#824: What Most Has My Attention Right Now — Credible (vs. Bogus) Vagus Nerve Stimulation

Kevin J. Tracey, MD is president and CEO of the Feinstein Institutes for Medical Research at Northwell Health, a pioneer of vagus nerve research and author of the recent book, The Great Nerve: The New Science of the Vagus Nerve and How to Harness Its Healing Reflexes https://www.amazon.com/gp/product/059371699X/?tag=offsitoftimfe-20. This episode is brought to you by: Eight Sleep Pod Cover 5 https://www.eightsleep.com/tim/ sleeping solution for dynamic cooling and heating: EightSleep.com/Tim https://www.eightsleep.com/tim/ (Use code TIM to get $350 off your very own Pod 5 Ultra.) AG1 https://drinkag1.com/Tim all-in-one nutritional supplement: https://DrinkAG1.com/Tim https://drinkag1.com/Tim (1-year supply of Vitamin D plus 5 free AG1 travel packs with your first subscription purchase.) 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Timestamps: 00:00 Tim’s intro: why he dismissed vagus-nerve hype 06:34 What the vagus nerve actually is, plus common myths 11:31 Breaking news: FDA approval for SetPoint’s RA implant + Kelly Owens’s turnaround 21:11 Inflammation 101: when healing turns harmful 31:37 Bioelectronic medicine: from lab insight to real devices 55:26 TNF, IL-1, and IL-6: immune drivers and what VNS modulates 56:06 Exercise & recovery: vagal signals, IL-6, and adaptation 56:30 Cold exposure & breathwork: sympathetic spike, parasympathetic payoff 59:04 Chronic inflammation today: prevalence, diagnostics, and uncertainty 59:53 Autoimmunity: genes, environment, infections 01:01:08 Stress hormones, personality traits, and metabolic fallout 01:05:41 VNS tech landscape: implants, focused ultrasound, and what’s just TENS 01:11:14 Ear maps, revisited: the real science behind auricular stimulation 01:27:52 Ulf Andersson: auricular TENS, famotidine, and a depression turnaround 01:36:48 Depression & inflammation: where VNS helps (and where it doesn’t) 01:41:38 Body-brain loop: how inflammation signals ride the vagus nerve 01:42:56 Why VNS can lift mood: a working theory 01:43:22 Ulf’s setup: electrode placement and twice-daily routine 01:44:37 Acupuncture, fertility, and plausible vagal links 01:47:23 Chronic pain through an inflammation lens 01:48:34 Neural “engrams”: how the brain can store inflammatory memories 02:02:35 Cervical TENS vs. true VNS: mechanisms and open questions 02:12:15 On stage with the Dalai Lama: blue energy and two vagus nerves 02:16:55 Closing thoughts: self-care vs. medical devices, and what’s next * For show notes and past guests on The Tim Ferriss Show https://tim.blog/podcast, please visit tim.blog/podcast https://tim.blog/podcast/?utm_source=podcast&utm_medium=podcast&utm_campaign=podcast-description. 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Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Tim Ferriss?

  Well, hello, boys and girls, ladies and germs. This is Tim Ferriss. Welcome to another episode of The Tim Ferriss Show, where it's 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 squirrely, 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 vagus nerve research and author of the recent book, The Great Nerve:

• 0:45Tim Ferriss?

  The New Science of the Vagus 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 vagus nerve 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 bioelectronic medicine, which investigates the therapeutic applications of vagus nerve stimulation to cure disease.

• 1:27Tim Ferriss?

  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. 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.

• 2:12Tim Ferriss?

  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.

• 2:27Tim Ferriss?

  Sleep is the key to it all. It is the foundation. Many of you heard me talk about how today's sponsor, Eight Sleep, has improved my sleep with its Pod cover. Well, they just launched their latest product, the Pod 5. I cannot wait to try it out, and here's why. The Pod 5 introduces Eight Sleep's latest product, the Blanket, which uses the same technology as the Pod's cover to extend temperature regulation across the entire body. So if you're too hot, too cold, you can fix it. If you're a couple and one of you is hot, one of you is cold, you can fix it as well. It all fits right over your existing mattress like a fitted sheet. On average, members report the Pod has helped them fall asleep 44% faster, 34% deeper sleep, and given them up to one added hour of sleep each night. Also, the Pod's snoring detection, my friend Albert might be interested in this,

• 3:12Tim Ferriss?

  and automatic elevating platform have reduced user snoring by 45%. So it does a lot. You'll also get a personalized report each morning, allowing you to track your sleep stages, heart rate variability, respiratory rate, and more, all without having any devices strapped on to you. So head over to eightsleep.com/tim and use code TIM to get $350 off of your very own Pod 5 Ultra. You can try it at home for 30 days and return if you don't like it. So why not? Give it a shot. Sleep is everything. Again, that's eightsleep.com/tim. You can spell it out, eightsleep.com/tim for $350 off. Shipping is available to many countries worldwide. One more time, eightsleep.com/tim.

• 3:54Tim Ferriss?

  It's been a while. Many of you know how deeply I love Japan and its culture of unwavering dedication to craft, refinement, commitment to continuous improvement. You can see it in their coffee. Try Glitch Coffee. You can see it in Jiro Dreams of Sushi. But why do I bring this all up? Well, the same focus on improving one thing, one product, over the span of years is found in today's sponsor, AG1. I met the founder way back in the day, randomly, in a coffee shop in Argentina. It must have been between 2005, 2007, and ever since then, one product. They are now unveiling AG1 Next Gen, the same, single-scoop, once-a-day product that I use myself, but now with more vitamins, more minerals, and five new...

• 4:36Tim Ferriss?

  Clinically studied probiotic strains shown to support digestive and immune health. I love it for its great taste. I just mix it with cold water. It's easy and the way it helps fill nutritional gaps in my diet. It's my nutritional insurance. AG1 is also NSF certified for sport, one of the most rigorous independent quality and safety certification programs in the supplement industry. NSF conducts annual audits of AG1's manufacturing facilities, reviews ingredients for toxicology, and ensures AG1's label claims are accurate. So check them out. Subscribe today to try the next gen of AG1. Listeners will also get a free bottle of D3K2 and AG1 Welcome Kit and five of the upgraded AG1

• 5:19Tim Ferriss?

  Travel Packs with your first order. So start your journey with AG1's next gen and experience the difference firsthand. Simply go to drinkag1.com/tim. That's drinkag1.com/tim.

• 5:36Tim Ferriss?

  At this altitude, I can run flat out for a half mile before my hands start shaking. Can I ask you a personal question? No, we're just in an appropriate time.

• 5:46Speaker 01

  I'm a cybernetic organism, living tissue over metal endoskeleton.

• 5:59Tim Ferriss?

  This podcast episode is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice, and no doctor-patient relationship is formed. The use of information in this podcast episode or materials linked from tim.blog is at the user's and listener's own risk. The content of this episode is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they may have and should seek the assistance of their healthcare professionals for any such conditions.

