The Tim Ferriss Show - #824: Dr. Kevin Tracey — Stimulating The Vagus Nerve to Tame Inflammation, Alleviate Depression, Treat Autoimmune Disorders (e.g., Rheumatoid Arthritis), and Much More

Starting point is 00:00:00 Well, hello, boys and girls, ladies and germs. This is Tim Ferriss. Welcome to another episode of The Tim Ferriss Show, where it is my job to deconstruct world-class performers to determine or identify, try to identify how they do what they do. In this episode, I have turned yet another conversation into a how-to-search for myself to help me with various things, chronic inflammation, and other issues that seem very squarely, difficult to treat with many frontline treatments. So who did I find? I found someone named Kevin J. Tracy, M.D. He is the president and CEO of the Feinstein Institutes for Medical Research at Northwell Health, a pioneer of Vegas nerve research and author of the recent book, The Great Nerve, the new science of the Vegas Nerve and how to harness its healing reflexes. Now, I say this in the interview, but there's so much nonsense floating around about the Vegas Nerve

Starting point is 00:00:54 and so many different hocus-pocus, hand-wavy things related to it that I discarded it. but Dr. Tracy is the real deal. His contributions include identifying the therapeutic action of monoclonal anti-TNF antibodies, we'll explain what TNF is, and discovering the specific reflex control of immunity by the nervous system called the inflammatory reflex. These discoveries launched the new scientific field called bio-electronic medicine, which investigates the therapeutic applications of Vegas nerve stimulation to cure disease. The case studies are tremendous, but also the published studies and just data overall are so compelling, there's a lot you can use here. And it all started with a mysterious death from sepsis of a toddler who was in his care.

Starting point is 00:01:43 That's how he started pursuing studies of inflammation. His lab has since revealed molecular mechanisms of inflammation and identified the use of vagus nerve stimulation to treat it. An inventor on more than 120 U.S. patents and the author of more than 450 scientific publications, he is among the most highly cited scientists in the world. He co-founded the Global Sepsis Alliance is the author of Fatal Sequence and is a national and international lecturer. So I'm so excited to introduce you guys to Kevin.

Starting point is 00:02:12 He is amazing. He is not only a world-class scientist, but he's also a world-class explainer, which you will get to taste firsthand. So we're going to get to that. First, just a few words from the people who make this podcast possible. Sleep is the key to it all. It is the foundation.

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Starting point is 00:06:21 Users should not disregard or delay in obtaining medical advice for any medical condition they may have and should seek the assistance of their health care professionals for any such conditions. Dr. Tracy, good sir. Nice to see you again. Thanks so much for making the time to have this conversation. Thanks so much for having me out. I'm really looking forward to it, Tim.

Starting point is 00:06:44 And I am really holding in my enthusiasm. which I'm not going to do for very long because we had a chat, brief chat, maybe a week or two ago. And I was bouncing around in my chair. I was overflowing with excitement to ask so many questions. And the reasons for that excitement will, I think, become very, very clear, very quickly. But let me as context for people listening, and you know some of this already, explain why I never looked at vagus nerve stimulation seriously up until very recently. And primarily it's because there's so much crap and so many charlatans, whether it's deliberate or not, floating around online, touting the most ridiculous approaches, devices at best innocuous,

Starting point is 00:07:37 sometimes probably putting people at risk. And at the checkout, they might be selling audio chakra cleanse soundtracks and just associated nonsense that shows that they wouldn't be able to find a logical argument if it bit them in the ass. And I thought, you know what, I'm just going to put this in the category of things that I should ignore. And also I'd been sent, and not to throw this under the bus, but maybe we'll get to it, a book on polyvagal theory. And I looked at it and I know just enough evolutionary biology to be dangerous. And I thought, I'm not convinced this actually makes a whole lot of sense. And again, came to the conclusion, I should just put this to the side, at least for now. The reason that changed is that a friend of mine who is quite technical,

Starting point is 00:08:29 he is one of the top performing investors in biotech and let's just call it medicine writ large when it comes to public equities and other types of investments. He has, has patents to his name. This is a very smart guy. And he reached out to me via text. This is a good friend of mine and asked if I'd ever looked at Vegas nerve stimulation. And I was like, no, absolutely not. Is there something interesting there? And he said, I think there is. And he'd been digging into the literature. He's also former tier one operator from the military. And he had been using, and we'll get to this because a device is not a device, it's not a device. There are a lot of differences, but he had been using something purchased off the internet and had tripled his heart

Starting point is 00:09:21 rate variability. And I mentioned the military piece because he has, I'm not sure if this is the right term, and I'm sure I'll misspeak a lot, so feel free to give me a polite smack when I do. But sympathetic overdrive, he would lay down to try to go to sleep. His heart would be racing, his glucose would be spiking, not from PTSD, but from a lot of other things. And he had tried meditation, and he's diligent. He will do what he assigns himself to do. He had tried all these interventions to improve heart rate variability, and maybe we'll talk about that.

Starting point is 00:09:54 But suffice to say, within the realm of, say, athletics and recovery and this, that, and the other thing, often higher HRV is a good thing. And all of these interventions he tried had bumped things, maybe 10%, maybe 15%, and then he used a vagus nerve stimulator for a few weeks and tripled his HRV. And he's setting personal records week after week. And I thought, okay, could be N of one and placebo, sure, but I should take a closer look. And he sent me an email with a bunch of citations. And I started going, as I do obsessively down this rabbit hole. And I listened to an interview. I want to give credit where credit is due on STEM talk. And they interviewed you. And I thought, okay, I should really, really reach out

Starting point is 00:10:44 to Dr. Tracy. And then, just coincidentally, was walking through a bookstore. And right in front of my face was your book, The Great Nerve. And I thought, okay, universe, not to get too woo-woo. But I got the message. Message received, reached out, and also read the book. I recommend everybody read this book. It's not only from a very credible source, but you are a good writer. It's very compelling. So let's skip my TED Talk. Thank you, everyone, for coming to my TED Talk, and go straight to the big news. I guess this was literally you emailed me, and now it's big. So what is the big news that literally has just been announced? It was just announced that the company Setpoint Medical, which will now be marketing a device to stimulate the vagus nerve, to treat rheumatoid arthritis, has received FDA approval.

Starting point is 00:11:44 So there'll be a product launch underway for everything we're about to talk about in the context of using a medical device that activates an evolutionarily conserved and ancient reflex through which the brain, can suppress inflammation when it's running out of control. We've discovered that signals travel from the brain through the vagus nerve. We'll talk about what the vagus nerve is, but these signals traveling in the vagus nerve are like the brakes on your car. And when you tap those brakes to slow your car barreling down the hill, when this device activates what we call the inflammatory reflex. So you talk about this being a current event.

Starting point is 00:12:26 As you and I both know, it's the front page story in the New York Times today, celebrating the successes at Setpoint Medical, and kudos to them, to Murthy, the CEO, to Dave Chernoff, the CMO. But it's based, as the article explains, also on 20 years of work by my colleagues and I at the Feinstein Institute at Northwell and New York, and all of which has been essentially replicated by dozens, if not hundreds of laboratories around the world. So it's a deep, it's a rich story of science converging on how the vagus nerve and switch off inflammation that culminates this morning, as you point out, in a story about patients who've

Starting point is 00:13:05 already been treated, some of whom had rheumatoid arthritis for decades, couldn't button their blouse, couldn't pick up a pencil. If you don't mind my interjecting. Yeah. I get excited too, Tim. I apologize. Oh, you get excited too. Please, I don't want you muted. I don't want muted, Kevin. I want excited, Kevin. And let's feed that fire a bit. Let's talk about specifically one of your patients who shows up multiple times in the book, but most memorably to me in the coda. And could you just tell her story in brief? It doesn't have to be super brief. Because I want people to understand just how drastic. And this is not going to be true for everybody with every condition, but just how significant the transformation can be. Kelly Owens is the patient you're referring to.

Starting point is 00:13:54 I know her story very well. I know her very well now. And when I think of her story, you just introduced it, I got goosebumps again, as I do every time. Kelly was a teenager when she was playing sports in high school and developed one night after a trivial injury, a major swelling in her knee that cascaded to a very serious problem, that ultimately was diagnosed as Crohn's disease, an inflammatory bowel disease complication affecting her joints. Kelly spent her teenage years and most of her 20s in and out of hospitals, in and out of wheelchairs. Her father actually gave her a cane for one of her birthdays. I'm not sure which one.

Starting point is 00:14:36 Now, it's really important. I should point out to him that these stories are so interesting and compelling because for much of her life, Kelly always loves to write. She still loves to write, and she blogged many of these stories in the public domain for much of her life. So all this is out there for other people to read. Kelly ultimately became a school teacher, but could not be treated. Her condition couldn't be fixed from New York to the Mayo Clinic to Hawaii and back. And it culminated when her physician told her and her husband, Sean, to plan on staying home without children because of all the medications she was on

Starting point is 00:15:13 and childbearing would be too risky and to get used to her life like that. Around that time, she saw me on a Huffington Post live internet interview, live stream, and she contacted me, and I don't recall that contact, but I recommended she look into Setpoint Medical, the company that I had co-founded in 2007 to do these clinical trials. And Kevin, can I pause you for just one second? Don't lose your train of thought, but also I recall, and fact check me here, chronic fatigue, having to lay down elevator legs. I mean, really just had trouble functioning on a day-to-day basis is my recollection. Absolutely. People think of, they hear the word arthritis. When they hear

Starting point is 00:15:55 rheumatoid arthritis, they hear arthritis. This is not the trivial sports injury you had in high school now. It's a rainy day and your knee or your elbow is sore. This is a serious condition that affects the whole body. It can affect the kidneys. It can affect the brain. It can affect your heart, similarly for inflammatory bowel disease. It's not, obviously, bouts of diarrhea and abdominal pain and nausea and vomiting can be disabling, but the inflammation that affects the intestines in inflammatory bowel disease or in Crohn's disease also affects other organs, the spine, the joints in Kelly's case, in her arms and legs. And so these are serious disabling conditions. They can cause depression. They can cause anxiety disorders. They can cause chronic fatigue.

Starting point is 00:16:37 So that's exactly right. All right. So she reaches out to you. You recommend she investigate set point medical. Then what happens? My hope was that although I wasn't optimistic because she lived in New Jersey and the clinical trials were being done in Europe. But now that I know Kelly, I understand how she was able to talk her way into a clinical

Starting point is 00:16:56 trial in Amsterdam. She and her husband, Sean, sold all their earthly belongings, as she said everything that wasn't tied down. Their friends and family through a GoFundMe kind of operation, the money they needed to move there for six months. She enrolled in the trial and was one of the first patients to receive an implant. I call it a Generation 1 implant. It was like a cardiac pacemaker under the collarbone, under the clavicle, with a lead or a wire that is tunneled up into the left neck where the vagus nerve travels next to the carotid artery. A couple weeks later, they're in

Starting point is 00:17:30 Amsterdam still, and Kelly is running a little bit late for her follow-up appointment as part of the clinical trial to get checked out by the doctors in the trial. There's elevated trains in Amsterdam and Kelly sees a train coming and runs up the stairs to hop on the train so she won't be late for her appointment. She turns around like, where the hell is Sean? Sean's at the bottom of the stairs with tears streaming down his face because Kelly, it was the first time he'd seen Kelly run up the stairs in years. Yeah, she had trouble walking on the cobblestones. She had trouble walking in the cobblestones. Not long before. Her father gave her a cane for her birthday that she used for many, many years when she wasn't in a wheelchair,

Starting point is 00:18:09 and now she's running up those metal stairs in Amsterdam to catch a train. So she had a remarkable response to this therapy. So a few months go by, and I didn't know any of this, a few months go by, I get an email. The subject line was, thank you for saving my life. So it was wedged in between a lobbyist in Washington talking about research expenses and my own corporate controller talking to me

Starting point is 00:18:33 about my laboratory's research expenses. So I read Kelly's email first. And I learned her story and that she wanted to thank me in person. And so I said, come on in. But I also brought on that first meeting a couple of my physician colleagues. And we talked at length about Kelly when she told me that she wanted to help us in the bio-electronic medicine universe be a patient advocate for this idea. We spent a great deal of time with her explaining that there are risks and benefits of this.

Starting point is 00:19:08 People resist change. The world is not ready for something truly new. The world's not ready to talk about a one-inch device in your neck instead of taking pills and injections. This is going to change everything. And if you're going to be a leading spokesperson on the patient side of this, you may be... People are going to tell you you're a placebo effect. Tim, all of those things happen. Oh, I'm sure.

Starting point is 00:19:29 The CEO of a major pharmaceutical company at a social event, told Kelly, this was many years ago, if you're real, I mean, how do you say this to a patient? If you're real, then everything I'm doing is at risk and I could be out of a job. Yeah, and not with a smile on the face. That was a real, a real important day in my life. She hugged me. I hugged her. She cried. I cried. And then she said she had a present for me. And I said, what's that? And she gave me a gift wrap cane. It was clearly a cane, the way she wrapped it. The handle was wrapped and the cane was wrapped with a big ball on it.

Starting point is 00:20:07 I opened the card, which I, of course, still have attached to the cane. The cane is still wrapped. The bow is still on it. And it sits in the corner of my office. And every day, if I'm having a tough day in the lab or any of my colleagues are, we come down and we look at Kelly's cane and reminds us why we do what we do and what we hope can happen when you do science in the hopes and dreams of discovering things that might help people someday because it can happen.

