300 for those guys because none of them have had a problem a thousand have been down there but you know in theory one in 300 risk of of death you know they went into war zones that were a higher risk for them than that you know and and they see this as an exit out of the kind of constant turmoil yeah I was going to say that that would be my gut instinct as to why Navy Seals and I think it was you that I've heard speak about this but I definitely heard somebody speak about this you know you can imagine a Navy SEAL they're in a combat zone they do something it goes wrong they accidentally kill a child or friendly fire or whatever and now that's a part of your mental map of who you are as a person and that's just tearing your guts out every day every night that's right and to be able to go do this thing that allows you to file it away properly because as you were describing this the thing that it makes me think of is um Time Heals all wounds now what that phrase is getting at is that when you sleep part of the memory consolidation process is to strip away the emotional charge of that memory and file it away neutrally but if for some reason you're locked in a PTSD like cycle that doesn't happen and so you're you're constantly reliving that emotion with the same level of emotional salience as when it first happened which I cannot imagine the hell that that would be if the worst things that have ever happened to me or God forbid I had done something that was horrendous and which honestly for me anyway would be worse and then I just living that at the same volume every time every time every time and so if I begin and obviously I'm pure speculation here but if ibogaine Works to sort of rapidly do what time is supposed to do which is strip that emotion away like if if life sleep does it slowly you know over weeks months years depending on how intense this thing is and ibogaine does it over 30 hours like suddenly you get why people would be willing to go do that difficult work the part that I struggled to wrap my head around is why it's tied to addiction like those seem like two very different things I think of maybe erroneously I think of addiction as being a biological thing where my body has gone I I have adjusted all of my internal levels to expect heroin cocaine whatever and why all of a sudden if I don't get that oh we're good no problem but you know a day before if I didn't get it I was vomiting I was shaking and sweating well you have to think about what yusuke Bor mate uh who's been on the show yeah I saw that he um works a lot of addicted individuals in Vancouver yeah his view which is interesting and I think it's probably right is that there's an in there's an underlying trauma driving you know particularly if you think about opiates you know opiates in this very short term put people in the state of of reduced pain not just physical pain but emotional pain and going back to the ketamine story right where like you need an opiate agonism to have an antidepressant effect from ketamine right so so this idea that you know substances actually do have a very immediate effect that is in the right direction the problem with these same substances they actually go totally in the opposite direction and create a big problem with chronic use you know and so you know acute use of of say buprenorphine which is which is a one of the opiates it's it's the active ingredient in Suboxone the kind of one of the drugs that we use for for taking people off of opiates but it's it's self an opiate and so if you give buprenorphine you can have an antidepressant effect if you give oxycodone chronically you can produce more treatment resistant depression you can actually make people more treatment resistance so it works for a minute but then it becomes a problem but then it becomes a problem and so you know there's a there's a pretty consistent finding that people that have depression before major exposure to opiates or PTSD have a higher risk of converting to opioid use disorder um I had a study I tried to get knighted a National Institute of drug abuse to pay for um you know four or five years ago with our neurostimulation approach um where we were we were saying we're going to treat these depressed individuals right before they go and get a total knee total hip replacement because it's incredibly painful and in those people if they're depressed they have like a 2.6 times the amount of opiates they're using by day three whoa compared to non-depressed people just being depressed makes you need more opiates yeah if you get the effect too yeah yeah yeah right and so because physical and emotional pain are processed in the same part of the brain in the singular yep that's so interesting man Jesus yeah yeah and so I think and then our you know our stimulation approach is targeted into the singular we were talking about earlier right so you and you can actually release endogenous opiates with stem so is this idea that we could what we were talking about earlier prophylax against um one psychiatric condition by treating another and so I said let's treat the depression they go and do surgery and then we see if we can in the active group knock down the amount of opiates they're using compared to the Sham group for the goal of trying to trying to treat the depression and reduce the risk just like anesthesiologists do for other things you don't go into surgery until your heart's skin until your vessels are good they won't let you you know and so it's this idea of could you do a pre-surgical risk reduction and it gives you a model for actually preventing a future addiction um that was a seemingly too radical idea at that time for Nida there I think it was having a little bit of a hard time kind of conceptualizing you know like are you treating you're not treating addiction you're treating depression you're applying to night you know and so it's where I think it gets a little bit complicated you know that's one of those things that really bums me up because if it works and like I get we don't think of them as being connected but if they are connected then you need to address it and so especially when you think about how many people end up getting addicted to opioids because they were put on legitimate pain medication to begin with and then it turns into an addiction and then they can't shake it and so uh knee surgery becomes a prison stint for opioid addiction that's right man that's really interesting yeah that's right yeah yeah so it's it's an interesting thing I mean I think we're getting to a place now where hopefully we can start thinking about that I mean the ideal world is we we just don't we we don't give somebody an opiate or we concurrently treat them if they need to have an opiate with something that essentially fixes the underlying problem that would that would cause the risk you know profile but but yeah I mean I think getting back to your original question about ibogain the the reason why it makes sense at a level is because the gdnf thing but also the the mouse self-administration thing I were talking about earlier but also that combo of that and that they're addressing some of the pain right some of that inherent pain from some of the trauma that somebody like gaboramate would talk about that probably drove them to that place in the you know to begin with right um and uh because not everybody you can give somebody Fentanyl and then never want finale again you know some people