FoundMyFitness - #041 Dr. Charles Raison on Depression, the Immune-Brain Interface & Whole-Body Hyperthermia

Episode Date: March 19, 2018

Charles Raison Charles Raison, M.D. is a professor at the School of Human Ecology at the University of Wisconsin-Madison and Founding Director of the Center for Compassion Studies in the College of Social and Behavioral Sciences at the University of Arizona. Dr. Raison's research focuses on inflammation and the development of depression in response to illness and stress. He also examines the physical and behavioral effects of compassion training on the brain, inflammatory processes, and behavior as well as the effect of heat stress as a potentially therapeutic intervention major depressive disorder. In this episode, you'll discover: (00:00) Introduction (06:26) Role of inflammation in depression (10:08) Evolutionary mechanism (16:19) Genetics of depression (22:57) How obesity causes depression biochemically (33:32) Does exercise treat depression (36:08) Hyperthermia as treatment (46:08) Inflammation promotes depression (53:39) Did we evolve to need hormetic stress? (01:03:38) Heat-shock proteins (01:06:10) Repurposing ancient wisdom (01:17:31) Psychedelics and meditation (01:27:51) What is the role of conventional pharmacotherapy? (01:35:19) Lifestyle modifications for depression (01:42:21) Why light and circadian rhythm are important for mental health If you're interested in learning more, you can read the full show notes here. Join over 300,000 people and get the latest distilled information on depression straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Welcome back, friends, to another episode of the Found My Fitness podcast, a magical place where simply through the act of listening, your genetic expression will start to take on a new, more wholesome character. Today's episode is a deep dive on the biological origins of depression, and frankly, a lot more as well. Often when we hear the word depression, we think of something that might be more akin to negative thinking. However, depression, real clinical depression, can have a biological organic cause that science is increasingly showing to be linked to the behavior of the immune system and its incredibly dynamic and rich interaction with the brain. This immune brain interface, as we'll learn today, can be central to behavior and is particularly

relevant when we're talking about clinical depression. But this relationship may be more complex than it appears at first glance. In today's episode, we learn that inflammation, more than having a simple relationship as an instigator, in other words, causing symptoms, can also be beneficial, especially by promoting their release of growth factors in the brain, at least on a short-term basis. As you might expect, just like everything in biology, context is everything. But we'll get into that shortly. For now, let's get down to business with a little bit about today's guest. Dr. Charles Rezon, MD, is a professor in the School of Medicine and Public Health

at the University of Wisconsin-Madison and founding director of the Center for Compassion Studies in the College of Social and Behavioral Sciences at the University of Arizona. Dr. Rezaan's research focuses on inflammation and the development of depression in response to illness and stress. He also examines the physical and behavioral effects of compassion training on the brain, inflammatory processes, and behavior as well as the effect of heat stress on major depressive disorder. How I first ran across Dr. Rezon's work was actually reading a paper on the influence of a treatment known as whole body hyperthermia, which uses what is really just a specialized type of sauna used in this type of research and its effects on ameliorating depression.

For those of you that have followed my podcast a while, that sounds totally up my alley, right? However, looking over his publication history, I realized that he was also deeply involved in researching the effects of the immune system and its signaling molecules on mood disorders and so much more. And it doesn't stop there. In this almost two-hour conversation, we talk about how depression as a disease may be subdivided based on whether or not there is involvement of chronic inflammation and how this could influence how it should be treated. The changes in functional brain connectivity that are associated with high inflammation

subtype of depression, the potential therapeutic effects of whole body hypothermia for major depressive disorder, the physiological similarity of hot yoga with whole body hypothermia from the standpoint of potentially therapeutically boosting body temperature, heat stress as a means to sensitize pathways important to thermoregulatory cooling that also affect brain regions implicated in the regulation of mood, an evolutionary biological explanation for why chronic inflammation shunts triptophan, an important precursor. for serotonin into a neurotoxic pathway that produces a substance called canurinine. How can urinine can then go on to become a metabolite called quinoletic acid, which is then

powerfully associated with depression. How our muscles actually help shift the metabolism of canyrenin away from quinoletic acid when we exercise, particularly if that exercise is endurance exercise. We also talk about some of the preliminary evidence that increased expression of a certain heat shock protein in the brain may influence behavior by protecting against stressed-induced depression, the biological wisdom that may be embedded in traditional spiritual practices when it comes to keeping depression at bay, especially the use of phasic high heat, often for use of healing or transcendent purposes, but also potentially other practices like fasting and ultra-long distance running. Some of the growing body of literature surrounding the effects of psychedelic

occasioned mystical experiences for depression, end-of-life anxiety among cancer patients, and even as an aid in smoking cessation. The ability of meditation to induce real changes in the gray matter region of the brain and some of the interesting evidence showing that the effects of meditation can begin to build and show up in as little as eight weeks. The possibility that antidepressants, by being a type of so-called unearned grace, may prevent enduring behavioral changes and create a type of long-term reliance and potentially increased vulnerability. The role bright light therapy may have in the amelioration of a variety of depressive disorders and how our modern relationships with screens that increase our light at night and office environments that reduce our light during

the day may disrupt our natural biological rhythms to our detriment. And we talk about so much more, always more. Before we jet off to the discussion, I want to talk about a few of my friends. Yes, that's right, I'm talking about the podcast supporters. You're listening right now and you may be one of them. Thank you for being a Found My Fitness supporting community member and making this episode happen if that's the case. This episode and all episodes of the Found My Fitness podcast are supported through a pay what you can mechanism whereby members of our listening community have taken the initiative to pledge a few bucks per month and amount of their choosing to support the podcast. It is through this mechanism that instead of just dumping some recorded audio off on you guys, we're able to

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CrowdSponser. Okay, that said, let's get the show going. To the podcast. Welcome back, my friends, to another episode of the Found My Fitness podcast. I'm sitting here with Dr. Charles Rezon, who is a professor at the School of Human Ecology at the University of Wisconsin-Madison, and who's also the founding director of the Center for Compassion Studies at the University of Arizona, as well as many other interesting things which you can hear about in this episode of the Found My Fitness podcast. So one of the reasons why

I wanted to have you on the podcast to have a discussion with you is because you've done some really interesting research on the effects of inflammation, on the development of depression, as well as using what is very similar, what I would think to be very similar as the sauna, its whole body hypothermia, as a treatment for major depressive disorder. So very, you know, interesting topics that I'm interested in. So maybe we can start by talking a little bit about the role of inflammation,

just generally speaking, in depression. Yeah, so it's interesting. You know, when people begin to realize back in the 80s that there was this link between the brain and the immune system that was more profound than we originally thought. I mean, originally people thought the immune system was down there dealing with infection. Their brain was about behavior. Now, of course, we know that there really one system. People thought about it in terms of immune suppression.

You know, I mean, I think so many things are lost from the lives of people with depression. That is sort of made thematic sense to think that your immune functioning might be lost too. So it was really quite a shock in the 90s when assays got better. and we begin to realize that if you measured inflammatory markers, so these are chemicals like cytokines to get kicked up when you get the flu, something like that. Then when you looked at those sort of chemicals, they were actually elevated in depressed people.

And this was shown sort of again and again. And then we began to realize that if you were exposed to these chemicals, you were likely to get depressed. So some of the research that we did and many other people did, beginning about 2000, was with drugs like interferon. So there's a thing called interferon. and alpha, which was used somewhat in cancer, but a great deal for many years to treat hepatitis C. And it's a chemical your body makes that basically turns on inflammation.

If I were to take you and inject a bunch of interferon alpha into your arm, within an hour you'd be feeling sick. You'd have a fever. You'd feel, you know, crappy, and you'd want to lay down. And it activates all these inflammatory chemicals in your body. Turns out that if people do that to themselves on a repeated basis for something like curing hepatitis C, a very significant proportion of them become depressed. Many become like really clinically depressed, suicidal, hopeless, helpless.

