Please enjoy this transcript of my interview with Dr. Kevin Tracey (@KevinJTraceyMD), 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. 

His contributions include identifying the therapeutic action of monoclonal anti-TNF antibodies 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.

Dr. Tracey, a neurosurgeon, pursued studies of inflammation after the mysterious death, from sepsis, of a toddler who was in his care. 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 US 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.

Transcripts may contain a few typos. With many episodes lasting 2+ hours, it can be difficult to catch minor errors. Enjoy!

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Tim Ferriss: Dr. Tracey, good sir. Nice to see you again. Thanks so much for making the time to have this conversation.

Dr. Kevin Tracey: Thanks so much for having me on. I’m really looking forward to it, Tim.

Tim Ferriss: And I am really holding in my enthusiasm, which I’m not going to do for very long because we had a brief chat maybe a week or two ago, and I was bouncing around in my chair. I was overflowing with excitement to ask so many questions. And the reasons for that excitement will, I think, become very, very clear very quickly. But let me as context for people listening, and you know some of this already, explain why I never looked at vagus nerve stimulation seriously up until very recently. And primarily it’s because there’s so much crap and so many charlatans, whether it’s deliberate or not, floating around online touting the most ridiculous approaches, devices, at best innocuous, sometimes probably putting people at risk. And at the checkout they might be selling audio chakra cleanse soundtracks and just associated nonsense that shows that they wouldn’t be able to find a logical argument if it bit them in the ass.

And I thought, you know what? I’m just going to put this in the category of things that I should ignore. And also I’d been sent, and not to throw this under the bus, but maybe we’ll get to it, a book on Polyvagal Theory. And I looked at it and I know just enough evolutionary biology to be dangerous. And I thought, I’m not convinced this actually makes a whole lot of sense. And again, I 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 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, that he’s also a 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 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, and 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 percent, maybe 15 percent. 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. Tracey. And then just coincidentally, I was walking through a bookstore, and right in front of my face was your book The Great Nerve. And I thought, okay, universe, not to get too woo-woo, but I got the message, message received, reached out, and also read the book. I recommend everybody read this book. It’s not only from a very credible source, but you are a good writer. It’s very compelling. 

So let’s skip my TED Talk, thank you everyone for coming to my TED Talk, and go straight to the big news. I guess this was literally you emailed me and now it’s big. So what is the big news that literally has just been announced?

Dr. Kevin Tracey: 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. 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 rich story of science converging on how the vagus nerve can switch off inflammation 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.

Tim Ferriss: If you don’t mind my interjecting.

Dr. Kevin Tracey: Yeah.

Tim Ferriss: Let’s — 

Dr. Kevin Tracey: I get excited too, Tim, I apologize.

Tim 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.

Dr. Kevin Tracey: 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 it’s really important, I should point out, Tim, 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 school teacher, but could not be treated. Her condition couldn’t be fixed from New York to the Mayo Clinic to Hawaii and back. And it culminated when her physician told her and her husband Sean to plan on staying home without children because of all the medications she was on, childbearing would be too risky, and to get used to her life like that. Around that time she saw me on a Huffington Post live internet interview, live stream, and she contacted me and I don’t recall that contact, but I recommended she look into SetPoint Medical, the company that I had co-founded in 2007 to do these clinical trials.

Tim 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, elevate her legs, I mean really just had trouble functioning on a day-to-day basis is my recollection.

Dr. Kevin Tracey: 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. They can cause depression, they can cause anxiety disorders, they can cause chronic fatigue. So that’s exactly right.

Tim Ferriss: All right, so she reaches out to you, you recommend she investigate SetPoint Medical, then what happens?

Dr. Kevin Tracey: 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 like a cardiac pacemaker under the collarbone, under the clavicle with a lead or a wire that is tunneled up into the left neck where the vagus nerve travels next to the carotid artery.

A couple 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’d seen Kelly run up the stairs in years.

Tim Ferriss: Yeah, she had trouble walking on the cobblestones in Europe —

Dr. Kevin Tracey: She had trouble walking on the cobblestones. 

Tim Ferriss: — not long before.

Dr. Kevin Tracey: 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.” 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 going to change everything. And if you’re going to be a leading spokesperson on the patient side of this you may be — people are going to tell you you’re a placebo effect. Tim, all of those things happened.

Tim Ferriss: Oh, I’m sure. 

Dr. Kevin Tracey: 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.”

Tim Ferriss: And not with a smile on his face.

Dr. Kevin Tracey: That was 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 it reminds us why we do what we do and what we hope can happen when you do science in the hopes and dreams of discovering things that might help people someday ’cause it can happen.

Tim 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.

Dr. Kevin Tracey: Right.

Tim Ferriss: But when you’re looking at six months out, 12 months out, and she furthermore — not to say this is more important than anything you just described, but certainly for a lot of people listening, and for me personally, having suffered from what I would describe as chronic fatigue for decades, and we might dig into some of that — she went from basically having a blinking battery empty for her day-to-day to having too much, 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. The lives that are lived by the former and the latter, the magnitude of that difference just can’t really be overstated. It’s two different experiences of life. Now I’m going to get all excited and lose my train of thought, but I’m going to scatter shot here for a second.

So just to also lay out a few things for folks. So part of what has been so exciting about this and why I want to pay a lot of attention to it, there are a few things feeding into it for me personally. So one is having some exposure to, I suppose what you might call bioelectric medicine through early, early generation TMS, but then also later accelerated TMS with better hardware, better 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 Volkow 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 SetPoint Medical 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, 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 an, oh, I just happened to be lethargic and I’m hunting for a diagnosis, going from quack to quack until I get Lyme disease. Eastern Long Island, look at the CDC map, it is as red as it gets. And thinking of, then, later neuro-inflammation, I have neurodegenerative disease 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 there’s some connective tissue tying this stuff together and started playing with the microbiome. Because changes in gut flora have been associated with, say, depression or animal models of depression or lack thereof.

Also looking at, say, the ketogenic diet or exogenous ketones as a way to reduce inflammation. And when you start looking at all this, and then when I read your book, the reason this ties into your book is, 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, in the news, Ozempic, Mounjaro, take 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/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 and sensitivity, the weight gain of the obese mice. Fascinating. But if you cut the vagus nerve, that doesn’t happen. So what the hell is going on? And all of these things are interconnected in the most interesting ways. There’s so much left to learn. 

But let’s begin with a definition of basic terms, vagus nerve. How should people think about the vagus nerve?

Dr. Kevin Tracey: 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 also should define, if you agree, bioelectronic medicine, because you talked about the connective tissue in the story, and then we should define inflammation.

Tim Ferriss: Let’s do it.

Dr. Kevin Tracey: 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. 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 a hundred thousand fibers. Each fiber is a unique nerve. That’s the part that’s lost almost immediately by 99 percent of the casual readers of vagus nerve stuff.