hate it or whatever right and so it's this idea that you you may be people that keep seeking it maybe tapping into actually a system that doesn't need fentanyl but needs something else that fentanyl is acting on right like neurostimulation like maybe like you know some of these psychedelic you know drugs maybe like ketamine whatever it is and uh it gives us clues about what the circuitry is and what the problem could be the underlying initial problem could be um but it's also why I think we've got to pour a lot more money into researching these things like we really you've gotten very far in cancer biology and Cancer Treatments over the last you know 20 30 years right we can you know we can treat previously untreatable Cancers and we we have drugs you know we even have ways of modifying the immune system to attack cancer now and you know recent Nobel Prize a couple years ago for somebody on that one um and um we know a lot about the heart but but if you look at the federal dollars that have gone into brain conditions really into psychiatric conditions it's a lot less but the but depression is the most disabling condition worldwide you know a lot of these things are and so what metric um by like you know standard disability scores you know so you can I can't get out of bed I can't go to work yeah I can't think through this thing yeah I mean and if you if you look to like our you know our conversation an hour ago around the cardiac thing and you know if you if you ask a cardiac patient just had a heart attack what's and they're having depression what's the worst part of what's going on it's depression take a Parkinson's patient with new Parkinson's and they've got all their shaking and all this stuff and they're depressed and you ask them what's the worst part of your Parkinson's it's the depression Jesus right depression is comorbid with almost everything maybe everything and it's um and it makes everything that it touches worse right if you have depression and you just had an uh a surgery your wound healing is going to be a day delayed compared to people that aren't depressed that's banana I mean I after what you told me about the heart I should not be surprised but I didn't know that yeah that's bananas so depression makes you need more opiates it slows down your healing and it increases your risk of heart attack does it increase your risk of cancer or other um chronic diseases the cancer story has been more inconclusive you know but there's a list there's a recent meta-analysis and there was a list of risks I mean there's one paper published in the American in the American Academy the the green Journal neurology and um and depression increases your risk your depression in your 30s and 40s increases your risk of having Parkinson's later in life Jesus Christ right and then Parkinson's increases your risk of depression just like the cardiac thing right so depression makes literally everything worse and produces a risk for you and so the idea that we're not putting like an insane amount of federal funding into understanding what depression is and answering many of these great questions that you've asked around what's causal and what drives what and how's the gut and the brain related and how is Diet all that stuff needs to be understood in a deep way probably with machine learning and AI embedded in those questions but you need you need like a dense amount of money to be able to figure out uh figure out how to do that you know and like all of our you know our accelerated stimulation approach that you know well looks like will ultimately end up on the inpatient unit and treat psychiatric emergencies we had we have a lot of federal support and a lot of federal funding now and very thankful for that um the original work was Grassroots donor funding you know and so people that had personal looks I'm guessing obviously but people that had personal experience that are like you can make this as legal as you want this is amazing yeah yeah and so a lot of the you know a lot of the really really early early stage mental illness Psychiatry kind of experimental Therapeutics work at least that we've done has been philanthropy funded and a good bit of my portfolio for the lab is from um you know private donors the with a whole lot of means that come in and they say you know my my kid or my parent or my spouse or whatever is suffering and there's just not anything for this that's how we got in the I began work you know that's how we got into the accelerated stimulation work and our like application and other indications you know how we're getting into some of like the direct brain recording work it's all philanthropy funded and and you know really where the federal agencies come in is in that you know in many many cases in that second step once we have a signal to kind of come in and expand the effect but you know in their defense they've got a limited budget you know so they really need to to invest in things that are somewhat de-risked and if societally we were able to put you know as much money proportionally based off of your question of these disability scores so the most disabling things get the most federal money to to kind of explore and to do really really moonshot sorts of things where it's really early and fund it from the get-go then we would know a lot more about this and so the hope is is that this generation of of teenagers and folks in their early 20s seemed to really embrace therapy and the kind of you know having a mental illness having a psychiatric diagnosis having even sub syndromal symptoms and needing a therapist and that sort of thing and as we like destigmatize this stuff and approach it from a different lens and you know in the case of psychedelics that in and of itself gets destigmatized I think that um we're going to make a lot more Headway and and my prediction is you know and by 20 2040 probably or something we'll be able to have a decent amount of um control over these illnesses will be able to people be able to come in then we'll you know we'll be able to to kind of stratify them and we'll be able to make you know decently predictive therapeutic decisions on them and and have a bigger part of the pie that's responding because if you look at the the numbers for any given oral antidepressant working it's not very good you know it's much less than a coin flip you know and so being able yeah for the standard oral antidepressants it's it's not not great right so you end up iterating across a bunch of different drugs to get to a point where where they're working you know some of these rapid acting drugs ketamine story you know what we're doing with neuromodulation a lot of psychedelic work looks better than that right and that's why people are willing to accept it because um you know people whether it be military or civilian government or whatever it is you know everybody's recognized this is such a big problem like we can't have these preconceived notions of this is a good or a bad thing or whatever it's like does it work or not and if it does let's add it to the list you know and uh and I like that because that's the way I think about it this is incredible what do you think about the fact that all of this like when you were talking about ibogaine specifically you know the profundity of that it auto happens that you will start cycling through your memories that it it creates a an environment that is useful that allows people to deal with