Starting point is 00:20:35 So I want to add a few things to that. What a story. And like you said, some people at the time are like, ah, placebo. But placebo effect, and I'm pulling directly from you here, rarely has durability past a certain point, right? But when you're looking at six months out, 12 months out, and she furthermore, not to say this is more important than anything you just described, but certainly for a lot of people listening and for me personally having suffered from what I would describe as chronic fatigue for decades. And we might dig into some of that. She went from basically having a blinking battery empty for her day to day to having almost too much energy, which isn't to say it was a problem, but just kind of running up the stairs, bouncing off the walls. And my God,

Starting point is 00:21:27 What a difference that the lives that are lived by the former and the latter, the magnitude of that difference is just can't really be overstated. It's two different experiences of life. So now I'm going to get all excited and lose my train of thought, but I'm going to scatter shot here for a second. So just to also lay out a few things for folks. So part of what has been so exciting about this and why I want to pay a lot of attention to it, There are a few things feeding into it, for me personally. So one is having some exposure to, I suppose, what you might call bioelectric medicine through early, early generation TMS, but then also later accelerated TMS with better hardware, better targeting for things like treatment-resistant depression. People can look at Nolan Williams out of Stanford and just some incredible data there. Focused ultrasound in conversation with Nora Volkov for potentially. potentially hitting the nucleus accumbens for addiction. And the possibility, not just the

Starting point is 00:22:34 possibility, but now a lot of compelling data, for instance, around set point medical and other forms of vagus nerve stimulation, but I know you might put some of them in quotation marks to be an option and alternative to biologics, right? Let's just say oral or intravenous or intramuscular medication that have a host of really non-trivial side effects. And for myself, looking at past depressive episodes, looking at, as I've tried to unwrap that for myself, which is very under control for the last, I'd say, 10 years. But looking at the Lyme disease, which I've had twice, and by the way, guys, that's not a, oh, I just happened to be lethargic and I'm hunting for a diagnosis going from quack to quack until I get Lyme disease. Eastern Long Island, look at the CDC map, it is just, it is as red as it gets. And thinking of then later neuroinflammation, I have neurodegenerative disease in my family on both sides. So looking

Starting point is 00:23:39 at all these things unfold and feeling like this is going to be a way overreach, but there seems like there might be, I don't want to say a unified theory, but there's some connective tissue tying this stuff together and started playing with the microbiome because changes in gut flora have been associated with, say, depression or animal models of depression or lack thereof. Also looking at, say, the ketogenic diet or exogenous ketones as a way to reduce inflammation. And when you start looking at all this, and then when I read your book, the reason this ties into your book, and we should probably define what the hell the Vegas nerve is, because it's more like Vegas nerves, and you'll give a great description.

Starting point is 00:24:29 I'll just give a couple of quick samplers, and then we can get back into them at any point. But GLP1 agonists, right? In the news, Zembeck-Majaro, take your pick. But at least in animals, my understanding is if you sever the Vegas nerve, those GLPGELB, op-1 agonists, they cease to exert a lot of their effects that you would otherwise see. And similarly, people may have heard these stories, which are based on research, of microbiome transplants from, say, obese mice to normal slash lean mice, let's just say. And lo and behold, this amazing thing happens, which is the normal mice take on the attributes,

Starting point is 00:25:16 the insulin insensitivity, the weight gain of the obese mice. Fascinating. But if you cut the vagus nerve, that doesn't happen. So what the hell is going on? And all of these things are interconnected in the most interesting ways. There's so much left to learn. But let's begin with a definition of basic terms. Vegas nerve. How should people think about the Vegas nerve? when you look online you'll find billions of web impressions of vagus nerve so i'll just describe it anatomically and functionally first and then we can cherry pick where to go we all should should define if you agree bioelectric medicine because yes you talked about the connective tissue in the story and then we should define inflammation so the vagus nerve we call it the vagus nerve and that's what

Starting point is 00:26:09 it's called but you have two of them so there's two vagus nerves like two thumbs on each side. Each one arises at about the level of your ear at the base of your brain, travels down both sides of your neck with the carotid artery, and then across the chest into the abdomen. And along the way, it sends out countless branches to all the organs in the chest and abdomen that you don't think about all day long. Now, within each of those two vagus nerves, left and right, you have 100,000 fibers. Each fiber is that you unique nerve. That's the part that's lost almost immediately by 99% of the casual readers of vagus nerve stuff. Each fiber, 200,000 fibers, each fiber has an origin in either the body

Starting point is 00:26:58 or the brain. 80% of them actually originating the body. They carry information about the organs and your body up into your brain. And then obviously the other 20% originate in the brain and they carry information back down to your organs. So again, I'm trying to clear up some misnomer along the way. The biggest misnomer is that you have one vagus nerve, like a solid copper wire. You don't. You have 200,000 vagus nerves if you treated each one as a wire. Let me ask if this is a fair visual to paint for people.

Starting point is 00:27:33 So imagine that from the base of the ear, roughly, this is Tim the layperson talking, but you have these two thick cables coming down on either side kind of tracing the carotid artery and they're like transatlantic cables just full of 100,000 fibers on either side and they go down and then they kind of branch out like the Mississippi Delta or something like that and innervate and touch I don't want to say just about everything imaginable but there are 200,000 of these right? Is that a fair visual to paint for people? or would you modify that? No, I wouldn't modify at all. In fact, if you go one step further, each nerve ends on either a cell in an organ or on another nerve. And those other nerves,

Starting point is 00:28:19 those secondary nerves that the vagus nerve ends on, those branch out further. Here's how I like to visualize it. I think we chatted about this a couple weeks ago. If I had a solution, if I had a vat of liquid that could magically dissolve all the cells in your body, and I submerged you in it for five minutes and pulled you back out again, you would still look like Tim. Because every cell in your body is essentially touched by or surrounded by nerves. You're a walking nerve net. And so one way of thinking of the vagus nerve,

Starting point is 00:28:52 if your body is a walking nerve net, all your organs in your body are encased in a nerve net, well then the cable that pulls the nerve net out of the sea is like the vagus nerve. Because it's connected to the brain, the brain would be like the fishermen operating. Now, all the signals traveling in these electric networks are traveling up and down the transatlantic cable, the cable connecting the nerve net in your body to the nerve networks

Starting point is 00:29:17 in your brain. And we know the identity of 200,000 individual fibers. What we don't know, Tim, is we don't know completely. We don't completely understand the code of the information that's being transmitted in each of those fibers, right? People talk about the action potentials. which are the spikes of voltage change that travel up and down a nerve fiber. Yes, we can study those.

Starting point is 00:29:41 Yes, those are very important. The question is, is that all the information that's being transmitted? That's an area of active research now that's very interesting to me. Because in one hand, 200,000 fibers is a lot. But on the other hand, 200,000 fibers isn't that many. And for instance, we know you can transmit on the same fiber optic cable, lots of TV shows, and lots of radio shows at the same time. So there's a lot of interesting questions embedded there.

Starting point is 00:30:08 And let's just say of those 200,000 fibers, do we know roughly how many affect HRV and cardiac function? It's a much smaller number than people think. We don't know exactly for sure. We know in mice, in some beautiful work out of Harvard Medical School by Steve Lieberliss and his colleagues, we know in mice that somewhere around 100 or 150 fibers, are sufficient to control breathing.

Starting point is 00:30:37 Now, a mouse vagus nerve has 5,000 fibers, not to 100,000, but it's still a really small fraction of the total number. And so, for instance, a few dozen of those fibers control when the mouse gets a full inhaled breath. And another few dozen of those fibers control the process of holding the breath and on down exhaling the breath. So in human beings, for instance, and we'll come back to this some more, but I estimate somewhere between 1,000, give or take, maybe 1,500, maybe 2,000 fibers

Starting point is 00:31:10 control the amount of inflammation cytokines being produced in the spleen. So you're looking at, we can map the identity of the number of fibers going to the heart. Again, it's a few thousand. The open question is, say we can assign the action of 10,000 fibers on each side. What are the other, what are the other 90,000 do? Yeah, exactly. Yeah. Just a quick thanks to one of our sponsors, and we'll be right back to the show.

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Starting point is 00:32:53 I want to keep giving people Scooby snacks here. Just because I'm so excited, I want to keep reiterating the potential payoff. of doing this the right way and you mentioned cytokine i want to double click on that for a second we don't need to get immediately into the technical definition of that i'm sure we will but people may know that word from what covid 19 cytokine storm boom can lead to fatality right in some patients and i suppose i'm curious to know then just in short form what happens to cytokine production when you stimulate the vagus nerve correctly? It gets turned off.

Starting point is 00:33:39 If you stimulate the fibers we were just talking about, it turns off cytokine production quite effectively. We discovered this by accident, actually, 27 years or so ago in the laboratory. We discovered we were working on experimental anti-inflammatory drug that we had developed, and we put it in the brains of animals with a stroke. and the idea was this anti-inflammatory drug in the brain would stop inflammation. And that did happen. And the stroke in the animals was smaller and we were very happy. But surprisingly and unexpectedly, when we looked at inflammation in the body of those animals with the drug in the brain, they also had less inflammation.

Starting point is 00:34:18 This was a head scratcher. This made no sense whatsoever. And is that's a head scratcher because the effect should have been sequestered to the brain because of the blood brain barrier? either the blood brain barrier, but also because we had put such small amounts of drug into the brain. There wasn't sufficient amounts to account for the saturating and stopping inflammation in the body. What we discovered years later was that the drug in the brain was actually turning on the vagus nerve. At the time we discovered the signals were in the vagus nerve, it sort of became obvious to me as a neurosurgeon working on cytokines in the lab, it became obvious that if the vagus nerve is turning off inflammation, then it should be possible to stimulate those fibers

Starting point is 00:35:05 in the vagus nerve with electrodes and treat inflammation with a device instead of a, instead of drugs. And so that's what we wrote on the back of a napkin 27 years ago that kind of led to where we are today. At the end of the day, we understand using techniques like optogenetics where you can make neurons in the mouse brain sensitive to laser light and other sophisticated molecular biology and genetic tools. I can explain to you how the brain through the vagus nerve turns off cytokines and inflammation. I'm sorry, Kevin, could I pause you for one second before we get there? And this is something I do not, I mean, I'm going to ask a lot of questions. I don't know the answers to it. Otherwise, interviews are pretty boring for me. So does this mean that you could use

Starting point is 00:35:50 as an acute intervention, vagus nerve stimulation, say hypothetically in the ER to stop anaphylaxis or to address asthma attacks or sepsis or anything like that? Once you understand

Starting point is 00:36:07 the basic signals that flow in the vagus nerve to control one aspects of the immune system, in this case how vagus nerve fibers can turn off cytokine production, you can ask new questions.

Starting point is 00:36:19 Yep. And let me, me answer your question by adding a definition because I think it's a perfect segue. So in order to understand the answer to your question, how to use vagus nerve stimulation and other conditions like asthma and other conditions, you have to back up a bit. You have to say, okay, what condition are we talking about? Let's look at how the pharmaceutical industry does this. Pharmaceutical industry starts by picking a disease, a condition. Let's do rheumatoid arthritis first as it'll become obvious why in a minute. We're going to look at rheumatoid arthritis. That's the condition. What's the

Starting point is 00:36:50 molecular mechanism. Well, the early research with using monoclonal antibodies against TNF showed that that helps about half the patients. So that's the mechanism. So now we can make monoclonal antibodies that hit the molecular target, TNF, to treat the disease. And now you sell your monoclonal antibodies and after they're approved for safety and efficacy by the FDA. Great. That's what the pharma industry does. We proposed some years ago, 15 years ago or so now, the idea of bio-electronic medicine as an approach to develop therapies. You begin in the same way. You pick your condition.

Starting point is 00:37:24 It's rheumatoor arthritis. Then you say, rather than screen for antibodies or other molecules to stop TNF, which is the target in rheumatoor arthritis, let's see if we can find nerves that control TNF production in the body in situ. If we can find such nerves, then we can build devices to control the nerves, and the devices become the therapy. The bio-electronic medicine story works as long as you know the molecular mechanism. And that's where people have to be really careful with vagus nerve stimulation.

Starting point is 00:37:57 So there are many conditions today that are treated with antipsychine therapy, anti-TNF, anti-IL-1, anti-IL-6. Those conditions include things like rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, psoriotic arthritis, and some other conditions. of them are autoimmune conditions. When you ask about asthma, and you mentioned earlier also depression and some other conditions, I go back to the basic starting point. What is the disease, asthma? What is the mechanism? Tim, no one knows. Yeah. That's a full stop. That's a full stop for me before saying, you know, Vegas nerve stimulation will or will not work. I remember one of my

Starting point is 00:38:40 mentors and friends, rest his soul, Frank Austin, was one of the least. leading experts on asthma research for decades. And a few years before he died, I said, Frank, I think I'm going to do some asthma research. He said, okay, what are you going to do? So we got this mouse model. He goes, Kevin, the last article that wrote in asthma was entitled, Mice Don't Wees. I like that. That's Mice Don't Weas. Well, you know what that makes me think of? And I mean, like, we're going to digress for a second here. But we need the animal research. And there's a lot you can do in a sort of metaphorical petri dish now with like synthetic biology and stuff. There's a lot coming down the pike, but still animal models are super important. But some of these, since I've funded so

Starting point is 00:39:23 much early research and some later stage stuff with respect to psychedelics since 2015 and psychedelic assisted therapy, but also basic science, some of the animal models are pretty hilarious, right, where they're looking at like the head twitching and paw licking in the case of like Barry Jacobs giving LLC to cats way back in the day decades ago at Princeton. And they're using, let's just say, the anti-depression animal models might involve like swim to exhaustion. And then you're like, okay, well, I guess methamphetamine is going to be one of the best antidepressants you could possibly give someone if we're using that as the proxy. And so a lot of it's imperfect. And yes, mice don't wheeze. So maybe, especially if you can't identify, like you said,

Starting point is 00:40:07 I guess the mechanism, you need to be able to at least hold on to some of the variables. So let me come to just depression for a second. I know this is going to be all over the place. It's like Tim after too much caffeine and a couple of glasses of wine, which is not where I am. I did have some pretty good ketone mono esters before our chat, though. And I wanted to come back to depression because it's a subject near and dear to my heart. It's something that affects a lot of people. and when people experience depression, it can also feed on itself in the sense.