• 6:34Tim Ferriss?

  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 on. I'm really looking forward to it, Tim. 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

• 7:14Tim Ferriss?

  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, 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.

• 7:59Tim Ferriss?

  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, 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 patents

• 8:44Tim Ferriss?

  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 vagus 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 is not a device. There are a lot of differences, but he had been using something purchased off the internet and had tripled his heart rate variability. And I mentioned the military piece because he has, I'm not sure if this is the right

• 9:27Tim Ferriss?

  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. 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%.

• 10:08Tim Ferriss?

  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 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.

• 10:53Tim Ferriss?

  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.

• 11:14Tim Ferriss?

  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?

• 11:31Speaker 02

  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. 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.

• 12:15Speaker 02

  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. 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 in 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 can switch off inflammation

• 13:00Speaker 02

  that culminates this morning, as you point out, in a story about patients who've already been treated, some of whom had rheumatoid arthritis for decades, couldn't button their blouse, couldn't pick up a pencil.

• 13:12Tim Ferriss?

  If you don't mind my interjecting.

• 13:13Speaker 02

  Yeah, I get excited too, Tim. I apologize.

• 13:16Tim Ferriss?

  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? 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.

• 13:51Speaker 02

  Kelly Owens is the patient you're referring to. I know her story very well. I know her very well now. And when I think of her story, as 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 twenties 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. Now,

• 14:36Speaker 02

  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 loved 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 schoolteacher, 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 and childbearing would be too risky, and to get used to her life like that. Around

• 15:18Speaker 02

  that time, she saw me on a Huffington Post Live Internet interview, livestream. 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.

• 15:34Tim Ferriss?

  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.

• 15:51Speaker 02

  Absolutely. People think of, they hear the word arthritis, when they hear rheumatoid arthritis, they hear arthritis. This is not the trivial sports injury you had in high school and 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.

• 16:33Speaker 02

  They can cause depression, they can cause anxiety disorders, they can cause chronic fatigue. So that's exactly right.

• 16:39Tim Ferriss?

  All right, so she reaches out to you, you recommend she investigate, Setpoint Medical, then what happens?

• 16:45Speaker 02

  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 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, raised 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 one implant. It was a, 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.

• 17:29Speaker 02

  Couple of weeks later, they're in 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's Sean?" Sean's at the bottom of the stairs with tears streaming down his face because Kelly, it was the first time he's seen Kelly run up the stairs in years.

• 17:57Tim Ferriss?

  Yeah, she had trouble walking on the cobblestones.

• 18:00Speaker 02

  She had trouble walking on the cobblestones?

• 18:02Tim Ferriss?

  Not long before.

• 18:04Speaker 02

  Her father gave her a cane for her birthday that she used for many, many years when she wasn't in a wheelchair 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 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."

• 18:46Speaker 02

  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 bioelectronic 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 to this. 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 gonna change everything and if you're gonna be a leading spokesperson on the patient's side of this, you may be... People are gonna tell you you're a placebo effect. Tim, all of those things happen.

• 19:28Tim Ferriss?

  Oh, I'm sure.

• 19:29Speaker 02

  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."

• 19:42Tim Ferriss?

  Yeah, and not with a smile on the face.

• 19:46Speaker 02

  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 wrapped cane. It was clearly a cane, the way she wrapped it, the handle was wrapped, and the cane was wrapped with a big bow on it. 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

• 20:27Speaker 02

  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.

• 20:35Tim Ferriss?

  So I want to add a few things to that. What a story. And like you said, some people at the time were like, ah, placebo. But placebo effect, and I'm pulling directly from you here, rarely has durability passed 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

• 21:18Tim Ferriss?

  to day, to having almost too much energy, which doesn't say it was a problem, but just kind of running up the stairs, bouncing off the walls. And my God, what a difference. That the lives that are lived by the former and the latter, the magnitude of the differences just can't really be overstated. It's too different. Experiences of life. So now I'm going to get all excited and lose my train of thought, but I'm going to scattershot 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,

• 21:57Tim Ferriss?

  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 software, 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 and conversation with Nora Volkov for potentially hitting the nucleus accumbens for addiction. And the possibility, not just the possibility, but now a lot of compelling data, for instance, around set point medical

• 22:38Tim Ferriss?

  and other forms of vagus nerve stimulation, but I know you might put some of them in quotation marks, to be an option, an 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 happen to be lethargic

• 23:18Tim Ferriss?

  and I'm hunting for a diagnosis, going from quack to quack until I get Lyme disease. Like 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, in my family on both sides. So looking 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 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

• 24:03Tim Ferriss?

  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 vagus nerve is because it's more like vagus nerves and you'll give a great description. I'll just give a couple of quick samplers and then we can get back into them at any point. But GLP-1 agonists, right? In the news, Ozempic, Monjaro, take

• 24:40Tim Ferriss?

  your pick. But at least in animals, my understanding is if you sever the vagus nerve, those GLP-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, the insulin insensitivity, the weight gain of the obese mice. Fascinating. But if you

• 25:21Tim Ferriss?

  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. Vagus nerve. How should people think about the vagus nerve?

• 25:45Speaker 02

  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 define, if you agree, bioelectronic medicine, because we 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 it's called. But you have two of them, so there's two vagus nerves, like two thumbs, one 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.

• 26:25Speaker 02

  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 a 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 or the brain. 80% of them actually originate in the body. They carry information about the organs in your body up into your brain.

• 27:07Speaker 02

  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 misnomers 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 treat it each one as a wire.

• 27:29Tim Ferriss?

  Let me ask if this is a fair visual to paint for people. 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?

• 28:09Speaker 02

  No, I wouldn't modify it 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, 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 of 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.

• 28:50Speaker 02

  And so, one way of thinking of the vagus nerve, 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 fisherman 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 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?

• 29:34Speaker 02

  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. 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 on 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.

• 30:07Tim Ferriss?

  And let's just say of those 200,000 fibers, do we know roughly how many affect HRV and cardiac?

• 30:19Tim Ferriss?

  Function.

• 30:20Speaker 02

  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 Lieberlis and his colleagues, we know in mice that somewhere around 100 or 150 fibers are sufficient to control breathing. Now, a mouse vagus nerve has 5,000 fibers, not 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, within human beings, for instance, and we'll come back to this some more, but I

• 31:04Speaker 02

  estimate somewhere between 1,000, give or take, maybe 1,500, maybe 2,000 fibers 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 90,000 doing? Yeah, exactly.

• 31:37Tim Ferriss?

  Just a quick thanks to one of our sponsors and we'll be right back to the show. This episode is brought to you by Wealthfront. It's a mess out there. The hyper complexities of the US economy, global economy can be very confusing and there's a lot of conflicting advice, but saving and investing doesn't have to be complicated. Here's something refreshingly simple to use and that's Wealthfront. Wealthfront is an app that helps you save and invest your money. Right now, you can earn 4% APY, that's annual percentage yield, on your cash from partner banks with the Wealthfront cash account. That's nearly 10 times the national average, according to FDIC.gov. So, don't wait. Earn 4% APY on your cash today.