the most traumatic things ever that it and this part I know is hypothesis but the fact that it can help with addiction potentially just from going oh that thing that you've been trying to cover up or run away from or whatever just by putting that in the right context in your brain use using whatever mechanisms the brain already has but you didn't have access to before um just by putting that in its right file folder and removing the emotion from it you no longer need heroin cocaine whatever that it comes from a root like that's just what what like that is from a co-evolution perspective I'm just like I'm sorry what like yeah huh yeah yeah no it's it I argue exactly what you said but with the kind of profound neurotrophic kind of plasticity effects probably concurrent right and that's why I think such a high-tech sort of idea that it marches you through all these psychological things and it has the kind of biology change that are that's happening concurrently you know my view and I've said this publicly is I think you could give you know the major drug companies 10 billion dollars 100 billion whatever whatever it is and say make a drug that works like IB game but I began in in theory IBM never existed yeah yeah and they they didn't have anything to work off of you know nobody can make nobody it's not their fault like we we don't have the Neuroscience to understand what this is doing at all like why would it produce these very characteristic um you know you know processes and like the that I mean about 80 the vast majority of people but it gets into that statement I said earlier right is that we we end up like evaluating Technology based off of Moore's Law you know we use we use computer think to evaluate everything else you know and I think that I think that you you can't kind of do that with the psychedelics you can't use well whatever is the most you know chronologically new has to be the most advanced I think I think that you have to use a different kind of what's the most what has the most inherent complexity you know um in a good way like what's kind of in this case therapeutic complexity to evaluate it but it's something like that and it's um it's hard to relay that kind of concept because obviously we're so programmed to get the iPhone 50 or whatever you know we're so programmed to get the next MacBook I mean we just don't even think about it like we just know that the next iPhone is better than the last one you know and so chronological time ends up being like you know but I think uh I think for these these Technologies right it's more about what does it do and um you know all the psychedelics at a level but I think particularly I began man I mean how does that even work you know and uh and it's it's interesting so it is very interesting is anybody looking at experimenting directly with um glial derived neurotrophic Factor there's been some there was some work with trying to do some of that for Parkinson's back in the day uh where actually they were doing like burholes and like surgeries and injecting it into into the because you can't digest it in an oral form you know ibogaine's the only way to kind of have those effects which obviously that was off limits 15 years ago but have those effects without you know essentially a direct injection and so um the study was inconclusive I think the the problem probably it from my perspective was dose right you give one one injection of this it's not gonna necessarily be enough to take somebody who's so far down the pipe for having full-blown Parkinson's so they're willing to do brain surgery to try to treat it to then you know um evaluating it it would be interesting if you could you know use and I began like substance you know even in Parkinson's right where you um you know you had something you know maybe without all the cardiac risk or something we had something that could upregulate your um you know your glue your glial neurotrophic factor and kind of you know ask the question of whether this could restore you know dopamine neuron function you know that that's where the similarity is between Parkinson's and addiction is that you know both have an effect on the dopamine system right in the case of Parkinson's it's a direct hit and degeneration of the Niagara which is feeds up to a lot of the motor parts of the dopamine system and then um the addiction acts on the ventral tegmental area nucleus accumbens reward system but yeah these are both dopamine population dopamine are on populations and so yeah a lot of you know an area that needs a lot more research and a lot more exploration to really understand it but but there's you know there's a good amount of basic science going on now I'll be interested to see if I had to guess that there may also be some amount of like the plant compound is so intricately evolved essentially to have a bunch of different things happening at the same time so that you get the effect like I know when you look at Ayahuasca which is multiple things put together and how on God's green earth someone figured out exactly how you have to prep this plan and that plan and put them together to get this effect and that one sort of works with the other you were talking earlier about you know there's there's a place where serotonin if you can break the cell membrane down enough that the serotonin can get in then it can have an impact and so you know how much of ibogaine or any of these other drugs if you isolate the thing you think is doing the vast majority of the work but maybe in reality it's only doing 80 of the work and that you actually do get additional benefits from the 20 of the other you know whatevers that come in that route or you know the sort of prime the system to receive it yeah that's also interesting but man does it let you know that nature is complex it is I mean I I think I had a it was a quote and I'm I'm probably I'm probably underestimating but I think it's like 10 000 plant species in the Amazon yeah it could be more than that but I'm sure more yeah if you know let's say it's ten thousand it maybe it probably is more than that you know the number of combinations and iterations and their poisonous ones I mean it's just it's hard to conceive of exactly what you said in the case of Ayahuasca and and really like you almost have to have a knowledge right that these two things this one thing is blocking the GI breakdown of this other thing you know in the case of of the reversible monominoxidase inhibitor piece that then allows for the the DMT to get into the brain um but yeah it's you know the iboga tree there's not it's a root bark you know they have to kind of if you watch the Ouija they're like digging it up like there's not like a clear Predator I mean it's it's a very um it's a very curious kind of anthropological question kind of neuroanthropological question around like what is going on with all that you know and people have written about it you know an anthropologist talked about it but it's it's not it's not clear you know and I think that I I actually think there's probably some real value to you know investing some money and that would probably be NSF or somebody like that but investing some money into really trying to understand why humans were ever doing this to to begin with right I mean we've yeah I think Western culture you know with the Mayans and with like coming into Central and South America and just kind of imposing in that time Christianity all that