Starting point is 00:40:41 And I speak from experience where you personalize it, like this is a me problem. This is a character flaw, and it's permanent, and it becomes this loop that can exacerbate the condition. I've long had this suspicion, and this is part of the reason for a lot of the research involvement, is that anti-inflammation or inflammation is sort of potentially at the core of a lot of this. Whether you look at, for instance, they're very potent anti-inflammatory effects of certain psychedelics in the phenethylene class, like 2CB, for instance, very, very significant at very, very low doses. And when I'm looking at some of my highlights, I have a ton of Kindle highlights

Starting point is 00:41:19 from your book, The Great Nerve, I'll mention it again, pick it up, guys, you will not be disappointed. But you can induce depression in animal models by causing inflammation. And people too, Tim. And people too. So, and I want to just read a little bit here because we've long had, and I think many, many doctors still ascribed to a chemical imbalance theory of, say, depression or mental illness writ large, but depression. So this is directly from your book. If an SSRI has helped you or someone you know, that's wonderful.

Starting point is 00:41:55 Large randomized clinical trials of SSRIs indicate they confer some clinical benefit in some patients, which is true. I've seen lives changed. now whether it's actually serotonin or not is a separate question but back to your book but these results in your personal experience do not prove causality or confirm that serotonin dysfunction is causing depression for example SSRIs may also inhibit inflammation and then here's kind of the clutch paragraph that i highlighted interestingly administering SSRIs to animals and patients with inflammation after receiving cytokines in the lab so you're deliberately trying to provoke inflammation administering SSRIs can alleviate depression causing by these cytokines. This anti-inflammatory role of SSRIs is little studied and incompletely understood, and I sincerely hope that my colleagues are inspired to investigate it further. So this raises some very, very, very interesting questions. And since we last spoke, I have been toying around. I use the word toy very deliberately with some devices that I may not

Starting point is 00:42:55 continue to use, but I have a variation that a friend recommended to me very low cost. that I'm going to be switching to, because I don't like the neck seizures very much. But nonetheless, I will say that the combination of the stimulation plus, and I realize I'm fussing with a number of variables, intermittent fasting and exogenous ketones. So I am throwing a lot against the wall here. But the addition of the stimulation, which is just a few minutes a day, and we'll definitely talk about your friend Ulf and his story, because that guy is not. wearing a tinfoil hat. He's credible, as credible as credible can be. The stability of my

Starting point is 00:43:37 mood is remarkable. And again, I think there are people out there just if I could throw some folks, not throw them under the bus, but just lay a criticism. There are some folks out there well-educated, but non-scientists who worship at the altar of science with a capital S or Scientism, perhaps it is. And so they'll criticize maybe a story like this or the story of your patient and say, ah, end of one, placebo. And they discard it that way. But a lot of very critical scientific investigations begin with case studies in the literature.

Starting point is 00:44:15 I'm looking at that right now with respect to Alzheimer's and exogenous ketones. There's some very interesting stuff out there. So could you, this is a very long-winded way of trying to set up inflammation right inflammation is one of those terms that gets used like it's specific but it's like saying business or sports or art it's a big umbrella term so what is inflammation in the context of what you have studied and observed as a clinician and as a researcher and inventor for that matter yeah we're going to have to do a couple of shows Tim yeah simply put, inflammation was defined thousands of years ago as the redness, the pain, the swelling,

Starting point is 00:45:05 and the heat that you feel when you sprain your ankle or get an infected wound on your body. Everybody's seen it, everybody's had it, and it's a good thing. It runs its course, and it's the product of cytokines in part and other molecules, TNFI-O-1, I-L-6, but other molecules made by white blood cells and other tissues in your body. So it's a good thing when it stops. It's a good thing because it helps heal the wound, helps proliferate stem cells, helps fight off infection or bacteria

Starting point is 00:45:35 that might settle in the wound. And it's a good thing if it stops. The problem is, we'll talk about why it stops, but the problem comes when it doesn't stop. And when it starts spinning out of control, like in Kelly Owen's case, then it becomes like the army showing up

Starting point is 00:45:51 with howitzers to break up a peaceful demonstration or a picket line. And you have these violent outbursts of inflammatory reactions that cause the problems in rheumatoid arthritis and inflammatory bowel disease and these other conditions. So that's what inflammation is. That's what the textbook say. That's what everybody knows. That's what everybody's taught.

Starting point is 00:46:11 That's what everybody talks about. That's the anti-inflammatory drugs we have today. Modify the molecules we just talked about, TNFs, the IL1s, the prostateans. That's how ibuprofins and other non-steroidals were. And we go down the list on all this. The problem is when you look in the brain of Alzheimer's patient, which everyone who studies Alzheimer's agrees has some contribution role or cause or contributing factor from inflammation in the brain, neuroinflammation, you don't see redness. You don't see swelling. It's not painful.

Starting point is 00:46:45 And the same is truly, you look in the adipocytes, the fat cells of an obese patient who has type 2 diabetes and has significant insulin resistance. Sometimes they have a few extra white blood cells and the fat, but it's not rip-roaring inflammation that you see in an infected wound. They might have upregulation of some of the cytokines. You might see the upregulated production of cytokines in the brains of Alzheimer's patients, but it's nothing like you see in a injured tissue or a rheumato arthritis. Some people have come up with new names, meta-inflammation, it's called sometimes when these kinds of changes occur. Inflammaging. inflammation. As tissues age, tissues from older people from the elderly, they have higher levels of cytokines and more insulin resistance. They call it inflammaging. So we do have an issue of semantics. But with that as a limitation, what's so important about this conversation, in light of everything else we've been talking about is you talked about a connective tissue in these stories. And the connective tissue is in many ways inflammation. So let's back up about what the problems facing the

Starting point is 00:47:53 human race are. So 60 million people die on the planet Earth every year. And 40 million of them die from heart disease, stroke, neurodegeneration, Alzheimer's, Parkinson's, metabolic syndrome, diabetes, and cancer. So two-thirds of the people that die every year on the planet Earth die of those conditions. And that's according to the WHO. Those conditions all have one thing in common. They're either caused by inflammation or made worse by inflammation. Now, if you look back at what happened in the last 80,000 years, 75,000 years since we came down from the trees and became sort of talking monkeys, in that time period, almost everybody until 100 years ago, 150 years ago, almost everybody died by the time they were 30. And what happened in the last 150 years can be

Starting point is 00:48:50 summarized in a very simple sentence, the human race in the last 150 years removed infection as the leading cause of death. And by doing that, we added 40, 50 years to health span, to lifespan. The question that wakes me up at 3 a.m. now is, what if we could cure inflammation? If we cured inflammation, what would that do to the death rate from cancer, heart disease, stroke, and all the conditions that kill two-thirds of the people on the planet Earth every year? look, there's still people that die of infection. People die to COVID. People die every day of malaria and tuberculosis. I'm not being Pollyanna about this. But if you look at the cold, hard numbers, the things that reduced death and increased survival of the human species all affected the eradication of the threat of infection. You know, cleaner water, ample food supply, less starvation. All these things converged on better vaccinations, antibiotics, obviously. All these things converged on improving. lifespan. I think something similar will happen maybe in the next 20 years if we can really understand how to modify inflammation. And one way I think we'll be able to do that is by

Starting point is 00:49:59 continuing to dive deeper and deeper into understanding how evolution itself put the brakes on too much inflammation. I said that inflammation is bad when it's not restrained, when it doesn't resolve. Well, evolution knew that hundreds of millions of years ago. So from the very beginning of the evolution of inflammation, there's been evolutionary mechanisms that evolved to suppress inflammation, to tame it, to put the brakes on it. What we've now discovered in the last 20 years is that the brain does this by sending signals through the vagus nerve. So you ask if this idea may have an application in other conditions, I'm convinced it will. It'll have to be worked through one condition at a time, one mechanism at a time, but I think it's a really important

Starting point is 00:50:43 no idea. Well, I guess once the devices are out in the wild, right, let's just say the implant, then docs may have some latitude to also experiment with patients. I mean, TBD, but let me do a few things. I'm going to allow us, if we want, just to abbreviate vagal nerve stimulation to VNS, if we want to just make it a little easier on ourselves. Let me ask a question that I asked in our last conversation, and I'm sure is on the mind of a lot of folks, which is a lot of, a lot of the lines of, wait a second, inflammation seems to serve, presumably, some important purpose, just like some people might label cortisol bad. It's like, if you get rid of cortisol completely, you're going to be in a world of trouble. So if you are, say, decreasing cytokine production

Starting point is 00:51:32 of release by 70, 90% with vagus nerve stimulation, could that not have downstream negative effects? how would you speak to that? And I was asking that, broadly speaking in our last conversation, but also with respect to weight training and physical adaptations where certain things, and I'm getting way over my skis here, but like interleukin-6, IL-6, and blah, blah, blah, temporarily at least or seem important for catalyzing some of these tissue adaptations. So are you at risk by sort of suppressing cytokines with vagusole? Do we know anything about the side effect profile? We know a great deal about the side effect profile,

Starting point is 00:52:18 but let me just first unpack the importance of what you're talking about. So if we know for certain, if you take biologics that like anti-TNF or anti-I-O-1 or anti-O-6, the UC advertised at the nightly news every night and all the NFL football games every weekend, these biologics, the way they're designed to work is they suppress 100% of the activity. of the cytokine. So if you take an anti-TNF and your monoclonal antibody in your body bumps into your TNF in your body, it's zero. The antibody takes away 100%. It's yes or no. Because you take away 100% of TNF or IL1, depending on what drug you're on, those drugs carry warnings are the most serious side effect warning the FDA can give called the black box warning because they

Starting point is 00:53:05 cause immunosuppression, which is exactly what you said. Immunalsuppression means now you no longer have enough immunological activity, or in this case, inflammation activity, to fight off infections. And so the risk is you'll get things like sepsis or other tuberculosis or other conditions, even cancer in some patients, because your immune system is no longer fully armed to defend itself against these threats. You ask, does Vegas nerve stimulation do that? The simple answer is no. And the reason we know this is because the FDA approved Vegas nerve stimulation to treat depression and epilepsy, actually, in the 1990s. So we have decades of experience implanting patients with vagus nerve stimulators. Now, there have been peer-reviewed studies

Starting point is 00:53:51 with 30 years of longitudinal follow-up in a quarter of a million patients. I estimate that millions of patients have actually been implanted with these devices. So we know that there is always a surgical risk of any surgery. The surgical risks of an incision are small. and the surgical risks of nerve damage are actually quite small, especially with the new set point device, which is only one inch large, completely encased in it. But immunosuppression-wise, we also know that vagus nerve stimulators do not have black box warnings.

Starting point is 00:54:24 There's no evidence after decades of any immunosuppression. There's no evidence of an increased risk of infection or cancer. Why is that? Well, it's because, and here we go back to laboratory studies, and even now in new human studies, When you stimulate the vagus nerve fibers that inhibit inflammation, the ones that travel from the brain to the spleen, for instance, to stop cytokine production, you inhibit, as you said, as you correctly said, about 70% of the cytokine production. You don't inhibit 100%.

Starting point is 00:54:55 So the best way I like to think of it is that if you have an excessive or a dangerous cytokine response, you're going to produce, call it 100 units of TNF. And that's going to to be very bad for your tissues and for you. The normal range should be 10 or 20. The vagus nerve stimulation therapy and the set point device is called actually the immunoregulation therapy because it's only one minute a day. That drives the TNF from 100 down to about 30 or so. So there's plenty left to have an appropriate immune response, but it takes the TNF effects from the toxic range that cause rheumatoid arthritis and Crohn's disease. The monoclonal antibodies, only hit one target at a time, either TNF or I-L-1 or the vagus nerve is actually suppressing the whole

Starting point is 00:55:43 system. So it's taking the toxic levels of I-L-1 down and the toxic levels of IL-6 down. Those things together, they act synergistically. So the effects are bigger than additive. So if you take them all from the toxic range to the healthy range, you're going to be a lot better off. And the IL-6 response in skeletal muscle response in weight training, that's still going to be down in the healthy range. And who knows, Tim? We don't know. know enough about it, but it may very well be that the vagus nerve signals that you activate during exercise, like on the sheep running on the treadmill in New Zealand, we could talk about, that those vagus nerve signals may, in fact, be contributing to the IL6 metabolism and

Starting point is 00:56:24 turnover that's going on. We don't know. Maybe we'll get to this, but who knows, because we're going to bounce around a lot. But also, another aspect of your book that is very compelling is it includes a discussion of meditation, it includes a discussion of cold exposure, and it includes a discussion of different breathing practices, and all of which seem to have applications to vagus nerve stimulation, and maybe it's vis-à-vis the vagus nerve, but parasympathetic activation, which might be very counterintuitive to folks. And so, for instance, breeding your research and reading your book and chatting with you has led me to do something more that I already do, which is, yeah, that's great, but why? And that's interesting, but why? That's

Starting point is 00:57:15 interesting, but why? Because, for instance, I've noticed for decades, and I think a lot of athletes have noticed, that if you do cold plunges and pretty much every division one soccer team, for instance, or you name it, is going to do some version of this, if you do it, not necessarily immediately after training, but say you wait an hour or two, and then you do cold exposure in a bath, that it seems to enhance recovery. Now, you could say, well, ice decreases inflammation, but then it's like, is that true? Could there be another explanation? And what you point out in your book, which is something that, again, intuitively now makes sense to me, is in the beginning when you're exposed to cold, and there's studies demonstrating this, whether it's in cold chambers for

Starting point is 00:58:03 hours, which sounds like more misery than I can handle. But suffice to say, initially, fight or flight response, sympathetic activation, adrenaline, nor adrenaline, etc. And then at some point, parasympathetic, rest and digest activation. And could it be that it's the cold is affecting the vagus nerve, which is affecting parasympathetic that helps with recovery? I don't know. But I've, for instance, always wondered why it is that after, a few minutes in a 45-degree bath, I start yawning. There's a lot of yawning, and I don't know if that's direct. Interestingly, that's also a very common onset symptom after, say, ingesting psychedelics like ayahuasca is yawning, yawning, lots of yawning, which is why all these things

Starting point is 00:58:54 seem to touch the hem of the same fabric. Anyway, I guess I was more of a monologue than a question, But let me ask you something that has been also front of mind. Is it true, and I could speculate, but does it seem like within patient populations we're dealing with more chronic inflammatory conditions? And is that because we have better diagnostics? For instance, you might say, oh, there's an explosion of brain cancer. It's like, yeah, well, we also have much better tools, and people are not dying of maybe things that are easily preventable by antibiotics.