Like long term? Oh, well, long term while you're getting the treatment. The interesting thing is that the vast bulk of people recover pretty much completely within a couple of weeks of stopping it. So it really is this sort of drag. You know, if you're constantly exposed to inflammatory stimuli at a high level, you know, people get exhausted, depressed, or sleep gets messed up. Yeah, unfortunately, there are actually a number of data points suggesting that some people do have long-term, you know, sort of mood disturbances after a chronic bout of inflammation from interferon.

We know it from other studies, sort of population studies, that if you have episodes of inflammation earlier in life, so for instance, if you have an autoimmune condition or if you have bad infections, the kind of infections that land you in the hospital, you're significantly more likely to subsequently more likely to subsequently. develop significant major depression. But significant schizophrenia and other disorders too, right? So it looks like there's something about chronic inflammatory activation that induces changes in the brain and body that tee you up for depression. In fact, we can talk about this. We know a lot about what those changes are. So there was this convergence of data suggesting that, yeah, that inflammation,

the sorts of acute, especially acute reactions your body does to dangerous pathogens, that those chemicals induce inflammation, induce depression. Now, we and others were some of the first to suggest that it may, in fact, there may be an evolutionary advantage to inflammation inducing depression. And we could talk about that. But the fact that those things are linked is pretty clear. Yeah, please do talk about the, because to me, what would be the advantage to developing depression from an evolutionary standpoint?

Well, the argument here is, is that human depression may have evolved out of sickness. And there's actually a fair amount of evidence to suggest that that may be the case. So for one thing, if you make a list of the symptoms that you have when you're acutely sick and you cross those with the symptoms you have when you're depressed, there's a really significant overlap. Depressed people are a little bit more likely to want to kill themselves, are a little bit more likely to have sort of be down on themselves.

That doesn't happen as often in sickness. But many symptoms, and some very surprising ones, are shared by depression and sickness. The example I often give is hyperthermia, right? So, you know, when you're really sick, when inflammation is activated, one of the things it does is induce a fever, right? We've known for many years that if you take medically healthy depressed people, they have chronic elevations in their body temperature. And it follows the same sort of diurnal pattern as,

as you see in sickness. So you see more of this elevation at night. And there's some very interesting data actually done up the road in Los Angeles, at UCLA in the 90s, that if you measure core body temperature of people that are not depressed versus people that are, the depressed people's body temperature is higher. Then if you treat them, in this case they used electroconvulsive therapy, which is very, very rapidly acting powerful treatment, you treat the depressed people, you measure their body temperature again,

bang, it goes right down to the level of control people. And we've known for a long time that depression is a hyperthermic state. But you know, if you look at the things that happen physiologically when you get sick, one of the things that happens is something called an acute phase reaction. So you get a change in the chemicals that your liver makes, right? So you get a downgrading of sort of housekeeping chemicals like albemant and you get uprising of things like CRP. And you tend to also do things like lose iron, lose zinc.

And you say, when you get sick, why do you punt your iron? Well, the answer is, is because microbes, especially intercellular bacteria, need the iron more than you do. They have to have that iron to replicate. You can live for a while without iron, but they can't. And there's all sorts of data showing that, for instance, iron supplementation kills you if you're infected. Or kids that are given iron in high pathogen, third world areas

are much more likely to die of infection. So, you know, what happens with evolution is you get to suite of reactions that although sometimes costly to the person or to the person's body are generally more costly to the bacteria. So the reason that we get sick when inflammation gets activated is not just because nature wants to torture us is because if you make a list of all the things that happen, many of them have been shown to be pathogen protective.

So for instance, hyperthermia, fever is a powerful pathogen protector for a couple of reasons. First off, it sort of ramps up immune functioning. But most microorganisms, are not built to last, they're built cheap. That's why they can actually mutate so quickly. So they tend to unwind at higher temperatures. And so, you know, a fever is an antipathogen.

It's an antibiotic strategy, right? And so it's very striking that depression is so reliably associated with things like shunting your iron or shunting your zinc, raising your body temperature. And so if you think about, you know, why would those characteristics, occur in a condition like depression that we think of as being largely psychosocial, you know, if your girlfriend dumps you and you get depressed, it might make sense while you weep and cry and, you know, maybe you sit down and it makes you reevaluate your life.

But why should it elevate your body temperature? Why should it cause your iron stores to be reduced? On the other hand, you know, if depression evolved out of sickness as a strategy for pathogen defense, all those things make a lot of sense, right? And so the argument is that if you look at the things that killed hominids and human beings before about 10,000 years ago, they were largely not the infectious agents that killed us across history, right? So most people died of things like malaria and smallpox and measles, these horrible crowd infections over the last 10,000 years since the invention of agriculture. Before that, most people died from trauma.

It's interesting, sometimes inflicted by other people just getting scraped, getting cut up. The things that kill you from trauma are much more likely to be extracellular or bacterial things. Those are the types of organisms that are especially likely to be wiped out by the kind of sickness reactions that get activated both in depression and sickness. So we and others have made the argument that this is the way to think about it, that until, modern times, stress was a reliable indicator that you were at significantly increased risk of wounding. And wounding is going to kill you because you're going to get infection. So stress becomes linked with a prepotent inflammatory activation so that your immune systems kind of run to their guard stations. It's like smoke alarm principle. You know, stress means you're at increased

risk of dying from a wounding-based infection. So stress becomes reliably associated with inflammation, right? Inflammation induces sickness, but sickness and depression share a lot in common. So over time, what happens is that anything that signals a need for increased inflammation activates the suite of behaviors that in humans, over time, also sort of evolves into depression. So it's an even deeper way of saying that, in fact, the link between inflammation, and depression may be deeper across evolutionary time for adaptive purposes than it actually is in terms of mechanism. That's interesting.

Very interesting, yeah, because I've always just sort of looked at the mechanism, and I know you've got a couple of papers on the evolution, yeah. Yeah, I didn't quite read too much into that, but that is certainly a very interesting hypothesis, and I'm not exactly sure how you would test that, but it makes sense. Well, there are some interesting ways to test it, right? So some of it, of course, is just cross-sectional. You can line up the genes that, you know, finding genes that are reliably associated with depression has been somewhat of a fool's errand because it's such a polygenic disorder.

But if you make a list of the best contenders and then you go ask, the genes, so SNPs in genes that we know the functional capacity of, right? the form of the gene that's associated with depression does it provide any antipathogen benefits? And it turns out that almost 100% of the time it does. So if you make a list, so we think about something like the MTHR gene, right, that's involved in folate metabolism, right? So there's a form of it that seems to be a depression risk factor.

So if you look at what it does immunologically, it is probably pro-inflatism. And it's strongly associated with increased survival in sub-Saharan Africa. Because in sub-Saharan Africa, so many people initially die of hepatitis B. And the form of the gene that may be a risk of act for depression is actually protective against that illness. So in one of our papers, we rustled up maybe for 30 genes and showed sort of across the board these really fascinating things, right? So there's that. There's evidence that forms of genes that are pro-inflammatory. increase your risk of death in low pathogen areas,

but increase your risk of survival in high pathogen areas. It's a fascinating study out of the Netherlands, actually. Now, probably 10 years ago, looking at Ghana, which is an interesting country because there's parts of the country that have sort of been cleaned up. They have fresh water, they have clean water from wells, and so pathogen deaths are low there. There's other parts of the country where people are still drinking

from polluted rivers. And they did this fascinating study, where they looked at this sort of haplogrs of haplotype in a TNF gene that is known to have an inflammatory. If you have one form of it, you have higher levels of inflammation. If you have the other, you have lower levels. As you predict, in parts of the country where you are protected, so clean water, not going to die from infection, if you have the high TNF, low IL-10, the sort of the pro-inflammatory haplotype, in the parts of the country with low pathogen, you die sooner. But in high-pathogen areas,

protective end protection all occurs in the early part of the lifespan up to the age of 40 where across evolutionary time that's where you want to survive because that's where you're going to reproduce and live long enough to probably get your kids into survival age

so there's that and then there's some really there's another really interesting thing which is you know you and I'm sure you share with me an interest in this possibility that part of the link between sort of metabolic immunodisturances

and behavioral disturbance may be an evolutionary mismatch in modern times, right? So we know that there's like, you can make a laundry list of factors of the modern world that are pro-inflammatory and that are associated with depression. And so there's an idea, and I've written a lot about this. I'm on both sides of this debate, it's interesting, but there is an argument that depression might be something of a more modern phenomenon arising from this sort of evolutionary mismatch between the way we live now that's so pro-inflammatory and how we evolved to.