on to those groups and then you know kind of ignoring a lot of those those traditions and you know kind of re-embracing and asking you know if we landed on Mars or whatever it was and saw you know an alien species doing this we'd spend a whole lot of money trying to figure out why they were doing it so why don't we go in and say in a really deep way like why were the Native Americans doing this why were the Central and South Americans doing this what is the reason why they were doing it it's probably there's probably and it's unlikely that it's the same reason why we habitually drink alcohol that'd be my view you know interesting for me they seem uh they're the same uh obviously guessing the same evolutionary branch one is elevated one is a lot more fun so when I think about um would I rather do ibogaine or MDMA I'd rather do MDMA no sure and especially if a Tom you have these uh traumatic experiences there are two ways that I can put them away you can confront it for 30 hours and like really contend with it uh put it away and then you're gonna be fine or uh you can have a great time look at it from a place of love and just overwhelming joy and everything's okay also put it away and be fine long term be like uh word I'll take the the loved one thank you very much and so alcohol for me anyway it makes me feel like I'm suppressing the urge to dance on a table but it's brutal on my body so I almost never do it yeah um if there were no side effects like if if I only experienced the part when I was drunk I I would drink like it's fun so I get how there to me they're both writing on the back of uh I'm gonna modulate your neurochemistry you're gonna go on a chemical ride is how I think about it again it might be circuitry but you're going to go on this ride of these things we call emotions are fun like you go to a movie even if it's a sad movie or a scary movie you like again controlled to your point you like the controlled experience of this so while I would not want to truly relive the trauma there is something about hey I'm gonna I'm gonna show you a demon but it's in a controlled fashion in that you can you know have people around you touching your hand everything's okay you know so I I think it it makes sense to me that the the more intense ones are gonna um propagate nested inside of a I'll shorten it to shamanistic tradition to where it this is this is a ritual this is not to be taken lightly whereas something like alcohol is going to propagate it's like just a fun thing that you can do you can take it a little bit it makes you feel a little fun or you can really push it and then look you're gonna suffer for a day but if there's no way especially back in the day for you to track that oh this has long-term consequences that it feels as close to cake and eating it too as you're gonna get in fact the one that feels even closer to your cake and eating it too is marijuana yeah tell I don't know if you've looked at this but like what I think people give I'm really gonna make people mad now I think people get marijuana free pass I don't understand if you're if you're taking a drug cool trade-off I'm totally for it like if it's worth it to you for the trade-off just seems impossible but when I do it I don't feel bad the next day at all I'm just like oh cool but it like if I so one I have noticed I don't do it often but I do it more than I drink and I didn't used to So for anybody that's listened to me for a long time um I have done it more frequently recently because I have noticed that it has a tremendous impact on my enjoyment of sex so that that has been a fun Discovery um but I've done both smoked and edible again I don't do it frequently but um smoking I can sort of feel the problem coming on so I have a much easier time of not overdoing it but with Edibles um again I'm I'm a very cautious person so I've never been like I know some people had really bad experiences I have not but it did get to the point where I was trying to watch a movie and I'm like I can't make like even the sentences add up so like I just watched an hour and a half of this movie I have no idea what happened so for something like that I just assume like there is some knock-on effect here you can't just play with this stuff and not have some sort of complication down the road well I think the base question that I it and you and you're kind of I think you're you're alluding to it in a way the base question that I have asked is this question of you know or even to back up a little bit do people does everybody have an addiction and what I mean broadly is in a behavioral addictions substance addictions control addictions you know and I'd argue that that probably right like probably everybody has something right whether it be like caffeine or control or you know repetitive behaviors or whatever it is you know and if everybody's it's not really an addiction in that sense what it is is your reward system is primed to repeat behaviors that are reinforcing right and so um for some people like me you know I've historically been like a very serious extreme sports guy like kitesurf and big waves and if it's not a big enough wave it's not exciting enough how big wave are we talking yeah like uh North Shore of Maui and stuff yeah okay yeah I I was a big martial artist and fought in in Taekwondo fights you know all over the world in my 20s and stuff and so you know and I'd argue that that's really just it's just really sensation seeking Behavior at a level right and we all do it you know in one way or another right and so if that's the case then do we do we end up sublimating certain rewarding behaviors that may end up being in the extreme you know kind of um ends addict what we call addictions but do we sublimate um you know certain behaviors for some core set of practices or behaviors or whatever that may balance us or put us centralize us or whatever right and so people have argued that for a long time like people that do yoga argue yoga people that are hardcore meditators argue that you know and there's there's like a a frame that you know if if these drugs like psilocybin and others what the end result ends up being is a loss of addiction because they're not themselves addictive which is I think the fundamental first question if they're not themselves addictive and there's a loss of an addiction it kind of It's Curious right of of whereas the substance you're talking about certainly cannabis there's there's cannabis cannabis use disorder certainly there's a you know alcohol problem obviously and so are those sublimations of other habitual behaviors that end up being kind of culturally embedded you know and back to the anthropological thing why do certain cultures you know ceremonially you know as a Sacrament take psychedelics and do those cultures and we don't know enough about this but do those cultures not have as much in the way of alcohol problems of nicotine problems of all that because because maybe it's getting to that course you know core kind of 5ht2a receptor um that kind of core circuitry modulation and um you know it's it's an open question you know it's one that we don't really have an answer to but one we probably should because if these are all just idiosyncratic behaviors that humans do with certain environments and certain plants and then it's then it just happens to be idiosocratic drugs that we're using randomly to drive behaviors down that we don't want to have versus the other