• 32:18Tim Ferriss?

  Plus, it's eligible for up to 8 million in FDIC insurance through partner banks. And when you open an account today, you'll get an extra $50 bonus with a deposit of $500 or more. There are already more than 1 million people using Wealthfront to save more, earn more, and build long-term wealth. So check it out. Visit wealthfront.com/tim to get started. One more time, that's wealthfront.com/tim. This is a paid endorsement of Wealthfront. Wealthfront brokerage isn't a bank. The APY is subject to change. For more information, see the episode description.

• 32:53Tim Ferriss?

  I want to keep giving people Scooby snacks here, just because I'm so excited. I want to keep reiterating the potential payoff, right, 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?

• 33:38Speaker 02

  It gets turned off. 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. This was a head-scratcher. This made no sense whatsoever.

• 34:22Tim Ferriss?

  And is that's a head scratcher because the effect should have been sequestered to the brain because of the blood-brain barrier?

• 34:29Speaker 02

  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 in the vagus nerve with electrodes and treat inflammation with a device instead of a, instead of drugs.

• 35:11Speaker 02

  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.

• 35:38Tim Ferriss?

  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 gonna ask a lot of questions I don't know the answers to, otherwise the interview is pretty boring for me. So, does this mean that you could use, as an acute intervention, vagus nerve stimulation, say hypothetically in the ER, to stop anaphylaxis, or to address like asthma attacks, or sepsis, or anything like that?

• 36:05Speaker 02

  Once you understand the basic signals that flow in the vagus nerve to control one aspect of the immune system, in this case...

• 36:15Speaker 02

  How vagus nerve fibers can turn off cytokine production. You can ask new questions. Yep. And let 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 in 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 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.

• 36:59Speaker 02

  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 bioelectronic medicine as an approach to develop therapies. You begin in the same way. You pick your condition. It's rheumatoid arthritis. Then you say, rather than screen for antibodies or other molecules to stop TNF, which is the target in rheumatoid arthritis, let's see if we can find nerves that control TNF production in the body inside too. If we can find such nerves, then we can build devices to control the nerves,

• 37:43Speaker 02

  and the devices become the therapy. The bioelectronic 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. So there are many conditions today that are treated with anti-cytokine therapy, anti-TNF, anti-IL-1, anti-IL-6. Those conditions include things like rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, psoriatic arthritis, and some other conditions. Most 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

• 38:28Speaker 02

  the mechanism? Tim, no one knows.

• 38:30Tim Ferriss?

  Yeah.

• 38:30Speaker 02

  That's a full stop.

• 38:31Tim Ferriss?

  There lies the rub.

• 38:32Speaker 02

  That's a full, that's a full stop for me before saying, you know, vagus nerve stimulation will or will not work.

• 38:38Tim Ferriss?

  Yeah.

• 38:39Speaker 02

  I remember one of my mentors and friends, rest his soul, Frank Austin, was one of the leading experts on asthma research for decades. And a few years before he died, I said, Frank, I think I'm gonna do some asthma research. He said, okay, what are you gonna do? I said, well, I got this mouse model. He goes, Kevin, the last article I wrote on asthma was entitled, "Mice Don't Wheeze."

• 38:59Tim Ferriss?

  I like that. It's mice don't wheeze. Well, you know what that makes me think of? And I mean, like, we're gonna 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 the, since I've funded so 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

• 39:41Tim Ferriss?

  giving LSC to cats way back in the day, decades ago at Princeton. And they're using, let's just say, the antidepressant animal models might involve like swim to exhaustion. And then you're like, okay, well, I guess methamphetamine is gonna 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, 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 monoesters before our chat, though.

• 40:25Tim Ferriss?

  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, 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, their very potent anti-inflammatory effects of

• 41:09Tim Ferriss?

  certain psychedelics in the phenethylamine 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 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 ascribe to a chemical imbalance theory of, say, depression or mental illness writ large, but depression. So this is directly from your book.

• 41:52Tim Ferriss?

  If an SSRIs helped you or someone you know, that's wonderful. 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 caused by these cytokines.

• 42:33Tim Ferriss?

  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 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.

• 43:16Tim Ferriss?

  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, is credible, as credible as credible can be. The stability of my 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,

• 43:59Tim Ferriss?

  perhaps it is, and so they'll criticize maybe a story like this, or the story of your patient, and say, "Ah, N of 1 placebo," and they discard it that way. But a lot of very critical scientific investigations begin with case studies in the literature. 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.

• 44:41Tim Ferriss?

  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?

• 44:51Speaker 02

  Yeah, we're gonna have to do a couple of shows, Tim.

• 44:56Speaker 02

  Yeah. Simply put, inflammation was defined thousands of years ago as the redness, the pain, the swelling, and the heat that you feel when you sprain your ankle or get an infected wound on your, 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, TNF, IOL1, IL6, but other molecules made by white blood cells and, 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 that might, might settle in the wound. And it's a good thing if it stops.

• 45:39Speaker 02

  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 Owens' case, then it becomes like the army showing up 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 textbooks say, that's what everybody knows, that's what everybody's taught, 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 prostaglandins,

• 46:20Speaker 02

  that's how ibuprofen's and other non-steroidals work. 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. And the same is true when you look in the adipocytes, the, 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 in the fat, but they, it's not rip-roaring inflammation that you see with, in an infected wound. They might have upregulation of some of the

• 47:04Speaker 02

  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 rheumatoid arthritis. Some people have come up with new names. Meta-inflammation. Inflammaging, it's called sometimes when these kinds of changes occur.

• 47:23Tim Ferriss?

  Inflammaging, that's pretty good.

• 47:25Speaker 02

  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 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,

• 48:10Speaker 02

  and cancer. So, 2/3 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 summarized in a very simple sentence.

• 48:53Speaker 02

  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 2/3 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.

• 49:38Speaker 02

  You know, cleaner water, ample foods 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 continuing to dive deeper and deeper into understanding how evolution itself put the brakes on too much inflammation. I said that inflammation's 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

• 50:20Speaker 02

  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 new idea.

• 50:44Tim Ferriss?

  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 Vagus 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 along 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...

• 51:28Tim Ferriss?

  If you are, say, decreasing cytokine production or 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, blah, temporarily at least, are seem important for catalyzing some of these tissue adaptations. So are you at risk by sort of suppressing cytokines with vagus nerve stimulation?

• 52:12Tim Ferriss?

  Do we know anything about the side effect profile?

