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

0:00:04 Well, hello boys and girls, ladies and germs. This is Tim Ferriss. Welcome to another episode
0:00:09 of the Tim Ferriss Show, where it is my job to deconstruct world-class performers to determine
0:00:16 or identify, try to identify how they do what they do. In this episode, I have turned yet
0:00:23 another conversation into a how-to search for myself to help me with various things,
0:00:28 chronic inflammation and other issues that seem very squirrely, difficult to treat with
0:00:34 many frontline treatments. So who did I find? I found someone named Kevin J. Tracy, MD. He is
0:00:40 the president and CEO of the Feinstein Institutes for Medical Research at Northwell Health, a pioneer
0:00:46 of vagus nerve research and author of the recent book, The Great Nerve, the new science of the vagus
0:00:51 nerve and how to harness its healing reflexes. Now I say this in the interview, but there’s so much
0:00:58 nonsense floating around about the vagus nerve and so many different hocus pocus, hand wavy things
0:01:05 related to it that I discarded it. But Dr. Tracy is the real deal. His contributions include identifying
0:01:11 the therapeutic action of monoclonal anti-TNF antibodies, we’ll explain what TNF is, and
0:01:17 discovering the specific reflex control of immunity by the nervous system called the inflammatory reflex.
0:01:22 These discoveries launched the new scientific field called bioelectronic medicine, which
0:01:28 investigates the therapeutic applications of vagus nerve stimulation to cure disease. The case studies
0:01:36 are tremendous, but also the published studies and just data overall are so compelling. There’s a lot
0:01:43 you can use here. And it all started with a mysterious death from sepsis of a toddler who was in his care.
0:01:49 That’s how he started pursuing studies of inflammation. His lab has since revealed molecular mechanisms of
0:01:54 inflammation and identified the use of vagus nerve stimulation to treat it. An inventor on more than
0:02:01 120 US patents and the author of more than 450 scientific publications, he is among the most highly cited
0:02:06 scientists in the world. He co-founded the Global Sepsis Alliance, is the author of Fatal Sequence,
0:02:15 and is a national and international lecturer. So I’m so excited to introduce you guys to Kevin. He is amazing. He is not only a
0:02:22 world-class scientist, but he’s also a world-class explainer, which you will get to taste firsthand. So we’re going to get to that
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0:06:40 Dr. Tracy, good sir. Nice to see you again. Thanks so much for making the time to have this
0:06:43 conversation. Thanks so much for having me on. I’m really looking forward to it, Tim.
0:06:52 I am really holding in my enthusiasm, which I’m not going to do for very long because we had a chat,
0:07:00 brief chat, maybe a week or two ago, and I was bouncing around in my chair. I was overflowing
0:07:07 with excitement to ask so many questions. And the reasons for that excitement will, I think,
0:07:12 become very, very clear very quickly. But let me, as context for people listening,
0:07:19 and you know some of this already, explain why I never looked at vagus nerve stimulation seriously
0:07:27 up until very recently. And primarily, it’s because there’s so much crap and so many charlatans,
0:07:34 whether it’s deliberate or not, floating around online, touting the most ridiculous approaches,
0:07:40 devices, at best innocuous, sometimes probably putting people at risk.
0:07:49 And at the checkout, they might be selling audio chakra cleanse soundtracks and just associated
0:07:53 nonsense that shows that they wouldn’t be able to find a logical argument if it bit them in the ass.
0:07:58 And I thought, you know what? I’m just going to put this in the category of things that I should
0:08:04 ignore. And also, I’d been sent, and not to throw this under the bus, but maybe we’ll get to it,
0:08:10 a book on polyvagal theory. And I looked at it, and I know just enough evolutionary biology to be
0:08:17 dangerous. And I thought, I’m not convinced this actually makes a whole lot of sense. And again,
0:08:23 came to the conclusion, I should just put this to the side, at least for now. The reason that changed
0:08:35 is that a friend of mine who is quite technical, he is one of the top performing investors in biotech,
0:08:42 and let’s just call it medicine writ large, when it comes to public equities and other types of
0:08:49 investments. He has patents to his name. This is a very smart guy. And he reached out to me via text,
0:08:55 this is a good friend of mine, and asked if I’d ever looked at vagus nerve stimulation. And I was
0:09:01 like, no, absolutely not. Is there something interesting there? And he said, I think there is.
0:09:07 And he’d been digging into the literature. He’s also a former tier one operator from the military.
0:09:14 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
0:09:20 lot of differences. But he had been using something purchased off the internet, and had tripled his
0:09:26 heart rate variability. And I mentioned the military piece, because he has, I’m not sure if this is the
0:09:31 right term, and I’m sure I’ll misspeak a lot. So feel free to give me a polite smack when I do.
0:09:37 But sympathetic overdrive, he would lay down to try to go to sleep, his heart would be racing,
0:09:44 this glucose would be spiking, not from PTSD, but from a lot of other things. And he had tried
0:09:49 meditation, and he’s diligent, he will do what he assigns himself to do. He tried all these
0:09:55 interventions to improve heart rate variability. And maybe we’ll talk about that. But suffice to say,
0:10:00 within the realm of say, athletics and recovery, and this, that and the other thing, often,
0:10:06 higher HRV is a good thing. And all of these interventions he tried had bumped things, maybe
0:10:14 10%, maybe 15%. And then he used a vagus nerve stimulator for a few weeks, and tripled his HRV.
0:10:22 And he’s setting personal records week after week. And I thought, okay, could be N of one and placebo,
0:10:28 sure. But I should take a closer look. And he sent me an email with a bunch of citations,
0:10:35 and I started going, as I do, obsessively down this rabbit hole. And I listened to an interview,
0:10:41 I want to give credit where credit is due, on STEM Talk. And they interviewed you. And I thought,
0:10:48 okay, I should really, really reach out to Dr. Tracy. And then, just coincidentally,
0:10:53 I was walking through a bookstore, and right in front of my face was your book, The Great Nerve. And I
0:11:00 thought, okay, universe, not to get too woo-woo. But I got the message, message received, reached out,
0:11:08 and also read the book. I recommend everybody read this book. It’s not only from a very credible source,
0:11:16 but you are a good writer. It’s very compelling. So let’s skip my TED Talk. Thank you, everyone,
0:11:23 for coming to my TED Talk. And go straight to the big news. I guess this was literally you emailed
0:11:30 me, and now it’s big. So what is the big news that literally has just been announced?
0:11:38 It was just announced that the company Setpoint Medical, which will now be marketing a device to
0:11:44 stimulate the vagus nerve to treat rheumatoid arthritis, has received FDA approval. So there’ll
0:11:51 be a product launch underway for everything we’re about to talk about in the context of using a
0:11:59 medical device that activates an evolutionarily conserved and ancient reflex through which the
0:12:06 brain can suppress inflammation when it’s running out of control. We’ve discovered that signals travel
0:12:11 from the brain through the vagus nerve. We’ll talk about what the vagus nerve is, but these signals
0:12:17 traveling in the vagus nerve are like the brakes on your car. And when you tap those brakes to slow your car
0:12:23 barreling down the hill when this device activates what we call the inflammatory reflex. So you talk
0:12:29 about this being a current event. As you and I both know, it’s the front page story in the New York Times
0:12:37 today celebrating the successes at Setpoint Medical. And kudos to them, to Murthy, the CEO, to Dave Chernoff,
0:12:44 the CMO. But it’s based, as the article explains, also on 20 years of work by my colleagues and I at the
0:12:49 Feinstein Institute at Northwell in New York, and all of which has been essentially replicated by
0:12:54 dozens, if not hundreds, of laboratories around the world. So it’s a deep, it’s a rich story of science
0:13:02 converging on how the vagus nerve can switch off inflammation that culminates this morning, as you
0:13:09 point out, in a story about patients who’ve already been treated, some of whom had rheumatoid arthritis for
0:13:11 decades, couldn’t buttoned their blouse, couldn’t pick up a pencil.
0:13:13 If you don’t mind my interjecting.
0:13:16 Yeah. I get excited too, Tim. I apologize.
0:13:20 Oh, you get excited too. Please, I don’t want you muted. I don’t want muted, Kevin. I want excited,
0:13:29 Kevin. And let’s feed that fire a bit. Let’s talk about specifically one of your patients who shows up
0:13:36 multiple times in the book, but most memorably to me in the coda. And could you just tell her story
0:13:43 in brief, doesn’t have to be super brief, because I want people to understand just how drastic,
0:13:48 and this is not going to be true for everybody with every condition, but just how significant
0:13:51 the transformation can be.
0:13:56 Kelly Owens is the patient you’re referring to. I know her story very well. I know her very well now.
0:14:02 And when I think of her story, as you just introduced it, I got goosebumps again, as I do every time.
0:14:10 Kelly was a teenager when she was playing sports in high school and developed one night after a trivial
0:14:18 injury, a major swelling in her knee that cascaded to a very serious problem that ultimately was
0:14:24 diagnosed as Crohn’s disease, an inflammatory bowel disease complication affecting her joints.
0:14:29 Kelly spent her teenage years and most of her twenties in and out of hospitals,
0:14:35 in and out of wheelchairs. Her father actually gave her a cane for one of her birthdays. I’m not sure
0:14:41 which one. Now, it’s really important. I should point out to him that these stories are so interesting
0:14:45 and compelling because for much of her life, Kelly always loved to write. She still loves to write,
0:14:50 and she blogged many of these stories in the public domain for much of her life. So all this is out there
0:14:57 for other people to read. Kelly ultimately became a school teacher but could not be treated. Her condition
0:15:05 couldn’t be fixed from New York to the Mayo Clinic to Hawaii and back. And it culminated when her
0:15:12 physician told her and her husband, Sean, to plan on staying home without children because of all the
0:15:17 medications she was on. Childbearing would be too risky. And to get used to her life like that.
0:15:24 Around that time, she saw me on a Huffington Post live internet interview, live stream. And she
0:15:30 contacted me. And I don’t recall that contact, but I recommended she look into Setpoint Medical,
0:15:34 the company that I had co-founded in 2007 to do these clinical trials.
0:15:38 And Kevin, can I pause you for just one second? Don’t lose your train of thought. But also,
0:15:47 I recall, and fact check me here, chronic fatigue, having to lay down, elevator legs. I mean, really
0:15:51 just had trouble functioning on a day-to-day basis is my recollection.
0:15:56 Absolutely. People think of, they hear the word arthritis. When they hear rheumatoid arthritis,
0:16:01 they hear arthritis. This is not the trivial sports injury you had in high school. Now it’s a rainy
0:16:06 day in your knee or your elbow is sore. This is a serious condition that affects the whole body. It
0:16:12 can affect the kidneys. It can affect the brain. It can affect your heart. Similarly, for inflammatory
0:16:18 bowel disease, it’s not, obviously, bouts of diarrhea and abdominal pain and nausea and vomiting can be
0:16:25 disabling. But the inflammation that affects the intestines in inflammatory bowel disease or in Crohn’s
0:16:31 disease also affects other organs, the spine, the joints in Kelly’s case, in her arms and legs. And
0:16:36 so these are serious disabling conditions. They can cause depression. They can cause anxiety disorders.
0:16:39 They can cause chronic fatigue. So that’s exactly right.
0:16:45 All right. So she reaches out to you. You recommend she investigate Setpoint Medical. Then what happens?
0:16:51 My hope was that, although I wasn’t optimistic because she lived in New Jersey and the clinical trials
0:16:55 were being done in Europe. But now that I know Kelly, I understand how she was able to talk her
0:17:01 way into a clinical trial in Amsterdam. She and her husband, Sean, sold all their earthly belongings.
0:17:06 As she said, everything that wasn’t tied down. Their friends and family, through a GoFundMe kind of
0:17:12 operation, raised the money they needed to move there for six months. She enrolled in the trial and was one
0:17:18 of the first patients to receive an implant. I call it a generation one implant. It was like a cardiac
0:17:24 pacemaker under the collarbone, under the clavicle with a lead or a wire that is tunneled up into the
0:17:30 left neck where the vagus nerve travels next to the carotid artery. A couple weeks later, they’re in
0:17:37 Amsterdam still. And Kelly is running a little bit late for her follow-up appointment as part of the
0:17:43 clinical trial to get checked out by the doctors in the trial. There’s elevated trains in Amsterdam and
0:17:47 Kelly sees a train coming and runs up the stairs to hop on the train. So she won’t be late for her
0:17:52 appointment. She turns around like, where the hell’s Sean? Sean’s at the bottom of the stairs with tears
0:17:57 streaming down his face. Because Kelly, it was the first time he’d seen Kelly run up the stairs in years.
0:18:00 Yeah, she had trouble walking on the cobblestones.
0:18:02 She had trouble walking on the cobblestones.
0:18:03 Not long before.
0:18:08 Her father gave her a cane for her birthday that she used for many, many years when she wasn’t in a wheelchair.
0:18:12 And now she’s running up those metal stairs in Amsterdam to catch a train.
0:18:19 So she had a remarkable response to this therapy. So a few months go by, and I didn’t know any of this.
0:18:24 A few months go by, I get an email. The subject line was, thank you for saving my life.
0:18:30 So it was wedged in between a lobbyist in Washington talking about research expenses
0:18:35 and my own corporate controller talking to me about my laboratory’s research expenses.
0:18:42 So I read Kelly’s email first. And I learned her story and that she wanted to thank me in person.
0:18:49 And so I said, come on in. But I also brought on that first meeting a couple of my physician
0:18:56 colleagues. And we talked at length about Kelly when she told me that she wanted to help us
0:19:02 in the bioelectronic medicine universe be a patient advocate for this idea.
0:19:07 We spent a great deal of time with her explaining that there are risks and benefits to this.
0:19:11 People resist change. The world is not ready for something truly new.
0:19:17 The world’s not ready to talk about a one-inch device in your neck instead of taking pills and injections.
0:19:19 This is going to change everything.
0:19:24 And if you’re going to be a leading spokesperson on the patient side of this, you may be…
0:19:28 People are going to tell you you’re a placebo effect. Tim, all of those things happen.
0:19:29 Oh, I’m sure.
0:19:34 The CEO of a major pharmaceutical company at a social event told Kelly, this was many years ago,
0:19:38 if you’re real… I mean, how do you say this to a patient? If you’re real,
0:19:42 then everything I’m doing is at risk and I could be out of a job.
0:19:45 Yeah. And not with a smile on the face.
0:19:53 That was a real important day in my life. She hugged me. I hugged her. She cried. I cried.
0:19:58 And then she said she had a present for me. And I said, what’s that? And she gave me
0:20:05 a gift-wrapped cane. It was clearly a cane, the way she wrapped it. The handle was wrapped and the
0:20:11 cane was wrapped with a big bow on it. I opened the card, which I, of course, still have attached
0:20:17 to the cane. The cane is still wrapped. The bow is still on it. And it sits in the corner of my office.
0:20:22 And every day, if I’m having a tough day in the lab or any of my colleagues are,
0:20:28 we come down and we look at Kelly’s cane and remind us why we do what we do and what we hope can happen
0:20:34 when you do science in the hopes and dreams of discovering things that might help people someday,
0:20:35 because it can happen.
0:20:40 So I want to add a few things to that. What a story. And like you said, some people
0:20:46 at the time were like, ah, placebo. But placebo effect, and I’m pulling directly from you here,
0:20:53 rarely has durability past a certain point, right? But when you’re looking at six months out,
0:21:00 12 months out. And she, furthermore, not to say this is more important than anything you just described,
0:21:05 but certainly for a lot of people listening and for me personally, having suffered from what I would
0:21:13 describe as chronic fatigue for decades, and we might dig into some of that, she went from
0:21:21 basically having a blinking battery empty for her day-to-day to having almost too much energy,
0:21:26 which isn’t to say it was a problem, but just kind of running up the stairs, bouncing off the walls.
0:21:34 And my God, what a difference that the lives that are lived by the former and the latter,
0:21:41 the magnitude of the differences just can’t really be overstated. It’s two different experiences of life.