idea which is that there's some core thing that some cultures did and that kept that culture in a certain domain and then you you don't have that and then all of a sudden other cultures have a problem you introduce drug a from culture a to drug B and all of a sudden you're seeing all these kind of vast therapeutic effects maybe it's because drug a culture a had its sorted culture B didn't you know and uh and it's it's a hard it's a very hard thing to answer but it's one that is really interesting you know um that that maybe a lot of it's just sublimation maybe drinking is just a sublimation of an instinct to do something else and drugs are fascinating I want to ask you a question you made reference to it earlier and do you think that we have a soul that is separate from our physiology you refer to it as mind something else mind brain well I think there's there's brain there's mind as we think about it and there's probably self you know um this gets out of like a scientific statement now this is just my personal beliefs right and so you know um I think that there's this you know and a lot of a lot of meditation practitioners believe this there's a there's a thought stream that his mind and many people their mind and their self are fused and they see mind and self is the same thing let me ignore brain for a second I can get back to that but mind and sulfur and so and you kind of pointed to this earlier you said you know once you realize that the anxiety was just happening it was physiological then you could kind of get yourself away from it right and distance yourself from it and I think what you're doing there is you're having that kind of theory theory of mind that your mind and yourself aren't the same thing and that you can see your mind do all of this stuff and you can be an observer of it from self and not act on it you know but for a fair amount of people mind and self are totally totally fused and I think that's really where a lot of a lot of the problems are and then and then then you get this other layer of brain right brain being essentially the organ that you know mind um is emergent from and probably self is emergent from too right but but it's you know so mind emerges from brain you can have an insult like a stroke like we talked about and have depression and have no reason why you'd be depressed but you know mind and and um you know mind is emergent from brain just like blood flow is emergent from your heart and so um if your heart if your blood isn't flowing it's because your heart isn't pumping so you got a structure but then you've got this emergent property and I think that um I think that part of you know part of mindfulness practices is to teach people how to you know in this kind of mind self you know dichotomy to be able to distance yourself from your thought stream psychedelics definitely seem to do that I actually think that brain stimulation can do it through the brain because you're if you can shut down the brain regions that are emerging the mind then yourself is left alone in many ways wow so you're saying the self would still survive so there there is an observer even as you the rest of you sort of goes offline I would say you go offline and say your mind goes offline you're you're like worrying mind or whatever it is right and so we had a couple people in our Saint Charles where they got well on Tuesday we kept treats there was zero on Tuesday and we just kept treating them on Thursday they came in and they said hey the weirdest thing happened last night I was driving home from um you know from treatment or whatever and um I uh I saw the beach and I just decided to go sit on the beach I never do that but I just decided to go sit on the beach and then and then for like an hour I was just like totally present in the present moment and I read about this in my like mindfulness course or whatever you know they're like and I like looked it up after and I was like I think I had like this mindful experience or whatever and you you know you hear one person say that as a scientist you're like okay that's great for you I don't really know what that means and you haven't and you know when you have five or six people and you're not telling anyone that anybody else is telling you this and they're all coming to you with this and it's always like they go through euthymia like they're totally nothing they're zeroed out on Tuesday and we have to say euthymia yeah like normal mood got it that's a fancy word oh sorry you thymia I've never heard that word yeah sorry uh they go through like basically zeroed out depressive symptoms and when they Transit through it if you keep treating them they get into these these places and it's the minority of people like it's only people that are you know actually less typically less treatment resistant it doesn't take them the whole week to get there and then by Thursday or Friday they're telling you this and and you see this post psychedelic it's not during the Psychedelic it's the day or two after really clear right and it's like your thinking mind this computer that you've got running that's I need to go grocery shopping I need to do this like I better not you know do this or this is gonna happen or whatever that's like kind of stuck in the past future thinking kind of goes away and what's left is you right it's U being able to be like Mindful and present you know which is the way that many of the Buddhist meditators say that they get there too right without any of this other stuff right but it's this idea that you can just be present and be here and be able to appreciate the now and um and really the mind is just a tool to like deal with the world right but it's not it's not you like it's your ability to you know make money or drive your car or do whatever you need to do to get to do the things that you you're the self wants to do and I think I think that to me as like a personal goal is a spiritual goal that people have or whatever um as well as potentially a scientific goal right is important to understand because I've never had anybody that I've I've observed in that space who's like I don't like this like I don't want to like get me out of this like being present thing I want to go back to being worried again or whatever everybody's feels like they like took a weight off and they're relieved you know like now I don't have to deal with all that I'm just able to like be here you know and um you know I think that's uh it's an interesting goal and trying to understand what that is you know from a physiologic perspective would be helpful because it may be a therapeutical you know may ultimately be a therapeutical not just a scale saying a person's only you know minimally symptomatic which is the way that we think about it now but actually like that they they can be present you know now does that imply to you that there is a part of you that can't be touched through brain damage or death um yeah it's I mean it's a great question we don't have tools to to to understand it right I mean that's kind of the fundamental the fundamental issue of all of that right and it's and these are these are extremely hard experiments to do you know but it's this question of is there a way to to separate it because you'd effectively have to separate it I mean I think that you know the the kind of Base understanding and Viewpoint that most neuroscientists in 2023 would say is that the you that you believe is you is all brain