200,000 fibers, each fiber has an origin in either the body or the brain. 80 percent of them actually originate in the body. They carry information about the organs and your body up into your brain, and then obviously the other 20 percent originate in the brain and they carry information back down to your organs. So again, we’ll try 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 treated each one as a wire.

Tim Ferriss: So let me ask if this is a fair visual to paint for people. So imagine that from the base of the ear, roughly, look, this is Tim, the lay person 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 a hundred thousand 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? And is that a fair visual to paint for people, or would you modify that?

Dr. Kevin Tracey: 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. So if you put in 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. 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? 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 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.

Tim Ferriss: And let’s just say, of those 200,000 fibers, do we know roughly how many affects HRV and cardiac function?

Dr. Kevin Tracey: 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 Liberles and his colleagues, we know in mice that somewhere around a 100 or 150 fibers are sufficient to control breathing. Now, a mouse vagus nerve has 5,000 fibers, not a hundred thousand, 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. In human beings, for instance, and we’ll come back to this some more, but I estimate somewhere between a 1,000, give or take, maybe 1,500, maybe 2,000 fibers control the amount of inflammation cytokines being produced in the spleen. We can map the identity of the number of fibers going to the heart. Again, it’s a few thousand. So the open question is say we can assign the action of 10,000 fibers on each side. What — 

Tim Ferriss: Yeah, the 90,000 — 

Dr. Kevin Tracey: — are the other 90,000 doing? Yeah, exactly.

Tim Ferriss: I want to keep giving people Scooby Snacks here just because I’m so excited. I want to keep reiterating the potential payoff of doing this the right way. And you mentioned cytokine. I want to double click on that for a second. We don’t need to get immediately into the technical definition of that. I’m sure we will. But people may know that word from, what, COVID-19, cytokine storm, boom, can lead to fatality in some patients. And I suppose I’m curious to know, and just in short form, what happens to cytokine production when you stimulate the vagus nerve correctly?

Dr. Kevin Tracey: It gets turned off. If you stimulate the fibers we were just talking about, it turns off cytokine production quite effectively. And we discovered this by accident actually, 27 years or so ago in the laboratory. We were working on an 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. And this was a head scratcher. This made no sense whatsoever.

Tim Ferriss: And that’s a head scratcher because the effect should have been sequestered to the brain because of the blood-brain barrier, or what is the reason?

Dr. Kevin Tracey: 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. Well, 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 drugs. And so that’s what we wrote on the back of a napkin 27 years ago that 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. 

Tim Ferriss: I’m sorry, Kevin, can I pause you for one second before we get there? And this is something I do not — I mean, I’m going to ask a lot of questions I don’t know the answers to, otherwise the interviews are 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 asthma attacks or sepsis or anything like that?

Dr. Kevin Tracey: Once you understand the basic signals that flow in the vagus nerve to control one aspect of the immune system, in this case, how vagus nerve fibers can turn off cytokine production? You can ask new questions. 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 and other conditions like asthma and other conditions, you have to back up a bit. You have to say, “Okay, what condition are we talking about?” Let’s look at how the pharmaceutical industry does this. Pharmaceutical industry starts by picking a disease, a condition. Let’s do rheumatoid arthritis first as it’ll become obvious why in a minute. We’re going to look at rheumatoid arthritis, the condition. What’s the molecular mechanism?

Well, the early research with using monoclonal antibodies against TNF show that that helps about half the patients, so that’s the mechanism. So now we can make monoclonal antibodies that hit the molecular target TNF to treat the disease. And now you sell your monoclonal antibodies and after they’re approved for safety and efficacy by the FDA, great, that’s what the pharma industry does. We proposed some years ago, 15 years ago or so now, the idea of 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 in situ.

If we can find such nerves, then we can build devices to control the nerves, 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 the mechanism? Tim, no one knows. That’s a full stop.

Tim Ferriss: Therein lies the rub.

Dr. Kevin Tracey: That’s a full stop for me before saying vagus nerve stimulation will or will not work. I remember one of my mentors and friends, rest his soul, Frank Austen, 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 going to do some asthma research.” He said, “Okay, what are you going to do?” I said, “Well, I’ve got this mouse model.” He goes, “Kevin, the last article I wrote in asthma was entitled ‘Mice Don’t Wheeze.’”

Tim Ferriss: I like that. ‘Mice Don’t Wheeze.’ Well, you know what that makes me think of, and we’re going to digress for a second here. But look, we need the animal research and there’s a lot you can do in a metaphorical Petri dish now with 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, where they’re looking at the head twitching and paw licking. In the case of Barry Jacobs giving LSD to cats way back in the day, decades ago at Princeton. And they’re using, let’s just say, the anti-depression animal models might involve swim to exhaustion.

And then you’re like, “Okay, well, I guess methamphetamine is going to be one of the best antidepressants you could possibly give someone if we’re using that as the proxy.” And so a lot of it’s imperfect. And yes, mice don’t wheeze, right? So maybe, especially if you can’t identify, like you said, it’s the mechanism, you need to be able to at least hold onto some of the variables. 

So let me come to just depression for a second, and 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. 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. But 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 potentially at the core of a lot of this. Whether you look at, for instance, a very potent anti-inflammatory effects of certain psychedelics in the phenethylamine class, like 2C-B 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’ll not be disappointed. But you can induce depression in animal models by causing inflammation.

Dr. Kevin Tracey: And people too, Tim.

Tim Ferriss: And people too. And I want to just read a little bit here. Because we’ve long had, and I think many, many doctors still ascribed to a chemical imbalance theory of say, depression or mental illness writ large, but depression. So this is directly from your book. If an SSRI has helped you or someone you know, that’s wonderful. 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 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.

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, and 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’ll say that the combination of the stimulation, plus, and I realize I’m fussing with a number of variables, intermittent fasting and exogenous ketones. So I am throwing a lot against the wall here. But the addition of the stimulation, which is just a few minutes a day, and we’ll definitely talk about your friend Ulf and his story, because that guy is not wearing a tinfoil hat, right?

Dr. Kevin Tracey: No.

Tim Ferriss: He’s credible. As credible as credible can be.

Dr. Kevin Tracey: Yes.

Tim Ferriss: 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, perhaps it is. And so they’ll criticize maybe a story like this or the story of your patient and say, “Ah, N of one 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 this is a very long-winded way of trying to set up inflammation. Inflammation is one of those terms that gets used like it’s specific, but it’s like saying business or sports or art. It’s a big umbrella term. So what is inflammation in the context of what you have studied and observed as a clinician and as a researcher and inventor for that matter?

Dr. Kevin Tracey: Yeah, we’re going to have to do a couple of shows, Tim. 

Tim Ferriss: Yeah.