live, right? And there's evidence that rates of depression have really kind of risen a great deal in many parts of the modern world in the last 50 years at exactly the times when our diets become more pro-inflammatory, where we've been separated from a lot of immunoregulatory organisms in the environment. But if that's the story, then you would not expect to see depression being ancient, for one thing, but especially you wouldn't expect to see any type of link between inflammatory activation and depression and people that are not living in a modern lifestyle, right? So one argument, and again, these are circumstantial arguments, but one argument for the fact that perhaps this link between inflammation and depression serves an evolutionary purpose

is that it should precede modern environments. And so these folks, they're anthropologists at the University of New Mexico, actually went down to this group called the tsunami, which they're, They're kind of agriculturalists, semi-hunter-gatherers down in the lowlands of Bolivia. So they actually went down there to test these ideas. And so they developed these really culturally appropriate depression questionnaires. And then they drew their blood and looked at their inflammatory status. And very consistent with the idea that this link between inflammation and depression is an evolved old thing. First off, they found it that the folks living in this completely different.

much closer to the way most humans lived across most of time. Depression looked very much like it does here. People do get depressed. They get depressed for a lot of the same reasons. Depression was powerfully correlated with increased inflammation. And interestingly, when they did functional assays, the depressed people showed better immune responses to some of the pathogens. Some of the types of things that would be pathogens in their world,

again, suggesting that there's a link between depression and actually increased survival from infection. So it turns on its head this idea that something, like depression is sort of a killer because it dampens your immunity. It really is the opposite. So anyway, there's a very, so I particularly think that the link between inflammatory activation and depression goes way back in mammalian phylogeny and really probably initially had to do with our ability to manage our relationships with microbial world, not as much our relationships with cons-specifics, although it later got usurped for con-specific stuff.

Yeah, yes, absolutely. Very, very fascinating. So sort of talk about, you know, I don't know if there's necessarily, if those things are mutually exclusive in terms of the depression being having this evolutionary origin and modern-day mismatch. Because... No, it's probably too hit. Too badness. Right. And if you think about it, for example, you mentioned, I mean, there's so many things in our environment that are pro-inflammatory, diet, you know, lack of the light exposure changing. But like, if you look at people that are obese or people that have metabolic syndrome, most of the time have very high markers of inflammation, not always, but, and they also

are more likely to get depressed, correct? Has there been any evidence to see whether or not the inflammation's driving for that? Oh, yes, absolutely. The best paper I know was done by Lucille Capiron and Andy Miller, Lucille's in Bordeaux, Andy's at Emory, where they looked at, you know, they looked at a cognitive behavioral disturbance, body mass index, and inflammation, and showed that the link between sort of, sort of obesity and these behavioral cognitive problems was mediated by the increased inflammation, right? So, and, you know, anybody in this field knows that, that body mass index, how fat you are,

is the 800-pound gorilla in the room when it comes to the link between inflammation and anything, right? So, you know, all this, I mean, there's just a linear relationship. I just did this huge study in like 600 people with a large pharmaceutical company where I worked with them under data looking at prediction of inflammation and response to medication. And, you know, it's just, man, it's just like a straight line. The more, the heavier you are, especially, unfortunately for us, man, especially here, big, big production of, because we know that fat cells are big producers of inflammation. Exactly, right.

And what about how there been studies looking at whether or not, so those people that are, for example, obese or overweight and are, you know, have higher levels of inflammatory biomarkers, if they lose the weight, you know, does their depression risk decrease? Like, is that, is there any evidence of that? The only data I know of from that are people that have had these gastric bypass surgeries for weight loss. And there's some, there's some data showing that, you know, they've administered, you know, kind of quality of life, well-being, mood stuff. People's moods get much better. Now, it's confound, though, of course.

Yeah, of course. Yeah. You know, all of a sudden you can get into your bikini sort of. Look better. Yeah. Yeah. So, but it would be consistent with that idea. Yeah.

It certainly would be interesting to look at that, you know. And in terms of some of those studies you mentioned where you're, you know, administering pro-inflammatory cytokines like interfere on alpha and I think, you know, endotoxin, which is a component of bacterial outer cell membranes that can induce inflammatory response, how those can immediately, you know, cause people to have depressive symptoms and then if they continue taking it. I actually have a friend of mine who has polycythemia, and he was, which you make too many red blood cells. And he was part of a clinical trial at Stanford where they were giving, they were administering interferon.

I don't know what, maybe it was alpha. I think it's beta for that. Oh, was a beta? Okay. I think so. But what was interesting is that he had to, like, leave the trial because his mood was dramatically affected. And he's usually like someone in really good spirits, very optimist, you know,

sort of person. And so he had to stop that treatment because it literally was making him, you know, depressed. So that was sort of an interesting anecdote. But in terms of like some of the mechanisms that are responsible, you know, people, like you said, we used to think the immune system was separate from the brain and like there's the blood brain bare and nothing's penetrating it. You know, now we know these things are connected, you know. In fact, the lymphatic systems connected to the brain.

these inflammatory mediators are crossing the blood-brain barrier, getting into the brain, and you know, disrupting neurotransmission. Absolutely. You know. Yeah, yeah. This is the work of Jonathan Kippen. It's fascinating, you know, that, well, so there's a couple things to say. But let me tell you something interesting about this business, about the endotoxin, the

LPS and the typhoid stuff. So, right. So the folks in London, Hugo Critchley's group, they tended to use typhoid and they showed, right, You know, you give normal folks a shot of typhoid, which activates its sort of acute, mild. It's not like interference like a sledgehammer, right? I mean, this is more like a thing. But you do that. And yeah, people report feeling more socially isolated.

They feel more dysphoric. And you see changes in their brain that are sort of speak to depressive brain functioning. And the folks at UCLA used the LPS endotoxin sort of saw the same thing, especially in women. Not so much in men. It seems like there's a tropism for women, which is interesting thing. There's an evolutionary story there perhaps, too. But what's interesting is there's a counter, there is a little bit of counter data. This was done years ago in Germany where they actually took people that were catastrophic.

It's a small study, but they took people that had been inpatient catastrophically depressed, and they shot them up with endotoxin and it produced a powerful antidepressant response. Now, what's interesting about that is that there's a relevant animal study from Razumia in Israel where they took mice and I'm pretty sure it's mice, not rats, and subjected to this 20-day horrible stressor. And they showed that the stressor crazy activates inflammation leads to apoptosis death of microgleal cells in the brain and huge, anxious, depressive behavior afterwards, right?

So what's interesting was they showed that if you blocked inflammation right before the start of the stressors, You sort of, it starts, you block it. You can prevent the apoptosis. You can prevent the downstream behavioral effects. It's protective, right? If you do nothing here, and you let the little rodents go through the horrible stressor, and you block inflammation afterwards, they do worse.

If you stimulate inflammation, they get an antidepressant response. So there's a little bit of a back current that I am just one of the few people, but there are some of us that are interested in this idea that inflammation is a funny thing, right? So these cytokines, these classic inflammatory molecules like TNF, 2M2N2st factor alpha, I-L-1 beta, IL6, at lower levels in the brain, they actually have neurotrophic effects. Kind of like a hormetic stressor where they're... We don't know. Is it a stressor or is it just that they evolved?