emergent um right there's nothing about you that isn't brain emergent right and and if I was testifying in front of Congress for like you know and they ask you that question I'd say you know is brain emergent you know um if you ask somebody like Stan Groff one of the you know the original um kind of OG you know psychedelic researchers um his answer is I've heard him say it is that um that the brain's more like an antenna right um which is you know very different a very different view right um and we don't we have no we have no way of proving any of that or understanding any of that right um what everyone wants to believe is that that you are completely an emergent property of this brain there's nothing else about you that's outside of the skull um you know it it and you know unless these things kind of float up into the heavens or something it's it's hard to conceptualize of what happens how you take that view and then you you kind of like converge that view with a view of of any sort of religion which there are neuroscientists pretty senior ones at Stanford that are also religious you know I haven't asked them this question but you know it's this question of like how do you kind of merge those views together so it's you know that's the base kind of we don't know and then to your your other point right you can knock out brain regions and you can dramatically change um Behavior you can change uh personality you can change levels of consciousness and and so people who knew you would then say you're not the same person I Used to Know right and and so that that would argue towards the kind of brain Centric the soul is just an emergent property the brain the self is just another emergent property of the brain outside of mind or whatever it's hard we don't have we don't have tools to sort it out um you know and it's also hard because many of the the the mechanisms that um that are in place are kind of helping that system to re to kind of self-regulate what goes in contrast to that is there are a number of patients who for instance never had a musical ability in their life they're a terrible singer how to play any instrument or whatever and they get frontotemporal dementia so they get they lost some prefrontal cortex and they have these spontaneous emergent Musical virtuosos right which is how do you interpret that because I have a strong interpretation of that oh you do okay but you know more about this than that yeah I mean you know it's yeah I mean there is I I will I'll just I will follow that with another Finding which is kind of interesting which if you take somebody that's learning how to sharpshoot and you knock out their prefrontal cortex you can actually make them sharpshoot better and sometimes that system you know anxiety for sure but that system may be you know having a actually fully functional maybe having a detrimental effect to doing things that are much more physical and fluid and perceptual and not necessarily in the thinking domain you know and as a martial artist to get back to what I was saying earlier like you you can't actually have a rational thought about being in a you know in a competitive fighting match right you you're reacting in much shorter periods of time right you know so some of that kick just kick yeah yeah yeah so some of it ends up being like kind of remember memorized and repetitive and instinctual and maybe Sharp Shooting is maybe maybe in some ways music is you know but yeah I'd love to hear your so the way that transcranial magnetic stimulation made it onto my radar was um around the idea that I think it was a lab in Australia would have people come in and say uh draw me a picture of a squirrel I can't draw just do it they draw a picture of the squirrel and then they would put TMS on them hit them draw squirrel again and by knocking out a region of their brain they could suddenly draw three or four times better and they're like what is happening yeah and so my wife is is a world-class artist she is unbelievable and so when I watch her do her thing I realize that she is she is seeing information that my brain filters out so it isn't necessarily that she I mean obviously she's trained as well but she her and her sister drew some her sister's older than her they drew something each for their grandma and gave it to their grandma and when they were young so like a two-year difference is gigantic at that age and her grandmother took the two drawings and was like well it's no fair because Lisa's younger assuming Lisa's drawing was the bad one but in reality Lisa's drawing was the good one so she's just had an ability forever and so I remember one time she's drawing and I'm like why are you spending time in that part of the drawing because she was doing it from a photo I'm like there's nothing in the photo that part of the photo is completely blank and she looked at me and she's like what and I'm like that part of the photo is completely blank she's like are you joking like what do you mean and I was being sincere I'm like that part of the photo has no detail in it what are you doing because I watched her spend like an hour on a part of the photo that to me was solid white and she was like you really don't see detailing no I don't and so I was like holy cow you actually see detail and then as I really sat and looked at it I was like I guess kind of so my brain was just like ah close enough those are roughly the same right move on and so buy and your brain has to do that right if you were if I was looking at you going there's this many photons bouncing off of that part of your head like uh you're never going to get anywhere and so your brain is constantly saying don't pay attention to this now the interesting thing is that particular example is indicative of my entire personality so part of the reason that like my wife will say to me all the time I wish I had your brain because I won't hold on to things so something could really upset me and I'm not joking five minutes later I'll be like oh oh yeah because I get completely absorbed in whatever I'm doing and I just let go now the problem is having a memory like that can be very frustrating because I will research the life out of something and remember 10 of it and I'm just like how is this possible like I've encountered that same idea like four times and I just can't hang on to it and so good in some areas bad in others but when I think about it my brain is like not essential not essential not essential not essential and so it's just letting go of all that stuff so with with TMS the thing that I found so interesting was that oftentimes your ability goes up not down as you knock a region offline because I always thought it would be a stacking like you you have to turn something on to get good at something versus turning something off so I can see how I mean look music is a little harder to explain I won't lie but like if there are let's say uh that my brain is saying the tonal difference between two things is irrelevant yeah and now I get a lesion it's like no no those little differences make a big deal and so now by knocking that area out I'm suddenly able to pay attention to those two things I could see or even like how the left and right hemisphere are telling each other to shut up most of the time which is why meditation is so interesting because as you relax areas of your brain that normally are offline suddenly they're they're not telling each other to be quiet and so