• 52:14Speaker 02

  We know a great deal about the side effect profile, 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-IL-1 or anti-IL-6 that you see advertised at the nightly news every night and on 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 IL-1, depending on what drug you're on, those drugs

• 52:59Speaker 02

  carry warnings, the most serious side effect warning the FDA can give called the black box warning, because they cause immunosuppression, which is exactly what you said. Immunosuppression 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, or 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 vagus nerve stimulation do that? The simple answer is no. And the reason we know this is because the FDA approved vagus nerve stimulation to treat depression. And epilepsy, actually, in the 1990s.

• 53:43Speaker 02

  So we have decades of experience implanting patients with vagus nerve stimulators. Now, there have been peer-reviewed studies 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, you know, one inch large, completely encased in it. But immunosuppression-wise, we also know that vagus nerve stimulators do not have black box warnings. There's no evidence after decades of any immunosuppression, there's no evidence of

• 54:28Speaker 02

  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%. 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 be very bad for your tissues and for you. The normal range should be 10 or 20.

• 55:13Speaker 02

  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 IL-1. The vagus nerve is actually suppressing the whole system. So it's taking the toxic levels of IL-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

• 55:58Speaker 02

  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 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 IL-6 metabolism and turnover that's going on. We don't know.

• 56:26Tim Ferriss?

  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 a vis the vagus nerve, but parasympathetic activation, which might be very counterintuitive to folks. And so, for instance, reading your research and reading your book and chatting with you

• 57:07Tim Ferriss?

  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 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?

• 57:51Tim Ferriss?

  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 are studies demonstrating this, whether it's in cold chambers for hours, which sounds like more misery than I can handle, but suffice to say, initially, fight or flight response, sympathetic activation, adrenaline noradrenaline, et cetera. 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

• 58:33Tim Ferriss?

  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 of these things seem to touch the hem of the same fabric. Anyway, I guess that 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?

• 59:17Tim Ferriss?

  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. So who knows? And 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?

• 59:53Speaker 02

  That is a billion dollar question for which, I'm not an epidemiologist, but 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 and some of them are more common at lower latitudes.

• 1:00:11Tim Ferriss?

  Huh, interesting, the latitude.

• 1:00:13Speaker 02

  Yep.

• 1:00:14Tim Ferriss?

  Wild.

• 1:00:14Speaker 02

  Yep.

• 1:00:15Tim Ferriss?

  I mean, correlation, I guess, doesn't prove causation, but it's interesting.

• 1:00:19Speaker 02

  It's very interesting. It always comes down to two things, pretty much, in biology. It's nature and nurture. It's genes and environment. And environment is writ large. It's the family you were brought up in. 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 and 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, turn out to be caused by previously unknown infections.

• 1:01:04Speaker 02

  One of my favorites is stories about this, of course, is peptic ulcer disease. Everyone, when I was a kid in medical school, everyone, we all knew that peptic ulcer disease was type A personalities and the...

• 1:01:16Tim Ferriss?

  Stress.

• 1:01:17Speaker 02

  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, and when you treat these people with...

• 1:01:26Tim Ferriss?

  What is that? H? Not H.

• 1:01:27Speaker 02

  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 communist operations in the hospital OR...

• 1:01:44Tim Ferriss?

  I thought you said communist for a second. I was like, oh, I didn't see that coming.

• 1:01:47Speaker 02

  One of the most common operations on the OR schedule was gastrectomy for peptic ulcer disease. You'd 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. And when you realize it's not the patient's fault, 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.

• 1:02:31Speaker 02

  But very, very few of these conditions do 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 you a question, Tim. Is that environment or genes? Well, I mean, it's environment, right? It's environment.

• 1:02:48Tim Ferriss?

  Well, I was also thinking like genetic predisposition to risk taking when they're like, "Ah, it'll be fine."

• 1:02:53Speaker 02

  Well, it's easier than that. It's easier than that. It's father and son, 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.

• 1:03:12Tim Ferriss?

  Well, to make it even more difficult, when we're talking about 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 wading 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 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 he's trying to go to sleep. Going back to the book. "This in turn increases your blood glucose levels.

• 1:03:53Tim Ferriss?

  Elevated glucocorticoid levels, as occurs in depressed patients, accelerates lipolysis, 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 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, where, yes, it's an infection, but there are certain...

• 1:04:38Tim Ferriss?

  Behaviors or genetic predisposition or who knows even jobs that make it more likely that you would be susceptible to such an infection. I don't know. I don't know.

• 1:04:47Speaker 02

  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. But I think the whole, last time I read about this, I'm not a psychologist, but the last time I probed 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.

• 1:05:20Tim Ferriss?

  Yeah, which is understandable.

• 1:05:22Speaker 02

  But it's interesting. You know, it's like at a scientific meeting was 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.

• 1:05:41Tim Ferriss?

  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 potentially. I'd say probably the greatest benefit is patient compliance. So 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

• 1:06:21Tim Ferriss?

  the story of your friend Wolf and just describe who he is and lead into his story, if you're open to it?

• 1:06:29Speaker 02

  On the set point device, the one the size of a fisher pole, 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 who are injecting themselves with drugs. Many of them can't afford anymore 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 pushups or try to do more things to help themselves."

• 1:07:10Speaker 02

  Well, I gotta be really, really outspoken on this because when you meet people that have these conditions, if it was easy as doing a couple of pushups or taking a yoga class or breathing differently, they would do it. If it made them better, they would do it. 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

• 1:07:51Speaker 02

  path, to have a small immunoregulator implanted in their 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...

• 1:08:03Tim Ferriss?

  What an effective mask I've created. Yeah, no, I'm generally well, yes.

• 1:08:09Speaker 02

  And me too, and I feel very fortunate for that. And so I try to do things that align with what people would call vagus 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 the stress from my life as much as possible. I mean, all the things that we all know we should be doing and your GP or your primary care provider should be telling you to do every day. All those things in one way or another that we've sort of been talking about can be said to stimulate directly or indirectly the vagus nerve.

• 1:08:48Speaker 02

  But there's other modalities that people also talk about using electrical devices to stimulate the vagus nerve by applying electrical devices or TENS 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 the third one, or the immunoregulator device from set point.

• 1:09:31Speaker 02

  That's the only FDA-approved way to stimulate your vagus nerve that directly, specifically stimulates your vagus nerve. Full stop. Experimentally, you can do it using focused ultrasound. And we've done that in the lab, my colleagues, Angita Shivan and Sabros Anos, we've published on this in the period of 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.

• 1:10:16Speaker 02

  And it's also been done, 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 ear, to the side of the head, or the face, those are all non-invasive and nonspecific and really shouldn't be called vagus nerve stimulators.

• 1:10:36Tim Ferriss?

  Nonetheless, nonetheless, some interesting stuff seems to happen.

• 1:10:42Speaker 02

  Okay.

• 1:10:43Tim Ferriss?

  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 GLP-1.

• 1:10:54Tim Ferriss?

  Administration, but I'm gonna call that a temptation and not an opportunity for the moment, and let's talk about your friend Olf and what happened to him.

• 1:11:03Speaker 02

  So I apologize for the digression, but I had to get that, as you understand, on the record.