Nature is so cheap, you know, it always wants to reuse things, and that's what makes things, evolutionary processes. do this constantly. And it's why things are, one of the reasons why biologic systems are hard to understand. You know, if they've generated TNF knockout mice, they can't find their way out of a bag. They're dumb as dirt, right? You know, so there's something about, there's something about lower levels of these mediators that may actually be beneficial in the CNS, at least. And then there's, there's sort of a U, and then all of a sudden, man, very, very rapidly. They become what we think of as counterproductive. You know, they become depressive, inducing.

cause tissue damage. Now, they evolve for a purpose. I mean, if that was just a negative thing, that would not happen. I mean, life is such a rough competitive game. And there's probably, it may be the case that the reason that you get to sort of CNS inflammation from either from peripheral cells coming into the CNS or from these resident macrophage type CNS cells being activated, it's probably a way of reducing the risk of pathogen manipulation. Where you basically, because if it's interesting, if you look at what, when inflammation, gets activated in CNS, it has trophic effects. It doesn't just go everywhere. It tends to go to an area called the cingulate cortex and the dopamine areas down in the ventral striatum. And we and others

have suggested it may be a way of trying to take these areas offline so that they're not able to be manipulated by pathogens. You know, you don't necessarily want bugs driving your system. And we now know that many of these sort of CNS organisms like, oh, what you know, the thing that, you know, the thing that it'll come to me that drives crazy dopamine behavior. A lot of times these microorganisms will actually, you know, change behavior in ways that benefit their survival and reproduction. So there's... Toxopasmosis going to be.

Yeah, toxin. So there's probably an evolutionary reason for why you see this U-shaped curve. But that may also explain why, you know, we've been working on the idea that people have been really, really chronically depressed. So if you look at people that are chronically depressed, And we talked about the fact that, you know, the inflammation is elevated in depression, right? It's true, but it's only true in a certain way. So what you really see is, you know, for any inflammatory biomarker, here's where it's at, if you're healthy.

Here's where it's at if you have the flu or you get rheumatoid arthritis, right? If you're healthy, here's where it's at. And if you're healthy and depressed, it's here, right? Now, day in, day out, day out, that's enough to set you up for every evil thing. heart attacks, strokes, dementia, because it's at gradual wear and tear. But if you look more closely, what you really see is this, so that there's a huge overlap between depressed people and not depressed people. So there's lots of depressed people that are desperately depressed that have low levels of inflammation.

And it's only some that are elevated. Now, I thought for many years, because I'm kind of a lumper, not a splitter, that maybe what you were looking at here was the depressed people, that, you know, that. They're all inflammatory, simple thing, that some depressed people just have higher inflammation, and that's what's doing it. And other people may be depressed because they're more sensitive to inflammation, but that it's all too much inflammation in one way or other, you know. We now are pretty sure that that's not true, that in fact, the reason that depression is

associated with increased inflammation is because there's a subgroup of depressed people that have elevated inflammation, and they're different than depressed people that don't. And this is the work of my mentor, Andy Miller, in the last five or seven years. They've just been world leaders showing that if you take regular old depressed people, he got like 250 of them and did this amazing series of studies. People that have, there's not a cutoff, but people that have higher levels of inflammation and depressed have different functional connectivity in their brains than people that have lower levels.

And we showed, Andy and I showed years earlier, that they also have very different responses to immune agents than people that have lower levels of inflammation. So I think, in fact, that there's a subgroup of very depressed people that might benefit from kind of a, not chronic inflammation, but a hit of inflammation. And when we get around to talking about hypothermia, I can tell you that there's some evidence that hyperthermia does that. Exercise acutely activates certain types of pathways we think about as being inflammatory. So I think in the next 10 years what we're going to find out is that, in fact, the immune system is probably involved in every case of depression. but the pattern is going to be subtler and more complex

than something just saying that depression is associated with increased inflammation. That's probably not going to turn out to be true. And with the exercise, I've read now several studies where, you know, exercise is, you know, aerobic exercise and now even strength training exercise, how it's almost, in some cases, as potent as some of these antidepressants that are out there in terms of treatment. And as you mentioned, you know, and this is kind of why I was thinking of this genetic effect because exercise does elevate inflammatory posthuses acutely and then there's

a response. Supress as a response, anti-o-oxidative response that is much more powerful than the initial stressor that occurred. So exercise is something that I think you had even published some studies or a study talking about the effects of exercise on what was very interesting to me, what you had called the inflammatory response that was induced post-pranidial, so after you eat a meal. Yes. It is. It is really, what's interesting to me is I've only really heard one other person,

a colleague of mine who's brilliant. His name is Mark Shiginaga. He is a gut expert, so he studies the gut, gut, gut health, microbiome. And he was, he, you know, talks about how this post-pranial inflammatory response occurs because, you know, food is hard on the gut. And it's a foreign substance. It's a risk. I mean, thousands of people die every year from eating out in the United States. Yeah, that's true.

But even in addition to that, in addition to the bacteria that can, you know, come along with eating some bad food, is that just that the gut itself, the gut barrier is sort of, you know, to some degree, gets compromised. With every meal, you're releasing a little bit of endotoxin in the bloodstream because your immune system's activated. You get a leaky gut? Yeah. And so you are getting, there is an inflammatory response that occurs, insulin, you know, in itself,

the insulin response and all that. So I thought it was very interesting that you were looking specifically at that and the effects of exercise, the exercise had on that. No, I don't think that. But we've written about this phenomenon. Oh, you written about it. Okay. Well, you know, and the other thing is, you know, when you eat, it kind of gives you a fever.

Do you know about diet-induced thermogenesis? So every time you eat, your body temperature elevates. It's why sometimes people say they sweat after they eat, you know, because it's not a fever per se, because I don't think it, I don't know whether it upregulates a thermoregulatory set point, but we've known for years that, and again, you think about, well, why, partly because you've got to burn off the energy, but it may also be that, again, hyperthermia has antibiotic effects, right? So it is true that when you, it is a, you know, anytime a foreign substance comes in contact with a vulnerable entry point into the body, there's a risk of infection and death, right? There's a There's a risk of infection death. There's a risk of pathogen manipulation. There's all sorts of things. So it shouldn't be surprising that that happens, right? Nor should it be surprising that fasting has a powerful anti-inflammatory effect.

And there's some beautiful data in animals, but also beautiful data in humans. There was a study, 19 normal volunteers, and they looked at the effect of a 24-hour fast on something called the NLRP3 inflammatory. It's right. It's the thing, it's an intercellular thing that connects up and it activates inflammation. It turns on to single I-Lyloin beta. So you fast, and that, the expression, the gene expression for that complex just goes down, down, down, down, down. Then you let the people eat again.

It goes up, up, up, up, up. And if they look at that sort of leaky gut, and you find it eating sort of opens the gut up to leakiness too. Which may be just a bummer. They may just be that we can't be built better than that. Or it may be an evolved adaptive mechanism to kind of activate a little bit of inflammation, you know. That way you kind of get kicked up in your body, you look around. I think the core idea here, and we were talking about this in terms of the evolution and depression, is nature is really smart.

It's a compromise. It's not perfect. But you go, oh, geez, man, that's bad. You get a leaky gut when you eat. Well, yeah, but across millions of years, if that was so bad, the gut would have figured out a way not to do that. It probably is an involved strategy that every time you're exposed to death by an infection, the body responds with a little bit of pre-potent infection. inflammatory response just to get everything kicked up and to deal with it, you know.

And of course, yeah, you pay a little bit of a price in terms of tissue damage, but it's like the smoke alarm principle. That little bit of damage is more than outweighed for the one time you don't do it, then you die. Yeah, right. And so it totally makes sense because the gut is what is exposed to the internal environment. So that's... Oh, I mean, that's the, you think about that's the big one, right? I mean, the skin is a much more robust protector against any membrane that's wet. It's just bad news, right, in that way. But it has to be. for us to survive and eat. And this is sort of the compromise that we've evolved.