0:21:46 So now I’m going to get all excited and lose my train of thought, but I’m going to scatter shot
0:21:52 here for a second. So just to also lay out a few things for folks. So part of what has been
0:21:58 so exciting about this and why I want to pay a lot of attention to it, there are a few things feeding
0:22:06 into it for me personally. So one is having some exposure to, I suppose, what you might call
0:22:15 bioelectric medicine through early, early generation TMS, but then also later accelerated TMS with better
0:22:19 hardware, better software, better targeting for things like treatment-resistant depression.
0:22:24 People can look at Nolan Williams out of Stanford and just some incredible data there.
0:22:29 Focused ultrasound in conversation with Nora Volkov for potentially hitting the nucleus accumbens for
0:22:36 addiction. And the possibility, not just the possibility, but now a lot of compelling data,
0:22:43 for instance, around setpoint medical and other forms of vagus nerve stimulation. But I know you
0:22:50 might put some of them in quotation marks to be an option and alternative to biologics, right? Let’s
0:22:55 just say oral or intravenous or intramuscular medication that have a host of really non-trivial
0:23:04 side effects. And for myself, looking at past depressive episodes, looking at, as I’ve tried to
0:23:12 unwrap that for myself, which is very under control for the last, I’d say, 10 years, but looking at the
0:23:18 Lyme disease, which I’ve had twice, and by the way, guys, that’s not a, oh, I just happen to be lethargic
0:23:24 and I’m hunting for a diagnosis going from quack to quack until I get Lyme disease. Like Eastern Long
0:23:33 Island, look at the CDC map. It is just, it is as red as it gets. And thinking of then later
0:23:39 neuroinflammation, I have neurodegenerative disease in my, in my family on both sides. So looking at all
0:23:46 these things unfold and feeling like this is going to be a way overreach, but there seems like there
0:23:51 might be, I don’t want to say unified theory, but there’s some connective tissue tying this stuff
0:24:01 together and started playing with the microbiome because changes in gut flora have been associated
0:24:10 with say depression or animal models of depression or lack thereof. Also looking at say the ketogenic
0:24:17 diet or exogenous ketones as a way to reduce inflammation. And when you start looking at all
0:24:23 this, and then when I read your book, the reason this ties into your book, and we should probably
0:24:28 define what the hell the vagus nerve is because it’s more like vagus nerves and you’ll give a great
0:24:35 description. I’ll just give a couple of quick samplers and then we can get back into them at any point.
0:24:44 GLP-1 agonists, right? In the news, Ozembek, Munjaro, take your pick. But at least in animals, my understanding
0:24:53 is if you sever the vagus nerve, those GLP-1 agonists, they cease to exert a lot of their effects
0:25:00 that you would otherwise see. And similarly, people may have heard these stories, which are based on research,
0:25:08 of microbiome transplants from say obese mice to normal slash lean mice, let’s just say.
0:25:16 And lo and behold, this amazing thing happens, which is the normal mice take on the attributes,
0:25:22 the insulin insensitivity, the weight gain of the obese mice. Fascinating. But if you cut the vagus nerve,
0:25:32 that doesn’t happen. So what the hell is going on? And all of these things are interconnected in the
0:25:38 most interesting ways. There’s so much left to learn, but let’s begin with a definition of basic
0:25:46 terms. Vagus nerve. How should people think about the vagus nerve? When you look online, you’ll find
0:25:53 billions of web impressions of vagus nerve. So I’ll just describe it anatomically and functionally
0:25:58 first, and then we can cherry pick where to go. We all should define, if you agree, bioelectronic
0:26:04 medicine, because you talked about the connective tissue in the story, and then we should define
0:26:10 inflammation. So the vagus nerve, we call it the vagus nerve, and that’s what it’s called. But you have
0:26:16 two of them. So there’s two vagus nerves, like two thumbs, one on each side. Each one arises at about
0:26:22 the level of your ear at the base of your brain, travels down both sides of your neck with the carotid
0:26:29 artery, and then across the chest into the abdomen. And along the way, it sends out countless branches to
0:26:35 all the organs in the chest and abdomen that you don’t think about all day long. Now, within each of
0:26:44 those two vagus nerves, left and right, you have 100,000 fibers. Each fiber is a unique nerve.
0:26:52 That’s the part that’s lost almost immediately by 99% of the casual readers of vagus nerve stuff.
0:27:00 Each fiber, 200,000 fibers, each fiber has an origin in either the body or the brain. 80% of them
0:27:06 actually originate in the body. They carry information about the organs and your body up
0:27:12 into your brain. And then obviously, the other 20% originate in the brain, and they carry information
0:27:20 back down to your organs. So again, I’m trying to clear up some misnomers along the way. The biggest
0:27:26 misnomer is that you have one vagus nerve, like a solid copper wire. You don’t. You have 200,000
0:27:32 vagus nerves if you treated each one as a wire. Let me ask if this is a fair visual to paint for
0:27:38 people. So imagine that from the base of the ear, roughly, this is Tim, the layperson talking,
0:27:45 but you have these two thick cables coming down on either side, kind of tracing the carotid artery.
0:27:51 And they’re like transatlantic cables, just full of 100,000 fibers on either side.
0:27:57 And they go down, and then they kind of branch out like the Mississippi Delta or something like that
0:28:03 and innervate and touch. I don’t want to say just about everything imaginable, but there are 200,000
0:28:09 of these, right? Is that a fair visual to paint for people? Or would you modify that?
0:28:15 No, I wouldn’t modify it at all. In fact, if you go one step further, each nerve ends on either a cell
0:28:21 in an organ or on another nerve. And those other nerves, those secondary nerves that the vagus nerve
0:28:28 ends on, those branch out further. Here’s how I like to visualize it. I think we chatted about this
0:28:35 a couple of weeks ago. If I had a solution, if I had a vat of liquid that could magically dissolve all the
0:28:39 cells in your body, and I submerged you in it for five minutes and pulled you back out again,
0:28:46 you would still look like Tim. Because every cell in your body is essentially touched by or surrounded
0:28:54 by nerves. You’re a walking nerve net. And so one way of thinking of the vagus nerve, if your body is a
0:29:00 walking nerve net, all your organs in your body are encased in a nerve net, well, then the cable that
0:29:06 pulls the nerve net out of the sea is like the vagus nerve. Because it’s connected to the brain,
0:29:11 the brain would be like the fisherman operating. Now, all the signals traveling in these electric
0:29:16 networks are traveling up and down the transatlantic cable, the cable connecting the nerve net in your
0:29:23 body to the nerve networks in your brain. And we know the identity of 200,000 individual fibers.
0:29:27 What we don’t know, Tim, is we don’t know completely. We don’t completely understand
0:29:35 the code of the information that’s being transmitted in each of those fibers, right? People talk about
0:29:40 the action potentials, which are the spikes of voltage change that travel up and down a nerve fiber. Yes,
0:29:46 we can study those. Yes, those are very important. The question is, is that all the information that’s
0:29:52 being transmitted? That’s an area of active research now that’s very interesting to me. Because on one hand,
0:29:58 200,000 fibers is a lot. But on the other hand, 200,000 fibers isn’t that many. And for instance,
0:30:04 we know you can transmit on the same fiber optic cable, lots of TV shows and lots of radio shows at
0:30:09 the same time. So there’s a lot of interesting questions embedded there. And let’s just say of
0:30:21 those 200,000 fibers, do we know roughly how many affect HRV and cardiac function? It’s a much smaller
0:30:27 number than people think. We don’t know exactly for sure. We know in mice, in some beautiful work out of
0:30:33 Harvard Medical School by Steve Lieberlis and his colleagues, we know in mice that somewhere around 100 or
0:30:42 150 fibers are sufficient to control breathing. Now, a mouse vagus nerve has 5,000 fibers, not 100,000. But it’s still a
0:30:48 really small fraction of the total number. And so for instance, a few dozen of those fibers control when
0:30:56 the mouse gets a full inhaled breath. And another few dozen of those fibers control the process of
0:31:03 holding the breath and on down, exhaling the breath. So in human beings, for instance, and we’ll come back to
0:31:10 this some more. But I estimate somewhere between 1,000, give or take, maybe 1,500, maybe 2,000 fibers
0:31:17 control the amount of inflammation, cytokines being produced in the spleen. So you’re looking at,
0:31:23 we can map the identity of the number of fibers going to the heart. Again, it’s a few thousand.
0:31:29 The open question is, say we can assign the action of 10,000 fibers on each side,
0:31:33 what are the other 90,000 doing? Yeah, exactly.
0:31:34 Yeah.
0:31:40 Just a quick thanks to one of our sponsors, and we’ll be right back to the show.
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0:32:59 I want to keep giving people scooby snacks here. Just because I’m so excited, I want to keep
0:33:09 reiterating the potential payoff of doing this the right way. And you mentioned cytokine. I want to
0:33:13 double-click on that for a second. We don’t need to get immediately into the technical definition of
0:33:21 that. I’m sure we will. But people may know that word from what? COVID-19. Cytokine storm, boom,
0:33:31 can lead to fatality in some patients. And I suppose I’m curious to know, just in short form,
0:33:37 what happens to cytokine production when you stimulate the vagus nerve correctly?
0:33:42 It gets turned off. If you stimulate the fibers we were just talking about,
0:33:48 it turns off cytokine production quite effectively. We discovered this by accident, actually, 27 years
0:33:56 or so ago in the laboratory. We discovered we were working on experimental anti-inflammatory drug that
0:34:01 we had developed. And we put it in the brains of animals with a stroke. And the idea was this
0:34:06 anti-inflammatory drug in the brain would stop inflammation. And that did happen. And the stroke
0:34:13 in the animals was smaller. And we were very happy. But surprisingly and unexpectedly, when we looked
0:34:17 at inflammation in the body of those animals with the drug in the brain, they also had less
0:34:21 inflammation. This was a head-scratcher. This made no sense whatsoever.
0:34:28 And that’s a head-scratcher because the effect should have been sequestered to the brain because of
0:34:29 the blood-brain barrier?
0:34:36 Either the blood-brain barrier, but also because we had put such small amounts of drug into the brain.
0:34:42 there wasn’t sufficient amounts to account for the saturating and stopping inflammation in the body.
0:34:48 What we discovered years later was that the drug in the brain was actually turning on the vagus
0:34:54 nerve. At the time we discovered the signals were in the vagus nerve, it sort of became obvious to me
0:35:00 as a neurosurgeon working on cytokines in the lab. It became obvious that if the vagus nerve is turning
0:35:06 off inflammation, then it should be possible to stimulate those fibers in the vagus nerve with
0:35:12 electrodes and treat inflammation with a device instead of drugs. And so that’s what we wrote on
0:35:19 the back of a napkin 27 years ago that kind of led to where we are today. At the end of the day,
0:35:27 we understand using techniques like optogenetics, where you can make neurons in the mouse brain
0:35:33 sensitive to laser light and other sophisticated molecular biology and genetic tools. I can explain
0:35:38 to you how the brain through the vagus nerve turns off cytokines and inflammation.
0:35:43 I’m sorry, Kevin, could I pause you for one second before we get there? And this is something I do not,
0:35:47 I mean, I’m going to ask a lot of questions I don’t know the answers to. Otherwise, the interviews are
0:35:53 pretty boring for me. So does this mean that you could use, as an acute intervention, vagus nerve
0:36:04 stimulation, say, hypothetically in the ER to stop anaphylaxis or to address like asthma attacks or sepsis or
0:36:10 anything like that? Once you understand the basic signals that flow in the vagus nerve to control one
0:36:17 aspect of the immune system, in this case, how vagus nerve fibers can turn off cytokine production,
0:36:23 you can ask new questions. Yep. And let me answer your question by adding a definition because I think
0:36:29 it’s a perfect segue. So in order to understand the answer to your question, how to use vagus nerve
0:36:33 stimulation and other conditions like asthma and other conditions, you have to back up a bit. You have to
0:36:37 say, okay, what condition are we talking about? Let’s look at how the pharmaceutical industry does
0:36:44 this. Pharmaceutical industry starts by picking a disease, a condition. Let’s do rheumatoid arthritis
0:36:49 first as it’ll become obvious why in a minute. We’re going to look at rheumatoid arthritis. That’s
0:36:54 the condition. What’s the molecular mechanism? Well, the early research with using monoclonal antibodies
0:36:59 against TNF showed that that helps about half the patients. So that’s the mechanism. So now we can
0:37:05 make monoclonal antibodies that hit the molecular target TNF to treat the disease. And now you sell
0:37:10 your monoclonal antibodies and after they’re approved for safety and efficacy by the FDA. Great. That’s
0:37:16 what the pharma industry does. We proposed some years ago, 15 years ago or so now, the idea of
0:37:22 bioelectronic medicine as an approach to develop therapies. You begin in the same way. You pick your
0:37:30 condition. It’s rheumatoid arthritis. Then you say, rather than screen for antibodies or other molecules
0:37:35 to stop TNF, which is the target in rheumatoid arthritis, let’s see if we can find nerves that
0:37:41 control TNF production in the body in situ. If we can find such nerves, then we can build devices
0:37:48 to control the nerves and the devices become the therapy. The bioelectronic medicine story works
0:37:54 as long as you know the molecular mechanism. And that’s where people have to be really careful
0:38:01 with vagus nerve stimulation. So there are many conditions today that are treated with
0:38:08 anti-cytokine therapy, anti-TNF, anti-IL-1, anti-IL-6. Those conditions include things like
0:38:14 rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, psoriatic arthritis, and some other
0:38:20 conditions. Most of them are autoimmune conditions. When you ask about asthma, and you mentioned
0:38:26 earlier also depression and some other conditions, I go back to the basic starting point. What is the
0:38:32 disease, asthma? What is the mechanism? Tim, no one knows. Yeah. That’s a full stop. Therein lies the
0:38:38 rub. That’s a full stop for me before saying, you know, vagus nerve stimulation will or will not work.
0:38:45 I remember one of my mentors and friends, rest his soul, Frank Austin, was one of the leading experts
0:38:50 on asthma research for decades. And a few years before he died, I said, Frank, I think I’m going
0:38:54 to do some asthma research. He said, okay, what are you going to do? So I got this mouse model. He goes,
0:38:59 Kevin, the last article I wrote on asthma was entitled, Mice Don’t Wheeze.
0:39:08 I like that. Mice Don’t Wheeze. Well, you know what that makes me think of? And I mean,
0:39:14 like we’re going to digress for a second here, but we need the animal research. And there’s a lot you can
0:39:18 do in a sort of metaphorical Petri dish now with like synthetic biology and stuff. There’s a lot coming
0:39:23 down the pike, but still animal models are super important. But some of the, since I’ve funded so
0:39:30 much early research and some later stage stuff with respect to psychedelics since 2015 and psychedelic
0:39:35 assisted therapy, but also basic science, some of the animal models are pretty hilarious,
0:39:40 right? Where they’re looking at like the head twitching and paw licking in the case of like
0:39:47 Barry Jacobs giving LSD to cats way back in the day, decades ago at Princeton. And they’re using,
0:39:53 let’s just say the antidepressant animal models might involve like swim to exhaustion. And then you’re
0:39:56 like, okay, well, I guess methamphetamine is going to be one of the best antidepressants you could
0:40:02 possibly give someone if we’re using that as the proxy. And so a lot of it’s imperfect and yes,
0:40:08 mice don’t wheeze. So maybe, especially if you can’t identify, like you said, I guess the mechanism,
0:40:15 you need to be able to at least hold on to some of the variables. So let me come to just depression
0:40:20 for a second. I know this is going to be all over the place. It’s like Tim after too much caffeine and a
0:40:24 couple of glasses of wine, which is not where I am. I did have some pretty good ketone monoesters before
0:40:31 our chat though. And I wanted to come back to depression because it’s a subject near and dear
0:40:37 to my heart. It’s something that affects a lot of people. And when people experience depression,
0:40:43 it can also feed on itself in the sense, and I speak from experience where you personalize it,
0:40:51 like this is a me problem. This is a character flaw and it’s permanent. And it becomes this
0:40:57 loop that can exacerbate the condition. I’ve long had this suspicion, and this is part of the reason
0:41:03 for a lot of the research involvement is that anti-inflammation or inflammation is sort of
0:41:07 potentially at the core of a lot of this. Whether you look at, for instance, there are very potent
0:41:12 anti-inflammatory effects of certain psychedelics in the phenethylamine class, like 2CB, for instance,
0:41:17 very, very significant at very, very low doses. And when I’m looking at some of my highlights,
0:41:22 I have a ton of Kindle highlights from your book, The Great Nerve. I’ll mention it again. Pick it up,
0:41:30 guys. You will not be disappointed. But you can induce depression in animal models by causing
0:41:32 inflammation. And people too, Tim.