Starting point is 00:59:27 So who knows, maybe it's not that, you know, cell phone towers are causing an explosion of brain cancer. It's very easily explained in other ways. But do we seem to be contending with population level greater incidences of chronic inflammatory diseases and question mark? Can we even know that? And then if it appears to be the case, are there any plausible explanations for why that is? That is a billion dollar question for which I'm not an epidemiologist, but I'm not an epidemiologist, I know there's no easy answer to that one. There are epidemiological studies showing an increase of autoimmune diseases. There are studies suggesting some of these conditions are more common at higher latitudes

Starting point is 01:00:08 and some of them more common at lower latitudes. Huh. Interesting. The latitude, wild. Yep. I mean, correlation, I guess, doesn't prove causation, but it's interesting. It's very interesting. It always comes down to two things pretty much in biology.

Starting point is 01:00:24 It's nature and nurture. It's genes and environment. and environment is writ large. It's the family you brought up, and it's your father's income when you were six. It's the germs, the pandemic outbreaks that were around your neighborhood when you were 10 and when you were 20, and on down the list. What you eat, what's in the environment, in the air you breathe, how much microplastics did you consume knowing it or not knowing it? So, genes, an environment, and sorting that out in real time is exceedingly difficult, especially when you think about the possibility that some of these things after decades of study

Starting point is 01:00:59 turned out to be caused by previously unknown infections. One of my favorites is stories about this, of course, is peptide ulcer disease. Everyone, when I was a kid in medical school, everyone, we all knew that peptic ulcer disease was type A personalities. Stress. It's the patient's fault. I mean, I love to say, and then it turns out that there's a bacteria. that causes peptic ulcer disease.

Starting point is 01:01:24 And when you treat these people with... What is that, H. Pylol. Not H. Pylori, yeah. And when you treat people with antibiotics to eradicate that infection, a large percentage of them get better. When I was a surgery resident, it wasn't that long ago. I'm not that old. I mean, it was... One of the commonest operations in the hospital...

Starting point is 01:01:43 I thought you said communist for a second. I was like, oh, I didn't see that coming. No, no. One of the most common operations on the OR schedule was gastrectomy for peptic ulcer disease. You never see that. It doesn't happen anymore because you take antibiotics. My adage for this thing is when you don't understand a disease, think of epilepsy. You start off, you blame God. So they do exorcisms, and that doesn't work. So if it's not God's fault, the next thing you do is you blame the patient. When you realize it's not the patient's fault,

Starting point is 01:02:14 in today's era, oftentimes we find out it's actually there's some infectious cause of this thing. And so, autoimmune disease may have an infectious cause. It may have an environmental cause. People talk about genetic causes. You inherit some level of risk for autoimmune diseases. But very, very few of these conditions do you actually inherit the condition? I mean, it's like the old story of the two guys playing golf and get hit by lightning. I'll ask your question, Tim.

Starting point is 01:02:41 Is that environment or genes? Well, I mean, it's environment, right? It's environment. I was also thinking like genetic predisposition to risk taking when they're like, oh, it'll be fine. Well, it's easier than that. It's easier than that. It's father and son.

Starting point is 01:02:58 And they play golf every afternoon in the summer in Florida. So it's like those kinds of analyses with two people are hard to do the statistics on. When you scale it up to a population, it's very, very, very difficult to give a simple answer to your question. Well, to make it even more difficult, right, when we're talking about H. H. Pylori or Pylori, I'm not sure how to pronounce it. I've only read it. But it seems like, tell me if I'm waiting too deep into my, the deep end of my ignorance pool here. So from your book, and this is not like a counter argument from your book, but I'll just read a paragraph that I highlighted. It's like, I'd known this, but it was put very well. Stress responses also activate your

Starting point is 01:03:38 adrenal glands to release glucocorticoids. Hormones that stimulate gluconeogenesis, the production of glucose in the liver. Yeah, anyway, that could explain, for instance, my friend's sympathetic overdrive and having glucose spikes at night when you're trying to go to sleep. Going back to the book, this in turn increases your blood glucose levels, elevated glucoracordicode levels, as occurs in depressed patients, accelerates lipolysis, lip, am I saying that correctly, the breakdown of fats into fatty acids while suppressing digestion, muscle growth, and reproduction. Glucocorticoids also inhibit the action of insulin, meaning that your cells are less responsive to insulin. This further increases blood glucose, sometimes even to dangerous levels. So the reason that I'm bringing this up

Starting point is 01:04:13 is that if someone is type A and if they're subjecting themselves to situations that produce chronic stress response, could maybe all the things I just mentioned and more make them predisposed to certain types of infections, right? So that they're actually just to complicate the picture further. Yes, it's an infection, but there are certain behaviors or genetic predisposition or who does even jobs that make it more likely that you would be susceptible to such an infection? I don't know. I don't know. Those kinds of studies are out there, and I think they tip both ways. Some suggest there is increased risk, and some suggest there isn't.

Starting point is 01:04:55 But I think the whole last time I read about this, I'm not a psychologist, but the last time I proved this literature a little bit, the whole nomenclature of type A and type B personality actually broke down. What was retained is hostility. most of the things that tracked with the classic type A personality correlated to how much hostility. So now you're back in the psychological domain of the top-down driving. So that's not me. Yeah, which is understandable.

Starting point is 01:05:22 But it's interesting. You know, it's like, I was a scientific meeting once when that data was being discussed. And somebody stood up in the front row and said, well, how hostile is hostile? How hostile do I have to be to be type A versus type B? And everybody stared at him like, do you hear yourself, man, relax? Let's talk about, because people are listening and the set point device, you know, it's like slightly, maybe slightly larger than an omega-3 capsule or something that's implanted in the neck has a number of huge benefits, but then I'm going to ask you about other tools

Starting point is 01:06:00 potentially. I'd say probably the greatest benefit is patient compliance. if you have to remember to take something or do something every day, there's going to be a lot of breakage in terms of patient compliance. So from just a straight, purely practical perspective, there are some great benefits to an implant. But could you tell the story of your friend Wolf and just describe who he is and lead into his story if you're open to it? On the set point device, the one the size of official pull, I think we have to talk about that in the context of people who are really sick. These are people who have spent decades sometimes disabled, oftentimes, as you said, chronically fatigued or depressed or in pain. And these are people

Starting point is 01:06:49 who are injecting themselves with drugs. Many of them can't afford any more, the drugs they have to take, the ones with these serious side effects. So there's a tendency not by you, but there's a tendency by some in the short form conversation of these kinds of things to say, well, it's a surgery and they should do more push-ups or try to do more things to help themselves. Well, I got to be really, really outspoken on this because when you meet people that have these conditions, if it was easy as doing a couple of push-ups or taking a yoga class or breathing differently, they would do it. If it made them better, they would do it.

Starting point is 01:07:24 These are serious medical conditions. And I think for those kinds of patients, there's always going to be a need because compliance is so difficult. You know, there's compliance with remembering, there's compliance with going to the doctors every month, there's compliance with going to the infusion center. There's compliance with injecting yourself. Compliance can break down at so many different places. So people with serious illnesses, you're absolutely right. The availability, not for all, but for those that are going to be able to go down that path, to have a small immune irregular implant or an

Starting point is 01:07:55 neck. It's going to be very interesting to see what happens. But for people who are essentially, mostly well, like you seem to be. And like, I seem to. What an effective mask I've created. Yeah, no, I'm generally well. And me too. And I feel very fortunate for that. And so I try to do things that align with what people would call Vegas nerve stimulation. So eat right, sleep right, try to get some regular exercise in, try to stay cognitively busy, try to enjoy my hobbies and my family, try to stay to alleviate stress from my life as much as possible. I mean, all the things that we all know we should be doing in your GP or your primary care provider should be telling you to do every day. All those things in one way or another

Starting point is 01:08:42 that we've sort of been talking about can be said to stimulate directly or indirectly the Vegas nerve. But there's other modalities that people also talk about using electrical devices to stimulate the Vegas nerve by applying electrical devices or 10 units, transcutaneous electrical nerve stimulators to the skin. Before I go any further, let me be 1,000% clear. These are not vagus nerve stimulators. There's only two ways to stimulate the vagus nerve directly and specifically. One is implant an electrode on the nerve and that's either with the devices for epilepsy or depression or there's another one now also increase the rehabilitation outcomes from patients who have strokes. That's a third one. Or the immunoregulator device

Starting point is 01:09:30 from that point. That's the only FDA-approved way to stimulate your vagus nerve that directly specifically stimulates your vagus. Full stop. Experimentally, you can do it using focus ultrasound. And we've done that in the lab, my colleague, Sangita Chavon and Sabroanos, we've published on this in the peer-reviewed journals. It's a special ultrasound, very similar to the one that you visualize to see the baby in the womb or the gallstones, but you have a different lens on the probe, and you can focus the energy to target nerves in the body. And we've done this in humans to reduce the inflammatory markers in the blood of healthy volunteers by focusing the ultrasound on the splenic nerve, where the vagus nerve controls it. And it's also done,

Starting point is 01:10:17 we've done it in animal models of diabetes and obesity and seen some very interesting effects. Everything else, the transcutaneous electrical nerve stimulation strategy to the neck, to the neck, the ear, to the side of the head or the face, those are all non-invasive and non-specific and really shouldn't be called Vegas nerve stimulators. Nonetheless, nonetheless, some interesting stuff seems to happen. Okay. So everything you said, so true, so on point. I'm also tempted to go to the hockey puck for, you know, like sort of electric GLP1 administration. But I'm going to call that a temptation and not an opportunity for the moment. And let's talk about your friend, Ulf, and what happened to him. So I apologize for the digression, but I had to get that as you

Starting point is 01:11:07 understand on the record. You got to do it. Now, what about other stuff, like a 10-Z unit? Let's give a little background there. Anybody interested in auricular therapy, meaning Oracle as ear, A-U-R, auricular therapy, and our auricular acupuncture knows that the ancient Chinese acupuncture maps date back tens of thousands of years and that there are points on the ear that map to various organs in the body and if you stimulate them with a needle, a small needle, a probe or a small electric current that you're supposedly able to affect the metabolism or the diseases of those organs. Everybody knows that's 10,000. Well, it turns out when I was writing the book, which I discovered, that those ancient acupuncture maps of the ear originated in France

Starting point is 01:11:54 in 1957 by a doctor named Dr. Paul Nogier, who had a patient who was being treated by a specialist, I think, in Corsica. And the specialist was grounded in ancient medicine and was cauterizing a piece of this patient's ear to treat the patient's sciatica, the pain going down their leg. Burning their ear. Yeah, burning or cutting a piece of it offers. I'm not exactly sure what they did. It wasn't clear, but there was a little hole on the edge of this patient's ear. And then he saw another one.