I'm pretty interested in you're mentioning this hyperthermia in terms of people that are depressed having elevated core body temperature. I'm super interested in the study that you published where you had used whole body hypothermia to treat major depressive disorder or at least a single bout of it seemed to have a lasting effect for six weeks. Whole body hyperthermia, to me, it sounds very similar to using something like a sauna. Would you say? Oh, yeah, yeah, yeah.

It's just the heat. I mean, the machine's fancy. It's like a $50,000 machine. It uses infrared lights. It kind of cooks you from the inside out, and that allows you to get hotter with less misery. You know, because saunas, I mean, you're getting at rate on your, it's hard, right? It's definitely hard. Yeah.

I mean, I'm a big steam room sauna fan, but the box is very different. So I put myself in this machine to see what I was doing. to people. And I've never been, so to back up, yes, you're right, and we did do a study, and we treat people to a core body temperature of 385 centigrade, which is 101. Something or other, which is unbelievably hot if you don't want to be that hot. I mean, you know, so I mean, I had never been that hot in my life. I mean, sweat was just pouring off my body, and I was huffing and puffing. I felt like I'd been running for 10 miles out in the Sonoran Desert summer, you know. It's really hot. It's mild hypothermia.

but it's hot. Now we have colleagues, David Michelin and Marin Nair at Harvard, that have joined us in the hypothermia work. And she especially has interested in as a grant to study hot yoga and convince people to wear a rectal probe while they're doing hot yoga. And hot yoga, which also, you know, makes people sweat like pigs, elevates core body temperature too. Interesting thing, exactly the same place. Oh, wow. Right. And, you know, a lot of people, when I talk about hypothermia, and give talks to folks, a lot of people, if it's a,

crowd will come up afterwards and say, well, you know, hot yoga. A lot of people are hooked on hot yoga. And it's because, I'm convinced, it's because it's an antidepressant strategy, that they're essentially doing something very similar to what we do in the box. And, you know, most people, it took about an hour, hour and a half for most people to get up to that 38-5. And then when that happened, we turned off the heat, but we left people in the box because it stayed warm I mean, their core body taper remains elevated for at least another hour. So even the timing of hot yoga is probably consistent with sort of our hypothermia machine. So the hot yoga, a sauna, I mean, maybe a hot bath, like you can say.

So basically anything that's... It's the heat. Yeah. And there's some interesting data on hot baths improving autistic symptoms, right? And there's people looking at this in New York, right? So, yeah, there's a story there. Yeah. So there's a personal story for me with, in terms of the sauna, one of the reasons why I got so into using the sauna was because in graduate school, I lived across the street from a YMCA, and they had a sauna there.

And so I was just, you know, using the sauna. And I'd go into this, I'd use the sauna before I would go into the lab and do my experiments for the day. And, you know, as you know, graduate school is extremely stressful, failed experiments, sometimes setting you back, you know, six months and lots of stress. Yeah, I mean, just 16-hour experiments you have to do and you've got to publish and then you've got to publish, you know, so it's very stressful. And what I started to notice was for whatever reason, the sauna, using the sauna, really, really lowered my anxiety and my ability to deal with the stress. Like I was so much, yeah, so much easier for me to deal with all the stress. And it was extremely noticeable. And enough for me, you know, to start to start.

to go, something's going on here. So I started looking in the literature. Of course, my husband, Dan, was doing the same thing, and he had definitely noticed the same thing. And so what was really interesting, I looked in the literature and found, you know, that using the heat stress in general increases, you dump a bunch of beta endorphins.

Okay, well, that's obvious. That happens with exercise. Absolutely. I think part of the, like you mentioned, you know, when you're running or exercising vigorously, your core body temperature is elevated, and that's sort of part of that endorphin response. But what was really interesting to me was, like, at the same time, a friend of mine who was doing some research on the opioid pathway, and he was looking at the capo opioid

pathway, so the mu opioid receptors bind endorphins, and capo opioid, or sort of the opposite of endorphins is sort of the dysphoric. Yeah, dysphoric feeling. You don't feel great. And he was telling me about some research, whether if you agonize the receptor, the capo opioid receptor, what ends up happening is a feedback where you have the mu opioid receptors much more sensitive to endorphins and you basically are having more of the receptors and they're more sensitive. So then I started to look in the literature and found

that something that we make in our brain endogenously called dynorphine is upregulated when you're exposed to heat because it cools your body down. And so I started to go, well, I wonder, you know, so for example, there are studies where you expose rats to heat stress and and they increase their dinorphin. And I said, well, what if the dinorphine binding to the capyroid receptor does actually sensitize meo opioid receptors to beta endorphine? So I thought, oh, maybe that's a possible mechanism

why I'm feeling so good, like a lasting effect, where it's like later on, weeks later, I'd still feel really good. So that's sort of an interesting personal story from me. I'm not sure if you've ever looked into the dinorphine or beta endorphine. So this is a fascinating thing. Yes, indeed. So it turns out, you know, that almost certainly within the next, certainly within the next six months, there's going to be a major FDA approval for a very novel antidepressant that does the opposite of what you're talking about. It antagonizes the caper receptor. So it's exactly the opposite. Now, interestingly, though, and I have an interest in psychedelic medicines, somebody called Salvinoran A is a cap agonist. And there's also some significant interest at lower doses as an antidepressant.

So here's an example of this phenomenon. It's a meta issue. I don't mean like meta, like the Buddhist meditation thing, but meta, you know, M-E-T-A, that opposites sometimes do the same thing. It's interesting. It's a thing called an antedromia. It goes all the way back to Heraclides, back and that,

right, sometimes you can get the same effect by doing opposite things. So right, the fact that hypothermia stimulates caporeceptors and the fact that blocking them could maybe also have an antidepressant effect, It's fascinating, but it's consistent with this sort of weird, again, maybe kind of you-shaped thing or the fact that opposites can sometimes do the same thing. We don't know from our studies.

We don't know the role that the opioid system played in our outcomes. This is something that, you know, we're going to look at down the road. We look at a bunch of immune stuff. And what did you find with the hypothermia? Well, we found that hypothermia does exactly. exactly the same thing that exercise does. Okay. Which is not so surprising, right?

But it, which is quite interesting. So, to kind of nerd out on the inflammatory pathway, right? When you get sick, what happens is you get activation of these two primary pro-inflammatory cytokines, interleukin-1 beta and this thing, tumenocerosis factor, TNF.

So I-L-1 beta and TNF, they get activated, they do all sorts of stuff. They're really pro-inflammatory. They secondarily activate another cytokine call interleukin 6 or aisle 6. Now, IL6 is a bad guy, I think. I mean, the studies, so it's the one that's most consistently elevated somewhat in depression.

There's all sorts of evidence that if it's elevated, if you're a Western person hanging around, if I measure your IL6 and if it's up, bad. You're going to get heart attacks, you get strokes, you're going to get cancer, you're going to get, you know, it's a bad deal to have your aisle 6 just going to shrink your hippocampus. We know a lot of stuff about that. So it's a bad boy, and it's activated by Isle 1, but it's a sort of secondary. We've also known for years that I say sometimes it's a Janus-faced cytokine. It faces two directions, because it also has anti-inflammatory effects, right?

It activates Isle 10. So what you see with bad infection, I-L-1, TNF, they shoot up, aisle 6 goes up, and you're sick, and that's how it is, right? What exercise seems to do is it activates aisle 6 like. crazy, but it doesn't activate I.L.1 or TNF. In the blood, if you really, really exercise like a maniac, yeah, you can get slight increases. If you look at sort of maybe less, you know, like horrible, you know, killer exercise, you see this big increase in IL6. If you pull out people's blood cells and stimulate them, you actually see reduced release of TNF and IL1,

and that's that anti-inflammatory thing you're talking about, right? So you get this IL6 response, and then you get this sort of IL10 coming along, which is, which is, which is a lot. which is powerfully anti-inflammatory. That's what we see with hypothermia. That's so cool. So in this study, the challenge, we did a first small, open, sort of clinical study in Switzerland.