Dr. Kevin Tracey: 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 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, in other molecules, TNF, IL-1, IL-6, but other molecules made by white blood cells and other tissues in your body. So it’s a good thing when it stops. It’s a good thing because it helps heal the wound, helps proliferate stem cells, helps fight off infection or bacteria that might settle in the wound. And it’s a good thing if it stops. The problem is, we’ll talk about why it stops, but the problem comes when it doesn’t stop. And when it starts spinning out of control, like in Kelly Owen’s case, then it becomes like the army showing up 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, the TNFs, the IL-1s, the prostaglandins. That’s how the ibuprofrens and other nonsteroidals work. And we go down the list on all this. The problem is, when you look in the brain of an 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 certainly doesn’t, it’s not painful. 

And the same is true when you look in the adipocytes, the fat cells of an obese patient who has type two diabetes and has significant insulin resistance. They also, sometimes they have a few extra white blood cells in the fat, but it’s not rip-roaring inflammation that you see in an infected wound. They might have an upregulation of some of the cytokines. You might see the upregulated production of cytokines in the brains of Alzheimer’s patients. But it’s nothing like you see in an injured tissue or a rheumatoid arthritis. Some people have come up with new names, meta-inflammation, inflammaging it’s called sometimes when these kinds of changes occur.

Tim Ferriss: Inflammaging.

Dr. Kevin Tracey: Inflammaging. 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 really, 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, and cancer. So two thirds of the people that die every year on the planet Earth die of those conditions. And that’s according to the WHO. Those conditions all have one thing in common — they’re either caused by inflammation or made worse by inflammation. 

Now, if you look back at what happened in the last 80,000 years, 75,000 years since we came down from the trees and became talking monkeys, in that time period, almost everybody until a hundred 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. 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. So the question that wakes me up at 3:00 a.m. now is, “What if we could cure inflammation?” If we cured inflammation, what would that do to the death rate from cancer, heart disease, stroke, and all the conditions that kill two-thirds of the people on the planet earth every year? Look, there’s still people that die of infection. People died of 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. Cleaner water, ample food supply, less starvation, all these things converged on better vaccinations, antibiotics, obviously. All these things converged on improving lifespan.

I think something similar will happen maybe in the next 20 years if we can really understand how to modify inflammation. And one way I think we’ll be able to do that is by continuing to dive deeper and deeper into understanding how evolution itself put the brakes on too much inflammation. I said that inflammation is bad when it’s not restrained, when it doesn’t resolve. Well, evolution knew that hundreds of millions of years ago. So from the very beginning of the evolution of inflammation, there’s been evolutionary mechanisms that evolved to suppress inflammation, to tame it, to put the brakes on it. And 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 and 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.

Tim Ferriss: Well, I guess once the devices are out in the wild, let’s say the implant, then docs may have some latitude to also experiment with patients. I mean, TBD. But let me ask. Let me do a few things. I’m going to allow us, if we want, just to abbreviate vagal nerve stimulation to VNS if we want to just make it a little easier on ourselves. Let me ask a question that I asked in our last conversation, and I’m sure is on the mind of a lot of folks, which is, along the lines of, wait a second, inflammation seems to serve presumably some important purpose. So just like some people might label cortisol bad, if you get rid of cortisol completely, you’re going to be in a world of trouble.

So if you are, say, decreasing cytokine production and release by 70, 90 percent 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, blah. Temporarily at least, or seem important for catalyzing some of these tissue adaptations. So are you at risk by suppressing cytokines with vagus nerve stimulation? Do we know anything about the side effect profile?

Dr. Kevin Tracey: 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 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 percent 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. And the antibody takes away a hundred percent. It’s yes or no. And because you take away a hundred percent of TNF or IL-1, depending on what drug you’re on, those drugs carry warnings. 

The most serious side effect warning the FDA can give is 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 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. 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 SetPoint device, which is only one inch large, completely encased in it. But immunosuppression-wise, we also know that vagus nerve stimulators do not have black box warnings. There’s no evidence after decades of any immunosuppression. There’s no evidence of an increased risk of infection or cancer.

Why is that? Well, it’s because, and here we go back to laboratory studies, and even now in new human studies. When you stimulate the vagus nerve fibers that inhibit inflammation, the ones that travel from the brain to the spleen, for instance, to stop cytokine production, you inhibit, as you correctly said, about 70 percent of the cytokine production. You don’t inhibit a  hundred percent. 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 a hundred 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. The vagus nerve stimulation therapy and the SetPoint device is called actually the immunoregulation therapy because it’s only one minute a day. That drives the TNF from a hundred 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 additives. So if you take them all from the toxic range to the healthy range, you’re going to be a lot better off. And the IL-6 response in skeletal muscle response in weight training, that’s 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.

Tim 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 has led me to do something more than I already do, which is, yeah, that’s great, but why? And that’s interesting, but why? Yeah, 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 I mean pretty much every division one soccer team, for instance, or you name it, is going to do some version of this.

If you do it not necessarily immediately after training, but say you wait an hour or two, and then you do cold exposure in a bath, that it seems to enhance recovery. Now you could say, “Well, ice decreases inflammation.” But then it’s like, is that true? Could there be another explanation? And what you point out in your book, which is something that again, intuitively now makes sense to me, is in the beginning when you’re exposed to cold, and there 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 cetera. And then at some point parasympathetic rest and digest activation. And could it be that the cold is affecting the vagus nerve, which is affecting parasympathetic, that helps with recovery? I don’t know. But I’ve, for instance, always wondered why it is that after a few minutes in a 45 degree bath, I start yawning. There’s a lot of yawning. And I don’t know if that’s direct. Interestingly, that’s also a very common onset symptom after say, ingesting psychedelics like ayahuasca, is yawning.

Yawning, lots of yawning, which is why all of these things seem to touch the hem of the same fabric. So anyway, now 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? For instance, you might say, “Oh, there’s an explosion of brain cancer.” 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 cellphone 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 instances 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?

Dr. Kevin Tracey: 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. 

Tim Ferriss: Interesting, the latitude. Wild.

Dr. Kevin Tracey: Yep. 

Tim Ferriss: I mean, correlation I guess doesn’t prove causation, but it’s interesting.

Dr. Kevin Tracey: 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 on. 

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

Tim Ferriss: Stress.

Dr. Kevin Tracey: — stress. And 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 — 

Tim Ferriss: What is that? Not H. pylori.

Dr. Kevin Tracey: 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, which wasn’t that long ago, I’m not that old. I mean, it was one of the commonest operations in the hospital.

Tim Ferriss: I thought you said communist for a second.

Dr. Kevin Tracey: No, no.

Tim Ferriss: I was like, “Oh, I didn’t see that coming.”

Dr. Kevin Tracey: No, no. One of the most common operations on the OR schedule was gastrectomy for peptic ulcer disease. You never see that. It doesn’t happen anymore because you take antibiotics. So my adage for this thing is, when you don’t understand a disease, think of epilepsy. You start off, you blame God. So they did 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 caused, there’s some infectious cause of this thing. And so autoimmune disease may have an infectious cause, it may have an environmental cause. People talk about genetic causes. You inherit some level of risk for autoimmune diseases, but very few of these conditions do you actually inherit the condition. 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?

Tim Ferriss: Well — 

Dr. Kevin Tracey: It’s environment, right?