• 1:11:08Tim Ferriss?

  You gotta do it.

• 1:11:09Speaker 02

  Now, what about other stuff, like a TENS unit? Let's give a little background there. Anybody interested in auricular therapy, I mean, auricle as ear, A U R, auricular therapy, and/or 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

• 1:11:50Speaker 02

  acupuncture maps of the ear originated in France in 1957 by a doctor named Dr. Paul Nozier, 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.

• 1:12:13Tim Ferriss?

  Burning their ear.

• 1:12:14Speaker 02

  Yeah, burning or cutting a piece of it off. 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, and in both times, the patient claimed, the two patients claimed that their sciatica got better. So Dr. Nozier 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 patients' 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 and many, many patients and ultimately published this and he presented it at an acupuncture meeting that was being held somewhere in

• 1:12:59Speaker 02

  the Mediterranean and it led to this overwhelming acclaim 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 1950s. So that's where the maps come from. They're fun to look at, they really are, and especially in light of the story I'm gonna 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, Sangita, Siobhan 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

• 1:13:42Speaker 02

  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 canal where you put your finger in your ear and where it looks like a seashell. So it's called the simba concha, that's where it gets its name, concha like shell. Now, this branch of the vagus 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

• 1:14:26Speaker 02

  brain called the nucleus tractus solitarius, 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 of it like the router in your house. Everything goes into one spot and then it goes back out again. 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.

• 1:15:08Tim Ferriss?

  Wow, wild.

• 1:15:10Speaker 02

  It's wild.

• 1:15:11Tim Ferriss?

  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 explodes, it doesn't seem to have any adaptive purpose for natural selection. But lo and behold, fish gills.

• 1:15:33Speaker 02

  Well, it's fish gills, but I didn't say it makes sense, Tim. You said that.

• 1:15:38Tim Ferriss?

  Well, no, I shouldn't say it makes sense. It's just like a vestigial

• 1:15:42Speaker 02

  Yes.

• 1:15:44Tim Ferriss?

  Architecture.

• 1:15:44Speaker 02

  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. Nozier'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 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 tense unit or your finger on the cartilage of the ear, you are

• 1:16:27Speaker 02

  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, I said it before, I don't have to say it again. It's not the same as electric stimulating. Okay.

• 1:16:38Tim Ferriss?

  Hitting the big cable.

• 1:16:39Speaker 02

  Right. Now, what happens? So now it gets really interesting. A long time ago, early Russian Investigator published a study where he took essentially an acupuncture needle and put it in the synbocentra and put in a little electric current and showed that he could get 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 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... we'll come back to that. So now you say, "Okay, what happens using other technology?"

• 1:17:24Speaker 02

  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. 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 per study, usually. And you can find brain imaging studies, FMRI, you can find PET studies, you can find far-field evoke responses, which looks at the inputs and outputs of... into various brainstem regions and how the brain is processing the higher network signals. 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

• 1:18:09Speaker 02

  that if you put this kind 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. What I find striking and interesting and needing further study 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 locus coeruleus, which is the top of the fight or flight chain, it's the top of the sympathetic chain.

• 1:18:50Speaker 02

  You see regions in the basal forebrain, the cholinergic 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.

• 1:19:09Tim Ferriss?

  In another 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.

• 1:19:27Speaker 02

  He has a great voice, too, Tim.

• 1:19:29Tim Ferriss?

  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, et cetera. So he was in conversation and they were discussing neuroplasticity and learning with respect to vagus 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, and that the effects seem to be durable for months after stimulation, which also in your book, just a quick note, writes stimulation for two weeks having an effect on insomnia for two or three months. I mean, what could be more interesting right now?

• 1:20:13Tim Ferriss?

  It's just like, it's so, so endlessly fascinating.

• 1:20:16Speaker 02

  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 frickin' crazy idea that I'm gonna target with an electrode the vagus nerve to stop sepsis and cytokine storm. And they said, okay, try it. What if it's yes?

• 1:20:33Tim Ferriss?

  Yeah, people think of the quote-unquote government as just this big, monolithic, slow-moving, stupid, inefficient thing. DARPA is an exception. You gotta 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.

• 1:20:56Speaker 02

  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 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.

• 1:21:33Tim Ferriss?

  Yeah, that's so cool.

• 1:21:34Speaker 02

  And then you say, "Oh, I can still see the airplane?" And then Jeff slams his hand on the desk and goes, "If you can see it, it's too late."

• 1:21:41Tim Ferriss?

  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, off track for a second.

• 1:21:57Speaker 02

  One more thing. You said another thing. I gotta respond. So, the cognition part of vagus 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 vagus nerve stimulator. This was years, 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 them a, I'm not a psychologist, I already gave that disclaimer once, but gave them a cognitive learning test of some form, very simple, and then turned the device on and repeated it, and

• 1:22:42Speaker 02

  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.

• 1:23:04Tim Ferriss?

  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, 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 assisted therapies, some types of brain stimulation, there are many different types, but let's

• 1:23:45Tim Ferriss?

  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 link because I advised 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, 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."

• 1:24:30Tim Ferriss?

  So the ketogenic diet was used in the early, I want to say, 1900s for epileptic children, and they'd 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, and these are kids who might have hundreds of seizures a day. And I'm looking at this study, and here's just a little excerpt. "Mice treated with antibiotics or reared germ-free are resistant to keto diet-mediated seizure protection. Enrichment of and no-biotic co-colonization with keto diet-associated Akkermansia and Parabacteroides, if I'm saying that correctly, restores seizure protection."

• 1:25:12Tim Ferriss?

  So I literally have probiotics downstairs that are Akkermansia 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 microbiota with potentially the vagus nerve with this two-way communication channel. 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, a lot of navel gazing and like, you know, crystal waving folks in the psychedelic world. No offense to

• 1:25:56Tim Ferriss?

  anyone who's falls in that demo. But there were some credible folks, including, for instance, Dr. Andrew Weil, who actually has an 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 so then I'm asking myself, well, maybe it's not the content, although I happen to believe the content of these experience matters. But maybe it's

• 1:26:39Tim Ferriss?

  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 to lose the story of

• 1:27:24Tim Ferriss?

  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?

• 1:27:52Speaker 02

  Ulf 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 that was focused primarily on cytokines, on inflammation and cytokines. So as you said before, this is a guy who knows his stuff.

• 1:28:11Tim Ferriss?

  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.

• 1:28:26Speaker 02

  It's arguably one of the best medical research institutes in the world, it's one of the largest in Europe, it's a major teaching center, it's a fantastic place, I've been there many, many times. Ulf and I have been close friends and collaborators for many decades, and he was diagnosed with a condition that was thought to be a cancer in his bile ducts, in his liver, that required a major surgery called a Whipple procedure, where they remove pancreas, most of the pancreas if not all of it, and they remove part of the liver, and they remove part of the bile duct system. This was a long time ago, but it was, 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

• 1:29:10Speaker 02

  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 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 Sangeeta 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.