These colleagues of mine found an old hypothermia machine in the basement of this crazy alternative treatment to psychiatric kind of castle hospital. One of the guys as an engineer, he rebuilt the thing, and we started just sticking people in it, and we saw this powerful antidepressure. press in response. We only looked at people five days later, but clearly five days later,

their scores were generally cut in half, right? So then we brought the work to America. And the challenge, of course, is that, you know, you're going to get a very big placebo response from, you know, you make a deal about it. You sit in this box, you get hot, you go, oh, my God, you're doing something for me. So we had to invent a placebo, some kind of comparator. What are you going to compare it to? So what we did was we took this fancy box that has these big infrared lights and we went down to Target. This was my colleague Walter Jansen, brilliant guy for all sorts of mechanical stuff. He just went to Target. He bought a bunch of desk lamps, painted them orange so that they looked just like the light of the thing, hid them so you couldn't see that

they were right there. The machine has a fan. We built a fake fan and the machine has these heating coils down at the bottom that kind of make you warm, kind of comfy, toasty, but not like you're going to die of the heat. And so we put people in the box. We turn on the fake lights. We turned on the heating coils down there in the fan. 70%, more than 70%, the people that got the fake treatment thought they got the real treatment. So we asked them afterwards,

did you get the real or the fake? And so the vast bulk said, oh, we got to reel, because they were warm and, you know, not everybody who got the reel thought they got the real. It's interesting. I mean, their sweats pouring off the body, but, again, masochistic,

they figure, you know, there must be something worse than this, right? So the fact that we saw this massive difference between the two suggests that it has to do with the heat. And the fact, we've, just recently, now realize that in fact the fake group, the sham group, they got more heat than we probably should have given them. And some of them actually went up.

And those people had the same kind of antidepressant response as the other people, right? So, yeah, so we know it's the heat. So compared to that sham as a group, their immune measures just stay flat. The people got the real heat, man. Their aisle six shoots up. Now we measured it beforehand after. And like dum-dums, we didn't have the, we should have measured. like six hours later, but we've measured a week later.

By a week later and four weeks later, all the immune measures are back. There's no move, right? There's this huge aisle six. We looked at maybe 12 of these cytokines. None of the other ones moved. So it's just aisle six. Now what's interesting is the higher year aisle six went up. If you look at the whole population, the higher year aisle six went up,

the more undepressed you were a week later. And it was a pretty strong correlation. The correlation is even stronger between how happy you were when you got out of the box. So the acute mood-elevating effect of what you noticed from taking the sauna is nicely correlated with increased IL-6. If you had an increased IL-6 response, you're going to be happier. Now this just flies in the face of this idea, right, that inflammation is just depressive-genic, right? It really suggests that it depends.

It depends on how long it is. It depends on how you think about something like I-L-6. So then we had this really interesting finding. And after we found this, I was sitting with one of the great fathers of our field, a guy named Robert Danzer down in Houston. And I said, you know, how could this be? And he said, well, measure something called neopterine. Neopterine is a chemical that's really only made by activated immune cells, by monocytes,

these innate immune pro-inflammatory cells. So we measured neopterine. Neopterine also went up. And it correlated very strongly with the aisle 6. So for quite a while I thought, wow, I guess we're doing some kind of weird immune activation that I don't understand. But what I've come to realize more recently, and this is really working with these folks at Harvard, Simi Foster and the folks I mentioned, David Michelin and Marin, I think what's

going on is that IL-6 is not just activated by immune cells. We were talking about earlier, it's activated by fat cells, but it's really activated by muscle cells in the context of exercise, right, or in the context of heat. And there's animal data showing that if you induce heat shocks, so if you really heat up a rodent, you get massive IL-6 production from the muscle cells that spills into the circulation and powerfully suppresses TNF and IL1, so you don't get a rise there, which is exactly what we saw. So now I think what's going on is that, you know, so, you know, you talk about, about the immune

system and the brain being one unified organ. Really, of course, so are the muscles. And IL6, which we think of as mostly an inflammatory cytokine in the context of sickness, is a myokine in the context of exercise. And we know in the context of exercise that IL6 plays a key role in exercise's ability to induce insulin sensitivity. So if you block Isle 6 in a road that exercises, you block all the beneficial metabolic effects. Oh, wow. Now, there's also a study, interestingly, showing that if you look at the beneficial effects

of exercise on sort of muscle restructuring, this is in humans. If you exercise and take a non-steroidal anti-inflammatory agent, you get rid of all those good effects. Right, right, yeah. You've seen that, right? I've seen that. Also, there was another study very similar to the anti-inflammatory. They're taking the NSAID, so there's another study that showed taking high-dose alphal and vitamin C, so antioxidants also suppressed the, the, you know, the, you know,

insulin sensitivity effects of exercise right possibly through because you're not activating that whole inflammatory well exactly you know you you you you you you you what you would like to do is sometimes activate these compensatory systems right right so you know you know so so you know if you can activate your inflammation in a way you know she think about exercise right so you you know we were talking off camera about I think we're off camera about the fact that you know I'm gonna I'm gonna go run around Mission Bay here and I'm gonna get an increase in my inflammation well with these cavi

that it's a certain pattern, but you get certainly your IL-6 is going to go off. But over time, the net result is a reduction in chronic inflammation. So it's like if you hit a system a certain kind of way, what I think is that it's like a spring. You know, you kind of want the dial to be over here. So you'd think the simple thing to do would be just to move the dial over here. But that often we can, this is you've been using the word hormesis, right? Right, exactly. Exactly.

That's idea. Doing this weakens the system. own sort of internal capacity. So what you get is a dependence on that external element to keep the system in that state, right? On the other hand, although it seems paradoxical, if you take it this way, but not chronically, but just, and you pull the spring back and you let it go, right? It sort of drives the system into that other state. So we have some evidence from this from hypothermia. It's interesting. So you would think if the world was simple, that if you're depressed and cold, I should heat you up. And if you're depressed and hot, I should cool you down. But in fact, the opposite's true. So in the European study, we actually very successfully measured core body temperature the day before they got to treatment five days after, right?

And what we found was that the hotter you were before you got into the box, the better antidepressant response you got. I was going to ask you about that. Right. And what we found from five days after being into box, everybody's core body temperature was really lower over 24 hours. So the box didn't make people hotter. It made them cooler.

What we were actually inducing was hypothermia. We used hyperthermia to induce hypothermia. Long term, you mean? Longer term. Right. Which would be almost like a hormonic. It is. It is a horse system.

We toughened the system. We toughened up the system. We recalibrated. We made, so what we think, and this is really the work of my colleague, Christopher Lowry at UC Boulder in Colorado. what we think we've done is sensitize thermoregulatory cooling pathways so that the heat actually exercised them in some ways or shocked them into being more sensitive. And there's a giant literature on this fact that thermoregulation is impaired, as we've said,

in depression. Depressed people can't cool off. They can't sweat. They can't cool off. And so what we think we've done is sensitize the pathways in the brain and the body that mediate those effects and that that's a marker. for that sort of, we've also then strengthened anti-inflammatory, or antidepressant. It'd be interesting to look at, like, dinorphin, that whole system, because that is a problem.