Starting point is 01:12:22 And in both times, the patient claimed, the two patients claimed that their sciatica got better. So Dr. Nogier was a very sort of clever guy and curious and careful. And he took a ballpoint pen and he took the ink out of it and he started probing all of his patient's ears. And he aligned various conditions in the patient with parts of the ear that he determined were most closely aligned with the symptoms and signs of the illness. And he made a map. Well, he did this for many, many years. many, many patients and ultimately published this, and he presented it at an acupuncture meeting that was being held somewhere in the Mediterranean, and it led to this overwhelming acclaim

Starting point is 01:13:03 for him. And the work was republished in China, which created the current textbooks of Chinese auricular acupuncture therapy based on a Frenchman's work in the 1950. So that's where the maps come from. They're fun to look at. They really are, and especially in light of the story, going to tell. So if you look, you can see where the spleen is and where the bladder is and where the stomach is. They're very clever. So we were reading Sengita Chavon and I, my lab co-head and I, many years ago, 15, 20 years ago, we were reading about vagus nerve biology and physiology, and we discovered that there was a branch of the vagus nerve that goes to the cartilage of the ear. And when I say the ear, it goes to the cartilaginous part. The part outside the ear, the ear

Starting point is 01:13:52 canal where you put your finger in your ear and what looks like a sea shell. So it's called the Simba Concha. That's where it gets its name. Concha like shell. Now, this branch of the Vegas nerve that goes from that cartilage is very, very special. It's the only place that the vagus nerve endings go to the skin, to the surface of the skin. And they are sensory. That means that when you stimulate the cartilage of the Simba Concha, you can activate the fibers that go carrying information into the brain and they go to the place in the brain called the nucleus

Starting point is 01:14:28 tractus solitarious which is the place where all the other sensory fibers of the vagus nerve go from your stomach and from your pancreas and from your liver so all the sensory input goes to the same place you can think we get like the router in your house everything goes into one spot and then it goes back out again

Starting point is 01:14:44 well why well it turns out fish you like evolution i heard you say at the beginning fish. Fish gills are cartilaginous and they're innervated. And what became our human vagus nerve was one of the branches of the fish's vagus nerve. And what became our cartilage of our ear used to be the cartilage of the fish gills. So it dragged it with it. Wild. It's wild. I'll be honest, as a non-biologist, long ago when I was shown these maps, I thought to myself, this makes absolutely no evolutionary sense, because why would you, if in battle, you get nicked by an axe and your spleen

Starting point is 01:15:25 explodes, it doesn't seem to have any adaptive purpose for natural selection. But lo and behold, fish kills. Well, it's fish kills, but I didn't say it makes sense, Tim. You said that. I didn't say it makes sense. Well, no, I shouldn't say it makes sense. It's just like a vestigial sort of architecture. It's definitely vestigial. How much of the architecture, that's another area that I can't say for sure we've, I actually can say for sure nobody, to my knowledge, has completely mapped out Dr. Nogier's ear maps to the human body in any convincing neuroanatomical function or neurophysiological way, but it's still interesting. So, with that information, you could think of the cartilage of the ear as a way to drive signals in to the brainstem

Starting point is 01:16:13 through a branch of the vagus nerve. Okay. Immediately people start calling that vagus nerve stimulation. It's kind of true, right? Because it's a sensory branch of the vagus nerve. And if you put a tend unit or your finger on the cartilage of the ear, you are technically stimulating the receptors in the skin that activate the sensory fibers that carry the signals into the NTS. But it's not the same as it. I said it before. I don't have to say it again. It's not the same as electric estimating. Okay. Hitting the big cable. Right. Now, what happens? So now it gets really A long time ago, an early Russian investigator published a study where he took essentially an acupuncture needle and put it in the Simba Concha and put in a little electric current and showed that he could get

Starting point is 01:16:56 changes in heart rate variability, essentially. And this goes back again to the 50s or 60s. That exact study, to my knowledge, has never actually been replicated the way he did it. This is the problem you talked about clinical trials and, you know, proving, I agree with you, The case studies are often the most important ways to start, but you still have to do the big clinical trials, randomized controls with the appropriate control population. That will come back to that. So now you say, okay, what happens using other technology? Well, it turns out now, I can't count all the publications that have been done by applying various forms of electric current into the ear and measuring. You can't count them all.

Starting point is 01:17:34 There's a lot. You can't count them all. They come out every day now. And people have done some very sophisticated studies. usually with about 10 or 20 people for a study, usually. And you can find brain imaging studies, fMRI, you can find pet studies. You can find far field evoked responses, which looks at the inputs and outputs of into various brainstem regions and how the brain is processing the higher network signals.

Starting point is 01:18:01 So you can see some really interesting stuff. And what comes out of it is lots of different information. That's the first problem. There's no single consensus that if you put this kind of. of electrode in your ear at this time for this many minutes, at this much current, you get this effect in this part of your brain in the morning and this part of your brain at noon and this part of your brain. No one knows. Put that aside for a second. And I put it in the book. I hope it was clear. But I find striking and interesting and needing further study

Starting point is 01:18:29 is that if you compare people with electrical inputs to their ear to people with electrical devices surgically implanted in their neck, there is some overlap in the brain centers that are activated. You see centers like the Locosurulius, which is the top of the fight or flight chain. It's the top of the sympathetic chain. You see regions in the basal forebrain, the colonergic regions, which are linked up to the hippocampus and to other areas that are really important for learning and memory. And there is clinical data that patients with implanted vagus nerve stimulators have enhanced neuroplasticity, enhanced learning, and enhanced cognition, alertness.

Starting point is 01:19:10 episode of STEM Talk, which has become one of my favorite new podcasts, there was one of the hosts, I think it's Dr. Ken Ford, who has served on a number of defense and intelligence-related advisory boards, including advisory roles at DARPA. He has a great voice, too, Tim. Oh, his voice is amazing. Yeah. So the defense advanced research projects agency is incredible. A lot of the technologies we use every day now originally came out of DARPA, ARPANET, etc. So he was in conversation, and they were discussing neuroplasticity and learning with respect to Vegas nerve stimulation. And I haven't looked into this yet, but I've spent time at the Defense Language Institute in Monterey. and they were talking about using vagus nerve stimulation to enhance language acquisition

Starting point is 01:20:01 and that the effects seem to be durable for months after stimulation, which also in your book, just a quick note, right, stimulation for two weeks having an effect on insomnia for two or three months. I mean, what could be more interesting right now? It's just like it's so endlessly fascinating. I have to respond to the DARPA. I wouldn't be talking to you right now if it wasn't for DARPA support on this idea in the 1990s when it was a freaking crazy idea that I'm going to target with an electrode the vagus nerve

Starting point is 01:20:29 to stop sepsis and cytokine storm. And they said, okay, try it. What if it's yes? Yeah, people think of the quote-unquote government as just this big monolithic, slow-moving, stupid and efficient thing. Darpa is an exception. You got to check out DARPA, like the brilliance and the innovation that comes out of that and their willingness to throw a lot against the wall, and it's science fiction, some of the stuff that comes out of DARPA. One of my heroes is actually a national hero. Jeff Lang, Dr. Jeff Lang, retired colonel, founded the biology technology office at DARPA. He used to instruct his team at DARPA when the guys and gals would come in with the

Starting point is 01:21:09 crazy, most crazy-ass ideas anyone could ever imagine. Like, you see that airplane out there? I can make it disappear. I can make it invisible. And then everybody leaves, and they go into Jeff's office, and he says to his team, what do you think? And they all say to Jeff, he's nuts. It's crazy. You can't make an airplane disappear. And Jeff looked at his team and says, what if it's yes? And that's where stealth technology came from. Yeah, that's so cool. And then you say, oh, I can still see the airplane. And then Jeff

Starting point is 01:21:37 slams his hand on the desk and goes, if you can see it, it's too late. Yeah, I mean, technology to be able to see figures around corners. I mean, it's, and that was years ago when I saw a rough description of that. In any case, they are doing lots of really interesting things. I took us off track for a second. One more thing. You said another thing. I got to respond.

Starting point is 01:22:00 So the cognition part of Vegas nerve stimulation is also a fascinating story that would require a full, long-form conversation. But in brief, patients who had epilepsy were implanted with Vegas nerve stimulators. This goes back 20 years or maybe 30. and a bunch of these folks did not get any significant benefit from the therapy. So the device was switched off. Well, a very clever researcher brought them into his lab and gave him a, I'm not a psychologist, I already gave that disclaimer once, but gave them a cognitive learning test

Starting point is 01:22:36 of some form, very simple, and then turned the device on and repeated it. And all their scores went up. It was very dramatic. And when they image these folks in subsequent studies, this is one of the studies that I mentioned before that pointed to the enhancement of activity in the regions of the brain that are really important for intention, learning, and memory. So there's a deep conversation there about neurocognition and vagus nerve inputs to the brain. Yeah. And this is also like fidgeting around in my chair because I get so excited about like finally trying to, and I'm not there

Starting point is 01:23:11 obviously, and I'm who am I, I'm a muggle. So I have to depend on pros like. you, but looking at, for instance, the few things that I have come across that really seem to have very impressive effect sizes on intractable or hard-to-treat psychiatric conditions that resist frontline treatments with biologics for 15, 20 years, until, for instance, just a few, some psychedelic cystic therapies, some types of brain stimulation. There are many different types, but let's just take accelerated TMS as one example for certain conditions, and then metabolic psychiatry or ketogenic diet generally in some variation. And a friend of mine, I'm going to pull this up just yesterday, and it's not necessarily a new study, but he sent me a

Starting point is 01:24:02 link because I advise that he try the ketogenic diet for certain types of overwhelm and anxiety he was experiencing, because the downside risk is so minimal, particularly if you're only doing it for a few weeks and your lipid profile is under control. And he sent me this study. The title, this is from cell. This is not from some random person's blog. And the title is the gut microbiota mediates the anti-seizure effects of the ketogenic diet. So the ketogenic diet was used in the early, I want to say 1900s for epileptic children. They would usually use heavy cream to make it easier for compliance, but had this, maybe it even predates that, this incredible effect on eliminating or reducing the frequency of seizures. These are kids who might have hundreds of seizures a day. And I'm looking

Starting point is 01:24:50 at this study, and here's just a little excerpt. Mice treated with antibiotics or rear germ-free are resistant to keto diet mediated seizure protection. Enrichment of and no-biotic co-colonization with keto diet associated acrimancia and parabacterioids, if I'm saying that correctly, restores seizure protection. So I literally have probiotics downstairs that are acrimancia from a company called pendulum, which is pretty legitimate. But what? I mean, okay. So it's mediated partially through the gut microbiota. And it's like, okay, well, then you have the interplay of the microbiota with potentially the vagus nerve. with this two-way communication channel.

Starting point is 01:25:38 And then you look at, for instance, psychedelic-assisted therapies, and there's a lot that we can get into there, but also, and this is finally, and I'm not saying there's a lot of nonsense and a lot of navel-gazing and, like, crystal-waving folks in the psychedelic world, no offense to anyone who falls in that demo.

Starting point is 01:25:58 But there were some credible folks, including, for instance, Dr. Andrew Weil, who actually has an incredible. incredible history of ethnobotany and is very, very technical. And he lost his allergy to cats after a number of experiences with, I believe was LSD. And these anecdotes on the underground, at least, with facilitators who have thousands, maybe tens of thousands of repetitions with patient sessions, the losing of allergies comes up pretty constantly. And then I'm asking myself, well, maybe it's not the content, although I happen to believe the content of

Starting point is 01:26:37 these experience matters, but maybe it's the anti-inflammatory effects. Okay, well, what does that mean? And then, okay, well, maybe it's having some immunomodulating effect. Okay, well, is the vagus nerve involved? Maybe. It's not beyond possibility. And then you look at neuroinflammation and the effects of whether it's different types of brainstem or the effects on, say, inflamed microglia by psychedelics, like reductions in TNF and all this stuff. TNF Alpha have been tracked in the scientific literature. And I just get really, really excited because I can't parse it all, but it seems like these things all to use an awkward phrasing are kind of touching the hem of the same garment in some way. So anyway, that was a whole bunch of word salad, but I don't want

Starting point is 01:27:23 to lose the story of Ulf, because we were talking about the maps. We're talking about the fact that yes, you should maybe at best put it in quotation marks, vagus nerve stimulation, but could you tell the story of Ulf, if I'm saying his name correctly, and maybe comically, one of only a handful of Swedes I know, is also named Ulf. So it makes me think that maybe it's the John of Sweden, I don't know. But who is Ulf? And why does he tie into this ear mapping that we're talking about? Olf Anderson is a retired professor of pediatric rheumatology at the Karolinska Institute. He practiced there for many decades, and throughout that whole time, he also ran a research laboratory

Starting point is 01:28:03 that was focused primarily on cytokines, on inflammation and cytokines. So as you said before, this is a guy who knows this stuff. Karolinska Institute is also top tier. I mean, they do some of the most fundamental kind of seminal work related to a lot of stem cell applications and so on has also happened at the same institute. It's arguably one of the best medical research institutes in the world is one of the largest in Europe. It's a major teaching center. It's a fantastic place. I've been there many, many times. Wolf and I have been close friends and collaborators for many decades. And he was diagnosed with a condition that was

Starting point is 01:28:45 thought to be a cancer in his bile ducts, in his liver that required a major surgery called the Whipple procedure where they remove pancreas of most of the pancreas, if not all of it, and they remove part of the liver, and they move part of the bioduck system. This was a long time ago, but at the time it was a death sentence, the cancer that they thought he had. It turned out to be benign, which was a blessing in disguise because he had to undergo this major surgery to have this. After the surgery, he developed, for the first time in his life, actually, he developed intermittent bouts of depression, serious depression, which he attributed to excessive inflammation in his GI tract, which was through unknown mechanisms coming episodically and causing this

Starting point is 01:29:31 depression, which as he talks about in the book, and he's written about on his own, led to the end of his marriage, and was really ruining his life. Well, this was around the time that Singita and I had discovered these funny acupuncture maps of the ear. and saw that some people were using tens units. And we had published a series of papers at that point, understanding how vagus nerve signals could turn off inflammation. And so we said, what the heck? We put tens unit over-the-counter product you can get anywhere

Starting point is 01:30:05 with the electrodes on the simba-concha, not the tragus, not the lump that sticks out on the side, not the pinna, not the earlobe, but on the simba concha. And then we drew blood on ourselves and other volunteers, healthy volunteers, and we measured cytokine production. It's a little complicated how we did that. It's not just drawing blood and doing an assay. We actually measured the ability of the white blood cells traveling around our bloodstream

Starting point is 01:30:32 to make new cytokines. And when we did those experiments, we could show very conclusively, and we published it all in peer-reviewed journals that most volunteers, about 70%, 7 or 8 out of 10 people, 16 or 17 out of 20, you could reduce the amount of inflammation that the white blood cells would make if you put this trobe in the ear for five minutes. And at that point, Ulf said, well, I think I have an inflammation problem. Vegas nerve stimulation stops inflammation. If you want to call this Vegas nerves. He can also call it transoricular nerve stimulation because there's lots of other nerves to the ear, but that's another matter. Oof said he decided he would try it. Now, I didn't

Starting point is 01:31:17 treat my friend Oolfe. He decided he would do this. He's a bona fide physician. He could do what he wants. I frankly was not very encouraging. I said, okay, whatever. Well, as he writes, and I know this for a fact, as I see him several times a year, it turned his whole life around. He added some antibiotic therapy, also to treat his bacterial overgrowth in his intestines, which comes with the surgery that he had, the Whipple. But he also uses this Tens unit in his left ear religiously twice a day, like brushing your teeth, he says. And he then subjected himself to a fascinating analysis. So you mentioned heart rate variability a while ago, and that's really complicated, but the more I try to learn about it, the more I'm like, wait a second.