• 1:29:54Speaker 02

  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, with the electrodes on the cymba concha, not the tragus, not the lump that sticks out on the side, not the pinna, not the ear lobe, but on the cymba 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 to make new cytokines. And when we did those experiments,

• 1:30:37Speaker 02

  we could show very conclusively, and we published it all in peer reviewed journals, that most volunteers, about 70%, seven or eight 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 probe in the ear for five minutes. And at that point, Wolf said, well, I think I have an inflammation problem. Vagus nerve stimulation stops inflammation. If you want to call this vagus nerve, you can also call it transauricular nerve stimulation, because there's lots of other nerves to the ear, but that's another matter. Wolf said he decided he would try it. Now, I didn't treat my friend Wolf. He decided he would do this. He's a bona fide physician. He could do what he wants.

• 1:31:22Speaker 02

  I frankly was not very encouraging. I said, okay, whatever. Well, as he writes, and I know this for a fact because 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...

• 1:32:01Tim Ferriss?

  The more I try to learn about it, the more I'm like, wait a second. 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.

• 1:32:10Speaker 02

  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 your wearable is. If it's a Fitbit or an iWatch or 10 other things that measure heart rate variability. I think this is 100% true. 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. Singh Eden and I have done this for a while. We worked on heart rate variability. We made our own devices and it gets incredibly complicated. And we dropped it because if you get a PVC, if you get a periventricular contraction

• 1:32:53Speaker 02

  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. So can't get into that now. However, Wolf 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 by. So if you want to do the experiment, your 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.

• 1:33:34Speaker 02

  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 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...

• 1:34:05Speaker 02

  You want to accelerate your heart and exhale, 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

• 1:34:49Speaker 02

  between respiratory sinus arrhythmia and the breathing cycle and heart rate variability in the cardiac cycle. And that's how you optimize oxygen uptake and delivery. It's really cool, right? And it's pretty sophisticated stuff.

• 1:35:01Tim Ferriss?

  So he ships the watch over to Olf, or not watch, device, yeah?

• 1:35:05Speaker 02

  So Olf 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. Now, that's a pretty good experiment. It isn't an F1 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 famotidine, the antacid, were significantly protected against some of the lethal complications of COVID.

• 1:35:49Speaker 02

  We actually did clinical studies of this drug. You can buy it for pennies over the counter at Amazon and 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.

• 1:36:08Tim Ferriss?

  Huh.

• 1:36:09Speaker 02

  Yeah.

• 1:36:10Tim Ferriss?

  Really? What was it called again?

• 1:36:12Speaker 02

  Famotidine is the generic name. It's got a bunch of brand names, including one of them is Pepsid. No kidding? Yeah, you read about it. It'll blow your mind, actually. Wow. So, when Olf combined, this is the end of the story, when Olf combined the famotidine with the TENS unit in his ear, he gets 100% overlap. He looks like a 21-year-old kid with this 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 of depression

• 1:36:55Speaker 02

  decades ago, and it's used a little bit more in Europe than it is in the US. In the US, 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." Well, in some of the people that it's worked in, they were suicidal and now they're not. What is that worth? In 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

• 1:37:37Speaker 02

  down into underst-- we don't know the mechanism, Tim. We don't know why Olf 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 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. Olf got better? Don't you work at a place with a bunch of scientists?

• 1:38:16Tim Ferriss?

  What's required for something like that to happen? Does it just require Scrooge McDuck to fund the study? I mean.

• 1:38:22Speaker 02

  I'm the president of a great organization with great scientists. Yes, I am. And there have been some, there is and will be more great work coming out of our place. But one place can't do it all alone. This is a call for everybody to get interested.

• 1:38:35Tim Ferriss?

  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 Oura 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 available to the company vis a vis, maybe

• 1:39:17Tim Ferriss?

  it's anonymized in some fashion, but the patients could make their actual Oura or whoop band or Fitbit data available to the company if it's not already available. So that could be pretty interesting. I recall actually Whoop, 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.

• 1:39:51Speaker 02

  You mentioned before depression, serotonin inflammation. Should we pick up on that for a second?

• 1:39:56Tim Ferriss?

  Yeah, let's do it.

• 1:39:57Speaker 02

  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 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.

• 1:40:29Speaker 02

  If we knew it caused depression, I think our chances of fixing it and more people would be better.

• 1:40:33Tim Ferriss?

  Well, also, depression is, I mean, in my mind, could be like, quote-unquote, inflammation. There could be many different species of depression, or many different causes. I don't know.

• 1:40:45Speaker 02

  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. 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, as their therapy, that are known to cause depression,

• 1:41:30Speaker 02

  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 IL-1, and the mouse will run in the corner of its cage, it'll huddle up, it'll, 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 cut the vagus nerve, back to your topic of before,

• 1:42:14Speaker 02

  if you cut the vagus nerve in those mice and give them IL-1, they don't, they don't get sick. They don't get depressed. And so, it puts the question, and, you know, the mind-body experts and far east religious dogmas focus on what we said before, that 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's there. We call that interoception. It's the subconscious sense that...

• 1:42:51Speaker 02

  Your organs are sending information about their status to your brain. If you have inflammation in your body, does it cause 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 Vagus nerve stimulators. It'll bring a tear to your eyes, some of their stories. And if you look at those people who have benefited. And Olf with his TENS unit in the ear.

• 1:43:22Tim Ferriss?

  Quick question, has Olf published his setup? Is that something that people can find online if they wanted to experiment with five minutes twice a day of auricular stim?

• 1:43:34Speaker 02

  Yes, he did. He published it in a peer-reviewed journal that I believe is open access. If you Google his name, Olf Anderson with two S's, Anderson.

• 1:43:41Tim Ferriss?

  Good, good old Swedish last name. I will link to that in show notes. We'll find that and put that in the show notes for everybody.

• 1:43:48Speaker 02

  I can send it to you for the show notes.

• 1:43:49Tim Ferriss?

  Okay, perfect, perfect. We'll do that. And I interrupted your train of thought.

• 1:43:55Speaker 02

  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.

• 1:44:14Tim Ferriss?

  That is, it's too clean, right?

• 1:44:16Speaker 02

  Yes.

• 1:44:18Tim Ferriss?

  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. 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.

• 1:45:01Tim Ferriss?

  Is it plausible that that is mediated by Vagus nerve stimulation?

• 1:45:06Speaker 02

  The simple answer is, yes, I don't like to speculate.

• 1:45:12Tim Ferriss?

  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?

• 1:45:22Speaker 02

  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 tens unit can reduce inflammation in the bloodstream 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

• 1:46:06Speaker 02

  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 vagus nerve stimulation do that? To my knowledge, nobody knows.

• 1:46:20Tim Ferriss?

  I was just, again, curious. And you know what? The first time this kind of, I'm probably using this term incorrectly, but sort of the homunculus on the ear came up in this podcast was with Martine Rothblatt, who I think has a quote on your book. Am I making that up?