0:41:40 And people too. So, and I want to just read a little bit here because we’ve long had, and I think
0:41:49 many, many doctors still ascribe to a chemical imbalance theory of, say, depression or mental illness
0:41:54 writ large, but depression. So, this is directly from your book. If an SSRI has helped you or someone
0:41:58 you know, that’s wonderful. Large randomized clinical trials of SSRIs indicate they confer
0:42:02 some clinical benefit in some patients, which is true. I’ve seen lives changed. Now, whether it’s
0:42:07 actually serotonin or not is a separate question, but back to your book. But these results in your
0:42:11 personal experience do not prove causality or confirm that serotonin dysfunction is causing
0:42:17 depression. For example, SSRIs may also inhibit inflammation. And then here’s kind of the clutch
0:42:22 paragraph that I highlighted. Interestingly, administering SSRIs to animals and patients
0:42:27 with inflammation after receiving cytokines in the lab. So, you’re deliberately trying to provoke
0:42:34 inflammation. Administering SSRIs can alleviate depression caused by these cytokines. This anti-inflammatory
0:42:38 role of SSRIs is little studied and incompletely understood. And I sincerely hope that my colleagues
0:42:45 are inspired to investigate it further. So, this raises some very, very, very interesting questions.
0:42:51 And since we last spoke, I have been toying around. I use the word toy very deliberately
0:42:59 with some devices that I may not continue to use, but I have a variation that a friend recommended
0:43:04 to me, very low cost that I’m going to be switching to because I don’t like the neck seizures very much.
0:43:12 But nonetheless, I will say that the combination of the stimulation plus, and I realize I’m fussing with
0:43:18 a number of variables, intermittent fasting and exogenous ketones. So, I am throwing a lot against
0:43:25 the wall here. But the addition of the stimulation, which is just a few minutes a day, and we’ll definitely
0:43:33 talk about your friend Ulf and his story because that guy is not wearing a tinfoil hat. He’s credible,
0:43:42 as credible as credible can be. The stability of my mood is remarkable. And again, I think there are
0:43:46 people out there, just if I could throw some folks, not throw them under the bus, but just
0:43:54 lay a criticism. There are some folks out there, well-educated, but non-scientists who worship at the
0:44:02 altar of science with a capital S or scientism, perhaps it is. And so, they’ll criticize maybe a
0:44:08 story like this or the story of your patient and say, ah, N of one placebo. And they discard it that
0:44:14 way. But a lot of very critical scientific investigations begin with case studies in the
0:44:19 literature. I’m looking at that right now with respect to Alzheimer’s and exogenous ketones.
0:44:26 There’s some very interesting stuff out there. So, could you, this is a very long-winded way of
0:44:33 trying to set up inflammation, right? Inflammation is one of those terms that gets used like it’s
0:44:43 specific, but it’s like saying business or sports or art. It’s a big umbrella term. So, what is
0:44:49 inflammation in the context of what you have studied and observed as a clinician and as a researcher
0:44:51 inventor for that matter?
0:44:53 Yeah, we’re going to have to do a couple of shows, Tim.
0:44:56 Yeah.
0:45:05 Simply put, inflammation was defined thousands of years ago as the redness, the pain, the swelling,
0:45:11 and the heat that you feel when you sprain your ankle or get an infected wound on your body.
0:45:17 Everybody’s seen it. Everybody’s had it. And it’s a good thing. It runs its course. And it’s the
0:45:22 product of cytokines in part and other molecules, TNF, IL-1, IL-6, but other molecules made by white
0:45:28 blood cells and other tissues in your body. So, it’s a good thing when it stops. It’s a good thing
0:45:35 because it helps heal the wound, helps proliferate stem cells, helps fight off infection or bacteria
0:45:42 that might settle in the wound. And it’s a good thing if it stops. The problem is, we’ll talk about
0:45:47 why it stops. But the problem comes when it doesn’t stop. And when it starts spinning out of control,
0:45:54 like in Kelly Owens’ case, then it becomes like the army showing up with howitzers to break up a
0:46:01 peaceful demonstration or a picket line. And you have these violent outbursts of inflammatory reactions
0:46:05 that cause the problems in rheumatoid arthritis and inflammatory bowel disease and these other
0:46:09 conditions. So, that’s what inflammation is. That’s what the textbooks say. That’s what everybody knows.
0:46:13 That’s what everybody’s taught. That’s what everybody talks about. That’s the anti-inflammatory
0:46:20 drugs we have today. Modify the molecules we just talked about, TNFs, the IL-1s, the prostaglandins.
0:46:26 That’s how ibuprofen and other non-steroidals work. And we go down the list on all this. The problem is,
0:46:34 when you look in the brain of Alzheimer’s patient, which everyone who studies Alzheimer’s agrees has some
0:46:40 contribution role or cause or contributing factor from inflammation in the brain, neuroinflammation.
0:46:46 You don’t see redness. You don’t see swelling. It’s not painful. And the same is true when you look
0:46:53 in the adipocytes, the fat cells of an obese patient who has type 2 diabetes and has significant insulin
0:46:59 resistance. Sometimes they have a few extra white blood cells in the fat, but it’s not rip-roaring
0:47:05 inflammation that you see with an infected wound. They might have a upregulation of some of the
0:47:09 cytokines. You might see the upregulated production of cytokines in the brains of Alzheimer’s patients,
0:47:15 but it’s nothing like you see in a injured tissue or a rheumatoid arthritis. Some people have come up
0:47:21 with new names. Meta-inflammation. Inflammaging, it’s called sometimes when these kinds of changes
0:47:29 occur. Inflammaging. Inflammaging. As tissues age, tissues from older people, from the elderly,
0:47:33 they have higher levels of cytokines and more insulin resistance. They call it inflammaging.
0:47:41 So we do have an issue of semantics. But with that as a limitation, what’s so important about this
0:47:46 conversation? In light of everything else we’ve been talking about is you talked about a connective
0:47:51 tissue in these stories. And the connective tissue is in many ways inflammation. So let’s back up about
0:47:57 what the problems facing the human race are. So 60 million people die on the planet earth every year.
0:48:06 And 40 million of them die from heart disease, stroke, neurodegeneration, Alzheimer’s, Parkinson’s,
0:48:15 metabolic syndrome, diabetes, and cancer. So two-thirds of the people that die every year on the
0:48:20 planet earth die of those conditions. And that’s according to the WHO. Those conditions all have one
0:48:25 thing in common. They’re either caused by inflammation or made worse by inflammation.
0:48:35 Now, if you look back at what happened in the last 80,000 years, 75,000 years since we came down from the
0:48:42 trees and became sort of talking monkeys, in that time period, almost everybody until 100 years ago,
0:48:49 150 years ago, almost everybody died by the time they were 30. And what happened in the last 150 years
0:48:57 can be summarized in a very simple sentence. The human race in the last 150 years removed infection
0:49:05 as the leading cause of death. And by doing that, we added 40, 50 years to healthspan, to lifespan.
0:49:11 The question that wakes me up at 3 a.m. now is what if we could cure inflammation? If we cured
0:49:16 inflammation, what would that do to the death rate from cancer, heart disease, stroke, and all the
0:49:20 conditions that kill two-thirds of the people on the planet earth every year? Look, there’s still
0:49:24 people that die of infection. People die to COVID. People die every day of malaria and tuberculosis.
0:49:31 I’m not being Pollyann about this, but if you look at the cold, hard numbers, the things that reduced
0:49:37 death and increased survival of the human species all affected the eradication of the threat of
0:49:43 infection. You know, cleaner water, ample food supply, less starvation. All these things converged on
0:49:50 better vaccinations, antibiotics, obviously. All these things converged on improving lifespan. I think
0:49:55 something similar will happen maybe in the next 20 years if we can really understand how to modify
0:50:00 inflammation. And one way I think we’ll be able to do that is by continuing to dive deeper and deeper
0:50:07 into understanding how evolution itself put the brakes on too much inflammation. I said that inflammation’s
0:50:13 bad when it’s not restrained, when it doesn’t resolve. Well, evolution knew that hundreds of millions of
0:50:17 years ago. So from the very beginning of the evolution of inflammation, there’s been evolutionary
0:50:25 mechanisms that evolved to suppress inflammation, to tame it, to put the brakes on it. What we’ve now
0:50:31 discovered in the last 20 years is that the brain does this by sending signals through the vagus nerve.
0:50:38 So you ask if this idea may have an application in other conditions. I’m convinced it will. It’ll have to be
0:50:43 worked through one condition at a time, one mechanism at a time, but I think it’s a really important new
0:50:51 idea. Well, I guess once the devices are out in the wild, right, let’s just say the implant, then docs may
0:50:56 have some latitude to also experiment with patients. I mean, TBD. But let me do a few things. I’m going to
0:51:02 allow us, if we want, just to abbreviate vagal nerve stimulation to VNS, if we want to just make it a
0:51:09 little easier on ourselves. Let me ask a question that I asked in our last conversation, and I’m sure
0:51:17 is on the mind of a lot of folks, which is along the lines of, wait a second, inflammation seems to serve
0:51:23 presumably some important purpose. Just like some people might label cortisol bad. It’s like, if you
0:51:29 get rid of cortisol completely, you’re going to be in a world of trouble. So if you are, say,
0:51:36 decreasing cytokine production and release by 70, 90% with vagus nerve stimulation,
0:51:44 could that not have downstream negative effects? How would you speak to that? And I was asking that
0:51:50 broadly speaking in our last conversation, but also with respect to weight training and physical
0:51:58 adaptations where certain things, and I’m getting way over my skis here, but like interleukin-6, IL-6,
0:52:02 and blah, blah, blah, blah, blah, temporarily, at least, or seem important for catalyzing some of these
0:52:12 tissue adaptations. So are you at risk by sort of suppressing cytokines with vagus nerve stimulation?
0:52:14 Do we know anything about the side effect profile?
0:52:20 We know a great deal about the side effect profile, but let me just first unpack the importance of what
0:52:29 you’re talking about. So if we know for certain, if you take biologics that like anti-TNF or anti-IL-1 or
0:52:35 anti-IL-6 that you see advertised at the nightly news every night and on all the NFL football games every
0:52:42 weekend, these biologics, the way they’re designed to work is they suppress 100% of the activity of the
0:52:48 cytokine. So if you take an anti-TNF and your monoclonal antibody in your body bumps into your TNF in
0:52:55 your body, it’s zero. The antibody takes away 100%. It’s yes or no. Because you take away 100% of TNF
0:53:02 or IL-1, depending on what drug you’re on, those drugs carry warnings. The most serious side effect
0:53:06 warning the FDA can give called the black box warning because they cause immunosuppression,
0:53:12 which is exactly what you said. Immunosuppression means now you no longer have enough immunological
0:53:17 activity or in this case inflammation activity to fight off infections. And so the risk is you’ll get
0:53:22 things like sepsis or other kind of tuberculosis or other conditions, even cancer in some patients
0:53:29 because your immune system is no longer fully armed to defend itself against these threats.
0:53:35 You ask, does vagus nerve stimulation do that? The simple answer is no. And the reason we know this
0:53:43 is because the FDA approved vagus nerve stimulation to treat depression and epilepsy actually in the 1990s.
0:53:50 So we have decades of experience implanting patients with vagus nerve stimulators. Now, there have been
0:53:55 peer-reviewed studies with 30 years of longitudinal follow-up in a quarter of a million patients.
0:54:00 I estimate that millions of patients have actually been implanted with these devices.
0:54:07 So we know that there is always a surgical risk of any surgery. The surgical risks of an incision are
0:54:12 small and the surgical risks of nerve damage are actually quite small, especially with the new
0:54:20 set point device, which is only one inch large, completely encased in it. But immunosuppression wise,
0:54:25 we also know that vagus nerve stimulators do not have black box warnings. There’s no evidence after
0:54:30 decades of any immunosuppression. There’s no evidence of an increased risk of infection or cancer. Why is
0:54:36 that? Well, it’s because, and here we go back to laboratory studies, and even now in new human
0:54:43 studies, when you stimulate the vagus nerve fibers that inhibit inflammation, the ones that travel from
0:54:49 the brain to the spleen, for instance, to stop cytokine production, you inhibit, as you said,
0:54:55 as you correctly said, about 70% of the cytokine production. You don’t inhibit 100%.
0:55:02 So the best way I like to think of it is that if you have an excessive or a dangerous cytokine
0:55:08 response, you’re going to produce, call it 100 units of TNF. And that’s going to be very bad for
0:55:15 your tissues and for you. The normal range should be 10 or 20. The vagus nerve stimulation therapy and
0:55:20 the set point device is called actually the immunoregulation therapy because it’s only one minute a day.
0:55:29 That drives the TNF from 100 down to about 30 or so. So there’s plenty left to have an appropriate immune
0:55:35 response, but it takes the TNF effects from the toxic range that cause rheumatoid arthritis and Crohn’s
0:55:42 disease. The monoclonal antibodies only hit one target at a time, either TNF or IL-1. The vagus nerve is
0:55:47 actually suppressing the whole system. So it’s taking the toxic levels of IL-1 down and the toxic
0:55:54 levels of IL-6 down. Those things together, they act synergistically. So the effects are bigger than
0:55:58 additive. So if you take them all from the toxic range to the healthy range, you’re going to be a
0:56:05 lot better off. And the IL-6 response in skeletal muscle response in weight training, that’s still going
0:56:09 to be down in the healthy range. And who knows, Tim, we don’t know enough about it, but it may very well
0:56:16 be that the vagus nerve signals that you activate during exercise, like on the sheep running on the
0:56:22 treadmill in New Zealand, we could talk about that those vagus nerve signals may in fact be contributing
0:56:26 to the IL-6 metabolism and turnover that’s going on. We don’t know.
0:56:32 Maybe we’ll get to this, but who knows, because we’re going to bounce around a lot. But also another
0:56:38 aspect of your book that is very compelling is it includes a discussion of meditation. It includes
0:56:46 a discussion of cold exposure, and it includes a discussion of different breathing practices,
0:56:56 and all of which seem to have applications to vagus nerve stimulation. And maybe it’s vis-a-vis the
0:57:03 vagus nerve, but parasympathetic activation, which might be very counterintuitive to folks.
0:57:08 And so for instance, reading your research and reading your book and chatting with you has led
0:57:14 me to do something more than I already do, which is, yeah, that’s great, but why? And that’s interesting,
0:57:19 but why? Yeah, that’s interesting, but why? Because for instance, I’ve noticed for decades,
0:57:28 and I think a lot of athletes have noticed that if you do cold plunges and pretty much every division
0:57:34 one soccer team, for instance, or you name it, is going to do some version of this. If you do it,
0:57:39 not necessarily immediately after training, but say you wait an hour or two, and then you do cold
0:57:45 exposure in a bath, that it seems to enhance recovery. Now you could say, well, ice decreases
0:57:51 inflammation. But then it’s like, is that true? Could there be another explanation? And what you
0:57:57 point out in your book, which is something that, again, intuitively now makes sense to me,
0:58:01 is in the beginning when you’re exposed to cold, and there are studies demonstrating this,
0:58:06 whether it’s in cold chambers for hours, which sounds like more misery than I can handle,
0:58:12 but suffice to say, initially, fight or flight response, sympathetic activation, adrenaline,
0:58:19 noradrenaline, et cetera. And then at some point, parasympathetic, rest and digest activation.