I know, because it's also, it's also, what do they call a cryogen? Yeah, yeah. You know, don't schizophrenics also have a similar problem in terms of thermoregulation? They do. They've got horrible, they've got really, really crazy thermoregulatory challenges, right? So, I mean, when you see folks out, you know, it's a tragedy, when you see them out on the street, one of the things you know about schizophrenics is it can be hot and they're weighing three or four coats, right? So they really, really have thermoregatory.

problems. And if I think about it for a minute, I'll be able to tell you there's a study, though, where they found that they do better. So what do they do better with? Do they do better with, they do worse with cold and better with heat, or they do worse with heat? One of the two. But it's interesting that it's not all bad. But their thermal regulation is absolutely whacked. Right, right. I mean, you see this. I mean, you see these guys, you know, and women, right. So it's not just depression. So I want to, I was making a mental note when you were talking about IL-6 being a myokine and the muscle. Because, you know, a very interesting, there's a few interesting studies I've been

cropping up over the last couple of years in terms of another mechanism by which exercise and specifically activating muscle cells helps treat depression through this kineine pathway. And I guess, you know, for people that aren't familiar with kineurin, it's basically a byproduct of triptophan metabolism when your immune gets, immune systems activated in the case of chronic inflammation, for example, you're not converting triptophan into serotonin. That's right. You're actually converting into something else called kineurin, which activates immune cells.

But the problem is that kineurin can form, is it quinolinic acid? You can find kineretic acid and quinolinic acid. And that gets... Quinaic acid is definitely a neurotoxic agent. Okay. It's evolved into depression somehow. Yeah, it is. So we actually did this study. Again, this is Andy Miller and I years ago. In the interferon alpha work, we had a good sense to do spinal taps on people, right? So we drew out the

fluid around the brain, spinal fluid, and looked to see, does chronic inflammation delivered by interferon alpha change serotonum metabolism? So Michael Moss and Lucille Capiron and a number of people in the early 2000s began to show that chronic inflammation activated an enzyme. called endolamine-2-3 dioxygenase, right? And this is an enzyme that basically, as you said, takes triptophan and shunts it away from serotonin into chinerin. Now, there's an evolutionary advantage to this, too.

You don't want your bugs to have the serotonin, and you don't want them to have the tryptophan. So you block that enzyme and death rates spiral in certain infections, and I can't remember, I used to know all this stuff, but there's certain infections where it's just lethal. I think Leishmaniasis is one of them. I think, but I'm not sure about that.

So anyway, yes, you get everything shunted to chynarine. So what we showed was that, so everybody thought, so we knew that the more that enzyme got kicked up, the more depressed people got under chronic inflammation. That was shown by several different groups. It seems to be a reliable thing. But of course, this was just in people's blood. You can look at the ratio of chineurin to tryptophan, and that tells you how active that enzyme is. We got spinal fluid and showed that indeed, and this is really interesting.

that the interferent definitely jacks up kinerinin. Kinerin levels in the blood and the spinal fluid are very, very similar. So we think it's getting across. But you see a massive increase in quinolinic acid and kinerinic acid. And setting aside to kinerinic acid, which is interesting. It's an NMDA antagonist. Quintilic acid is an NMDA agonist. It causes neurotoxic effect.

effects, quinolinic acid skyrocketed under interferon treatment. That's what associated with depression powerfully. Now, on the other hand, we actually measured tryptophan into blood and the spinal fluid around the brain, and there was no effect. Cryptophan falls in the periphery, but is maintained in the brain. So there's a, I can't remember the name of it, but there's a, it's an amino acid pump. It's got a fancy name that basically actively transports amino acids. So So although we never really followed up on this, the suggestion is that when you're under chronic inflammation, there's some sort of, what's what I want to use, accommodation that's made so that your triptophan, you preferentially shunt triptophan into the central nervous system, probably

because you've got to have serotonin there, right? Right. So what I know, at least with the inflammation, I'm not sure, but I know that exercise itself, and I'm getting sidetracked with what I originally wanted to say, but the exercise, so the transport, the transports triptophan and the brain also, you know, the, the transports triptophan and the brain also transports branching amino acids, like lusine, isolucin, which unfortunately outcompete tryptophan. However, exercise causes those branching amino acids to be taken up into muscle cells,

and it sort of alleviates the competition. So you get more triptophenousin. You get more seroton. Right. Right. So that interesting. So right. So inflammation is hit upon sort of the same thing.

So really it looks like exactly is that Kynurin and its metabolites may be almost, I mean, those are the results that have been replicated. But probably they're probably more relevant bad actors through that pathway in terms of depressive genesis in the context of inflammation than is the drop in serotonin. Right. Right. Yeah. And so the studies that I was wanting to talk about or tell you about, you probably have even seen them, but where exercise, this has been shown now, it's first was shown in animal studies and then more recently in the past, I think it was 2017, it's been shown in human. where it causes muscle cells take up chineurine,

so they can't form acolytic, which then means you're not getting that. So you're not getting all that, that's right. So this is another mechanism. It's fascinating. Yeah, by which, you know, and I'm not exactly sure why that happens or, you know, all the logistics. But that's another very interesting way, you know, this exercise inducing the hypothermic effect and, you know, the anti-inflammatory, you know, effect after the inflammation's generated, this hormetic effect.

the serotonin, you know, increased serotonin getting the brain because it's so many different mechanisms by which exercise seems to affect a depression in a positive way and, again, the hyperthermia itself. So, you know, whether it's through the exercise or the hot yoga or the sauna or the hot bath or the steam shower. Yes, these things interditiate with each other's in really interesting ways, don't they? Yeah, they do. Have you, are you familiar with heat chock proteins? Well, that's what we're starting to look.

That's what we'll look at with the Harvard folks. Oh, really? Take a look at, if you're not familiar with this study, I may have sent it to you, heatchalk protein 105. So there was a study in mice where I'm not sure I don't, I didn't read the whole method section how they induced the heatchalk protein 105 in mice, and then they subjected them to a battery of, you know, stress tests that they do to make depressive symptoms in animals as best they can. But what was found was that animals that were, that had increased heat shock protein 105 were protected from these depressive symptoms, you know, after their, whatever stress test they did.

And that was correlated with an increase in brain-derived neurotrophic factor in one part of the brain region. I can't remember. So the heat shock protein was causing an increase. Like you were saying, I think inflammation itself can do that. So what we think now is actually the heat is probably activating these heat shock proteins, which is then, you know, contributing to the IL-6 being released proper from the muscles. which is then we haven't done this study yet, so I don't know.

But we're going to dump some Isle 6 on immune cells to see if it can produce neopterine. Because then it would be sweet. Then we'd know, well, you know, that the neopterin was, it wasn't that the immune cells were making the aisle 6. It's the aisle 6 then is maybe driving secondary immune effects, right? So, no, I'd like, please do send me that because, you know, I'm trying to bone up on, you know. This is the greatest thing about science as opposed to art, unless you're just a great, great artist is, you know, in art, you're always trapped in your own head, right? That's why, like, you know, pop stars, their songs all sound similar, right? Because they're operating in their own head. Science, nature is so much more complex

than our imaginations, that it takes you places. You know, I mean, I started out running emergency psychiatry at UCLA, you know, I mean, and somehow over the last 20 years, I'm now having to teach myself about heat shock proteins. Right. How did this happen? You know, that was an immune system guy, just trying to mind my own business. And, but, you know, the subtlety of evolved natural processes, take you places. Isn't it the best? I mean, the same thing happens with me. I'm, I, you know, coming from a, a biochemistry background and studying metabolism and

cancer and all of a sudden I'm like into the brain and autism and, you know, and churning serotonin and, you know, I love it, you know, it's absolutely true that it takes you to very interesting places. And certainly biology is always surprising, surprising you, you know, it's never like you predict. No, that's right. But we were talking a little bit, like, off camera, about. some of the you know you're talking about these these some societies that were doing these like running long-term running as a as a sort of possible

treatment for depression well well not treatment for depression these are spiritual practices okay so so one of my interest and this is what we were talking about off camera was I it's complex how I came to this but but you know so I was a clinician saw thousands of thousands of patients a year And then I became a kind of a researcher and focused on exactly what we're talking about, this immune brain interface. And one thing led to another, and it's interesting to trace the steps, but I began to realize, you know, we began to look at interventions based on these things. And I began to realize that the scientific data were pointing to the fact that a number of things that people seem to have repeatedly discovered across human history, in widely different cultures, mostly for healing and spiritual purposes,