they can start talking to each other so you'll get you'll combine really weird ideas that I wouldn't have had when my brain is so busy saying not essential not essential not essential yeah yeah that that is super intriguing to me now for me I thought you were gonna be like I'm a physicalist and it took us a long time to get to the part where you said if I was testifying that I would say uh that it's brain derived so is some part of you conflicted on whether that's all brain derived I think that it's a it's a difference between you know what you're trained and what's your you know where the you know sparse but uh available evidences and what where one's intuition is right you approach it with humility yeah I think so I mean we just don't it you know it's like everything else I mean the big bang is a end of one event right I mean that these are the problems with a lot of these questions is they're very hard to they're very hard to answer at the end of the day you know and I think that um the tools that we have for answering them aren't that great you know and so um you know being able to have better tools to understand the nature of the brain the nature of the Mind the nature of the self is the mind and the self you know the the the meditators will say that these are can be fused together in people and can be separated is that really actually a thing is that a phenomenological thing you're just tricking yourself into thinking that you're just tricking yourself it's as f look I have strong convictions loosely held if data came up that was like no there really is like you are an antenna and this is all being broadcast from the Andromeda galaxy or heaven or whatever okay cool I have I have no need to be right but I also my brain just models everything I see and it's like ah based on what I see and know this is how I'm going to think about it for now and again humility is the right way to approach things but I also think people should be unafraid to say this is what I think of it now so right now my opinion is very much that it's all arising from your brain but they're a separate phenomena in your brain that you can learn to tease out or you can learn like I really think again data comes out that proves that I'm wrong no problem but I really think as AI comes online where we're going to realize these are all patterns and that I can put a monk that's been meditating for 40 years and be like oh looking at that pattern I know right now he's practicing loving kindness whatever oh looking at that person there in a bout of anxiety over oh interesting something to do with a pet you know what I mean like I really think it's going to get that good yeah but it it may be that right these may just be modes it could be you know it could be something else there's some base signal right and then there's signal from inside or outside you know it's probably inside you know what we what we understand it is to be inside you know uh Francis Crick thought it you know it it came from something called the clouston as being a central kind of Rhythm generator in the brain but you know whatever some system that's kind of the base self system and then anxiety is layered on top of it you know but that's different than switching between two modes right switching between a mode of thinking about self and and being anxious um so I I'd argue more that way right that you've got some you've got some core probably self-representation something driving the networks to start going in a direction because there has to be something moving the system you know the reason why I've done a lot of hypnosis research is because you externalize control right so you can have a suggestion come into your brain and then you act on that suggestion right so you can hit highly hypnotizable people they will um people that get absorbed in things they will get um you know they they will be very suggestible to all sorts of things that are out of their volition you know and I used to not I used to think this is kind of BS like when I got to Stanford it was you know hypnosis is a big thing I attended David Spiegel's course and I you know I had this um had this experience I'm not that suggest you know not that hypnotizable had this experience of doing a group hypnosis there was a bunch of doctors in the room right and so I'm supposed to have my eyes closed but I'm kind of like you know looking watching this and I see all these guys they tell them to put the arm up and they're like fixed in the air and I went up to all of them after and I was like you know you'd like just did that to be compliant right like no no like I had no volition over it I want to be hypnotizable but from what I can tell I am mildly hypnotizable at best um if you if you think about that though if you're externalizing to some other entity to drive Behavior there's got to be something driving that behavior internally that's a representation either representation of self or mind or some combination of that but we just don't we don't even know where that originates right why would you say that so my read of that would be that your brain evolved to know that data will be coming from the outside and to do things with that data oh for sure it's it's two different there has to be a a source point in the brain or a a primary Network in the brain that's driving that's causal you know it to to be able to have volition you have to have that you have to have some some organ some circuit however you want to think about it in the brain that's driving it you know if not then because nah so I may be misunderstanding you do you say that because you assume that we have free will um I say that because well yeah I'm assuming we have a free will yeah interesting I don't think we have free will though the illusion is so compelling I don't spend any time thinking like oh I don't have free I act as if I do but when I really stop and think about what I know about the universe so far I'm just like nah probably not like this is probably all mappable meaning if you knew everything like there was a theory of everything you understand physics completely there's nothing that's unknown or unexpected that you could then map out how every billiard ball will react when hit by any other billiard ball and the amount of friction on the table Etc et cetera and that all of our neuronal firing and all of that stuff is it's all trackable we just don't have the data to be able to track it yeah I mean absolutely I think that's totally true it's it's more about at the end of the day if you if what you're saying is true then it's all just reward reinforcement that where our entire experience is you know assuming what you're saying it's all just reward reinforcement we're just being driven completely by externalized stimuli being processed this threat or pleasure or some derivation of that welcome to my world view that's why I say like you're having a biological experience understand how this all works the great news is that as you enter as you become aware of it what I'll call awake in The Matrix I wish that word wasn't getting a weird reputation uh but as you become awake in The Matrix you can suddenly intercept some of these things and go oh I would like to react now in this way I'm not just going to be beholden to my emotions and you really can insert a level of awareness even if whether you get that level of awareness is something you can choose to do or not which I doubt but it certainly