0:58:27 And could it be that the cold is affecting the vagus nerve, which is affecting parasympathetic
0:58:33 that helps with recovery? I don’t know, but I’ve, for instance, always wondered why it is that
0:58:39 after a few minutes in a 45 degree bath, I start yawning. There’s a lot of yawning,
0:58:46 and I don’t know if that’s direct. Interestingly, that’s also a very common onset symptom after,
0:58:53 say, ingesting psychedelics, like ayahuasca, is yawning, yawning, lots of yawning, which is why
0:58:59 all these things seem to touch the hem of the same fabric. Anyway, I guess that was more of a monologue
0:59:06 than a question. But let me ask you something that has been also front of mind. Is it true? And I could
0:59:12 speculate, but does it seem like within patient populations, we’re dealing with more chronic
0:59:18 inflammatory conditions? And is that because we have better diagnostics? For instance, you might say,
0:59:21 oh, there’s an explosion of brain cancer. It’s like, yeah, well, we also have much better tools and
0:59:28 people are not dying of maybe things that are easily preventable by antibiotics. So who knows?
0:59:34 Maybe it’s not that, you know, cell phone towers are causing an explosion of brain cancer. It’s very
0:59:40 easily explained in other ways. But do we seem to be contending with population level greater instances
0:59:48 of chronic inflammatory diseases? And question mark, can we even know that? And then if it appears to be
0:59:52 the case, are there any plausible explanations for why that is?
0:59:58 That is a billion dollar question for which I’m not an epidemiologist, but I know there’s no easy
1:00:03 answer to that one. There are epidemiological studies showing an increase of autoimmune diseases.
1:00:09 There are studies suggesting some of these conditions are more common at higher latitudes and some of them
1:00:10 are more common at lower latitudes.
1:00:14 Huh. Interesting. The latitude. Wild.
1:00:15 Yep.
1:00:18 I mean, correlation, I guess, doesn’t prove causation, but it’s interesting.
1:00:25 It’s very interesting. It always comes down to two things, pretty much, in biology. It’s nature and
1:00:31 nurture. It’s genes and environment. And environment is writ large. It’s the family you were brought up in.
1:00:37 And it’s your father’s income when you were six. It’s the germs, the pandemic outbreaks that were
1:00:42 around your neighborhood when you were 10 and when you were 20. And on down the list, what you eat,
1:00:47 what’s in the environment, the air you breathe, how much microplastics did you consume, knowing it or
1:00:52 not knowing it. So genes and environment and sorting that out in real time is exceedingly difficult,
1:00:59 especially when you think about the possibility that some of these things after decades of study
1:01:06 turn out to be caused by previously unknown infections. One of my favorites is stories about
1:01:11 this, of course, is peptic ulcer disease. Everyone, when I was a kid and in medical school,
1:01:18 everyone, we all knew that peptic ulcer disease was type A personalities and the stress, it’s the
1:01:23 patient’s fault. I mean, I love to say, and then it turns out that there’s a bacteria that causes
1:01:27 peptic ulcer disease. And when you treat these people with… What is that? H-pylori? Not H-pylori.
1:01:33 H-pylori, yeah. And when you treat people with antibiotics to eradicate that infection, a large
1:01:38 percentage of them get better. When I was a surgery resident, which wasn’t that long ago, I’m not that
1:01:43 old. I mean, it was… One of the commonest operations in the hospital…
1:01:46 I thought you said communist for a second. I was like, oh, I didn’t see that coming.
1:01:53 No, no. One of the most common operations on the OR schedule was gastrectomy for peptic ulcer
1:01:58 disease. You never see that. It doesn’t happen anymore because you take antibiotics. My adage
1:02:03 for this thing is when you don’t understand a disease, think of epilepsy, you start off,
1:02:09 you blame God. So they do exorcisms and that doesn’t work. So if it’s not God’s fault,
1:02:14 the next thing you do is you blame the patient. And when you realize it’s not the patient’s fault,
1:02:20 in today’s era, oftentimes we find out it’s actually there’s some infectious cause of this thing. And so
1:02:25 autoimmune disease may have an infectious cause. It may have an environmental cause. People talk about
1:02:32 genetic causes. You inherit some level of risk for autoimmune diseases, but very, very few of these
1:02:36 conditions do you actually inherit the condition. I mean, it’s like the old story of the two guys
1:02:42 playing golf and get hit by lightning. I’ll ask you a question, Tim. Is that environment or genes?
1:02:48 Well, I mean, it’s environment, right? It’s environment.
1:02:52 Well, I was also thinking like genetic predisposition to risk-taking when they’re like,
1:02:53 ah, it’ll be fine.
1:02:59 Well, it’s easier than that. It’s easier than that. It’s father and son, and they play golf every
1:03:05 afternoon in the summer in Florida. So it’s like those kinds of analyses with two people are hard
1:03:11 to do the statistics on. When you scale it up to a population, it’s very, very, very difficult to give
1:03:12 a simple answer to your question.
1:03:18 Well, to make it even more difficult, right, when we’re talking about H. H. pylori or pylori,
1:03:23 I’m not sure how to pronounce it. I’ve only read it. But it seems like, tell me if I’m
1:03:30 wading too deep into the deep end of my ignorance pool here. So from your book, and this is not like
1:03:34 counter-argument from your book, but I’ll just read a paragraph that I highlighted. It’s like,
1:03:38 I’d known this, but it was put very well. Stress responses also activate your adrenal glands to
1:03:43 release glucocorticoids, hormones that stimulate gluconeogenesis, the production of glucose in the
1:03:48 liver. Yeah, anyway, that could explain, for instance, my friend’s sympathetic overdrive and
1:03:52 having glucose spikes at night when he’s trying to go to sleep. Going back to the book, this in turn
1:03:56 increases your blood glucose levels. Elevated glucocorticoid levels, as occurs in depressed
1:04:01 patients, accelerates lipolysis, am I saying that correctly? The breakdown of fats into fatty acids
1:04:06 while suppressing digestion, muscle growth, and reproduction. Glucocorticoids also inhibit the
1:04:10 action of insulin, meaning that your cells are less responsive to insulin. This further increases
1:04:14 blood glucose, sometimes even to dangerous levels. So the reason that I’m bringing this up is that if
1:04:21 someone is type A, and if they’re subjecting themselves to situations that produce chronic
1:04:29 stress response, could maybe all of the things I just mentioned and more make them predisposed to
1:04:34 certain types of infections, right? So that they’re actually, just to complicate the picture further,
1:04:41 for it. Yes, it’s an infection, but there are certain behaviors or genetic predisposition or
1:04:46 who knows, even jobs that make it more likely that you would be susceptible to such an infection. I
1:04:52 don’t know. I don’t know. Those kinds of studies are out there, and I think they tip both ways. Some
1:04:57 suggest there is increased risk and some suggest there isn’t. But I think the whole, last time I read
1:05:01 about this, I’m not a psychologist, but the last time I probed this literature a little bit, the whole
1:05:08 nomenclature of type A and type B personality actually broke down. What was retained is hostility. Most of
1:05:15 the things that tracked with the classic type A personality correlated to how much hostility. So
1:05:19 now you’re back in the psychological domain of the top-down driving. So that’s not me.
1:05:22 Yeah. Yeah. Which is understandable.
1:05:27 But it’s interesting. You know, it’s like I was at a scientific meeting once when that data was being
1:05:31 discussed. And somebody stood up in the front row and said, well, how hostile is hostile?
1:05:37 How hostile do I have to be to be type A versus type B? And everybody stared at him like,
1:05:38 do you hear yourself, man? Relax.
1:05:48 Let’s talk about, because people are listening, and the setpoint device, you know, it’s like slightly,
1:05:54 maybe slightly larger than an omega-3 capsule or something that’s implanted
1:06:00 in the neck has a number of huge benefits. But then I’m going to ask you about other tools,
1:06:07 potentially. I’d say probably the greatest benefit is patient compliance. So if you have to remember to
1:06:13 take something or do something every day, there’s going to be a lot of breakage in terms of patient
1:06:19 compliance. So from just a straight, purely practical perspective, there are some great benefits to
1:06:27 an implant. But could you tell the story of your friend Wolf and just describe who he is and lead
1:06:33 into his story, if you’re open to it? On the setpoint device, the one the size of a fishbowl pull,
1:06:39 I think we have to talk about that in the context of people who are really sick. These are people who
1:06:47 have spent decades, sometimes disabled, oftentimes, as you said, chronically fatigued or depressed or
1:06:53 in pain. And these are people who are injecting themselves with drugs. Many of them can’t afford
1:06:58 any more of the drugs they have to take, the ones with these serious side effects. So there’s a
1:07:03 tendency, not by you, but there’s a tendency by some in the short form conversation of these kinds of
1:07:10 things to say, well, it’s a surgery and they should do more push-ups or try to do more things to help
1:07:16 themselves. Well, I got to be really, really outspoken on this because when you meet people that have these
1:07:21 conditions, if it was easy as doing a couple of push-ups or taking a yoga class or breathing
1:07:26 differently, they would do it. If it made them better, they would do it. These are serious medical
1:07:31 conditions. And I think for those kinds of patients, there’s always going to be a need because compliance is so
1:07:35 difficult. You know, there’s compliance with remembering, there’s compliance with going to the doctors
1:07:39 every month, there’s compliance with going to the infusion center, there’s compliance with injecting
1:07:45 yourself. Compliance can break down at so many different places. So people with serious illnesses, you’re
1:07:52 absolutely right. The availability, not for all, but for those that are going to be able to go down that path to
1:07:58 have a small immunoregular implant on the neck, that’s going to be very interesting to see what happens. But for
1:08:03 people who are essentially mostly well, like you seem to be, and like I seem…
1:08:09 What an effective mask I’ve created. Yeah, no, I’m generally well, yes.
1:08:19 And me too, and I feel very fortunate for that. And so I try to do things that align with what people would call
1:08:26 vagus nerve stimulation. So eat right, sleep right, try to get some regular exercise in, try to stay
1:08:33 cognitively busy, try to enjoy my hobbies and my family, try to stay, to alleviate stress from my life
1:08:38 as much as possible. I mean, all the things that we all know we should be doing in your GP or your primary
1:08:43 care provider should be telling you to do every day. All those things in one way or another that we’ve sort
1:08:47 of been talking about can be said to stimulate directly or indirectly the vagus nerve.
1:08:55 But there’s other modalities that people also talk about using electrical devices to stimulate
1:09:01 the vagus nerve by applying electrical devices or TENS units, transcutaneous electrical nerve
1:09:08 stimulators to the skin. Before I go any further, let me be 1000% clear. These are not vagus nerve
1:09:16 stimulators. There’s only two ways to stimulate the vagus nerve directly and specifically. One is implant an
1:09:22 electrode on the nerve and that’s either with the devices for epilepsy or depression or there’s another
1:09:27 one now also increase the rehabilitation outcomes from patients who have strokes. That’s the third one
1:09:34 or the immunoregulator device from set point. That’s the only FDA approved way to stimulate your vagus nerve
1:09:41 that directly specifically stimulates your vagus. Full stop. Experimentally, you can do it using focus
1:09:47 ultrasound and we’ve done that in the lab. My colleagues, Sangeeta Shavan and Stavros Zanos, we’ve
1:09:54 published on this in the peer-reviewed journals. It’s a special ultrasound, very similar to the one that you
1:10:00 visualize to see the baby in the womb or the gallstones, but you have a different lens on the probe and you can
1:10:07 focus the energy to target nerves in the body. And we’ve done this in humans to reduce the inflammatory
1:10:14 markers in the blood of healthy volunteers by focusing the ultrasound on the splenic nerve where the vagus nerve
1:10:22 controls it. And it’s also been done, we’ve done it in animal models of diabetes and obesity and seen some very
1:10:28 interesting effects. Everything else, the transcutaneous electrical nerve stimulation strategy to the neck, to the
1:10:35 ear, to the side of the head or the face, those are all non-invasive and non-specific and really shouldn’t be called
1:10:42 vagus nerve stimulators. Nonetheless, nonetheless, some interesting stuff seems to happen. Okay. So
1:10:50 everything you said, so true, so on point. I’m also tempted to go to the hockey puck for, you know, like
1:10:59 sort of electric GLP-1 administration, but I’m going to call that a temptation and not an opportunity for
1:11:03 the moment. And let’s talk about your friend Ulf and what happened to him.
1:11:08 So I apologize for the digression, but I had to get that as you understand on the record.
1:11:08 You got to do it.
1:11:15 Now, what about other stuff like a TENS unit? Let’s give a little background there. Anybody interested
1:11:23 in auricular therapy, I mean, auricle as ear, A-U-R, auricular therapy, and or auricular acupuncture
1:11:30 knows that the ancient Chinese acupuncture maps date back tens of thousands of years and that
1:11:35 there are points on the ear that map to various organs in the body. And if you stimulate them with
1:11:41 a needle, a small needle, a probe, or a small electric current, that you’re supposedly able to
1:11:46 affect the metabolism or the diseases of those organs. Everybody knows that’s 10,000. Well,
1:11:52 it turns out when I was writing the book, which I discovered, that those ancient acupuncture maps of
1:11:59 the ear originated in France in 1957 by a doctor named Dr. Paul Nogier, who had a patient who was
1:12:07 being treated by a specialist, I think in Corsica. And the specialist was grounded in ancient medicine
1:12:13 and was cauterizing a piece of this patient’s ear to treat the patient’s sciatica, the pain going down
1:12:17 their leg. Burning their ear. Yeah, burning or cutting a piece of it off. I’m not exactly sure
1:12:21 what they did. It wasn’t clear, but there was a little hole on the edge of this patient’s ear.
1:12:26 And then he saw another one. And in both times, the patient claimed, the two patients claimed that their
1:12:34 sciatica got better. So Dr. Nogier was a very sort of clever guy and curious and careful. And he took a
1:12:40 ballpoint pen and he took the ink out of it and he started probing all of his patient’s ears. And he aligned
1:12:48 various conditions in the patient with parts of the ear that he determined were most closely aligned with the
1:12:52 symptoms and signs of the illness. And he made a map. Well, he did this for many, many years and many,
1:12:58 many patients and ultimately published this. And he presented it at an acupuncture meeting that was
1:13:04 being held somewhere in the Mediterranean. And it led to this overwhelming acclaim for him.
1:13:13 And the work was republished in China, which created the current textbooks of Chinese auricular
1:13:19 acupuncture therapy based on a Frenchman’s work in the 1950s. So that’s where the maps come from.
1:13:23 They’re fun to look at. They really are. And especially in light of the story I’m going to tell.
1:13:27 So if you look, you can see where the spleen is and where the bladder is and where the stomach is.
1:13:33 They’re very clever. So we were reading, Sangeeta, Siobhan and I, my lab co-head and I,
1:13:41 many years ago, 15, 20 years ago, we were reading about vagus nerve biology and physiology. And we
1:13:47 discovered that there was a branch of the vagus nerve that goes to the cartilage of the ear.
1:13:54 And when I say the ear, it goes to the cartilaginous part, the part outside the ear canal where you put
1:13:59 your finger in your ear and what looks like a seashell. So it’s called the Simba concha. That’s where it
1:14:05 gets its name. Concha like shell. Now, this branch of the vagus nerve that goes from that cartilage
1:14:11 is very, very special. It’s the only place that the vagus nerve endings go to the skin, to the surface of
1:14:18 the skin. And they are sensory. That means that when you stimulate the cartilage of the Simba concha,
1:14:26 you can activate the fibers that go carrying information into the brain. And they go to the
1:14:32 place in the brain called the nucleus tractus solitarius, which is the place where all the
1:14:37 other sensory fibers of the vagus nerve go from your stomach and from your pancreas and from your liver.
1:14:41 So all the sensory input goes to the same place. You can activate like the router in your house.
1:14:48 Everything goes into one spot and then it goes back out again. Well, why? Well, it turns out fish,
1:14:56 you like evolution. I heard you say at the beginning, fish, fish gills are cartilaginous and they’re
1:15:03 innervated. And what became our human vagus nerve was one of the branches of the fish’s vagus nerve.
1:15:08 And what became our cartilage of our ear used to be the cartilage of the fish gills. So it dragged it
1:15:08 with it.
1:15:09 Wow. Wild.
1:15:10 It’s wild.
1:15:17 I’ll be honest, as a non-biologist, long ago when I was shown these maps, I thought to myself,
1:15:25 this makes absolutely no evolutionary sense because why would you, if in battle you get nicked by an axe
1:15:31 and your spleen explodes, that doesn’t seem to have any adaptive purpose for natural selection.