Tim Ferriss: Good question.

Dr. Kevin Tracey: It’s environment, unless — 

Tim Ferriss: Well, I’m also thinking genetic predisposition to risk taking when they’re like, “Ah, it’ll be fine.”

Dr. Kevin Tracey: 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. 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.

Tim 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 the deep end of my ignorance pool here. From your book, and this is not a counter argument from your book, but I’ll just read a paragraph that I highlighted. Which, 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.” 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, 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.”

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 of the things I just mentioned and more make them predisposed to certain types of infections? So that they’re actually, just to complicate the picture further. Where, yes, it’s an infection, but there are certain 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.

Dr. Kevin Tracey: Those kinds of studies are out there, and I think they tip both ways. Some suggest there is an 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, tracked or correlated to how much hostility. Now you’re back in the psychological domain of the top-down driving. That’s not me.

Tim Ferriss: Yeah. Which is understandable. 

Dr. Kevin Tracey: But it’s interesting. I was at a scientific meeting once when that data was being discussed, and somebody stood up in the front row and said, “Well, how hostile is hostile? How hostile do I have to be to be type A versus type B?” And everybody stared at him like, “Do you hear yourself, man? Relax.”

Tim Ferriss: Let’s talk about — because people are listening. And the SetPoint device, it’s 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. 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. From a purely practical perspective, there are some great benefits to an implant. But could you tell the story of your friend, Ulf, and just describe who he is, and lead into his story? If you’re open to it.

Dr. Kevin Tracey: Sure. On the SetPoint device, the one the size of a fish oil pill, 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 any more of the drugs they have to take, the ones with these serious side effects. There’s a tendency, not by you, but there’s a tendency by some in the short form conversation of these kinds of things to say, “Well, it’s a surgery, and they should do more push-ups or try to do more things to help themselves.” Well, I’ve got to be really, really outspoken on this, because when you meet people that have these conditions, if it was as easy as doing a couple of push-ups or taking a yoga class or breathing differently, they would do it. And 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, 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. People with serious illnesses, you’re absolutely right. The availability, not for all, but for those that are going to be able to go down that path, to have a small immunoregulator implanted in the neck, that’s going to be very interesting to see what happens. But for people who are essentially mostly well, like you seem to be, and I seem like — 

Tim Ferriss: What an effective mask I’ve created. Yeah. No, I’m generally well, yes.

Dr. Kevin Tracey: And me too, and I feel very fortunate for that. I try to do things that align with what people would call vagus nerve stimulation. 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 alleviate the stress from my life as much as possible. 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 been talking about, can be said to stimulate directly or indirectly the vagus nerve. But there’s other modalities that people also talk about using electrical devices to stimulate the vagus nerve by applying these electrical devices or TENS units, transcutaneous electrical nerve stimulators, to the skin.

Before I go any further, let me be 1,000 percent clear. These are not vagus nerve stimulators. There’s only two ways to stimulate the vagus nerve directly and specifically. One is to implant an electrode on the nerve, and that’s either with the devices for epilepsy or depression. Or there’s another one now also to increase the rehabilitation outcomes from patients who have strokes. That’s a third one. Or the immunoregulator device from SetPoint. 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 Sangeeta Chavan and Stavros Zanos, we’ve published on this in the peer-reviewed journals. It’s a special ultrasound. It’s very similar to the one that you visualize to see the baby in the womb or the gallstones, but you have a different lens on the probe, and you can focus the energy to target nerves in the body. And we’ve done this in humans to reduce the inflammatory markers in the blood of healthy volunteers by focusing the ultrasound on the splenic nerve, where the vagus nerve controls it. And 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 side of the head or the face, those are all non-invasive and non-specific, and really shouldn’t be called vagus nerve stimulators.

Tim Ferriss: Nonetheless, some interesting stuff seems to happen.

Dr. Kevin Tracey: Okay.

Tim Ferriss: Everything you said, it’s so true. So on point. I’m also tempted to go to the hockey puck for electric GLP-1 administration, but I’m going to call that a temptation and not an opportunity for the moment. And let’s talk about your friend Ulf, and what happened to him.

Dr. Kevin Tracey: I apologize for the digression, but I had to get that as you — 

Tim Ferriss: No. You’ve got to do it.

Dr. Kevin Tracey: — understand on the record.

Tim Ferriss: You’ve got to do it.

Dr. Kevin Tracey: Now, what about other stuff like a TENS unit? Let’s give a little background there. Anybody interested in auricular therapy, meaning 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 small needle, a probe, or a small electric current, that you’re supposedly able to affect the metabolism or the diseases of those organs. Everybody knows that’s 10,000 — 

Well it turns out, when I was writing the book, which I discovered that those ancient acupuncture maps of the ear originated in France in 1957 by a doctor named Dr. Paul Nogier, who had a patient who was being treated by a specialist, I think in Corsica. And the specialist was grounded in ancient medicine and was cauterizing a piece of this patient’s ear to treat the patient’s sciatica, the pain going down their leg.

Tim Ferriss: Burning their ear?

Dr. Kevin Tracey: 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 two patients claim that their sciatica got better. Dr. Nogier was a very clever guy, and curious and careful, and he took a ballpoint pen and he took the ink out of it, and he started probing all of his patient’s ears. And he aligned various conditions in the patient with the 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 in many, many patients, and ultimately published this. And he had presented it at an acupuncture meeting that was being held somewhere in 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. That’s where the maps come from. They’re fun to look at. They really are. And especially in light of the story I am going to tell. If you look, you can see where the spleen is and where the bladder is and where the stomach is. They’re very clever.

We were reading, Sangeeta Chavan and I, my lab co-head and I, many years ago. 15, 20 years ago. We were reading about vagus nerve biology and physiology, and we discovered that there was a branch of the vagus nerve that goes to the cartilage of the ear. And when I say the ear, it goes to the cartilaginous part, the part outside the ear canal where you put your finger in your ear, and what looks like a seashell. It’s called the cymba 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 surface of the skin, and they are sensory.

That means that when you stimulate the cartilage of the cymba concha, you can activate the fibers that go carrying information into the brain. And they go to the place in the brain called the nucleus 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. 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 that fish — you like evolution, I heard you say at the beginning. 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.

Tim Ferriss: Wow. Wild.

Dr. Kevin Tracey: It’s wild.

Tim 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 ax and your spleen explodes? That doesn’t seem to have any adaptive purpose for natural selection. But lo and behold, fish gills. Well — 

Dr. Kevin Tracey: It’s fish gills. But I didn’t say it makes sense, Tim. You said that. I didn’t say it makes sense.

Tim Ferriss: Well, no, I shouldn’t say it makes sense. It’s just like a vestigial architecture.

Dr. Kevin Tracey: It’s definitely vestigial. How much of the architecture, that’s another area that I can’t say for sure we’ve— I actually can say for sure. Nobody to my knowledge has completely mapped out Dr. Nogier’s ear maps to the human body in any convincing neuroanatomical function or neurophysiological way. But it’s still interesting.