• 1:46:37Speaker 02

  Martine is a, is a, is a close friend and a-

• 1:46:40Tim Ferriss?

  Also phenom. What a wild background. She's such a polymath.

• 1:46:46Speaker 02

  Martine's another national hero. I mean, she, 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. Yeah, Martine's wonderful. We talk a lot about this stuff.

• 1:47:07Tim Ferriss?

  All right. So just wanted to give a shout out. If people want to get to know Martine, 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-

• 1:47:37Tim Ferriss?

  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. 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. And it relates to this piece that came up, maybe, which is why I wanted to talk about

• 1:48:21Tim Ferriss?

  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 memory, 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.

• 1:49:02Tim Ferriss?

  It might not be, but could you just explain what I'm very clumsily trying to evoke or I guess elicit from you?

• 1:49:11Speaker 02

  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 evolved over hundreds of millions of years. But in some people, not all, if you look at MRI scans, right? Everybody else's back looked just like yours, right?

• 1:49:56Tim Ferriss?

  Yeah, they look all messed up.

• 1:49:57Speaker 02

  They all look the same.

• 1:49:58Tim Ferriss?

  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 framinol stenosis at blah, blah, blah, blah, blah. But

• 1:50:08Speaker 02

  So does everybody else?

• 1:50:10Tim Ferriss?

  Yeah, you can look at like hamburger meat on an MRI of a back and they're asymptomatic.

• 1:50:15Speaker 02

  Right. So why, why does your back hurt and somebody's MRI scan would be indistinguishable from your doesn't hurt? Well, you could maybe pinpoint the position on your MRI scan. 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 to, because Wolf's back pain got better too, by the way. He had injured his neck in a sailing. He was a world-class sailing champion. I don't know if that made the book or not.

• 1:50:47Tim Ferriss?

  I don't think that was in there. Love this guy.

• 1:50:50Speaker 02

  He and his brother, Jan Anderson, won the European World Championships in, in

• 1:50:55Tim Ferriss?

  Of course they did.

• 1:50:58Speaker 02

  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, the UCLA, the LA Olympics. Anyways, his back got better. And so the question is, why did his 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. 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

• 1:51:42Speaker 02

  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 rheumatoid arthritis, actually. It's the signals are switching the white blood cells as they pass through the spleen. So when they go to the elbow, or the knee, or the hand, they tend to heal the cartilage.

• 1:52:21Tim Ferriss?

  It's M2 instead of M1.

• 1:52:22Speaker 02

  It's 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, is 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, 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

• 1:53:04Speaker 02

  is actually forming a neural network in your brain, which you can think of as a memory. It's called, neuroscientists call it an engram.

• 1:53:12Tim Ferriss?

  So would that also be like a phantom limb? Or is that a different thing? I don't want to take us off-track.

• 1:53:16Speaker 02

  It would be similar to a phantom limb, but it's more concrete. And I'll tell you why. And this is what's so amazing about it. So, neuroscience has studied memories and engrams 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.

• 1:53:58Speaker 02

  So, the neurons that get activated by the presence of, say, colitis, inflammation in the bowel, they turn red, and they stay red. So you can study them later, even, you know, weeks and months later. And that's exactly what Professor Rolls 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,

• 1:54:42Speaker 02

  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 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.

• 1:55:26Speaker 02

  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 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.

• 1:55:48Tim Ferriss?

  Right. It's a constellation that is recognizable by the brain.

• 1:55:52Speaker 02

  It's a constellation. Exactly right. Well, nobody before Ash's 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.

• 1:56:11Tim Ferriss?

  Not to interrupt, but since I'm, every podcast I do is self-interested in some way.

• 1:56:18Tim Ferriss?

  Is there a way to delete, Ctrl Z, those constellations so that you don't have this hair-trigger response to triggering colitis or low-back pain response, right? And in this book that I was mentioning, Explained Pain, they talk about how surfers in instances, sometimes when they get their leg bitten off by a gray 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 overwrite

• 1:56:57Tim Ferriss?

  it, or, I guess, fix my fucking low-back pain is the short answer, without taking bottles and bottles of Aleve?

• 1:57:07Speaker 02

  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, you ask all the right questions. We could do the experiments if you come in.

• 1:57:16Tim Ferriss?

  Well, you're not that far away. I mean, don't threaten me with a good time.

• 1:57:22Speaker 02

  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 targets 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. And 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, whether it's Neuralink or somebody else, I mean, they're smaller than a human hair. And they go in and they don't injure blood vessels and they don't even injure, sometimes

• 1:58:06Speaker 02

  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. I'm dead serious. Asch's paper has been out a couple of 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, Sangita, Chavon, and Okito Hashimoto, and Eric Chang. We're asking a very simple question. Can we make engrams, memories, neural networks in mouse brains of specific cytokines?

• 1:58:50Speaker 02

  We're writing the manuscript as I speak, 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 engram, we can see where the neurons in the brain are and see what they do. When we do the same experiment with IL-1, which also gives a sickness response, but has a very different sort of metabolic physiologic, you can separate them, they're unique. TNF and IL-1 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? I think the brain, you know, a human brain has, what, 100 billion neurons, give or

• 1:59:33Speaker 02

  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. And that's what this data tells me.

• 1:59:49Tim Ferriss?

  What are the possible implications of identifying the constellations? 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 engram, so to speak. What are the implications of identifying the engram signature of TNF-alpha, IL-1, et cetera?

• 2:00:14Speaker 02

  What are the implications of it?

• 2:00:16Tim Ferriss?

  Yeah. Well, how would that translate, or might it translate to some type of clinical practice?

• 2:00:21Speaker 02

  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 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.

• 2:00:41Tim Ferriss?

  Yeah, that's wild.

• 2:00:42Speaker 02

  It is. You said it right. I mean, people used to think it was impossible to track an incoming missile from the moon, right? 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 explain 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 colored square, but if you swap that one square and make it a really bright color or a really black color, you actually can see it. 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.

• 2:01:26Speaker 02

  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.

• 2:01:37Tim Ferriss?

  Yeah.

• 2:01:38Speaker 02

  Even for heart rate variability.

• 2:01:40Tim Ferriss?

  Yeah.

• 2:01:41Speaker 02

  You and I can't talk about heart rate variability because we don't know enough about the individual functions of the individual wiring diagrams.

• 2:01:47Tim Ferriss?

  Yeah, and also we can talk about kind of a 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.

• 2:02:03Speaker 02

  Yes, yes.

• 2:02:04Tim Ferriss?

  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 overemphasis on the imaging, 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 transcutaneous auricular stimulation.

• 2:02:49Tim Ferriss?

  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, right, tracking or stimulating the vagus nerve where it would correspond to your pulse, let's just say, carotid artery or arteries. And you can find a number of publications on PubMed that talk about the data. But what might be 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

• 2:03:30Tim Ferriss?

  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?