1:15:33 But lo and behold, fish gills.
1:15:36 Well, it’s fish gills, but I didn’t say it makes sense, Tim. You said that.
1:15:38 I didn’t say it makes sense.
1:15:44 Well, no, I shouldn’t say it makes sense. It’s just like a vestigial sort of architecture.
1:15:48 It’s definitely vestigial. How much of the architecture, that’s another area that
1:15:52 I can’t say for sure. I actually can say for sure. Nobody, to my knowledge,
1:15:58 has completely mapped out Dr. Nogier’s ear maps to the human body in any convincing
1:16:04 neuroanatomical function or neurophysiological way, but it’s still interesting. So with that
1:16:13 information, you could think of the cartilage of the ear as a way to drive signals in to the brainstem
1:16:17 through a branch of the vagus nerve. Okay. Immediately people start calling that vagus
1:16:21 nerve stimulation. It’s kind of true, right? Because it’s a sensory branch of the vagus
1:16:27 nerve. And if you put a TENS unit or your finger on the cartilage of the ear, you are technically
1:16:32 stimulating the receptors in the skin that activate the sensory fibers that carry the signals into the
1:16:36 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
1:16:43 okay. Hitting the big cable. Right. Now what happens? So now it gets really interesting. A
1:16:49 long time ago, an early Russian investigator published a study where he took essentially an
1:16:56 acupuncture needle and put it in the simbaconsha and put in a little electric current and showed that
1:17:01 he could get changes in heart rate variability, essentially. And this goes back again to the 50s
1:17:06 or 60s. That exact study, to my knowledge, has never actually been replicated the way he did it.
1:17:11 This is the problem. You talked about clinical trials and proving. I agree with you. The case
1:17:16 studies are often the most important ways to start, but you still have to do the big clinical trials,
1:17:21 randomized controls with the appropriate control population. We’ll come back to that. So now you
1:17:27 say, okay, what happens using other technology? Well, it turns out now I can’t count all the
1:17:32 publications that have been done by applying various forms of electric current into the ear
1:17:36 and measuring. There’s a lot. You can’t count them all. There’s a lot. You can’t count them all.
1:17:41 They come out every day now. And people have done some very sophisticated studies, usually
1:17:51 And you can find brain imaging studies, FMRI. You can find PET studies. You can find far-field-evoked
1:17:59 responses, which looks at the inputs and outputs into various brainstem regions and how the brain is
1:18:04 processing the higher network signals. So you can see some really interesting stuff. And what comes out of
1:18:10 is lots of different information. That’s the first problem. There’s no single consensus that if you put
1:18:16 this kind of electrode in your ear at this time for this many minutes at this much current, you get this
1:18:19 effect in this part of your brain in the morning and this part of your brain at noon and this part of
1:18:24 your brain. No one knows. Put that aside for a second. And I put it in the book. I hope it was clear.
1:18:32 What I find striking and interesting and needing further study is that if you compare people with
1:18:38 electrical inputs to their ear to people with electrical devices surgically implanted in their
1:18:44 neck, there is some overlap in the brain centers that are activated. You see centers like the locus
1:18:50 coeruleus, which is the top of the fight or flight chain. It’s the top of the sympathetic chain. You
1:18:58 see regions in the basal forebrain, the cholinergic regions, which are linked up to the hippocampus and
1:19:02 to other areas that are really important for learning and memory. And there is clinical data that patients
1:19:08 with implanted vagus nerve stimulators have enhanced neuroplasticity, enhanced learning, and enhanced
1:19:14 cognition, alertness. In another episode of STEM Talk, which has become one of my favorite new
1:19:24 podcasts, there was one of the hosts. I think it’s Dr. Ken Ford, who has served on a number of defense
1:19:27 and intelligence-related advisory boards, including advisory roles at DARPA.
1:19:29 He has a great voice too, Tim.
1:19:34 Oh, his voice is amazing. Yeah. So the Defense Advanced Research Projects Agency is incredible.
1:19:42 A lot of the technologies we use every day now originally came out of DARPA, ARPANET, etc. So he was in
1:19:49 conversation and they were discussing neuroplasticity and learning with respect to vagus nerve stimulation.
1:19:54 And I haven’t looked into this yet, but I’ve spent time at the Defense Language Institute in Monterey.
1:20:01 And they were talking about using vagus nerve stimulation to enhance language acquisition and
1:20:06 that the effects seem to be durable for months after stimulation, which also in your book, just a quick
1:20:12 note, right? Stimulation for two weeks having an effect on insomnia for two or three months. I mean,
1:20:16 what could be more interesting right now? It’s just like, it’s so, so endlessly fascinating.
1:20:20 I have to respond to the DARPA. I wouldn’t be talking to you right now if it wasn’t for DARPA
1:20:27 support on this idea in the 1990s when it was a freaking crazy idea that I’m going to target with
1:20:33 an electrode, the vagus nerve to stop sepsis and cytokine storm. And they said, okay, try it. What
1:20:33 if it’s yes?
1:20:41 Yeah. People think of the quote unquote government as just this big monolithic, slow moving, stupid,
1:20:47 inefficient thing. DARPA is an exception. You got to check out DARPA, like the brilliance and the
1:20:52 innovation that comes out of that and their willingness to throw a lot against the wall. And
1:20:56 it’s science fiction. Some of the stuff that comes out of DARPA.
1:21:03 One of my heroes is actually a national hero. Jeff Lang, Dr. Jeff Lang, retired colonel,
1:21:07 founded the biology technology office at DARPA. He used to instruct his team at DARPA when the guys
1:21:12 and gals would come in with the crazy, most crazy ass ideas anyone could ever imagine. Like you see
1:21:19 that airplane out there? I can make it disappear. I can make it invisible. And then everybody leaves and
1:21:22 they go into Jeff’s office and he says to his team, what do you think? And they all say to
1:21:28 Jeff, he’s nuts. It’s crazy. You can’t make an airplane disappear. And Jeff looked at his team
1:21:33 and says, what if it’s yes? And that’s where stealth technology came from.
1:21:34 Yeah. That’s so cool. I mean,
1:21:39 And then you say, oh, I can still see the airplane. And then Jeff slams his hand on the desk and goes,
1:21:41 if you can see it, it’s too late.
1:21:48 Yeah. I mean, technology to be able to see figures around corners. I mean, it’s, and that was years ago
1:21:54 when I saw a rough description of that. In any case, they are doing lots of really interesting
1:21:59 things. I took us off, off track for a second. One more thing. You said another thing. I got to
1:22:05 respond. So the cognition part of vagus nerve stimulation is also a fascinating story that
1:22:13 would require a full long form conversation. But in brief, patients who had epilepsy were
1:22:17 implanted with vagus nerve stimulators. This was years ago. This goes back 20 years or maybe 30.
1:22:23 And a bunch of these folks did not get any significant benefit from the therapy. So the
1:22:29 device was switched off. Well, a very clever researcher brought them into his lab and gave
1:22:35 them a, I’m not a psychologist. I already gave that disclaimer once, but gave them a cognitive
1:22:43 learning test of some form, very simple, and then turned the device on and repeated it. And all their
1:22:48 scores went up. It was very dramatic. And when they image these folks in subsequent studies,
1:22:53 this is one of the studies that I mentioned before that pointed to the enhancement of activity in the
1:22:59 regions of the brain that are really important for intention, learning, and memory. So there’s a deep
1:23:04 conversation there about neurocognition and vagus nerve inputs to the brain.
1:23:09 Yeah. And this is also like fidgeting around in my chair because I get so excited about like
1:23:14 finally trying to, and I’m not there obviously, and I’m, who am I? I’m a muggle. So I have to depend
1:23:23 on pros like you, but looking at, for instance, the few things that I have come across that really seem
1:23:31 to have very impressive effect sizes on intractable or hard to treat psychiatric conditions that resist
1:23:40 frontline treatments with biologics for 15, 20 years until, for instance, just a few, some psychedelic
1:23:45 assisted therapies, some types of brain stimulation. There are many different types, but let’s just
1:23:51 take accelerated TMS as one example for certain conditions and then metabolic psychiatry or ketogenic
1:23:57 diet generally in some variation. And a friend of mine, I’m going to pull this up just yesterday,
1:24:04 and it’s not necessarily a new study, but he sent me a link because I advised that he try
1:24:10 the ketogenic diet for certain types of overwhelm and anxiety he was experiencing because the downside
1:24:15 risk is so minimal, particularly if you’re only doing it for a few weeks and your lipid profile is under
1:24:23 control. And he sent me this, this study, the title, this is from Cell. This is not from some random
1:24:29 person’s blog. And the title is The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic
1:24:35 Diet. So the ketogenic diet was used in the early, I want to say, 1900s for epileptic children. And they’d
1:24:41 usually use heavy cream to make it easier for compliance, but had this, maybe even predates that,
1:24:47 this incredible effect on eliminating or reducing the frequency of seizures. And these are kids who might
1:24:52 have hundreds of seizures a day. And I’m looking at this study, and here’s just a little excerpt.
1:24:59 Mice treated with antibiotics or rear germ-free are resistant to keto diet-mediated seizure protection.
1:25:09 Enrichment of and no biotic co-colonization with keto diet-associated acromantia and parabacterioides,
1:25:13 if I’m saying that correctly, restores seizure protection. So I literally have probiotics downstairs
1:25:20 that are acromantia from a company called Pendulum, which is pretty legitimate. But what? I mean,
1:25:30 okay. So it’s mediated partially through the gut microbiota. And it’s like, okay, well,
1:25:35 then you have the interplay of the microbiota with potentially the vagus nerve with this
1:25:42 two-way communication channel. And then you look at, for instance, psychedelic-assisted therapies.
1:25:49 And there’s a lot that we can get into there. But also, and this is finally, and I’m not saying
1:25:55 there’s a lot of nonsense and a lot of navel-gazing and crystal-waving folks in the psychedelic world.
1:26:01 No offense to anyone who falls in that demo. But there were some credible folks, including,
1:26:07 for instance, Dr. Andrew Weil, who actually has an incredible history of ethnobotany and is very,
1:26:16 very technical. And he lost his allergy to cats after a number of experiences with, I believe,
1:26:22 was LSD. And these anecdotes on the underground, at least, with facilitators who have thousands,
1:26:31 maybe tens of thousands of repetitions with patient sessions, the losing of allergies comes up pretty
1:26:36 constantly. And so then I’m asking myself, well, maybe it’s not the content, although I happen to
1:26:41 believe the content of these experience matters. But maybe it’s the anti-inflammatory effects. Okay,
1:26:49 well, what does that mean? And then, okay, well, maybe it’s having some immunomodulating effect.
1:26:56 Okay, well, is the vagus nerve involved? Maybe. It’s not beyond possibility. And then you look at
1:27:00 neuroinflammation and the effects of whether it’s different types of brainstem or the effects on,
1:27:06 say, inflamed microglia by psychedelics, like reductions in TNF and all this stuff. TNF-alpha
1:27:12 have been tracked in the scientific literature. And I just get really, really excited because I can’t
1:27:17 parse it all. But it seems like these things all, to use an awkward phrasing, are kind of touching the
1:27:23 hem of the same garment in some way. So anyway, that was a whole bunch of word salad. But I don’t want
1:27:28 to lose the story of Ulf because we were talking about the maps. We’re talking about the fact that,
1:27:36 yes, you should maybe at best put it in quotation marks, vagus nerve stimulation. But could you tell
1:27:41 the story of Ulf, if I’m saying his name correctly? And maybe comically, one of only a handful of Swedes
1:27:45 I know is also named Ulf. So it makes me think that maybe it’s the John of Sweden. I don’t know.
1:27:52 But who is Ulf and why does he tie into this ear mapping that we’re talking about?
1:27:59 Ulf Anderson is a retired professor of pediatric rheumatology at the Karolinsk Institute. He practiced
1:28:03 there for many decades. And throughout that whole time, he also ran a research laboratory that
1:28:10 was focused primarily on cytokines, on inflammation and cytokines. So as you said before, this is a guy
1:28:18 who knows his stuff. Karolinsk Institute is also top tier. I mean, they do some of the most fundamental
1:28:25 kind of seminal work related to a lot of stem cell applications and so on has also happened at the same
1:28:30 institute. It’s arguably one of the best medical research institutes in the world. It’s one of the
1:28:35 largest in Europe. It’s a major teaching center. It’s a fantastic place. I’ve been there many,
1:28:43 many times. Ulf and I have been close friends and collaborators for many decades. And he was
1:28:48 diagnosed with a condition that was thought to be a cancer in his bile ducts, in his liver,
1:28:56 that required a major surgery called the Whipple procedure, where they remove pancreas of most of the
1:28:59 pancreas, if not all of it. And they remove part of the liver and they move part of the bile duct
1:29:04 system. This was a long time ago, but at the time it was a death sentence, the cancer that they thought
1:29:10 he had. It turned out to be benign, which was a blessing in disguise because he had to undergo this
1:29:15 major surgery to have this. After the surgery, he developed, for the first time in his life,
1:29:20 actually, he developed intermittent bouts of depression, serious depression, which he attributed
1:29:28 to excessive inflammation in his GI tract, which was through unknown mechanisms coming episodically
1:29:34 and causing this depression, which as he talks about in the book, and he’s written about on his own,
1:29:40 led to the end of his marriage and was really ruining his life. Well, this was around the time that
1:29:48 Sangeeta and I had discovered these funny acupuncture maps of the ear and saw that some
1:29:55 people were using TENS units. And we had published a series of papers at that point, understanding how
1:30:02 vagus nerve signals could turn off inflammation. And so we said, what the heck? We put TENS unit,
1:30:08 over-the-counter product you can get anywhere, with the electrodes on the simbaconsha, not the tragus,
1:30:14 not the lump that sticks out on the side, not the pinna, not the earlobe, but on the simbaconsha.
1:30:21 And then we drew blood on ourselves and other volunteers, healthy volunteers, and we measured
1:30:27 cytokine production. It’s a little complicated how we did that. It’s not just drawing blood and doing
1:30:32 an assay. We actually measured the ability of the white blood cells traveling around our bloodstream to
1:30:39 make new cytokines. And when we did those experiments, we could show very conclusively,
1:30:44 and we published it all in peer-reviewed journals, that most volunteers, about 70%, seven or eight out
1:30:53 of 10 people, 16 or 17 out of 20, you could reduce the amount of inflammation that the white blood cells
1:31:02 would make if you put this probe in the ear for five minutes. And at that point, Ulf said, well,
1:31:07 I think I have an inflammation problem. Vagus nerve stimulation stops inflammation. If you want to
1:31:11 call this vagus nerve, you can also call it transauricular nerve stimulation, because there’s
1:31:17 lots of other nerves to the ear, but that’s another matter. Ulf said he decided he would try it. I didn’t
1:31:21 treat my friend Ulf. He decided he would do this. He’s a bona fide physician. He could do what he wants.
1:31:29 I frankly was not very encouraging. I said, okay, whatever. Well, as he writes, and I know this for a
1:31:35 fact, as I see him several times a year, it turned his whole life around. He added some antibiotic therapy
1:31:42 also to treat his bacterial overgrowth in his intestines, which comes with the surgery that he had,
1:31:47 the Whipple. But he also uses this TENS unit in his left ear religiously twice a day,
1:31:54 like brushing your teeth, he says. And he then subjected himself to a fascinating analysis. So
1:31:59 you mentioned heart rate variability a while ago, and that’s really complicated. But
1:32:05 the more I try to learn about it, the more I’m like, wait a second. It’s like quantum mechanics or
1:32:10 something. I’m like, wait, I thought I kind of knew what the hell you’re talking about. Now I don’t.
1:32:14 If you understand it, then you don’t understand. If you think you understand it, like Richard Feynman
1:32:18 said, you don’t understand it, right? I think we don’t have to get into it now, but suffice it to say,
1:32:23 it doesn’t matter what your wearable is. If it’s a Fitbit or an iWatch or 10 other things that measure
1:32:29 heart rate variability, I think this is 100% true. It might only be 90% true. They’re measuring different
1:32:34 things. Not because they all start with measuring the distance between individual heartbeats,
1:32:39 which is instantaneous heart rate. They all start with that. But what they do statistically after that
1:32:44 can vary dramatically. I’ve done this. Sangeet and I have done this for a while. We worked on
1:32:50 heart rate variability. We made our own devices and it gets incredibly complicated. And we dropped it
1:32:54 because if you get a PVC, if you get a periventricular contraction, or you get two irregular beats
1:32:58 in a five minute recording, you know, you’ve got hundreds and hundreds of heartbeats. It shouldn’t
1:33:03 do much, right? It messes everything up. It changes all the statistics. So can’t get into that now.