Starting point is 01:32:04 It's like quantum mechanics or something. I'm like, wait, I thought I kind of knew what the hell you're talking about. Now I don't. If you understand it, then you don't understand. If you think you understand it, like Richard Feynman said, you don't understand it, right? I think we don't have to get into it now, but suffice it to say, it doesn't matter what you're wearable is, if it's a Fitbit or an eyewatch or 10 other things that measure heart rate variability, I think this is 100% true.

Starting point is 01:32:26 It might only be 90% true. They're measuring different things, not because they all start with measuring the distance between individual heartbeats, which is instantaneous heart rate. They all start with that. But what they do statistically after that can vary dramatically. I've done this. Shingheed and I have done this for a while. We worked on heart rate variability.

Starting point is 01:32:45 We made her own devices. And it gets incredibly complicated. And we dropped it because if you get a PVC, if you get a peri ventricular contraction, or you get two irregular beats in a five-minute recording, you know, you've got hundreds and hundreds of heartbeats. It shouldn't do much, right? It messes everything up. It changes all the statistics.

Starting point is 01:33:02 So you can't get into that now. However, Bolf was contacted by a guy in Finland who sent him a watch he had invented that recorded heart rate variability as a function of respiratory sinus arrhythmia, which is what heart rate variability is actually, quote-unquote, controlled right. So if you want to do the experiment, if you're listeners want to do this, it's very easy. Take a couple of big breaths in, two hard sniffs in through the nose, fill your lungs completely, and you'll feel your heart rate speed up a little bit. and then breathe out slowly for seven or eight seconds.

Starting point is 01:33:34 That increase in heart rate during inspiration is partly due to the change in pressure in your chest cavity, your thorax. As your diaphragm drops and you increase the volume, the pressure has to decrease. And then as you exhale slowly, you're actually increasing the pressure in your chest in your thorax because you can compress the volume. Those changes in pressure all activate sensory signals in the vagus nerve, which go into your brain, which accelerate or decelerate, your heart. Why? Well, because when you inhale, you want to accelerate your heart and exhale,

Starting point is 01:34:08 you want to decelerate your heart. That's the optimal physiological linkage. That's the optimal physiological mechanism to maximize the amount of oxygen in your blood. This guy in Finland invented a way from the EKG of looking at the changes in the size of the QRS wave as an indicator of the heart shifting left and right, which also happens when your diaphragm goes down and comes back up. And so he found a way to measure respirations from the EKG and link it to the instantaneous changes in heart rate. What his HRV indicator is, in this method, is actually a correlation between the overlap between respiratory sinus arrhythmia and the breathing cycle and heart rate variability in the cardiac cycle. And that's how you optimize oxygen uptake

Starting point is 01:34:57 and delivery. It's really cool, right? And it's pretty sophisticated stuff. So he ships the watch over to Ulf, or not watch device, yeah. So Ilf puts it on and he's got a terrible correlation between his heart rate variability and his respiratory sinus arrhythmia until he does his vagus nerve stimulation and then it got a lot better. That's a pretty good experiment. It isn't enough one. And somebody, I'd love to see somebody repeat that on 50 people, but it's still hard to explain because he does it over and over again on many different days and many different conditions. The real kicker is during COVID, my colleagues and I at Northwell did a clinical study. We heard of results out of China, out of Wuhan, actually, where patients taking to homodidine,

Starting point is 01:35:44 the antacid, were significantly protected against some of the lethal complications of COVID. We actually did clinical studies of this drug. You can buy it for pennies over the counter at Amazon. in Costco and CVS and everywhere. It's a safe antacid. And it turns out, we did the clinical studies in Northwell, and we did then laboratory studies in my lab. It's a pharmacological vagus nerve stimulator.

Starting point is 01:36:09 Huh. Yeah. Really? What was it called again? Fomoda means the generic name. It's got a bunch of brand names, including one of them, is Pepsid. No kidding. Yeah, you read about it.

Starting point is 01:36:20 It'll blow your mind, actually. Wow. So, when Ulf combined, this is, the end of the story. When Ulf combined the Fomotidine with the Tens unit in his ear, he gets 100% overlap, but he looks like a 21-year-old kid with his overlap between respiratory sinus arrhythmia and heart rate variability. He's written about it. He's published his own personal recordings. It's a remarkable story, and it's remarkable not because it's a story of one, but because let's go back to what we said before. The FDA approved vagus nerve stimulation for the treatment

Starting point is 01:36:53 of depression decades ago. And it's used a little bit more in Europe than it is in the U.S. In the U.S., it's not routinely covered by insurance payment. So there's been tremendous resistance to applying this. It helps about half the patients. Now, once again, like we said with the rheumatoid arthritis, let's be concrete about this. Let's not be the standoff folks who say, well, it only works half the time. It shouldn't be used.

Starting point is 01:37:18 Well, in some of the people that it's worked in, they were suicidal and now they're not. what is that worth? And some of the people it's worked in, they're back at work, taking care of their kids, taking care of the family. I think that we should be doing it or not doing it based on the data we know so far. There should be a screaming call that we should be diving down and to understand. We don't know the mechanism, Tim. We don't know why Wolf got better. We don't know why half the patients with depression got better. I think somebody should do a really simple study. We should segregate the patients into some sort of inflammatory group. groups, risk groups or activity groups with depression and treat the ones with the most inflammation with the vagus nerve stimulation and see if they get better because you've stopped their inflammation. And the other ones have depression from another, another etiology, another cause, another factor. These are the important questions. Both got better? Don't you work at a place with a bunch of scientists?

Starting point is 01:38:15 What's required for something like that to happen? Does it just require Scrooge McDuck to fund the study? I'm the president of a great organization with great scientists. Yes, I am. And there is and will be more great we're coming out of our place. But one place can't do it all alone. This is a call for everybody to get interested. It's also potentially a call for some interesting distributed, I guess we could call them studies. They're not going to be RCTs, but hey, something is better than nothing if it has recognition of its limitations. For instance, the people who manufacture, whoop bands, the people who make aura ring, I mean, they could potentially put out a call to customers to try to do some type of distributed study. Of course, you might be dealing, well, actually, you're not going to be dealing with self-reporting. You'd be dealing with self-reporting perhaps in documenting using a quote-unquote vagus nerve stimulator, but the data is going to be

Starting point is 01:39:13 available to the company vis-a-vis. Maybe it's anonymized in some fashion, but the patients could make their actual aura or Woop Band or Fitbit data available to the company if it's not already available. So that could be pretty interesting. I recall actually Woop, I believe, doing something like that with veterans who were on a sort of standardized dosing of, I think it was microdosing of psychedelics looking at impact on HRV or potential impact on HRV. HRV fluctuations associated with. Let's put it that way. You mentioned before depression, serotonin inflammation. Should we pick up on that for a second? Yeah, let's do it. As you read the excerpt before, there is evidence that some patients with depression get better with SSRIs and some patients don't. And there's also evidence

Starting point is 01:40:07 that SSRIs can even make people who have known inflammation or experimental inflammation gain some benefit. There's also information that SSRIs in experimental conditions, clinical studies and experimental studies in the lab, can actually reduce inflammation. What we have to agree on is we don't know what causes depression. And if we knew it caused depression, I think our chances of fixing it and more people would be better.

Starting point is 01:40:33 Well, also depression is, I mean, in my mind, could be like, quote unquote, inflammation. There could be many different species of depression are many different causes. I don't know. I think there are. I think you're right. And I think that's not been parsed out very well yet because the focus has been this sort of excessive focus on serotonin as the hypothesis that has to be dealt with. And there's lots of reasons for that that we won't get into now.

Starting point is 01:41:02 But what I do like to raise, again, as a call to action, if you will, and a message of hope, is we know that inflammation produces depression in animals and in people. It's to the point now. There are some inflammatory molecules that are used to treat some conditions, some forms of cancer, for instance. And when patients are signed up and they're going to receive these therapies, this administration of cytokines that has their therapy that are known to cause depression, they're often given a prescription to go see the psychiatrist to go on the SSRIs before they go get their therapy. So we know inflammation causes depression. We don't know completely how. There's overwhelming. evidence from many labs, including my own, that the presence of inflammation in the body activates signals that travel up. You guessed it, the vagus nerve. So you could take a mouse, for instance, and inject it with I-O-1, and the mouse will run in the corner of its cage. It'll huddle up. It'll look like it doesn't feel well, like when you have the flu. It will avoid eating. It'll avoid sex. It'll avoid playing with toys in the cage. It looks depressed. If you

Starting point is 01:42:11 cut the vagus nerve, back to your topic of before, if you cut the vagus nerve in those mice and give them I-L-1, they don't get sick. They don't get depressed. And so it puts the question, and the mind-body experts and Far East religious dogmas focus on what we said before, the brain networks and the body networks are connected. What I said before is the vagus nerve is a principal connector. So if you have disruption of inflammation in the body, which you're not even, maybe nothing hurts in your body, but your brain knows the inflammation is there. We call that interoception. It's the subconscious sense that your organs are sending information about their status to your brain. If you have inflammation in your body, does it cause

Starting point is 01:42:58 depression? That's an important question. Because maybe that's why those patients who do get better. And go on YouTube and type in some videos of these depressed patients whose lives were turned around with Vegas nerve simulators. It'll bring a tear to your eyes, some of their stories. And if you look at those people who have benefited, and Ulf, with his 10th unit in the ear. Quick question. Has Ulf published his setup? Is that something that people can find online if they wanted to experiment with five minutes twice a day of auricular stem? Yes. Yes. Yes. Yes, he did. He published it in a peer review journal that I believe is open access. If you Google his name, Ulf Anderson with two S's, Anderson. Good, good old Swedish last name. I will link to that

Starting point is 01:43:45 in show notes. We'll find that and put them in the show notes for everybody. I can send it to you for the show notes. Okay, perfect. Perfect. We'll do that. And I interrupted your train of thought. No, it was the end. I just want to call the question out to my colleagues that we should study the influence of interoception, the presence of inflammation in the body being sensed by the brain and causing depression in some patients. And can we treat that with vagus nerve stimulation? Is that why it works? And the 50% of, why 50%? Isn't that kind of a funny number? It works. It's too clean, right? It's like, it's too clean. Yeah, I got scammed recently on my credit card at a gas station and it was $175. And I was like, that's too clean. That's absolutely a scam charge.

Starting point is 01:44:28 Plus, I know gas is expensive, but it's not $175. But in any case, yeah, when the numbers are that clean, you're like, wait a second here. Let me ask you, this is out of personal curiosity. And I was goofing around going all over PubMed, which is sometimes a dangerous business when you're a muggle. But it seems like there are some interesting data around acupuncture in the ears and fertility or pregnancy. and I know you don't like to speculate, but maybe people have looked at this closely. Is it plausible that that is mediated by a vagus nerve stimulation?

Starting point is 01:45:06 The simple answer is, yes, I don't like to speculate. But I'm just saying mechanistically, would stimulating the vagus nerve have some downstream, possible downstream effect on the ability to conceive or anything like that? I don't know the studies that you're referring to. I really don't. and I don't know if acupuncture in the ear would stimulate the vagus nerve to stop inflammation. I know that what I did with an electrical tinge unit can reduce inflammation in the bloodstream

Starting point is 01:45:37 of healthy volunteers. I can answer the question in the context of, are there some conditions in the abdomen, whether in the ovaries or the uterus, the fallopian tubes, where the presence of inflammation would be restrictive or would, make getting pregnant more difficult? The answer to that's a simple yes. Now the question is if we had ways of selectively reducing that inflammation in the context of getting pregnant, if you could specifically reduce that inflammation, would you increase the chances of getting pregnant? Well, you know, yeah, it's quite logical. It's plausible. Can Vegas nerve stimulation do that?

Starting point is 01:46:18 To my knowledge, nobody knows. I was just, again, curious. And you know what? The first time this kind of, you're probably using this term incorrectly, but sort of the homunculus on the ear came up in this podcast was with Martin Rothblatt, who I think has a quote on your book. Am I making that up? Martine is a close friend. Also a phenom. What a wild background. Just such a polymath.

Starting point is 01:46:46 Martine's another national hero. I mean, she's a satellite launcher. She's a satellite communications expert. She's an accomplished pilot, including flying her own battery-powered helicopter and setting land speed records and distance records. And she's a good friend and the CEO of United Therapeutics. Martin's wonderful. We talk a lot about this stuff. All right.