• 2:03:45Speaker 02

  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 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 stenosis, 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

• 2:04:29Speaker 02

  of these devices have been subjected to FDA approval.

• 2:04:34Speaker 02

  In the context of putting electrodes on your neck, there are some FDA-approved devices that are called vagus nerve stimulators. 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 milliamps. 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 pletismus muscle, the muscles of facial expression, in your neck will twitch or your lip will twitch.

• 2:05:12Tim Ferriss?

  Pull your lip down, make some goofy faces.

• 2:05:16Speaker 02

  That's happened to you, right?

• 2:05:17Tim Ferriss?

  Yes.

• 2:05:18Speaker 02

  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 pletismus muscle, through the layer of subcutaneous fascia, through the sternocleidomastoid 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.

• 2:05:57Tim Ferriss?

  Right, so it seems like the TENS unit is not going to hit the vagus nerve.

• 2:06:01Speaker 02

  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, 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...

• 2:06:27Tim Ferriss?

  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?

• 2:06:38Speaker 02

  I have a very good answer for you.

• 2:06:40Tim Ferriss?

  Collective delusion and placebo?

• 2:06:42Speaker 02

  No, no, 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 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 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 Cahal back in the early 1900s, he wrote a famous book, which I recommend to anyone, even casual

• 2:07:26Speaker 02

  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. 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 quadriceps femoris, your leg pops up and you said, shit, who did that? That's a reflex.

• 2:08:08Speaker 02

  In the context of inflammation, there's inflammation in your body, the signal goes up your vagus nerve, signals come 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 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 cord. Once it gets in the brain or the spinal cord, there's the big router. The brain can decide how to send it out.

• 2:08:51Speaker 02

  In some 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 tension headache? Maybe, we don't know. Nobody knows.

• 2:09:19Tim Ferriss?

  Yeah, I mean, it's exciting to me that there are so many open questions. So just sees like it just enough of a teaser and a taste test of something to make it really tantalizing to investigate further. And my friend, he's using a cervical device, the one who tripled his HRV. So who the hell knows, right? And 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, seems like your device is working for you. And I don't want to burst the placebo effect. But also, doesn't seem to be a vagus nerve stimulator, but we were joking and I think one of us is 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

• 2:10:04Tim Ferriss?

  really care if, you know, 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. Right? So whatever is happening, it would be great to understand what's happening under the hood. But it's like, you might like driving your Tesla. You don't, 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.

• 2:10:46Speaker 02

  Well, I don't 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 effect your friend has. Now, that's really interesting. Why? You know, this is where some people like to reach too far when they're hawking their wares.

• 2:11:07Tim Ferriss?

  Yes, some of the websites selling these things are so bad.

• 2:11:10Speaker 02

  Yeah.

• 2:11:11Tim Ferriss?

  So bad. You expect them to be selling boner pills and kratom and some sketchy, shitty cryptocurrency at the same time in the checkout process. They're so bad.

• 2:11:22Speaker 02

  Yeah, and you know, people say, oh, well, is it safe? Well, that's important, 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.

• 2:11:41Tim Ferriss?

  Science is expensive. Good science is expensive.

• 2:11:44Speaker 02

  Yes.

• 2:11:45Tim Ferriss?

  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 of 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, whether that's breath work, 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?

• 2:12:29Tim Ferriss?

  The Dalai Lama? How the hell does he fit into the? Yeah, all right. So please tell that because it's just fun. I mean, it's so fun. It's also fascinating, but it's fun.

• 2:12:39Speaker 02

  Back in the day, I was at 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 Bouchelle, who is 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 in meditation. The Dalai Lama, of course, famously has participated 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 tenants of his religion are true.

• 2:13:24Speaker 02

  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, then 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 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 like the woods, I like to camp, I like to be outside.

• 2:14:03Tim Ferriss?

  I've driven by this place, it is in the middle, I mean, middle, middle of the woods, yeah.

• 2:14:07Speaker 02

  They own the whole mountain, right?

• 2:14:08Tim Ferriss?

  Yeah.

• 2:14:09Speaker 02

  So, it's dark, it's nighttime, and they give me keys to a cabin in the middle of the woods, and as I'm going out the door, the woman says, "Don't mind the bears." And I'm like, "Fine, I'm gonna walk in the dark, let's through the bears to my cabin." I said, "Well, I'll make a joke." And I said, "Well, I know they were here first, right? 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, this isn't like the concert." So, so, the next day-

• 2:14:40Tim Ferriss?

  Good evening, sir.

• 2:14:41Speaker 02

  Exactly.

• 2:14:43Speaker 02

  The next day, I'm onstage. The next day was two days of scientific talks, a whole series of times. I gave one. I remember Liz Blackwell was there. And when she was there was the time. It was during the meeting. It was announced that she'd won the Lasker 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 if we would summarize the meeting for His Holiness, the Dalai Lama onstage in front of all the attendees. So we said, sure. So Liz gave a talk and then I gave a talk. We got, I'll never forget, I was onstage 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,

• 2:15:28Speaker 02

  Columbia University. And a translator sat between us. And I explained the vagus nerve and I said, and he asked the question you did, you know, where is this vagus nerve? And I said, well, it travels down your neck and into your, across 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? And 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.

• 2:16:11Speaker 02

  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 energy over our heads that we channel in two waves down each side of the neck, across both sides of the chest, down into the abdomen. And I said, cool. And the monk said, yeah, it's very cool.

• 2:16:41Tim Ferriss?

  Not everybody gets Dalai Lama's 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 a 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?

• 2:17:09Speaker 02

  One thing, these things in the book and that a lot of people talk about for self-help, they're good. I do them. I don't 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

• 2:17:50Speaker 02

  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 could talk about next time, maybe.

• 2:18:04Tim Ferriss?

  Yeah, maybe round to cognitive enhancement with vagus 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 the links in the show notes to many different studies, to Olf Anderson's protocol for the five minutes twice a day, of course, to set points, the New York Times piece as well, and to the book, The Great Nerve. And you'll be able to find all of that at tim.blog/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 vagus, or vagus nerve, and this will pop right up.

• 2:18:46Tim Ferriss?

  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.

• 2:18:58Tim Ferriss?

  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 from me every Friday that provides a little fun before the weekend? Between 1.5 and 2 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 every Friday to share the coolest things I've found or discovered, or have started exploring over that week. It's kinda 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.

• 2:19:41Tim Ferriss?

  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/friday, type that into your browser, tim.blog/friday, drop in your email, and you'll get the very next one. Thanks for listening. It's been a long time. Many of you know how deeply I love Japan and its culture of unwavering dedication to craft, refinement, commitment to continuous improvement. You can see it in their coffee, try Glitch Coffee, you can see it in Giro Dreams of Sushi, but why do I bring this all up? Well, the same focus on improving one thing,

• 2:20:26Tim Ferriss?

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• 2:21:51Tim Ferriss?

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• 2:22:34Tim Ferriss?

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