With that information, you could think of the cartilage of the ear as a way to drive signals into the brainstem through a branch of the vagus nerve. Immediately people start calling that vagus nerve stimulation. It’s kind of true, because it’s a sensory branch of the vagus nerve. And if you put a TENS unit or your finger on the cartilage of the ear, you are technically stimulating the receptors in the skin that activate the sensory fibers that carry the signals into the NTS. But it’s not the same as — I said it before, I don’t have to say it again. It’s not the same as electrostimulant — 

Tim Ferriss: Hitting the big cable.

Dr. Kevin Tracey: Right. Now, what happens? Now it gets really interesting. A long time ago, an early Russian investigator published a study where he took, essentially, an acupuncture needle and put it in the cymba concha, 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. We’ll come back to that. Now you say, okay, what happens using other technology? Well, it turns out now, I can’t count all the publications that have been done by applying various forms of electric current into the ear and measuring.

Tim Ferriss: There’s a lot.

Dr. Kevin Tracey: You can’t count them all.

Tim Ferriss: There’s a lot.

Dr. Kevin Tracey: 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. But you can look at and you can find brain imaging studies, FMRI. You can find pet studies. You can find far field evoked responses, which looks at the inputs and outputs into various brainstem regions and how the brain is processing the higher network signals. You can see some really interesting stuff. And what comes out of it is lots of different information. That’s the first problem. There’s no single consensus that if you put this kind of electrode in your ear at this time for this many minutes at this much current, you get this effect and 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. 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.

Tim 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.

Dr. Kevin Tracey: He has a great voice too, Tim.

Tim Ferriss: Oh, his voice is amazing. 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. 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. Stimulation for two weeks, having an effect on insomnia for two or three months. What could be more interesting? Now it’s just so endlessly fascinating. 

Dr. Kevin Tracey: I have to respond to the DARPA.

Tim Ferriss: Yeah, please.

Dr. Kevin Tracey: I wouldn’t be talking to you right now if it wasn’t for DARPA’s support on this idea in the 1990s, when it was a freaking crazy idea that I’m going to target, with an electrode, the vagus nerve to stop sepsis and cytokine storm. And they said, “Okay, try it. What if it’s yes?”

Tim Ferriss: Yeah, people think of the “government” as just this big, monolithic, slow moving, stupid, inefficient thing. DARPA is an exception. You’ve got to check out DARPA. 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.

Dr. Kevin Tracey: One of my heroes is actually a national hero. Geoff Ling. Dr. Geoff Ling, 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 most crazy-ass ideas anyone could ever imagine. “You see that airplane out there? I can make it disappear. I can make it invisible.” And then everybody leaves and they go into Geoff’s office and he says to his team, “What do you think?” And they all say to Geoff, “He’s nuts. It’s crazy. You can’t make an airplane disappear.” And Geoff looked at his team and says, “What if it’s yes?” And that’s where stealth technology came from.

Tim Ferriss: Yeah. That’s so cool.

Dr. Kevin Tracey: And then you say, “Oh, I can still see the airplane.” And then Geoff slams his hand on the desk and goes, “If you can see it, it’s too late.”

Tim Ferriss: Technology to be able to see figures around corners, and that was years ago when I saw a rough description of that. In any case, they are doing lots of really interesting things. I took us off track for a second.

Dr. Kevin Tracey: One more thing. You said another thing; I’ve got to respond. 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 stimulators. This was years ago. 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 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. There’s a deep conversation there about neurocognition and vagus nerve inputs to the brain.

Tim Ferriss: I’m fidgeting around in my chair because I get so excited about finally trying to — and I’m not there, obviously. Who am I? I’m a muggle. 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 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’s under control. And he sent me this study. And 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.” 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 is just a little excerpt. “Mice treated with antibiotics or reared germ-free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides,” If I’m saying that correctly. “restores seizure protection.”

I literally have probiotics downstairs that are akkermansia from a company called Pendulum, which is pretty legitimate. But, what? 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 and a lot of navel gazing and crystal waving folks in the psychedelic world. No offense to anyone who falls in that demo. But there were some credible folks, including, for instance, Dr. Andrew Weill, 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 it was LSD.

And these anecdotes on the underground, at least, with facilitators who have thousands, maybe tens of thousands of repetitions with patient sessions, the losing of allergies comes up pretty constantly. And then I’m asking myself, well, maybe it’s not the content. Although, I happen to believe the content of these experience matters. But maybe it’s the anti-inflammatory effects. Okay, well, what does that mean? And then, okay, well, maybe it’s having some immunomodulating effect. Okay, well, is the vagus nerve involved? Maybe. It’s not beyond possibility. And then you look at neuroinflammation and the effects of whether it’s different types of brainstem or the effects on, say, inflamed microglia by psychedelics. Like reductions in TNF and all this stuff, TNF alpha have been tracked in the scientific literature. And I just get really, really excited because I can’t parse it all, but it seems like these things all, to use an awkward phrasing, are touching the hem of the same garment in some way.

Anyway, that was a whole bunch of word salad, but I don’t want to lose the story of Ulf, because we’re 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. 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?

Dr. Kevin Tracey: Ulf Andersson 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. As you said before, this is a guy who knows his stuff.

Tim Ferriss: Karolinska Institute is also top tier. 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.

Dr. Kevin Tracey: 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 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 at the time it was a death sentence. The cancer that they thought he had, it turned out to be benign, which was a blessing in disguise, because he had to undergo this major surgery to have this. After the surgery he developed, for the first time in his life actually, he developed intermittent bouts of depression. Serious depression. Which he attributed to excessive inflammation in his GI tract. Which was, through unknown mechanisms, coming episodically and causing this 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, understanding how vagus nerve signals could turn off inflammation. And so we said, “What the heck?”

We put TENS unit — an over-the-counter product you can get anywhere — with the electrodes on the cymba conchae, not the tragus, not the lump that sticks out on the side, not the pinna, not the earlobe, but on the cymba conchae. And then, we drew blood on ourselves and on 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, we could show very conclusively, and we published it all in peer-reviewed journals that in most volunteers, about 70 percent, 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, Ulf said, “Well, I think I have an inflammation problem.” Vagus nerve stimulation stops inflammation. If you want to call this vagus nerves, you can also call it transauricular nerve stimulation, because there’s lots of other nerves to the ear, but that’s another matter. And Ulf said, he decided he would try it.

Now, I didn’t treat my friend, Ulf. He decided he would do this. He’s a bonafide physician. He could do what he wants. And I frankly was not very encouraging. I said, “Okay, whatever.” Well, as he writes, and I know this for a fact, I see him several times a year. It turned his whole life around. He added some antibiotic therapy also to treat the 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 — 

Tim Ferriss: Yeah, the more I try to learn about it, the more I’m like, “Wait a second.” Quantum mechanics or something, I’m like, “Wait, I thought I kind of knew what the hell you were talking about. Now, I don’t.