Starting point is 01:47:08 So I want to give a shout out. If people want to get to know, Martin, definitely suggest my interview with her. And I wanted to come to something that you mentioned at the end of your STEM talk interview. And I really don't have context on this, but it's of interest to me because I have, for the last few years, had chronic low back pain, which is if you want to wander into the Bermuda triangle of hand-wavy imprecision in at least pain diagnoses or orthopedics, low back is a good place to go. And what I have figured out, there are certain things that help.

Starting point is 01:47:50 and putting aside the biomechanics and strength training and so on for a moment, I know that anti-inflammation helps. There seems to be an inflammatory component. So whether it's through applying cold or taking oral anti-inflammatories or injectables for that matter, it suppresses symptoms. I know that. And I'm reading a number of books. Lorimer Mosley and his co-author have actually a very interesting book called Explain Pain.

Starting point is 01:48:16 And it relates to this piece that came up maybe, which is why I wanted to talk about it, because sometimes, like you said, the response to the equivalent of a picket line in your body is the entire Navy showing up with rockets blazing, and it's a severe overreaction. So this relates to Professor Rolls, and I guess I'm going to try to word this in a way that makes sense, but how specific molecules inform memories slash n grams in the brain and the implications of that. Could you just unpack that for me because you guys didn't really get into it in the STEM talk? But I was like, wait, wait, wait, wait. I want to hold on to this because it seems very interesting. And it might somehow be relevant to me.

Starting point is 01:49:03 It might not be. But could you just explain what I'm very clumsily trying to evoke or I guess elicit from you? Yes, I would love to. Let's start with the picket line. The picket line in the low back situation. And I've also had on and off sciatica from a herniated disc in my back with pain down my leg. So I can relate to this. In those instances, you have something in one of the joints of your back or potentially a fragment of a disc that's pushing on a nerve, causing pressure on the nerve, which sets up a cycle, which would be the picket line, right? There's some injury there. There's some injury. Injury to the nerve or there's some injury in the joint. And that's the picket line. It shouldn't be a big deal to the human body having

Starting point is 01:49:48 involved over hundreds of millions of years. But in some people, not all, if you look at MRI scans, right, everybody else's back look just like yours, right? Yeah, they look all messed up. They all look the same. It's just like you get wrinkles on your face. Your spine starts to look pretty funky. So I've got arthropathy. I've got the right phraminal stenosis at blah, blah, blah, blah, blah. But. So does everybody else? Yeah, you can look at like hamburger meat on an MRI. of a back and they're asymptomatic. Right. So why does your back hurt and somebody's MRI scan would be indistinguishable from your

Starting point is 01:50:20 doesn't hurt? Well, you can maybe pinpoint the position on your MRI skin. Now the question's different, right? Now the question is, why is your body sending the Navy with rockets blazing to the picket line in your back, but not, you know, not the guy next door? Well, that is the question. So how can we connect that to two things? One, two, because Wolf's back pain got better, too, by the way.

Starting point is 01:50:41 He had injured his neck and a sailing. He was a world-class sailing champion. I don't know if that made the book or not. I don't think that was in there. I love this guy. He and his brother, Jan Anderson, won the European World Championships in the J-Fuss. Of course they did.

Starting point is 01:50:58 In the 1960s. And, of course, Abba sent them to the world championships when they were in New Zealand or Australia or something, and they competed in the Olympics of the L.A. Olympics. Anyways, his back got better. And so the question is, why did this back get better because the signals from the ear to the brain stem went down the vagus nerve to the spleen and reduced the turnover of the inflammatory cells? Well, that's a definite maybe. And what we know from very careful experiments in animals and some experiments in humans is that when those vagus nerve signals end up in the spleen, they switch the white blood cells.

Starting point is 01:51:34 Now, the spleen gets 20% of cardiac output. So all your white blood cells are racing through the spleen all day long. and when they pass through and pick up this nerve signal, they switch from a state called M1 to M2. M1 macrophages and monocytes, white blood cells. They're the Navy, shooting guns, full blazing that you said. M2 are the doctors and nurses in the ambulances who race to the scene to heal. And so that's an important area that a lot of people are chasing. And that's in the context of therapy that we've been talking about. That's probably how it works in or arthritis, actually. It's the signals are switching the white blood cells as they pass

Starting point is 01:52:16 through the spleen. So when they go to the elbow or the knee or the hand, they tend to heal the cartilage. It's M2 instead of M1. M2 is better than M1. Exactly right. So yeah, M1 to M2. So that's a take-home point. That's a simple way to think of how you get a nerve, the vagus nerve, stimulation, which doesn't go to your elbow and it doesn't go to your wrist. But that's why they probably get better because it changes the white blood cells that are going to the scene. So what else is happening? Well, when that inflammation settles in, say, the colon,

Starting point is 01:52:47 Asher rolls in a brilliant, I think one of the most important scientific papers in the field of what we call neuroimmunology, maybe in the last 25 years, she discovered that what's happening in the inflamed tissues in the colon in this case is actually forming a neural network in your brain. brain, which you can think of as a memory. It's called, neuroscientists call it an n-gram. So would that also be like a phantom limb, or is that a different thing? I don't want to take us off track. It would be similar to a phantom limb, but it's more concrete, and I'll tell

Starting point is 01:53:20 you why. And this is what's so amazing about it. So neuroscience has studied memories and n-grams for many years and using a method that we call trapping technology. And so what you do is you have a genetically engineered mouse, a mouse with special genes that you can put in when it's an embryo. And the mouse grows up with these genes. And now when you do something to the mouse, if you co-administer, say you give the mouse a drug or you give the mouse inflammation, when you do that at the same time, you give the mouse a drug that activates these special genes that turn the neurons red, for instance. But only the active neurons. So the neurons they get activated by the presence of, say, colitis, inflammation in the bowel, they turn red and they stay red. So you

Starting point is 01:54:07 can study them later, even, you know, weeks and months later. And that's exactly what Professor Rawls did. She used another very sophisticated trick with what's called stereotactic injections, injecting virus particles into specific parts of the brain that she had mapped from looking at the red neurons. So she knew these are the neurons that get activated by colitis. So she'd had the mice. She let them recover from colitis. And then she injected the virus into those neurons and reactivated now just the neurons, not all the neurons in the brain, just the ones that remembered the place of the colitis. And they got colitis again. The changes in the brain neurons, I call it a neural network. She does too. I mean, we all call

Starting point is 01:54:54 it an engram or a neural network. Lots of neuroscientists have talked about this on lots of podcasts, but they call it the Jennifer Aniston neuron or the Santa Claus neuron. I'm a recovering neurosurgeon, right, Tim. So you can do brain surgery under local anesthesia. And this is done a lot of times for epilepsy surgery, for instance, when you want to make sure that you don't injure any part of the brain involved in speech. So you can be talking to the patient during brain surgery. Now, you can put electrodes in various parts of the brain and ask the patient what's happening. And there's a famous story of a patient, well, I just saw Santa Claus or I see Jennifer Aniston. And so euphemistically, people call that, well, that you have a Jennifer Aniston.

Starting point is 01:55:35 neuron. You actually don't have a Jennifer Aniston neuron because you could put an electrode in another part of the brain and you say, well, friends, the TV show and Jennifer Aniston's neuron will light up in that because they're part of a network. Right. It's a constellation that is recognizable by the brain. It's a constellation. Exactly right. Well, nobody, before Asha studies, nobody thought that a constellation in the brain would recognize inflammation in a way, that would not only sort of remember the effects of it, but could then reactivate it. Not to interrupt,

Starting point is 01:56:12 but since every podcast I do is self-interested in some way. Is there a way to delete Control Z those constellations so that you don't have this hair trigger response to triggering colitis or low back? pain response. And in this book that I was mentioning explained pain, they talk about how surfers and instances, sometimes when they get their leg bitten off by a great white, they report it as a thump. It wasn't painful, whereas you get a paper cut and it's excruciating. And there's so much variability. So is there a way to deactivate a constellation or

Starting point is 01:56:57 overwrite it or I guess fix my fucking low back pain is the short answer without taking bottles and bottles of a leave. This is about the third time in this chat we've had that I wanted to offer you a job in my lab. You ask all the right questions. We can do the experiments if you come in. Well, you're not that far away. Don't threaten me with a good time.

Starting point is 01:57:22 The simple answer is that's what we want to do, right? So you might not have to remove the whole network. You might just have to disrupt a little bit of it. And the question is, can you disrupt it with a molecule that target selective neurons? You know, that's tricky, but not impossible. You have to figure out what the neurons are, figure out what the receptors are, figure out what's unique.

Starting point is 01:57:39 Then you have to design a drug to do that. That would be one approach. But the approach I like, and again, I'm a recovering neurosurgeon, so call me what you want. But there are millions of people walking around with deep brain electrodes, millions. And it sounds like this horrendous, terrible thing. But it's not. The electrodes that people are putting in now,

Starting point is 01:57:59 whether it's Neurrelink or somebody else, I mean, they're small than a human hair. and they go in and they don't injure blood vessels and they don't even injure sometimes, they don't even injure neurons. They go next to the neuron. You could imagine a time in our lifetimes, I hope, when if we knew how to target those neurons or map them in advance, right, that you could put these electrodes in and inhibit them. And yeah, that is the right question.

Starting point is 01:58:24 I'm dead serious. Now, Astros paper spent out a couple years. I said before, I think it's one of the most important studies that I've read in many years. And we have, of course, pursued it. We've been asking questions. My colleagues and I, Singita Chivon and Okito Hashimoto and Eric Chang, we're asking a very simple question. Can we make ngrams, memories, neural networks in mouse brains of specific cytokines? We're writing the manuscript as I speak.

Starting point is 01:58:52 And the answer is yes. We can show that when you give a mouse TNF, which causes a sickness behavior, you know, it looks like it has the flu. And then a bunch of other metabolic things that are specific to TNF and map an Ngram, we can see where the neurons in the brain are and see what they do. When we do the same experiment with IL1, which also gives a sickness response, but has a very different sort of metabolic, physiologic, can separate them. They're unique.

Starting point is 01:59:18 TNF and IL1 are different. The physiology is different. We see a different neural network. So now it's complicated, right? Because how many cytokines are there and how many physiological states? It's, I think the brain, you know, a human brain has, what, 100, 100 billion neurons, give or take, and trillions of synapses. So it's more complicated than we think it is. But I think it's accessing, processing, and potentially storing all the information that we haven't even begun to imagine yet.

Starting point is 01:59:48 And that's what this data tells me. What are the possible implications of identifying the constellations that I just keep thinking about stars, right? It doesn't take much to screw up Orion's belt. right like if you move one or two things around you could disrupt that ngram so to speak what are the implications of identifying the ngram signature of tnf alpha i all one etc what are the implications of it yeah well how would that translate or might it translate to some type of clinical practice i think you could literally if you knew where to put the electrodes into the brain you could have an electrode in the brain that communicates with an app on your iPhone

Starting point is 02:00:31 and you could dial it to upregulate or downregulate your inflammatory response to a specific cytokine or condition in a specific part of your body. Yeah, that's wild. It is. And you said it right. I mean, people used to think it was impossible to track an incoming missile from the moon, right?

Starting point is 02:00:50 But now they know how to do that. And the best example I like, and you're better at this than I am, but someone explained the analogy I like the most. If you look at a TV screen with all the pixels and you see a picture of the Alps, you can't possibly pick out the black square or the alter color square. But if you swap that one square and make it a really bright color or really black color, you actually can see it.

Starting point is 02:01:13 It's about subtracting, right? It's about subtracting to pick out what you don't know. In order to do that in humans, there's been all this rush to do brain imaging and brain anatomy. me, we still have a long ways to go, because to my satisfaction, as someone who thinks about systems interacting in biology, we haven't put enough emphasis on function. Yeah. Even for heart rate variability. You and I can't talk about heart rate variability because we don't know enough about the

Starting point is 02:01:45 individual functions of the individual wiring diagrams. Yeah. And also, we can talk about kind of science and studies and so on, maybe separately over a glass of wine or something, but sometimes the imaging tail wags the dog also for a host of reasons. Yes. Yes. You get these beautiful pictures and there's maybe some status associated with getting a bunch of money to play with the latest toys and then you can slice and dice the data to create all these different publications. There's an allure that I think can sometimes lead to an over-emphasis on the imaging,

Starting point is 02:02:26 which is not to negate some really, really incredible applications of the imaging, but I think what you said carries a lot of weight. Let me ask, because there will be people listening who are curious about this, cervical tens units. So we talked about the

Starting point is 02:02:45 transcutaneous auricular stimulation. There are devices, including some that are FDA-approved for, say, I believe, cluster headaches and or migraines, I can't recall exactly, that are neck-based and could be applied to one side, could be applied to both sides, but effectively, supposedly, tracking or stimulating the vagus nerve where it would correspond to your pulse, let's just say, crowded artery or arteries. And you can find a number of publications

Starting point is 02:03:16 on PubMed that talk about the data. But what might be the... the, if in fact they are doing something that is beyond placebo effect, what might the mechanism of action be? And you can start wherever you like. I'm just curious about the cervical devices because they're floating around out there. And there are, I've seen at least a few studies. And I'm like, huh, okay. Well, what the hell is going on here if in fact there is a signal instead of just noise? I think it's important to say that when you dive into these kinds of questions, there's lots of factors. So the first is, you know, can you afford to buy lots of devices and try lots of different things? That's one approach. And second, you know, do you like

Starting point is 02:03:59 self-experimentation? That's another approach. A third is, well, always check with your doctor first, because there are some things you probably shouldn't do around the area of your neck. You have carotid stenosis. You don't want to put any pressure on your carotid artery. If you have cervical synosis, you don't want to turn your head certain ways, check with your doctor. So those are actually important disclaimers. That's not a joke. People should check with their doctor before they do these things unless, of course, what they're doing is FDA approved. And some of these devices, most of them not, but some of these devices have been subjected to FDA approval. In the context of putting electrodes on your neck, there are some FDA approved devices that are called Vegas nerve stimulators.