1:33:11 However, Wolf was contacted by a guy in Finland who sent him a watch he had invented that recorded
1:33:16 heart rate variability as a function of respiratory sinus arrhythmia, which is what heart rate variability
1:33:22 is actually quote unquote controlled by. So if you want to do the experiment, if your listeners want
1:33:27 to do this, it’s very easy. Take a couple of big breaths in, two hard sniffs in through the nose,
1:33:30 fill your lungs completely, and you’ll feel your heart rate speed up a little bit.
1:33:36 And then breathe out slowly for seven or eight seconds. That increase in heart rate during
1:33:41 inspiration is partly due to the change in pressure in your chest cavity, your thorax.
1:33:45 As your diaphragm drops and you increase the volume, the pressure has to decrease.
1:33:50 And then as you exhale slowly, you’re actually increasing the pressure in your chest, in your
1:33:56 thorax, because you can compress the volume. Those changes in pressure all activate sensory signals in
1:34:01 the vagus nerve, which go into your brain, which accelerate or decelerate your heart. Why?
1:34:09 Well, because when you inhale, you want to accelerate your heart and exhale, you want to decelerate your
1:34:16 heart. That’s the optimal physiological linkage. That’s the optimal physiological mechanism to
1:34:19 maximize the amount of oxygen in your blood.
1:34:26 This guy in Finland invented a way from the EKG of looking at the changes in the size of the QRS wave
1:34:32 as an indicator of the heart shifting left and right, which also happens when your diaphragm goes down and
1:34:39 comes back up. And so he found a way to measure respirations from the EKG and link it to the
1:34:46 instantaneous changes in heart rate. What his HRV indicator is in this method is actually a
1:34:52 correlation between the overlap between respiratory sinus arrhythmia and the breathing cycle and heart
1:34:58 rate variability in the cardiac cycle. And that’s how you optimize oxygen uptake and delivery. It’s
1:35:01 really cool, right? And it’s pretty sophisticated stuff.
1:35:05 So he ships the watch over to Ulf or not watch device. Yeah.
1:35:11 So Ulf puts it on and he’s got a terrible correlation between his heart rate variability and his
1:35:16 respiratory sinus arrhythmia until he does his vagus nerve stimulation. And then it got a lot better.
1:35:23 Now that’s a pretty good experiment. It isn’t an F1 and somebody I’d love to see somebody repeat that
1:35:28 on 50 people, but it’s still hard to explain because he does it over and over again on many different
1:35:34 days and many different conditions. The real kicker is during COVID, my colleagues and I at Northwell did
1:35:42 a clinical study. We heard of results out of China, out of Wuhan actually, where patients taking
1:35:49 famotidine, the antacid, were significantly protected against some of the lethal complications of COVID.
1:35:55 We actually did clinical studies of this drug. You can buy it for pennies over the counter at Amazon
1:36:01 and Costco and CVS and everywhere. It’s a safe antacid. And it turns out we did the clinical
1:36:07 studies in Northwell and we did then laboratory studies in my lab. It’s a pharmacological vagus
1:36:14 nerve stimulator. Huh. Yeah. Really? What was it called again? Famotidine is the generic name that
1:36:20 it’s got a bunch of brand names, including one of them is Pepsid. No kidding. Yeah. You read about
1:36:27 it. It’ll blow your mind actually. Wow. So when Ulf combined, this is the end of the story. When Ulf
1:36:34 combined the famotidine with the TENS unit in his ear, he gets a hundred percent overlap. He looks like a
1:36:40 21 year old kid with this overlap between respiratory sinus arrhythmia and heart rate variability. He’s
1:36:45 written about it. He’s published his own personal recordings. It’s a remarkable story and it’s remarkable
1:36:50 not because it’s a story of one, but because let’s go back to what we said before. The FDA approved
1:36:59 vagus nerve stimulation for the treatment of depression decades ago. And it’s used a little
1:37:03 bit more in Europe than it is in the US. In the US, it’s not routinely covered by insurance payment.
1:37:11 So there’s been tremendous resistance to applying this. It helps about half the patients. Now, once again,
1:37:15 like we said with the rheumatoid arthritis, let’s be concrete about this. Let’s not be the standoff
1:37:20 folks who say, well, it only works half the time. It shouldn’t be used. Well, in some of the people
1:37:25 that it’s worked in, they were suicidal and now they’re not. What is that worth? In some of the
1:37:29 people it’s worked in, they’re back at work, taking care of their kids, taking care of the family.
1:37:35 I think that we should be doing it or not doing it based on the data we know so far. There should be a
1:37:40 screaming call that we should be diving down into. We don’t know the mechanism, Tim. We don’t know why
1:37:46 Wolf got better. We don’t know why half the patients with depression got better. I think somebody should
1:37:52 do a really simple study. We should segregate the patients into some sort of inflammatory
1:37:59 groups, risk groups or activity groups with depression and treat the ones with the most inflammation
1:38:03 depression with the vagus nerve stimulation and see if they get better because you’ve stopped their
1:38:08 inflammation. And the other ones have depression from another, another etiology, another cause,
1:38:13 another factor. These are the important questions. Wolf got better. Don’t you work at a place with a bunch
1:38:21 of scientists? What’s required for something like that to happen? Does it just require a Scrooge McDuck to fund
1:38:27 the study? I mean, I’m the president of a great organization with great scientists. Yes, I am. And there have
1:38:32 been some, there is and will be more great work coming out of our place, but one place can’t do it all
1:38:39 alone. This is a call for everybody to get interested. It’s also potentially a call for some interesting
1:38:46 distributed, I guess we could call them studies. They’re not going to be RCTs, but hey, something is
1:38:51 better than nothing if it has recognition of its limitations. For instance, the people who manufacture
1:38:58 whoop bands, the people who make Oura Ring, I mean, they could potentially put out a call to customers
1:39:03 to try to do some type of distributed study. Of course, you might be dealing, well, actually, you’re
1:39:08 not going to be dealing with self-reporting. You’d be dealing with self-reporting perhaps in documenting
1:39:16 using a quote-unquote vagus nerve stimulator, but the data is going to be available to the company
1:39:22 vis-a-vis. Maybe it’s anonymized in some fashion, but the patients could make their actual Aura or
1:39:29 Whoop band or Fitbit data available to the company if it’s not already available. So that could be pretty
1:39:36 interesting. I recall actually, Whoop, I believe, doing something like that with veterans who were
1:39:44 on a sort of standardized dosing of, I think it was micro dosing of psychedelics looking at impact on
1:39:51 HRV or potential impact on HRV. HRV fluctuations associated with, let’s put it that way.
1:39:55 You mentioned before depression, serotonin, inflammation. Should we pick up on that for a
1:40:02 second? Yeah, let’s do it. As you read the excerpt before, there is evidence that some patients with
1:40:10 depression get better with SSRIs and some patients don’t. And there’s also evidence that SSRIs can even
1:40:16 make people who have known inflammation or experimental inflammation gain some benefit. There’s also
1:40:22 information that SSRIs in experimental conditions, clinical studies and experimental studies in the lab,
1:40:26 can actually reduce inflammation. What we have to agree on is we don’t know what causes
1:40:32 depression. And if we knew what caused depression, I think our chances of fixing it in more people would
1:40:39 be better. Well, also depression is, I mean, in my mind, could be like, quote unquote, inflammation.
1:40:44 There could be many different species of depression or many different causes. I don’t know.
1:40:50 I think there are. I think you’re right. And I think that’s not been parsed out very well yet
1:40:58 because the focus has been this sort of excessive focus on serotonin as the hypothesis that has to be
1:41:03 dealt with. And there’s lots of reasons for that that we won’t get into now. But what I do like to
1:41:09 raise, again, as a call to action, if you will, and a message of hope is we know that inflammation
1:41:14 produces depression in animals and in people. It’s to the point now, there are some inflammatory
1:41:20 molecules that are used to treat some conditions, some forms of cancer, for instance. And when
1:41:26 patients are signed up and they’re going to receive these therapies, this administration of cytokines
1:41:32 as their therapy that are known to cause depression, they’re often given a prescription to go see the
1:41:37 psychiatrist to go on the SSRIs before they go get their therapy. So we know inflammation causes
1:41:43 depression. We don’t know completely how. There’s overwhelming evidence from many labs, including
1:41:49 my own, that the presence of inflammation in the body activates signals that travel up, you guessed it,
1:41:56 the vagus nerve. So you could take a mouse, for instance, and inject it with IL-1 and the mouse will
1:42:01 run in the corner of its cage. It’ll huddle up. It’ll look like it doesn’t feel well, like when you have
1:42:09 the flu, it will avoid eating. It’ll avoid sex. It’ll avoid playing with toys in the cage. It looks
1:42:15 depressed. If you cut the vagus nerve, back to your topic of before, if you cut the vagus nerve in those
1:42:22 mice and give them IL-1, they don’t get sick. They don’t get depressed. And so it puts the question,
1:42:31 and the mind-body experts and Far East religious dogmas focus on what we said before, that the
1:42:36 brain networks and the body networks are connected. What I said before is the vagus nerve is a principal
1:42:41 connector. So if you have disruption of inflammation in the body, which you’re not even, maybe nothing
1:42:46 hurts in your body, but your brain knows the inflammation’s there. We call that interoception.
1:42:55 It’s the subconscious sense that your organs are sending information about their status to your
1:43:00 brain. If you have inflammation in your body, does it cause depression? That’s an important question.
1:43:08 because maybe that’s why those patients who do get better and go on YouTube and type in some videos
1:43:12 of these depressed patients whose lives were turned around with vagus nerve stimulators. It’ll bring a
1:43:18 tear to your eye, some of their stories. And if you look at those people who have benefited,
1:43:27 and Ulf with his 10-tunit in the ear. Quick question. Has Ulf published his setup? Is that something that
1:43:33 people can find online if they wanted to experiment with five minutes twice a day of auricular stim?
1:43:38 Yes, he did. He published it in a peer review journal that I believe is open access. If you Google his
1:43:46 name, Ulf Andersen with two S’s, Andersen. Good, good old Swedish last name. I will link to that in show
1:43:49 notes. We’ll find that and put that in the show notes for everybody. I can send it to you for the
1:43:54 show notes. Okay, perfect. Perfect. We’ll do that. And I interrupted your train of thought.
1:43:59 No, it was the end. I just want to call the question out to my colleagues that we should study
1:44:05 the influence of interoception, the presence of inflammation in the body being sensed by the brain
1:44:10 and causing depression in some patients. And can we treat that with vagus nerve stimulation? Is that
1:44:14 why it works? And the 50%? Why 50%? Isn’t that kind of a funny number? It works.
1:44:22 It’s too clean, right? It’s like, it’s too clean. Yeah, I got scammed recently on my credit card at a
1:44:28 gas station and it was $175. And I was like, that’s too clean. That’s absolutely a scam charge. Plus,
1:44:36 I know gas is expensive, but it’s not $175. But in any case, yeah, when the numbers are that clean,
1:44:40 you’re like, wait a second here. Let me ask you, this is out of personal curiosity. And I was
1:44:46 goofing around going all over PubMed, which is sometimes a dangerous business when you’re a muggle.
1:44:55 But it seems like there are some interesting data around acupuncture in the ears and fertility or
1:45:01 pregnancy. And I know you don’t like to speculate, but maybe people have looked at this closely.
1:45:05 Is it plausible that that is mediated by vagus nerve stimulation?
1:45:09 The simple answer is, yes, I don’t like to speculate.
1:45:17 But I’m just saying mechanistically, would stimulating the vagus nerve have some downstream,
1:45:21 possible downstream effect on the ability to conceive or anything like that?
1:45:28 I don’t know the studies that you’re referring to. I really don’t. And I don’t know if acupuncture in
1:45:33 the ear would stimulate the vagus nerve to stop inflammation. I know that what I did with an
1:45:40 electrical TENS unit can reduce inflammation in the bloodstream of healthy volunteers. I can answer
1:45:47 the question in the context of, are there some conditions in the abdomen, whether in the ovaries or
1:45:56 the uterus, the fallopian tubes, where the presence of inflammation would be a restrictive or would make
1:46:02 getting pregnant more difficult? The answer to that is simply yes. Now the question is, if we had ways of
1:46:09 selectively reducing that inflammation in the context of getting pregnant, if you could specifically reduce
1:46:15 that inflammation, would you increase the chances of getting pregnant? Well, you know, yeah, it’s quite
1:46:19 logical. It’s plausible. Can vagus nerve stimulation do that? To my knowledge, nobody knows.
1:46:26 I was just, again, curious. And you know what? The first time this kind of, probably using this term
1:46:33 incorrectly, but sort of the homunculus on the ear came up in this podcast was with Martine Rothblatt,
1:46:37 who I think has a quote on your book. Am I making that up?
1:46:40 Martine is a close friend.
1:46:46 Also a phenom. What a wild background. Just such a polymath.
1:46:53 Martine’s another national hero. I mean, she’s a satellite launcher. She’s a satellite communications
1:46:58 expert. She’s an accomplished pilot, including flying her own battery-powered helicopter and setting
1:47:04 land speed records and distance records. And she’s a good friend and the CEO of United Therapeutics.
1:47:07 Martine’s wonderful. We talk a lot about this stuff.
1:47:10 All right. So I just wanted to give a shout out. If people want to get to know Martine,
1:47:18 definitely suggest my interview with her. And I wanted to come to something that you mentioned
1:47:26 at the end of your STEM talk interview. And I really don’t have context on this, but it’s of interest to
1:47:34 me because I have, for the last few years, had chronic low back pain, which is, if you want to wander into the
1:47:44 Bermuda Triangle of hand-wavy imprecision in at least pain diagnoses or orthopedics, low back is a good place to
1:47:53 go. And what I have figured out, there are certain things that help. And putting aside the biomechanics and
1:47:59 strength training and so on for a moment, I know that anti-inflammation helps. There seems to be an
1:48:04 inflammatory component. So whether it’s through applying cold or taking oral anti-inflammatories or
1:48:11 injectables for that matter, it suppresses symptoms. I know that. And I’m reading a number of books.
1:48:17 Lorimer Mosley and his co-author have actually a very interesting book called Explain Pain. And it relates
1:48:22 to this piece that came up, Maybe, which is why I wanted to talk about it. Because sometimes, like you
1:48:30 said, the response to the equivalent of a picket line in your body is the entire Navy showing up with
1:48:40 rockets blazing. And it’s a severe overreaction. So this relates to Professor Rawls. And I guess I’m
1:48:45 going to try to word this in a way that makes sense. But how specific molecules inform memory,
1:48:52 memories slash n-grams in the brain and the implications of that. Could you just unpack that
1:48:57 for me? Because you guys didn’t really get into it in the STEM talk. But I was like, wait, wait, wait,
1:49:02 wait. I want to hold on to this because it seems very interesting. And it might somehow be relevant to
1:49:09 me. It might not be. But could you just explain what I’m very clumsily trying to evoke or I guess
1:49:15 elicit from you? Yes, I would love to. Let’s start with the picket line. The picket line in the low back
1:49:21 situation. And I’ve also had on and off sciatica from a herniated disc in my back with pain down my
1:49:26 leg. So I can relate to this. In those instances, you have something in one of the joints of your back
1:49:34 neck or potentially a fragment of a disc that’s pushing on a nerve, causing pressure on the nerve,
1:49:40 which sets up a cycle, which would be the picket line, right? There’s some injury there. There’s
1:49:45 some injury, injury to the nerve, or there’s some injury in the joint. And that’s the picket line.
1:49:50 It shouldn’t be a big deal to the human body having evolved over hundreds of millions of years.