Dr. Kevin Tracey: Yeah, yeah, 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 if you have a — 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 a hundred percent true. It might only be 90 percent 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, Sangeet and I have done this for a while. We worked on heart rate variability and we made our own devices, and it gets incredibly complicated. And we dropped it because if you miss — if you get a PVC, if you get a periventricular contraction or you get two irregular beats in a five-minute recording, you’ve got hundreds and hundreds of heartbeats. It shouldn’t do much, right? It messes everything up. It changes all the statistics.

So we can’t get into that. Now, however, Ulf 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, if 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. 

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, 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.

Now, 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.

And what his HRV indicator is, in this method, is actually a correlation between the overlap between respiratory sinus arrhythmia and the breathing cycle and heart rate variability in the cardiac cycle. And that’s how you optimize oxygen uptake and delivery. It’s really cool, right?

Tim Ferriss: Yeah, it’s cool.

Dr. Kevin Tracey: And it’s pretty sophisticated stuff.

Tim Ferriss: So he ships the watch over to Ulf? Or — not watch. Device? Yeah.

Dr. Kevin Tracey: So Ulf 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 is an N of one — 

Tim Ferriss: Yeah.

Dr. Kevin Tracey: 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.

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.

Tim Ferriss: Really? What was it called again?

Dr. Kevin Tracey: Famotidine is the generic name. It’s got a bunch of brand names, including one of them is Pepcid.

Tim Ferriss: No kidding.

Dr. Kevin Tracey: Yeah, you read about it, it will blow your mind, actually.

Tim Ferriss: Wow. Okay.

Dr. Kevin Tracey: So, when Ulf combined, this is the end of the story. When Ulf combined the famotidine with the TENS unit in his ear, he gets 100 percent 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. And 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 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.

Tim Ferriss: Yeah.

Dr. Kevin Tracey: What is that worth?

Tim Ferriss: Yeah.

Dr. Kevin Tracey: 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 it shouldn’t be — we should be doing it or not doing it based on the data we know so far. There should be a screaming call that we should be diving down into. We don’t know the mechanism, Tim.

Tim Ferriss: Yeah.

Dr. Kevin Tracey: We don’t know why Ulf 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 etiology, another cause, another factor. These are the important questions.

Tim Ferriss: Don’t you work at a place with a bunch of scientists? What’s required for something like that to happen? Does it just require a Scrooge McDuck to fund the study? I mean — 

Dr. Kevin Tracey: I’m the president of a great organization with great scientists. And yes, I am, and there is and will be more great work coming out of our place. But one place can’t do it all alone.

Tim Ferriss: Yeah.

Dr. Kevin Tracey: This is a call for everybody to get interested.

Tim 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 “Vagus nerve stimulator.” But the data is going to be available to the company vis-à-vis. Maybe 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 standardized dosing of, I think it was microdosing of psychedelics looking at impact on HRV or potential impact on HRV. HRV fluctuations associated, let’s put it that way. 

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

Tim Ferriss: Yeah, let’s do it.

Dr. Kevin Tracey: 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. And if we knew what caused depression, I think our chances of fixing it in more people would be better.

Tim Ferriss: Well, also, depression is, I mean, in my mind, could be like “Inflammation,” right? There could be many different species of depression or many different causes. I don’t know.

Dr. Kevin Tracey: 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, 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. And so you can 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 will look like it doesn’t feel well, like when you have the flu. It will avoid eating. It will avoid sex. It will avoid playing with toys in the cage. It looks depressed.

If you cut the vagus nerve back to your topic before, if you cut the vagus nerve in those mice and give them IL-1, they don’t get sick. They don’t get depressed. And so it puts the question, and the mind body experts and the far east religious dogmas focus on what we said before, the brain networks and the body networks are connected. And what I said before is the vagus nerve is a principal connector.

So if you have disruption of inflammation in the body, which you’re not even, maybe nothing hurts in your body, but your brain knows the inflammation is there, we call that interoception. It’s the subconscious sense that your organs are sending information about their status to your brain. If you have inflammation in your body, does it cause depression? That’s an important question.

Tim Ferriss: Yeah.

Dr. Kevin Tracey: 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 will bring a tear to your eyes, some of their stories. And if you look at those people who have benefited — and Ulf with his TENS unit in the ear.

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

Dr. Kevin Tracey: Yes, yes, he did. He published it in a peer-reviewed journal that I believe is open access. If you Google his name, Ulf Andersson, with two Ss, Andersson.

Tim 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.

Dr. Kevin Tracey: Oh, I can send it to you for the show notes.

Tim Ferriss: Okay, perfect, perfect. We’ll do that. And I interrupted your train of thought.

Dr. Kevin Tracey: No, that 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 in causing depression in some patients, and can we treat that with vagus nerve stimulation? Is that why it works in the 50 percent of the — why 50 percent? Isn’t that kind of a funny number? It works.

Tim Ferriss: That is. It’s too clean, right? 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 there may be people who have looked at this closely. Is it plausible that that is mediated by a vagus nerve stimulation?

Dr. Kevin Tracey: The simple answer is, yes, I don’t like to speculate.

Tim 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?

Dr. Kevin Tracey: I don’t know the studies that you’re referring to. I really don’t.

Tim Ferriss: Yeah.

Dr. Kevin Tracey: 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 or 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. I mean, now the question is, if we had ways of selectively reducing that inflammation in the context of getting pregnant, if you could specifically reduce that inflammation, would you increase the chances of getting pregnant? Well, yeah, it’s quite logical. It’s plausible. Can vagus nerve stimulation do that? To my knowledge, nobody knows.

Tim 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?

Dr. Kevin Tracey: Martine is a close friend and another — 

Tim Ferriss: Also, phenom, what a wild background and such a polymath.

Dr. Kevin Tracey: Martine’s another national hero. I mean, she’s a satellite launcher. She’s a satellite communications expert. She’s an accomplished pilot including flying her own battery powered helicopter and setting land speed records and distance records, and she’s a good friend, and the CEO of United Therapeutics. Yeah, Martine’s wonderful. We talk a lot about this stuff.

Tim Ferriss: All right. So I’ll leave 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 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 Moseley 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 it. Because sometimes, like you said, the response to the equivalent of a picket line in your body is the entire Navy showing up with rockets blazing and it’s a severe overreaction.

So this relates to Professor Rolls, and I guess I’m going to try to word this in a way that makes sense. But how specific molecules inform memories/engrams 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 onto this because it seems very interesting and it might somehow be relevant to me. It might not be. But could you just explain what I’m very clumsily trying to evoke or I guess elicit from you?

Dr. Kevin Tracey: Yes, I would love to. So 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.

Tim Ferriss: Yeah.

Dr. Kevin Tracey: So, 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 looks just like yours, right?

Tim Ferriss: Yeah, they look all messed up.

Dr. Kevin Tracey: They all look the same.

Tim Ferriss: It’s just like you get wrinkles on your face, your spine starts to look pretty funky.