Starting point is 02:04:43 and they are essentially tens units. They deliver pulses of electric current, spikes of electric current, usually between 20, 30 hertz, usually on the order of millie amps, and you know it's working because you feel a buzzing or a tingling. And when you put it on your neck, usually you know that the current is spreading around through the skin and through the nerves of your neck because your platisma muscle, the muscles of facial expression and your neck will twitch or your lip will twitch. Pull your lip down.

Starting point is 02:05:14 You can make some goofy faces. That's happened to you, right? Yes. Yeah. So that's evidence that the electric current is activating lots of nerves and lots of muscles. Now, time for a slight digression. The carotid artery is encased in a sheath with the vagus nerve. So to get to the vagus nerve, you have to go through the skin, through the botysma muscle,

Starting point is 02:05:38 through the layer of subcutaneous fascia, through the sternoclodon. mastoid muscle, which is that big, thick strap muscle in your neck, thicker in some than others, but it's there, down to the carotid sheath, maybe through another layer of fascia, through the carotid sheath, and then somehow either around or through the carotid artery. Right. So it seems like the tense unit is not going to hit the vagus nerve. Engineers I've spoken to at length about this say, and I said it very politely and clearly in the beginning of the show. The only way to directly stimulate the vagus nerve is to put an electrode on the vagus nerve. That's not this. You're putting the electrode on the skin.

Starting point is 02:06:15 Or to use focused ultrasound, which would penetrate all those tissues and could be focused to the vagus nerve in the neck, but those devices are not available for us to use at home. So your question was, could it work anyways? It's FDA approved to treat migraine. And the answer is... Well, my question was, what the hell might the mechanism be? If it's not actually getting through all that stuff to hit the vagus nerve? I have a very good answer for you. collective delusion and placebo. No, no. No, no. To defend the manufacturers and the FDA, patients who put this on their neck and use it according to the FDA label and have severe migraines, a significant percentage of them

Starting point is 02:06:53 do better than for patients who don't use the device. So there's, this is an example that we talked about before where you have a device. We don't necessarily know how it works. It might work through some other mechanisms, but it seems to work in a statistical way in, in FDA approved randomized clinical trials. Put that aside, right? How could it work? We're talking now science here. Well, Charles Sherrington, one of the two fathers of neuroscience with Ramone E. Cahall back in the early 1900s, he wrote a famous book, which I recommend to anyone, even casual readers of neuroscience, should read Charles Sherrington's book, The Integrative Action of the Nervous System. The title alone is brilliant, the integrative actions of the nervous system.

Starting point is 02:07:36 He taught us this. It's so simple, you'll never forget it. you have to understand a simple reflex because there's an input and then some sort of connection or process and an output. And that's what happens when the doctor taps your knee. That's what happens when inflammation happens in your body and the signal goes in. And, well, in the knee case, the rubber hammer stretches the tendon. The tendon sends a signal up your sensory nerves to the spinal cord. Spinal cord sends the signal back down to your quadricepsiformis. Your leg pops up and you said, shit, who did that? That's a reflex. In the context, of inflammation. There's inflammation in your body. The signal goes up your vagus nerve. Signals come

Starting point is 02:08:14 back down. Stop the inflammation. That's the inflammatory reflex. Got it. Okay, Charles, we got that. What's next? And he said, if you assemble a couple of reflexes, you can start to build a nervous system. This is, again, this is your field more than mine. It's a neural networking. You can assemble things. You can build up complex systems by just adding one more reflex, right? One more input, one more output. And then he goes, end of the day, there's no such thing as a simple reflex because every nerve in your body is connected. So you put electricity on your neck. Some of it's going to end up stimulating nerves that go into your brain or your spinal core. Once it gets in the brain or the spinal core, there's the big router. The brain can decide how to send it out. In some

Starting point is 02:08:51 patients, does it relax the muscles of the neck to interfere with the headache pathogenesis? Maybe. In some patients, does the brain send signals down the vagus nerve to stop inflammation contributing to migraine? Maybe. In some patients, does the brain send signals up to the resistance arteries that are controlling blood flow in and out of your brain that can give you a attention headache? Maybe. We don't know. Nobody knows. Yeah. I mean, it's exciting to me that there are so many open questions. So just he's like just enough of a teaser and a taste test of something to make it really tantalizing to investigate further. And my friend, he, he's using a cervical device, the one who tripled his HRV. So who the hell knows, right? And

Starting point is 02:09:40 ultimately, he and I were talking because after our first chat, I was like, hey man, I might have some good news, bad news. And I was like, it seems like your device is working for you. And I was like, I don't want to burst the placebo effect. But also, it doesn't seem to be a vagus nerve stimulator, but we were joking. And I think one of us was probably me because I'm a goofy ass a lot of the time. But I said, you know, I guess at the end of the day, you know, ultimately you don't really care if you're somehow summoning Odin to come down with a magic unicorn and pierce you through your forehead with the spike like a narwhal to fix your low back pain or increase your HRV. You just want the output. So whatever is happening, it would be great

Starting point is 02:10:24 to understand what's happening under the hood, but it's like you might like driving your Tesla. How many people actually know how it works or the microwave or the refrigerator? which is not to say that you want the larger scale RCTs and mechanisms of action. So I'm not trying to dismiss the importance of all that or the power of placebo. Well, I know if it's placebo. You said it's the power. It could be the power of one. And it could be that if 100 patients were subjected to this and 75% of them have the

Starting point is 02:10:55 effect your friend has, now, that's really interesting. Why? You know, this is where some people. people like to reach too far when they're hawking their wares. Yes. Some of the websites selling these things are so bad. Yeah. I mean, so bad. You expect them to be selling boner pills and cratim and some sketchy, you know, shitty, shitty cryptocurrency at the same time in the checkout process. They're so bad. Yeah. And, you know, people say, oh, well, is it safe? Well, that's important.

Starting point is 02:11:26 But then you raise people's hopes and then you take their money and you don't know what you're doing. there's real questions there. I'm not saying it's easy. Look, what people would say is the simplest, stupidest clinical trial of one of these devices might cost $5 million or more. Science is expensive. Good science is expensive. Yes. All right. We've covered a lot of grounds. I highly, highly, highly recommend people check out the great nerve if you want, not just things we've talked about, but we could do like three rounds on the podcast. I didn't even get through a small portion of my notes. Also in your book, I want to point out, because this is important, you have an entire section dedicated to different types of tools with some really remarkable results,

Starting point is 02:12:11 whether that's breathwork, cold exposure, meditation. You know what? Maybe just as a fun way to bookend this, could you please tell the story, you've got some amazing stories in the book. Could you please tell the story of the Dalai Lama. People are like, what? The Dalai Lama, how the hell does he fit into this? Yeah, okay, so please tell that because it's just fun. I mean, it's so fun. It's also fascinating, but it's fun.

Starting point is 02:12:39 Back in the day, I was it about 2007, give or take. I can't remember the year. It's in the book, maybe 2010. I got a call from the Dalai Lama's New York office. Would I like to go to a conference? Now, the call came from a gentleman named Bill Bouchel, who was a scientist in his own right, who was working full-time in the Dalai Lama's organization. And he had been following my work because of these questions on the role of the vagus nerve and meditation.

Starting point is 02:13:07 The Dalai Lama, of course, famously has participated in and supported many, some very sophisticated brain imaging studies and meditation studies. And the Dalai Lama is on the record of saying that he's convinced that the major tenets of his religion are true. in a quantum mechanical way, as you alluded to before, from any perspective, his tenants are like the speed of light. They don't change. And he said to the point that, in fact, if quote-unquote Western science or New World Science could disprove any of his tenants, and he would change the tenants. So he has a deep interest in science. So he hosted a meeting here in Phoenician, New York, on the top of a mountain where they own a compound, right outside of Woodstock, where the rock concert was. And so I drove up there. Not all the funny stories made the book, Tim, but

Starting point is 02:13:54 one I have to tell is when I'm checking in, I got there late, it was dark, and I'm in the middle of the woods. And I'm in the woods. I like the woods. I like to camp. I like to be out there by this place. It is in the middle, I mean, middle, middle of the woods. Yeah. They own the whole mountain, right? So it's dark. It's nighttime. And they give me keys to a cabin in the middle of woods. And as I'm going out the door, the woman says, don't mind the bears. And I'm like, fine, I'm going to walk in the dark. It's through the bears. My cabin. I said, well, I'll make a joke. And I said, well, I know they were here first, right? Ha, ha, ha, ha. And she looks at me with, like, steely eyes. It's like, okay, welcome. Welcome to Woodstock. I'm like, this isn't, like, the concert.

Starting point is 02:14:37 So, so, uh, the next day. Good evening, sir. Exactly. The next day, I'm on stage. The next day was two days of scientific talks, a whole series of time. I gave one. I remember Liz Blackwell was there. And when she was there, it was the time it was during the meeting. It was announced that she'd won the Alaska Prize. I think a year or two later, she won the Nobel Prize. So Liz and I were there and a bunch of other scientists. And the last day, the organizers came up to us and asked Liz and I,

Starting point is 02:15:04 if we would summarize the meeting for His Holiness, the Dalai Lama, on stage in front of all the attendees. So we said, sure. So Liz gave a talk, and then I gave a talk. I'll never forget. I was on stage with the Dalai Lama, with Bob Thurman, who was sitting to his, side, and that's Uma Thurman's dad, and he's a professor of Tibetan studies and other studies at Columbia at the time, Columbia University, and a translator sat between us. And I explained the Vegas nerve, and I said, and he asked the question you did, you know, where is this Vegas

Starting point is 02:15:36 nerve? And I said, well, it travels down your neck, into your, cross your chest, into your abdomen, he goes, oh. And then he said, through Bob, he said, is it in the front or the back? I said, well, it's in the front. And then he said, is there one or two? I said, well, there's two. And then he smiled at me, and then that was that. And then afterwards, he left, and a few monks came up to me in their long, flowing orange robes, as Bill Murray would say, striking, you know. And they said to me, His Holiness asked you those questions. Do you know why he asked you those questions? I said, no, I haven't a clue. And they said, well, we like to practice one form of Tibetan meditation is we like to practice a cloud of blue

Starting point is 02:16:23 energy over our heads that we channel in two waves down each side of the neck across both side of the chest down into the abdomen. And I said, cool. And the monk said, yeah, it's very cool. Not everybody gets a dollar llama story. Yeah, that is a good one. Well, people can find The Great Nerve, which includes so much more anywhere that you find your books, Dr. Kevin Tracy, T-R-A-C-E-Y. And is there anything else you'd like to say as we wind to close? Anything you'd like to add, point people to requests, reminders, public complaints, anything you'd like to say before we land the plane? One thing, these things in the book and that a lot of people talk about for self-help, they're good. I do them.

Starting point is 02:17:14 I know, meditation's good. exercise is good. Watching your weight is good. Getting enough sleep is good. All of these things, I think, are good to reduce the inflammation in your body, and they are good to probably do, to give your vagus nerve some exercise and improve your heart rate variability. It's all good. I just don't like to say that it's the cure for some of these serious medical conditions. And the fact that we now have a path to connect decades, literally decades of science, to now 15 years, 12 years, of clinical trials on this science that gives hope to some patients

Starting point is 02:17:50 with serious inflammatory conditions that stimulating their vagus nerve with this immunoregulator is what we really call it. It's an exciting time. And I really appreciate you having me on the show and there's more questions we can talk about next time, maybe.

Starting point is 02:18:04 Yeah, maybe round to cognitive enhancement with vaguest nerve stimulation. I mean, I could keep going, keep going for many, many hours, but I'll call it here for now. And everybody listening, we will provide links in the show notes to many different studies, to Ulf Anderson's protocol for the five minutes twice a day, of course, to set point to the New York Times piece as well, and to the book, The Great Nerve, and you'll be able to find all of that

Starting point is 02:18:33 at tim.blog slash podcast for the show notes. Just search. My friend Kevin Rose will pop up a lot if you search Kevin, so search Tracy, T-R-A-C-E-Y, or Vegas, or Vegas Nerve, and this will pop right up and until next time folks be just a bit kinder than is necessary not just to others but also to yourself and as always thanks for tuning in hey guys this is tim again just one more thing before you take off and that is five bullet friday would you enjoy getting a short email for me every friday that provides a little fun before the weekend between one and a half and two million people subscribe to my free newsletter my super short newsletter called Five Bullet Friday. Easy to sign up, easy to cancel. It is basically a half page that I send out

Starting point is 02:19:21 every Friday to share the coolest things I've found or discovered or have started exploring over that week. It's kind of like my diary of cool things. It often includes articles I'm reading, books I'm reading, albums perhaps, gadgets, gizmos, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcast guests. And these strange esoteric things end up in my field and then I test them and then I share them with you. So if that sounds fun, again, it's very short, a little tiny bite of goodness before you head off for the weekend, something to think about. If you'd like to try it out, just go to tim.blog slash Friday. Type that into your browser, tim.org slash Friday, drop in your email and you'll get the very next one.

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The Tim Ferriss Show - #824: Dr. Kevin Tracey — Stimulating The Vagus Nerve to Tame Inflammation, Alleviate Depression, Treat Autoimmune Disorders (e.g., Rheumatoid Arthritis), and Much More

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