feels like you can and so uh becoming aware that awareness isn't I mean I suppose you could argue that's reward driven as well but the sort of thing that people who are you know serious meditators maybe some of the Psychedelic crew you know that that whole set of writers you know it doesn't it doesn't map onto the way that standard reinforcement happens in the brain you know I think that's really the I agree with you that there are probably a lot of people walking around the world that are Dr you know kind of driven com their mind brain their mind brain self is kind of all fused together and they're being driven primarily by these reward version loops right um but the sort of like meditative descriptions that people say unless you can argue that that's all being driven by some other way of reinforcing reward doesn't play on to the to this you know more standard kind of reward story you know can you give me uh an example specifically of what they would say because like and while you think of that to all the people out there I get this every time I bring this up they're like as soon as you do psychedelics you're going to realize that your world view is just absolutely ridiculous cool fair enough I'm very open to that data point and and it is merely at this actually there's two things that stop me legality and uh I recently read a story about a guy that did um psilocybin for the first time and it sent him off on like a four month or longer like manic episode and he said it ended up ruining his life and I was like whoa that was sort of the first um calming thing I was like ready to go yeah uh and that was like oh maybe not I don't advocate for anybody to take psychedelics for you know personal reasons in the in that kind of a context if that makes sense um is kind of as a physician I think they're useful within a kind of diagnostic framework what I can tell you is the people that do advocate for those things you know you know that that's the sort of thing that you hear the risk as you've aptly pointed out is there are certain people particularly people that are on the kind of psychotic um you know hypomanic bipolar Spectrum in which psychedelics are um really contraindicated right and all the trials like intentionally strip out anybody that has a threat of that although there there is an ongoing trial interestingly of people with an established psychotic disorder um diagnosis um being explored right now which I'm really like with psychedelics Wow and and they've given you know schizophrenic full-blown schizophrenic patients Academy anything and they don't have a worsening of their their psychotic symptoms so uh Carol tominga down at UT Southwestern did a lot of that work but um yeah I mean I think that what you hear from people if you go to psychedelic science or you talk to patients that receive this is there there ends up being an experiential stripping of these things apart and and that could all just be you know a construction right as you as you aptly point out and that's that's why all of this is all theoretical like there's no like what you're saying I think is theoretical what I the various things I'm saying are all theoretical your personal worldview is most aligned with I'd say the majority of neuroscientists walking on Earth today right so your view is what if we had a polling at Society for Neuroscience what most of those folks would would say if you deploying at psychedelic science 2023 it'd be a majority of those folks probably you know and so it's just one of these things where it's hard to it's I I don't like to kind of and the reason why I'm not giving you a firm answer on this and why I'm giving you a lot of like open questions is because I don't I don't like to have opinions maybe to your point I don't like to have opinions that aren't testable and at the current state of things your what while you're views align with the majority of neuroscientists you know they're that's some of that's probably an extrapolation from animal studies and stuff like that which I would argue the whole Human Experience is beyond what animal cognition is um you know and then the you know the Psychedelic crew um or even maybe some of the hypnosis researchers having a different viewpoint on this is all experiential and maybe at the end of the day to your point just kind of self fulfilling prophecy or self-deluding or self or beliefs that are that are kind of getting entangled in in World Views around what the science is but you know to your point we don't have the tools to to measure it so it's it's it in 2023 an impossible question to answer but an important a very important one you know and and once we get a handle on that if we really if it really is that the brain is truly just you know self-propagating and you kill a part of the brain and you kill that part of the person forever and that's just that part of that person is dead um or until we find ways to regenerate the brain dead or whatever then um you know then it aligns with the the sort of way you're thinking about it um but yeah I don't I don't love I don't love I try to bite off chunks that are more proximal to the tech we have now and then that allows for me to have a real bet and then have an answer that's yielded out of it so this idea of like moving hypnotizability up transiently like we had enough science to be able to go and say yeah we can we can do that or being able to figure out you know you know kind of slick ways of of cutting you know speed of stimulation um down to really short periods of time and asking questions about moving brain circuitry quickly or slowly or what's the nature in some ways what's the nature of the brain circuitry so we have a study now where we scan people every day and then we look at you know the change in the circuitry as it relates to the change in symptoms so does the circuitry change precede the behavioral change or vice versa tells you something inherently about you know when you know based off what you're saying you'd assume the circuitry has to either change concurrently or before and then you'd have a behavior change I actually don't I think that there is something where you could you can do it in either direction and that's part of what's utterly fascinating it's like smiling and then feeling better or feeling better and then smiling you can actually go either direction well at this it would be it would be weird if the stimulation changed the behavior without a brain change from what you were saying earlier right like you'd have to assume that the brain changed for for ex for a stimulation induced experiential change to happen it's interesting I think you have to bypass like physics principles um we'd oh God we didn't really open up a can of worms there uh so I will I'll tap out with that question hanging in the air uh brother this has been so fascinating I've absolutely love this where can people follow you so Stanford brand stimulation lab is uh the best place to follow our work and yeah happy to particularly have patients come in and you know be interested in some of the studies so amazing boys and girls if you haven't already be sure to subscribe and until next time my friends be legendary take care peace if you want to learn more about the use of psychedelics to treat depression and I hope you do check out this conversation with Dan Engel ebook is a fascinating medicine because you can have people addicted to heroin decades long go through one treatment