Dr. Kevin Tracey: Exactly.

Tim Ferriss: So, I’ve got arthropathy. I’ve got the right foraminal stenosis at blah, blah, blah, blah, blah. But — 

Dr. Kevin Tracey: So does everybody else.

Tim Ferriss: Yeah, you can look at hamburger meat on an MRI of a back, and they’re asymptomatic.

Dr. Kevin Tracey: Right. So why does your back hurt and somebody’s MRI scan would be indistinguishable from it doesn’t hurt? Well, if you could maybe pinpoint the position on your MRI scan. Now, the question is 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 the guy next door?

Tim Ferriss: Yeah.

Dr. Kevin Tracey: Well, that is the question. So how can we connect that to two things? One to — because Ulf’s back pain got better. Two, 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.

Tim Ferriss: I don’t think that was in there. I love this guy.

Dr. Kevin Tracey: He and his brother Jan Andersson won the European World Championships in the J class.

Tim Ferriss: Of course they did. Of course they did.

Dr. Kevin Tracey: 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 at UCLA at the L.A. Olympics.

Tim Ferriss: Wow. Wow.

Dr. Kevin Tracey: Anyways, his back got better. And so, the question is, why did his back get better? Because the signals from the ear to the brainstem 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 percent of cardiac output. So all your white blood cells are racing through the spleen all day long. And when they pass through and pick up this nerve signal, they switch from a state called M1 to M2. M1 macrophages and monocytes, white blood cells, they’re the Navy shooting guns full blazing that you said. M2 are the doctors and nurses in the ambulances who race to the scene to heal.

Tim Ferriss: Mm-hmm.

Dr. Kevin Tracey: 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, is 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 of the joint.

Tim Ferriss: That’s M2 instead of M1?

Dr. Kevin Tracey: 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 or your — 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, Asya Rolls, in a brilliant, I think one of the most important scientific papers in the field of what we call neuroimmunology, and maybe in the last 25 years, she discovered that what’s happening in the inflamed tissues in the colon in this case is actually forming a neural network in your brain, which you can think of as a memory. It’s called — neuroscientists call it an engram.

Tim Ferriss: So, that also be like a phantom limb. Would that be a, or is that a different thing? I don’t want to take us off track.

Dr. Kevin Tracey: No, 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.

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 weeks and months later. And that’s exactly what Professor Rolls did. She used another very sophisticated trick to take 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 and she let them recover from colitis, and then she injected the virus into those neurons and reactivated. Now, just the neurons, not all the neurons in the brain, just the ones that remembered the place of the colitis, and they got colitis again.

The changes in the brain neurons. I call it a neural network. She does too. I mean, we all call it an engram or a neural network. There’s lots of neuroscientists have talked about this on lots of podcasts, but they call it the Jennifer Aniston neuron or the Santa Claus neuron. I’m a recovering neurosurgeon, right, Tim?

So you can do brain surgery under local anesthesia, and this is done a lot of times for epilepsy surgery, for instance, when you want to make sure that you don’t injure any part of the brain involved in speech. So, you can be talking to the patient during brain surgery. Now, you can put electrodes in various parts of the brain and ask the patient what’s happening. And there’s a famous story of a patient, “Well, I just saw Santa Claus,” or “I see Jennifer Aniston.”

And so it’s euphemistically, people call that, “Well, you have a Jennifer Aniston neuron.” Well, 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.

Tim Ferriss: Right. It’s a constellation that is recognizable by the brain as — 

Dr. Kevin Tracey: It’s a constellation. Exactly right. Well, nobody before Asya’s studies, nobody thought that a constellation in the brain would recognize inflammation in a way that would not only remember the effects of it, but could then reactivate it.

Tim Ferriss: Not to interrupt, but since every podcast I do is self-interested in some way, is there a way to delete, control Z, those constellations so that you don’t have this hair trigger response to triggering colitis or low back pain response, right? And in this book that I was mentioning, Explain Pain, they talk about how surfers in instances, sometimes when they get their leg bitten off by a great white, they report it as a thump. It wasn’t painful. Whereas you get a paper cut and it’s excruciating, and there’s so much variability.

So is there a way to deactivate a constellation or overwrite it, or I guess fix my fucking low back pain is the short answer, without taking bottles and bottles of Aleve?

Dr. Kevin Tracey: This is about the third time in this chat we’ve had that I wanted to offer you a job in my lab. You ask all the right questions. We could do the experiments if you come in.

Tim Ferriss: Well, you’re not that far away. I mean, don’t threaten me with a good time.

Dr. Kevin Tracey: The simple answer is that’s what we want to do. 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? 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. 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 sometimes they don’t even injure neurons. They go next to the neuron. You could imagine a time in our lifetimes, I hope, when, if we knew how to target those neurons or map them in advance, that you could put these electrodes in and inhibit them. And yeah, that is the right question. I’m dead serious.

Now Asya’s paper has been out a couple years. I said before, I think it’s one of the most important studies that I’ve read in many years, and we have, of course, pursued it. We’ve been asking questions, my colleagues and I, Sangeeta Chavan 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?

And 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, 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 because how many cytokines are there and how many physiological states? I think the brain, a human brain has what a hundred billion neurons give or take, and trillions of synapses. So it’s more complicated than we think it is, but I think it’s accessing, processing, and potentially storing all the information that we haven’t even begun to imagine yet. And that’s what this data tells me.

Tim Ferriss: What are the possible implications of identifying the constellations? I just keep thinking about stars. It doesn’t take much to screw up Orion’s belt, right? 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-a IL-1, et cetera?

Dr. Kevin Tracey: What are the implications of it?

Tim Ferriss: Yeah, well, how would that translate or might it translate to some type of clinical practice?

Dr. Kevin Tracey: Well, 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 up regulate or down regulate your inflammatory response to a specific cytokine or condition in a specific part of your body. Yeah.

Tim Ferriss: Yeah. That’s wild.

Dr. Kevin Tracey: It is. You said it right. I mean, people used to think it was impossible to track an incoming missile from the moon, but now they know how to do that. And the best example I like, and you’re better at this than I am, but someone explained the analogy I like the most. If you look at a TV screen with all the pixels and you see a picture of the Alps, you can’t possibly pick out the black square or the altered 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. We still have a long ways to go because to my satisfaction, as someone who thinks about systems interacting and biology, we haven’t put enough emphasis on function.

Tim Ferriss: Yeah. 

Dr. Kevin Tracey: And I think even for heart rate variability, you and I can’t talk about heart rate variability ’cause we don’t know enough about the individual functions of the individual wiring diagrams.

Tim Ferriss: Yeah. And also, we can talk about 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.

Dr. Kevin Tracey: Yes, yes.

Tim 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. There are devices, including some that are FDA-approved for, say, I believe cluster headaches and/or migraines, I can’t recall exactly, that are neck-based and could be applied to one side, could be applied to both sides, but effectively, supposedly, tracking or stimulating the vagus nerve where it would correspond to your pulse, let’s just, say carotid artery or arteries.