1:49:55 But in some people, not all, if you look at MRI scans, right? Everybody else’s back look just like
1:49:59 years, right? Yeah, they look all messed up. They all look the same. It’s just like you get
1:50:05 wrinkles on your face, your spine starts to look pretty funky. So I’ve got arthropathy. I’ve got
1:50:09 the right foraminal stenosis at blah, blah, blah, blah, blah, but… So does everybody else?
1:50:15 Yeah, you can look at like hamburger meat on an MRI of a back and they’re asymptomatic.
1:50:20 Right. So why does your back hurt and somebody’s MRI scan would be indistinguishable from your doesn’t
1:50:25 hurt? Well, you can maybe pinpoint the position on your MRI scan. Now the question’s different,
1:50:29 right? Now the question is, why is your body sending the Navy with rockets blazing to the
1:50:34 picket line on your back, but not, you know, not the guy next door? Well, that is the question. So
1:50:41 how can we connect that to two things? One, two, because Wolf’s back pain got better too, by the way.
1:50:46 He had injured his neck in a sailing. He was a world-class sailing champion. I don’t know if that
1:50:51 made the book or not. I don’t think that was in there. I love this guy. He and his brother,
1:50:56 Jan Anderson won the European world championships in the J-class. Of course they did.
1:51:03 In the 1960s. Of course they did. And of course, ABBA sent them to the world championships when they
1:51:07 were in New Zealand or Australia or something. And they competed in the Olympics at UCLA,
1:51:08 the LA Olympics. Wow.
1:51:15 Anyways, his back got better. And so the question is why did his back get better? Because the signals
1:51:21 from the ear to the brainstem went down the vagus nerve to the spleen and reduced the turnover of the
1:51:26 inflammatory cells. Well, that’s a definite maybe. And what we know from very careful experiments in
1:51:32 animals and some experiments in humans is that when those vagus nerve signals end up in the spleen,
1:51:38 they switch the white blood cells. Now the spleen gets 20% of cardiac output. So all your white blood
1:51:44 cells are racing through the spleen all day long. And when they pass through and pick up this nerve
1:51:52 signal, they switch from a state called M1 to M2. M1 macrophages and monocytes, white blood cells,
1:51:59 they’re the Navy shooting guns, full blazing that you said. M2 are the doctors and nurses in the
1:52:05 ambulances who race to the scene to heal. And so that’s an important area that a lot of people are
1:52:10 chasing. And that’s in the context of therapy that we’ve been talking about. That’s probably how it
1:52:15 works in rheumatoid arthritis, actually. It’s the signals are switching the white blood cells as they
1:52:20 pass through the spleen. So when they go to the elbow or the knee or the hand, they tend to heal the
1:52:27 cartilage. It’s M2 instead of M1. M2 is better than M1. Exactly right. So yeah, M1 to M2. So that’s a
1:52:32 take-home point. That’s a simple way to think of how you get a nerve, the vagus nerve stimulation,
1:52:37 which doesn’t go to your elbow and it doesn’t go to your wrist. But that’s why they probably get
1:52:42 better is because it changes the white blood cells that are going to the scene. So what else is
1:52:49 happening? Well, when that inflammation settles in, say, the colon, ask your roles in a brilliant,
1:52:55 I think one of the most important scientific papers in the field of what we call neuroimmunology,
1:53:02 maybe in the last 25 years, she discovered that what’s happening in the inflamed tissues in the
1:53:09 colon in this case is actually forming a neural network in your brain, which you can think of
1:53:14 as a memory. It’s called, neuroscientists call it an engram. So would that also be like a phantom limb
1:53:18 or is that a different thing? I don’t want to take us off track. It would be similar to a phantom limb,
1:53:22 but it’s more concrete. And I’ll tell you why. And this is what’s so amazing about it.
1:53:30 So neuroscience has studied memories and engrams for many years and using a method that we call
1:53:35 trapping technology. And so what you do is you have a genetically engineered mouse, a mouse with special
1:53:41 genes that you can put in when it’s an embryo. And the mouse grows up with these genes. And now when you
1:53:46 do something to the mouse, if you co-administer, say you give the mouse a drug or you give the mouse
1:53:52 inflammation, when you do that at the same time, you give the mouse a drug that activates these special
1:54:00 genes that turn the neurons red, for instance, but only the active neurons. So the neurons that get
1:54:06 activated by the presence of, say, colitis, inflammation in the bowel, they turn red and they
1:54:11 stay red. So you can study them later, even, you know, weeks and months later. And that’s exactly
1:54:19 what Professor Rawls did. She used another very sophisticated trick with what’s called stereotactic
1:54:26 injections, injecting virus particles into specific parts of the brain that she had mapped from looking
1:54:32 at the red neurons. So she knew these are the neurons that get activated by colitis. So she’d had the
1:54:40 mice, she let them recover from colitis, and then she injected the virus into those neurons and
1:54:45 reactivated now just the neurons, not all the neurons in the brain, just the ones that remembered
1:54:52 the place of the colitis. And they got colitis again. The changes in the brain neurons, I call it a neural
1:54:58 network. She does too. I mean, we all call it an engram or a neural network. Lots of neuroscientists have
1:55:03 talked about this on lots of podcasts, but they call it the Jennifer Aniston neuron or the Santa
1:55:08 Claus neuron. I’m a recovering neurosurgeon, right, Tim? So you can do brain surgery under local
1:55:13 anesthesia. And this is done a lot of times for epilepsy surgery, for instance, when you want to
1:55:19 make sure that you don’t injure any part of the brain involved in speech. So you can be talking to
1:55:25 the patient during brain surgery. Now you can put electrodes in various parts of the brain and ask the
1:55:30 patient what’s happening. And there’s a famous story of a patient, well, I just saw Santa Claus, or I see
1:55:35 Jennifer Aniston. And so euphemistically, people call that, well, that you have a Jennifer Aniston
1:55:40 neuron. You actually don’t have a Jennifer Aniston neuron because you could put an electrode in another
1:55:46 part of the brain and you say, well, friends, the TV show, and Jennifer Aniston’s neuron will light up in
1:55:47 that because they’re part of a network.
1:55:52 Right. It’s a constellation that is recognizable by the brain.
1:56:01 A constellation. Exactly right. Well, nobody before Ash’s studies, nobody thought that a constellation
1:56:09 in the brain would recognize inflammation in a way that would not only sort of remember the effects of
1:56:11 it, but could then reactivate it.
1:56:16 Not to interrupt, but since every podcast I do is self-interested in some way.
1:56:25 Is there a way to delete, control Z, those constellations so that you don’t have this
1:56:38 hair trigger response to triggering colitis or low back pain response, right? And in this book that I was
1:56:43 mentioning explain pain, they talk about how surfers in instances, sometimes when they get their leg
1:56:48 bitten off by a great white, they report it as a thump. It wasn’t painful. Whereas you get a paper
1:56:54 cut and it’s excruciating and there’s so much variability. So is there a way to deactivate
1:57:02 a constellation or overwrite it? Or I guess fix my fucking low back pain is the short answer
1:57:07 without taking bottles and bottles of Aleve.
1:57:12 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
1:57:15 all the right questions. We could do the experiments if you come in.
1:57:20 Well, you’re not that far away. I mean, don’t threaten me with a good time.
1:57:27 The simple answer is that’s what we want to do, right? So you might not have to remove the whole
1:57:31 network. You might just have to disrupt a little bit of it. And the question is, can you disrupt it
1:57:36 with a molecule that targets selective neurons? You know, that’s tricky, but not impossible. You have to
1:57:40 figure out what the neurons are, figure out what the receptors are, figure out what’s unique. Then you
1:57:44 have to design a drug to do that. That would be one approach. But the approach I like, and again,
1:57:50 I’m a recovering neurosurgeon, so call me what you want. But there are millions of people walking
1:57:56 around with deep brain electrodes, millions. And it sounds like this horrendous, terrible thing,
1:58:00 but it’s not. The electrodes that people are putting in now, whether it’s Neuralink or somebody
1:58:05 else, I mean, they’re smaller than a human hair. And they go in and they don’t injure blood vessels,
1:58:09 and they don’t even injure, sometimes they don’t even injure neurons. They go next to the neuron.
1:58:16 You could imagine a time in our lifetimes, I hope, when if we knew how to target those neurons or map
1:58:23 in advance, right? That you could put these electrodes in and inhibit them. And yeah,
1:58:27 that is the right question. I’m dead serious. Now, Astra’s paper has been out a couple of years.
1:58:31 I said before, I think it’s one of the most important studies that I’ve read in many years.
1:58:37 And we have, of course, pursued it. We’ve been asking questions, my colleagues and I, Sangeeta
1:58:44 Siobhan and Okito Hashimoto and Eric Chang. We’re asking a very simple question. Can we make
1:58:51 n-grams, memories, neural networks in mouse brains of specific cytokines? We’re writing the manuscript
1:58:58 as I speak. And the answer is yes. We can show that when you give a mouse TNF, which causes a
1:59:04 sickness behavior, you know, it looks like it has the flu. And then a bunch of other metabolic things
1:59:09 that are specific to TNF. And map an n-gram. We can see where the neurons in the brain are and see
1:59:14 what they do. When we do the same experiment with IL-1, which also gives a sickness response,
1:59:18 but has a very different sort of metabolic physiologic. It can separate them. They’re
1:59:23 unique. TNF and IL-1 are different. The physiology is different. We see a different neural network. So
1:59:28 now it’s complicated, right? Because how many cytokines are there and how many physiological
1:59:33 states? I think the brain, you know, a human brain has what, a hundred, a hundred billion neurons,
1:59:40 give or take, and trillions of synapses. So it’s more complicated than we think it is. But I think
1:59:47 it’s accessing, processing, and potentially storing all the information that we haven’t even begun to
1:59:49 imagine yet. And that’s what this data tells me.
1:59:56 What are the possible implications of identifying the constellations? I just keep thinking about
2:00:00 stars, right? It doesn’t take much to screw up Orion’s belt, right? Like if you move one or two
2:00:07 things around, you could disrupt that n-gram, so to speak. What are the implications of identifying
2:00:14 the n-gram signature of TNF-alpha, IL-1, et cetera?
2:00:16 What are the implications of it?
2:00:21 Yeah. Well, how would that translate or might it translate to some type of clinical practice?
2:00:26 I think you could literally, if you knew where to put the electrodes into the brain,
2:00:31 you could have an electrode in the brain that communicates with an app on your iPhone,
2:00:37 and you could dial it to up-regulate or down-regulate your inflammatory response to a specific
2:00:40 cytokine or condition in a specific part of your body.
2:00:41 Yeah.
2:00:42 Yeah, that’s wild.
2:00:47 It is. And you said it right. I mean, people used to think it was impossible to track an incoming
2:00:53 missile from the moon, right? But now they know how to do that. And the best example I like,
2:00:57 and you’re better at this than I am, but someone explained the analogy I like the most.
2:01:02 If you look at a TV screen with all the pixels and you see a picture of the Alps,
2:01:09 you can’t possibly pick out the black square or the altered colored square. But if you swap that one
2:01:13 square and make it a really bright color or a really black color, you actually can see it.
2:01:18 It’s about subtracting, right? It’s about subtracting to pick out what you don’t know.
2:01:25 In order to do that in humans, there’s been all this rush to do brain imaging and brain anatomy.
2:01:31 We still have a long ways to go because to my satisfaction as someone who thinks about systems
2:01:37 interacting in biology, we haven’t put enough emphasis on function.
2:01:38 Yeah.
2:01:45 You and I can’t talk about heart rate variability because we don’t know enough about the individual
2:01:47 functions of the individual wiring diagrams.
2:01:55 Yeah. And also we can talk about kind of a science and studies and so on, maybe separately over a glass
2:02:03 of wine or something. But sometimes the imaging tail wags the dog also for a host of reasons.
2:02:11 Yes. You get these beautiful pictures and there’s maybe some status associated with getting a bunch
2:02:17 of money to play with the latest toys. And then you can slice and dice the data to create all these
2:02:25 different publications. There’s an allure that I think can sometimes lead to an overemphasis on the
2:02:33 imaging, which is not to negate some really, really incredible applications of the imaging. But I think
2:02:37 what you said carries a lot of weight. Let me ask, because there will be people listening who are
2:02:48 curious about this. Cervical TENS units. So we talked about the transcutaneous auricular stimulation.
2:02:54 There are devices, including some that are FDA approved for, say, I believe, cluster headaches
2:03:02 and or migraines, I can’t recall exactly, that are neck-based and could be applied to one side,
2:03:08 could be applied to both sides. But effectively, supposedly, right, tracking or stimulating the
2:03:12 vagus nerve where it would correspond to your pulse, let’s just say, carotid artery or arteries.
2:03:22 And you can find a number of publications on PubMed that talk about the data. But what might be the,
2:03:29 if in fact they are doing something that is beyond placebo effect, what might the mechanism of action
2:03:33 be? And you can start wherever you like. I’m just curious about the cervical devices because
2:03:38 they’re floating around out there. And I’ve seen at least a few studies and I’m like, huh, okay,
2:03:44 well, what the hell is going on here? If in fact there is a signal instead of just noise.
2:03:48 I think it’s important to say that when you dive into these kinds of questions,
2:03:55 there’s lots of factors. So the first is, you know, can you afford to buy lots of devices and try lots of
2:04:00 different things? That’s one approach. And second, you know, do you like self-experimentation? That’s
2:04:06 another approach. A third is, well, always check with your doctor first because there are some things you
2:04:11 probably shouldn’t do around the area of your neck. You have carotid stenosis. You don’t want to put
2:04:15 any pressure on your carotid artery. If you have cervical stenosis, you don’t want to turn your head
2:04:20 certain ways. Check with your doctor. So those are actually important disclaimers. That’s not a joke.
2:04:25 People should check with their doctor before they do these things. Unless, of course, what they’re
2:04:31 doing is FDA approved. And some of these devices, most of them not, but some of these devices have been
2:04:40 subjected to FDA approval. In the context of putting electrodes on your neck, there are some FDA approved
2:04:47 devices that are called vagus nerve stimulators. And they are essentially TENS units. They deliver
2:04:54 pulses of electric current, spikes of electric current, usually between 20, 30 hertz, usually on the order of
2:05:00 milliamps. And you know it’s working because you feel a buzzing or a tingling. And when you put it on your
2:05:06 neck, usually you know that the current is spreading around through the skin and through the nerves of
2:05:12 your neck because your platysma muscle, the muscles of facial expression in your neck will twitch or your
2:05:17 lip will twitch. Pull your lip down. You can make some goofy faces. That’s happened to you, right?
2:05:23 Yes. Yeah. So that’s evidence that the electric current is activating lots of nerves and lots of
2:05:31 muscles. Now, time for a slight digression. The carotid artery is encased in a sheath with the vagus
2:05:38 nerve. So to get to the vagus nerve, you have to go through the skin, through the platysma muscle,
2:05:44 through the layer of subcutaneous fascia, through the sternocleodomastoid muscle, which is that big,
2:05:49 thick strap muscle in your neck, thicker in some than others, but it’s there, down to the carotid
2:05:54 sheath, maybe through another layer of fascia, through the carotid sheath, and then somehow either
2:06:00 around or through the carotid artery. Right. So it seems like the tense unit is not going to hit the
2:06:06 vagus nerve. Engineers I’ve spoken to at length about this say, and I said it very politely and clearly in
2:06:11 the beginning of the show, the only way to directly stimulate the vagus nerve is to put an electrode on
2:06:16 the vagus nerve. That’s not this. You’re putting an electrode on the skin. Or to use focused ultrasound,
2:06:21 which would penetrate all those tissues and could be focused to the vagus nerve in the neck, but those
2:06:25 devices are not available for us to use at home. So your question was, could it work anyways? It’s
2:06:31 FDA approved to treat migraine. And the answer is… Well, my question was, what the hell might the
2:06:38 mechanism be if it’s not actually getting through all that stuff to hit the vagus nerve?
2:06:42 I have a very good answer for you. Collective delusion and placebo? No, no, no, no.