And there are a number of, 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 like. I’m just curious about the cervical devices because they’re floating around out there, and 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?”

Dr. Kevin Tracey: 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, can you afford to buy lots of devices and try lots of different things? That’s one approach. And second, do you like self-experimentation? That’s another approach. A third is, well, always check with your doctor first ’cause there are some things you probably shouldn’t do around the area of your neck. If 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.

Tim Ferriss: For sure.

Dr. Kevin Tracey: Check with your doctor. So those are actually important disclaimers. That’s not a joke. People should check with their doctor before they do these things, unless of course what they’re doing is FDA-approved. And some of these devices, most of them not, but some of these devices have been subjected to FDA approval.

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

Tim Ferriss: Pull your lip down. You can make some goofy faces.

Dr. Kevin Tracey: That’s happened to you, right?

Tim Ferriss: Yes.

Dr. Kevin Tracey: 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 platysma 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.

Tim Ferriss: Right. So it seems like the TENS unit is not going to hit the vagus nerve.

Dr. Kevin Tracey: 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 an 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 — 

Tim 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?

Dr. Kevin Tracey: I have a very good answer for you.

Tim Ferriss: All right. Collective delusion and placebo — 

Dr. Kevin Tracey: No, no, no.

Tim Ferriss: Mass placebo? No?

Dr. Kevin Tracey: 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 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. How could it work? We’re talking now science here. Well, Charles Sherrington, one of the two fathers of neuroscience with Ramon Y Cajal back in the early 1900s, he wrote a famous book which I recommend to anyone, even casual readers of neuroscience should read Charles Sherrington’s book, The Integrative Action of the Nervous System. The title alone is brilliant, The Integrative Actions of the Nervous System.

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. Well, in the knee case, the rubber hammer stretches the tendon. The tendon sends a signal up your sensory nerves to the spinal cord. The 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.

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?” Then he said, “If you assemble a couple of reflexes, you could start to build a nervous system.” This is, again, this is your field more than mine is 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 they start to connect. And then he goes, “End of the day, there’s no such thing as a simple reflex ’cause 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. In some patients, does it relax the muscles of the neck to interfere with a 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.

Tim Ferriss: I mean, it’s exciting to me that there are so many open questions. So just these like, 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 ’cause 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, it doesn’t seem to be a vagus nerve stimulator.” But we were joking, and I think one of us is probably me ’cause I’m a goofy ass a lot of the time, but I said, “I guess at the end of the day, ultimately you don’t really care if you’re somehow summoning Odin to come down with a magic unicorn and pierce you through your forehead with the spike like a narwhal to fix your low back pain or increase your HRV. You just want the output.”

So whatever is happening, it would be great 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 of that or the power of placebo.

Dr. Kevin Tracey: 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 a hundred patients were subjected to this and 75 percent 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. 

Tim Ferriss: Some of the websites selling these things are so bad, I mean, 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.

Dr. Kevin Tracey: Yeah. 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. I mean, there’s real questions there. I’m not saying it’s easy. Look, the simplest, what people would say is the simplest, stupidest clinical trial of one of these devices might cost $5 million or more.

Tim Ferriss: Yes, science is expensive. Good science is expensive.

Dr. Kevin Tracey: Yes. Yes.

Tim Ferriss: Yeah. All right. So we’ve covered a lot of ground. I highly, highly, highly recommend people check out The Great Nerve if you want, not just things we’ve talked about. We could do three rounds of the podcast. I didn’t even get through a small portion of my notes. And 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? You got it. I mean, people are like, “What, the Dalai Lama? How the hell. It’s a good fit into this. Yeah. All right, so please, please tell that because it’s just fun. I mean, it’s so fun. It’s also fascinating, but it’s fun.

Dr. Kevin Tracey: Back in the day, was it about 2007, give or take? I can’t remember the year. It’s in the book. Maybe 2010. I got a call from the Dalai Lama’s New York office, would I like to go to a conference? Now the call came from a gentleman named Bill Bushell, 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 and 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 tenets of his religion are true in a quantum mechanical way, as you alluded to before, from any perspective. His tenets are like the speed of light. They don’t change.

And he said, to the point that in fact, if Western science or new world science could disprove any of his tenets, then he would change the tenets. He has a deep interest in science. He hosted a meeting here in Phoenicia, New York on the top of a mountain where they own a compound, right outside of Woodstock where the rock concert was. 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, so 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.

Tim Ferriss: I’ve driven by this place. It is in the middle, I mean middle of all of the woods, yeah.

Dr. Kevin Tracey: They own the whole mountain, right? So it’s dark, it’s nighttime. And they give me keys to a cabin in the middle of 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 going to walk in the dark.” It was through the bears to my cabin. And I said, “Well,” I’ll make a joke. And I said, “Well, I know they were here first, right? Ha ha.” And she looks at me with steely eyes. It’s like, “Okay, welcome to Woodstock.” I’m like, “This isn’t like the concert.” So the next day — 

Tim Ferriss: “Good evening, sir.”

Dr. Kevin Tracey: Exactly. The next day I’m on stage. The next day was two days of scientific talks, a whole series of times — I gave one. I remember Liz Blackburn 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 on stage in front of all the attendees. So we said, “Sure.”

So Liz gave a talk, and then I gave a talk. I’ll never forget, I was on stage with the Dalai Lama with Bob Thurman who was sitting to his side. And that’s Uma Thurman’s dad. And he’s a professor of Tibetan studies and other studies at Columbia at the time, Columbia University. And a translator sat between us.

And I explained the vagus nerve and I said the vagus nerve. And he asked the question you did, “Where is this vagus nerve?” And I said, “It travels down your neck, 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 that was that.

And then afterwards he left and a few monks came up to me, and In their long, flowing orange robes, as Bill Murray would say, striking, and they said to me, “His Holiness asked you those questions. Do you know why he asked you those questions?” I said, “No, I haven’t a clue.” And they said, “Well, we like to practice. One form of Tibetan meditation is we like to practice a cloud of blue 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.”

Tim Ferriss: Not everybody gets a Dalai Lama 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 Tracey, T-R-A-C-E-Y. 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?

Dr. Kevin Tracey: One thing. These things in the book and that a lot of people talk about for self-help, they’re good. I do them. Meditation is 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 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 literally decades of science to now 15 years, 12 years of clinical trials on this science that gives hope to some patients with serious inflammatory conditions that stimulating their vagus nerve with this immunoregulator is what we really call it, this is 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.

Tim Ferriss: Yeah, maybe round two of 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 links in the show notes to many different studies to Ulf Andersson’s protocol for the five minutes, twice a day, of course, to SetPoint to the New York Times piece as well, and to the book, The Great Nerve. And you’ll be able to find all of that 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 Tracey, T-R-A-C-E-Y, or vagus or vagus nerve, and this will pop right up. And until next time, folks, be just a bit kinder than is necessary not just to others but also to yourself. And as always, thanks for tuning in.