2:06:48 Mass placebo? No. No, no. To defend the manufacturers and the FDA, patients who put this on their neck and
2:06:54 use it according to the FDA label and have severe migraines, a significant percentage of them do
2:06:59 better than for patients who don’t use the device. So there’s, this is an example that we talked about
2:07:05 before where you have a device. We don’t necessarily know how it works. It might work through some other
2:07:12 mechanisms, but it seems to work in a statistical way in FDA approved randomized clinical trials. Put that aside,
2:07:19 right? How could it work? We’re talking now science here. Well, Charles Sherrington, one of the two fathers of
2:07:25 neuroscience with Ramon Icahal back in the early 1900s. He wrote a famous book, which I recommend to
2:07:32 anyone, even casual readers of neuroscience should read Charles Sherrington’s book, The Integrative Action
2:07:36 of the Nervous System. The title alone is brilliant, The Integrative Actions of the Nervous System.
2:07:42 He taught us this. It’s so simple, you’ll never forget it. You have to understand a simple reflex because
2:07:47 there’s an input and then some sort of connection or process and an output. And that’s what happens
2:07:52 when the doctor taps your knee. That’s what happens when inflammation happens in your body and the
2:07:58 signal goes in. And well, in the knee case, the rubber hammer stretches the tendon. The tendon sends a
2:08:03 signal up your sensory nerves to the spinal cord. Spinal cord sends the signal back down to your
2:08:09 quadriceps femoris. Your leg pops up and you said, shit, who did that? That’s a reflex. In the context of
2:08:14 inflammation, there’s inflammation in your body. The signal goes up your vagus nerve. Signals come
2:08:19 back down. Stop the inflammation. That’s the inflammatory reflex. Got it. Okay, Charles, we got
2:08:24 that. What’s next? And he said, if you assemble a couple of reflexes, you can start to build a nervous
2:08:28 system. This is, again, this is your field more than mine. It’s a neural networking. You can assemble
2:08:33 things. You can build up complex systems by just adding one more reflex, right? One more input, one more
2:08:37 output. And then he goes, end of the day, there’s no such thing as a simple reflex because every nerve in your
2:08:43 body is connected. So you put electricity on your neck. Some of it’s going to end up simulating
2:08:47 nerves that go into your brain or your spinal cord. Once it gets in the brain or the spinal cord, there’s
2:08:54 the big router. The brain can decide how to send it out. In some patients, does it relax the muscles of
2:09:02 the neck to interfere with the headache pathogenesis? Maybe. In some patients, does the brain send signals
2:09:08 down the vagus nerve to stop inflammation contributing to migraine? Maybe. In some patients,
2:09:14 does the brain send signals up to the resistance arteries that are controlling blood flow in and out
2:09:18 of your brain that can give you a tension headache? Maybe. We don’t know. Nobody knows.
2:09:25 Yeah. I mean, it’s exciting to me that there are so many open questions. So just enough of a teaser
2:09:34 and a taste test of something to make it really tantalizing to investigate further. And my friend,
2:09:41 he’s using a cervical device, the one who tripled his HRV. So who the hell knows, right? And ultimately,
2:09:46 he and I were talking because after our first chat, I was like, hey man, I might have some good news,
2:09:52 bad news. And I was like, seems like your device is working for you. And I was like, I don’t want to
2:09:58 burst the placebo effect. But also, it doesn’t seem to be a vagus nerve stimulator, but we were joking.
2:10:02 And I think one of us was probably me because I’m a goofy ass a lot of the time. But I said, you know,
2:10:07 I guess at the end of the day, you know, ultimately, you don’t really care if, you know, you’re somehow
2:10:13 summoning Odin to come down with a magic unicorn and pierce you through your forehead with the
2:10:19 spike like a narwhal to fix your low back pain or increase your HRV. You just want the output.
2:10:26 So whatever is happening, it would be great to understand what’s happening under the hood. But
2:10:29 it’s like, you might like driving your Tesla. You don’t know how many people actually know how it
2:10:39 works or the microwave or the refrigerator, which is not to say that you want the larger scale RCTs
2:10:45 and mechanisms of action. So I’m not trying to dismiss the importance of all that or the power
2:10:49 of placebo. Well, I know if it’s placebo, you said it’s the power. It could be the power of one. And it
2:10:56 could be that if a hundred patients were subjected to this and 75% of them have the effect your friend
2:11:03 has now. But that’s really interesting. Why? You know, this is where some people like to reach too
2:11:10 far when they’re talking their wares. Yes. Some of the websites selling these things are so bad.
2:11:18 Yeah. So bad. You expect them to be selling boner pills and kratom and some sketchy, you know,
2:11:22 shitty cryptocurrency at the same time in the checkout process. They’re so bad.
2:11:27 Yeah. And you know, people say, oh, well, is it safe? Well, that’s important. But then you raise
2:11:32 people’s hopes and then you take their money and you don’t know what you’re doing. There’s real
2:11:36 questions there. I’m not saying it’s easy. Look, what people would say is the simplest, stupidest
2:11:43 clinical trial of one of these devices might cost $5 million or more. Science is expensive. Good science
2:11:49 is expensive. Yes. All right. We’ve covered a lot of ground. I highly, highly, highly recommend
2:11:55 people check out The Great Nerve if you want. Not just things we’ve talked about, but we could do
2:11:59 like three rounds on the podcast. I didn’t even get through a small portion of my notes.
2:12:04 Also in your book, I want to point out, because this is important, you have an entire section
2:12:12 dedicated to different types of tools with some really remarkable results, whether that’s breath work,
2:12:19 cold exposure, meditation. You know what? Maybe just as a fun way to bookend this,
2:12:25 could you please tell the story? You’ve got some amazing stories in the book. Could you please tell
2:12:32 the story of the Dalai Lama? People are like, what? The Dalai Lama? How the hell does he fit into this?
2:12:38 Yeah. Okay. So please tell that because it’s just fun. I mean, it’s so fun. It’s also fascinating,
2:12:43 but it’s fun. Back in the day, I was at about 2007, give or take. I can’t remember the year. It’s in
2:12:51 the book, maybe 2010. I got a call from the Dalai Lama’s New York office. Would I like to go to a
2:12:56 conference? Now, the call came from a gentleman named Bill Buschel, who is a scientist in his own
2:13:03 right, who was working full-time in the Dalai Lama’s organization. He had been following my work
2:13:08 because of these questions on the role of the vagus nerve in meditation. The Dalai Lama, of course,
2:13:15 famously has participated in and supported many, some very sophisticated brain imaging studies and
2:13:22 meditation studies. And the Dalai Lama is on the record of saying that he’s convinced that the major
2:13:27 tenants of his religion are true in a quantum mechanical way, as you alluded to before, from any
2:13:32 perspective. His tenants are like the speed of light. They don’t change. And he said to the point that,
2:13:37 in fact, if quote unquote, Western science or new world science could disprove any of his tenants,
2:13:42 then he would change the tenants. So he has a deep interest in science. So he hosted a meeting
2:13:48 here in Phoenicia, New York, on the top of a mountain where they own a compound, right outside of Woodstock,
2:13:54 where the rock concert was. And so I drove up there. Not all the funny stories made the book, Tim, but
2:14:00 one I have to tell is when I’m checking in, I got there late. It was dark and I’m in the middle of the
2:14:04 woods and I like the woods. I like to camp. I like to be outside. I’ve driven by this place. It is in the
2:14:10 middle, I mean, middle, middle of the woods. Yeah. They own the whole mountain, right? So it’s dark, it’s
2:14:15 nighttime. And they give me keys to a cabin in the middle of the woods. And as I’m going out the door,
2:14:21 the woman says, don’t mind the bears. And I’m like, fine, I’m going to walk in the dark,
2:14:27 puts through the bears to my cabin. I said, well, I’ll make a joke. And I said, well, I know they
2:14:34 were here first, right? And she looks at me with like steely eyes. It’s like, okay, welcome to Woodstock.
2:14:40 I’m like, this isn’t like the concert. So the next day-
2:14:41 Good evening, sir.
2:14:47 Exactly. The next day I’m on stage. The next day was two days of scientific talks,
2:14:52 a whole series of times. I gave one. I remember Liz Blackwell was there. And when she was there
2:14:55 was the time it was during the meeting, it was announced that she’d won the Lasker prize. I
2:14:59 think a year or two later, she won the Nobel prize. So Liz and I were there and a bunch of other
2:15:05 scientists. And the last day, the organizers came up to us and asked Liz and I, if we would summarize
2:15:11 the meeting for his holiness, the Dalai Lama on stage in front of all the attendees. So we said,
2:15:17 sure. So Liz gave a talk. And then I gave a talk. I’ll never forget. I was on stage with
2:15:23 the Dalai Lama, with Bob Thurman, who was sitting to his side. And that’s Uma Thurman’s dad. And he’s a
2:15:29 professor of Tibetan studies and other studies at Columbia at the time, Columbia University.
2:15:33 And a translator sat between us and I explained the vagus nerve. And I said,
2:15:37 and he asked the question you did, you know, where is this vagus nerve? And I said,
2:15:42 well, it travels down your neck and into your, across your chest, into your abdomen. He goes,
2:15:47 oh. And then he said through Bob, he said, is it in the front or the back? I said, well,
2:15:53 it’s in the front. And then he said, is there one or two? And I said, well, there’s two. And then he
2:16:00 smiled at me. And then that was that. And then afterwards he left and a few monks came up to me
2:16:07 in their long flowing orange robes, as Bill Murray would say, striking, you know. And
2:16:13 they said to me, his holiness asked you those questions. Do you know why he asked you those
2:16:20 questions? I said, no, I haven’t a clue. And they said, well, we like to practice one form of Tibetan
2:16:28 meditation is we like to practice a cloud of blue energy over our heads that we channel in two waves
2:16:32 down each side of the neck, across both sides of the chest, down into the abdomen.
2:16:37 And I said, cool. And the monk said, yeah, it’s very cool.
2:16:47 Not everybody gets a Dalai Lama story. Yeah, that is a good one. Well, people can find The Great
2:16:54 Nerve, which includes so much more anywhere that you find your books. Dr. Kevin Tracy, T-R-A-C-E-Y.
2:17:00 And is there anything else you’d like to say as we wind to a close, anything you’d like to add,
2:17:07 point people to requests, reminders, public complaints, anything you’d like to say before
2:17:08 we land the plane?
2:17:13 One thing, these things in the book and that a lot of people talk about for self-help, they’re good.
2:17:18 I do them. I don’t know. Meditation’s good. Exercise is good. Watching your weight is good.
2:17:23 Getting enough sleep is good. All of these things, I think, are good to reduce the inflammation in your
2:17:29 body. And they are good to probably do, to give your vagus nerve some exercise and improve your
2:17:35 heart rate variability. It’s all good. I just don’t like to say that it’s, it’s the cure for some of
2:17:41 these serious medical conditions. And the fact that we now have a path to connect decades, literally
2:17:49 decades of science to now 15 years, 12 years of clinical trials on this science that gives hope
2:17:54 to some patients with serious inflammatory conditions that stimulating their vagus nerve with this
2:17:59 immunoregulator is what we really call it. It’s an exciting time. And I really appreciate you having
2:18:03 me on the show and there’s more questions we could talk about next time, maybe.
2:18:11 Yeah, maybe round to cognitive enhancement with vagus nerve stimulation. I mean, I could keep going,
2:18:17 keep going for many, many hours, but I’ll call it here for now. And everybody listening, we will provide
2:18:25 the links in the show notes to many different studies, to Ulf Anderson’s protocol for the five minutes,
2:18:31 twice a day, of course, to set points, the New York times piece as well. And to the book,
2:18:36 The Great Nerve. And you’ll be able to find all of that at tim.blog slash podcast for the show notes,
2:18:41 just search. My friend, Kevin Rose will pop up a lot if you search Kevin. So search Tracy,
2:18:48 T-R-A-C-E-Y or Vegas or Vegas nerve, and this will pop right up. And until next time, folks,
2:18:55 be just a bit kinder than is necessary, not just to others, but also to yourself. And as always,
2:18:56 thanks for tuning in.
2:19:04 Hey guys, this is Tim again. Just one more thing before you take off. And that is Five Bullet Friday.
2:19:08 Would you enjoy getting a short email from me every Friday that provides a little fun
2:19:13 before the weekend? Between one and a half and 2 million people subscribe to my free newsletter,
2:19:18 my super short newsletter called Five Bullet Friday. Easy to sign up, easy to cancel. It is
2:19:24 basically a half page that I send out every Friday to share the coolest things I’ve found or discovered
2:19:29 or have started exploring over that week. It’s kind of like my diary of cool things. It often includes
2:19:36 articles I’m reading, books I’m reading, albums perhaps, gadgets, gizmos, all sorts of tech tricks
2:19:42 and so on that get sent to me by my friends, including a lot of podcast guests. And these strange,
2:19:48 esoteric things end up in my field and then I test them and then I share them with you. So if that
2:19:54 sounds fun, again, it’s very short, a little tiny bite of goodness before you head off for the weekend,
2:19:59 something to think about. If you’d like to try it out, just go to Tim.blog slash Friday, type that into
2:20:06 your browser, Tim.blog slash Friday, drop in your email and you’ll get the very next one. Thanks for
2:20:14 listening. Many of you know how deeply I love Japan and its culture of unwavering dedication to craft,
2:20:19 refinement, commitment to continuous improvement. You can see it in their coffee, Tri-Glitch Coffee.
2:20:25 You can see it in Geo Dreams of Sushi. But why do I bring this all up? Well, the same focus on improving
2:20:31 one thing, one product over the span of years is found in today’s sponsor, AG1. I met the founder way back
2:20:38 in the day, randomly in a coffee shop in Argentina. It must have been between 2005, 2007, and ever since
2:20:45 then, one product. They are now unveiling AG1 Next Gen, the same single scoop, once a day product that I
2:20:51 use myself, but now with more vitamins, more minerals, and five new clinically studied probiotic strains
2:20:57 shown to support digestive and immune health. I love it for its great taste. I just mix it with cold
2:21:02 water. It’s easy. And the way it helps fill nutritional gaps in my diet. It’s my nutritional
2:21:09 insurance. AG1 is also NSF certified for sport, one of the most rigorous independent quality and safety
2:21:15 certification programs in the supplement industry. NSF conducts annual audits of AG1’s manufacturing
2:21:21 facilities, reviews ingredients for toxicology, and ensures AG1’s label claims are accurate.
2:21:27 So check them out. Subscribe today to try the next gen of AG1. Listeners will also get a free bottle
2:21:35 of D3K2, an AG1 welcome kit, and five of the upgraded AG1 travel packs with your first order.
2:21:40 So start your journey with AG1’s next gen and experience the difference firsthand. Simply go to
2:21:50 drinkAG1.com slash Tim. That’s drinkAG1.com slash Tim. Sleep is the key to it all. It is the
2:21:55 foundation. Many of you heard me talk about how today’s sponsor, Eight Sleep, has improved my sleep
2:22:00 with its pod cover. Well, they just launched their latest product, the pod five. I cannot wait to try
2:22:05 it out. And here’s why. The pod five introduces Eight Sleep’s latest product, the blanket, which uses the
2:22:10 same technology as the pods cover to extend temperature regulation across the entire body. So if you’re too hot,
2:22:15 too cold, you can fix it. If you’re a couple and one of you is hot, one of you is cold, you can fix it
2:22:20 as well. It all fits right over your existing mattress like a fitted sheet. On average, members
2:22:27 report the pod has helped them fall asleep 44% faster, 34% deeper sleep, and given them up to one
2:22:32 added hour of sleep each night. Also, the pod’s snoring detection, my friend Albert might be interested
2:22:38 in this, and automatic elevating platform have reduced user snoring by 45%. So it does a lot. You’ll also
2:22:43 get a personalized report each morning, allowing you to track your sleep stages, heart rate variability,
2:22:48 respiratory rate, and more, all without having any devices strapped onto you. So head over to
2:22:56 eightsleep.com slash Tim and use code Tim to get $350 off of your very own pod five ultra. You can try
2:23:01 it at home for 30 days and return if you don’t like it. So why not give it a shot? Sleep is everything.
2:23:09 Again, that’s eightsleep.com slash Tim. Spell it out, eightsleep.com slash Tim for $350 off. Shipping is
2:23:14 available to many countries worldwide. One more time, eightsleep.com slash Tim.