seem to have biological effects and behavioral effects that might be relevant for depression. And so I sometimes say I'm like the ultimate retread guy, that really a lot of what I end up doing is looking at what I sometimes call ancient practices and seeing how can we kind of repurpose them for the modern world. So a lot of my work over the last five years is based on this idea that human beings, although we're really remarkably flexible animals. We have a lot of species, typical behaviors, and we have, I think, a lot of species typical needs from the environment. There were certain signals across, you know, a couple million years of hominid evolution that reliably

signaled either well-being and sort of evolutionary success or danger and failure. And we sort of need those signals to orient ourselves rightly in time, and space, and behavior. And a lot of have been just profoundly disrupted by the modern world. And so what you get in the modern world is this wonderful opportunity to do things you never could have done in any sort of hunter-gatherer society. This is a wonderful time to be alive, but it's an astoundingly disorienting time to be alive. And so what I'm interested in is trying to, in a sort of intelligent way, sort of bring back some ways to bring back these ancient well-being inputs and integrate them more into our lives

so that we get to sort of foundation of a felt mind-body sense of sort of stability and well-being, right? And so it turns out that some of the really interesting ways to do that were co-opted way back. A lot of the easy, low-hanging fruit, easy tricks were discovered, probably in Paleolithic times, but certainly, you know, in the last 10,000 years. You can make a list of them,

and it turns out that there are a lot of things we were talking about. Immune system stuff, not so much, except that humans co-evolved to, you know, we co-evolve with so many different types of microorganisms that really we should look at ourselves as this sort of, not as individuals, but as communities. Now, those connections have been profoundly disrupted in the modern world, and that accounts for a lot of the sort of allergic, asthmatic, autoimmune problems we have. But I also think there's sort of a lot of depressive problems. You're talking about the gut microbiome?

Gut microbiome, but also not just in the gut. but there was a lot of pseudo-comensal micro... So we existed in a world where trillions of environmental organisms passed through us all the time, right? They didn't live in us, but they're constantly passing through us. So over time, we become reliant on them to calibrate our immune systems correctly.

And of course, the things that pass through us also then modulate the ones that live within us. They form kind of a whole rate. So in that way, there's an immunologic story around ancient associations, around the fact that really we would do well to sort of recalibrate ourselves. We don't want to be hanging out with, you know, we don't want to go back to the times when 50% of everybody born was dead by 15 from infection,

but we don't want to throw the baby out with the bathwater. We want to reintegrate these sort of beneficial bacteria and not just bacteria, but viruses and fungus. We want to get that. But then if you look at things that humans have done repeatedly to induce well-being, to induce healing, to induce sort of transcendent states, you can make a list.

heat, right? So it's astounding the number of cultures in the world that use phasic exposure to high heat for healing purposes or for transcendent purposes, right? So, I mean, we're sitting in the new world and certainly the use of things like sweat lodges and temiscolans were just rampant in new world indigenous cultures. But across the old world too, you know, if you look at the healing rights in the ancient world, you know, hot baths were just a huge part. So it's It's a wide-spread human thinking. All around the globe, so many groups recognized, you know, it's not just living in a chronically hot environment.

It's this outrageous heat for a time-limited basis, right? Why would you repeatedly stuff yourself in a smoky, hideous, dark, miserable sweat lodge, right? And answer, because that sort of phase of heat exposure induces profound states of positive well-being that have antidepressant effects, right? There's one. Fasting. Almost every religion worth its salt. Both indigenous and these sort of world religions have fasting as a key element. Well, what does fasting do? Fasting has powerful anti-inflammatory

effects. It has powerful beneficial metabolic effects. And although to my knowledge, nobody has rigorously studied fasting as a treatment for depression. There's a lot of literature looking at fasting for sort of related things like pain. And many studies have given mood questionnaires, fasting has powerful mood-elvading effects, and it almost certainly has anti-depressant effects, running. So the reason I'm giving this whole preamble is it is amazing to me the number of cultures in the world that have used intense, maybe excessive running as a way of inducing, you know, sort of powerful spiritual states. You see it all around the Native American world, right? I mean, oh, it's just crazy how many cultures use this. And it's become a movement nowadays,

in Native American communities to use running as a way to sort of overcome a lot of the challenges, alcoholism and drug use and things that exist in those communities. And it's been very successful. It's interesting. There's communities, for instance, in Navajo land, they've got some great things going on where they're re-exposing kids to sort of long-distance running. I have a long connection with Tibetan Buddhism, and that was very much a practice there. In Buddhism, I mean, we were talking about this off-camera,

But there's, in Japanese Zen, they're the world record holders. They have this seven-year, crazy, crazy, crazy running protocol training where at the end of it, people run more than 50 miles a day for 100 days straight. And many people die doing this. Because they have to run carrying all their books, and they run in these crazy wooden shoes, and only 48 people have successfully done it since the 1850s. But, you know, why would you do this? Well, you do this, because it's believed to be a massive inducer of transcendent states.

way to achieve buddha'hood in one lifetime. And buried deep within very esoteric Tibetan Buddhist tantra medical texts are descriptions of natural states that are closest to the mind of the Buddha. So if you ask, you know, what are the states that these are not states of enlightenment, but if you want to know as you wander around in your life, what are the states where you come closest to the mind of a Buddha? One of them is running to the point of exhaustion. Now others are sneezing, urinating, defecating. There's a whole list of them.

They're all, it turns out that from a Tantric Buddhist perspective, rapid shifts in autonomic nervous system functioning seem to be the sort of a semaculum for the mind of enlightenment. But running to the point of exhaustion being one of them.

So running, especially, because you know you think about across evolutionary time, you know, they didn't have bicycles, they didn't have the things we have now. he's not so surprising. Now, of course, you know, this ties in, because I'm kind of a reductionist,

so I'm always interested in how these sort of spiritual practices were exacted out of behaviors that were necessary for survival and reproduction. And, you know, there's this really interesting, it's, Dan Lieberman's kind of the famous guy at Harvard, but there's this idea that, you know, that human brains may have evolved largely in response to long distance running.

Do you know about like persistence hunting, right? Yeah, I didn't know about this theory. Oh, yeah, yeah, yeah, yeah. So this is really, really interesting stuff. You ever want to go do it? I can hook you up with the guys to do this. Humans are the greatest thermoregulators in the animal world, right? And it turns out that humans, if you ask, you know,

what is the animal that can run 100 miles the fastest, it's humans probably. And the hotter it is, the truer that gets, right? There's not an animal on the face of the earth that can outrun human beings. for 100 miles in the hot environment. And so we know that the human foot evolved long before the human brain. People had modern feet before they had modern brains. The human foot is remarkably evolved for running.

The arch is a whole huge story on this. So there's this idea that humans, that one of the reasons humans were able to develop these huge brains, which take up 30% of all the energy utilization in our body, was that we were first able to stand upright and thermoregulate, that we were able to sweat, that we were able to cool off. Remember we were talking about thermoregulation being abnormal depression. Thermoregulation is one of the royal roads into human consciousness

in ways that are really profound, including this. So humans are able to thermoregulate, and are able essentially to outrun animals. Because it turns out that all other animals, especially four-legged animals, can only cool off by panting, and they can't gallop and pant at the same time. So as long as you can keep an animal just at the pace where they have to gallop every once in a while, they can't cool off.

And essentially, humans can outrun them and outrun them, meaning that the animal develops heat, stroke, and dies. So there's some great footage. You can just on Google. If you just type in persistence hunting, David Attenborough, back now, I think 30, 40 years ago, went out with a group of Sahn Bushman and showed that they could run an eel into death. It's astounding. They run a huge animal. The animal runs, but just keep it moving enough that it can't cool off.

And then finally it just stands there and it goes, phew. Because he can't sweat. It can't sweat. It's dying of heat. The guy just goes up, piqu, kills it, hauls it back, it eats it, right? And so humans, you know, I think that this, I think many, many of these ancient practices that induce heightened states of awareness evolved out of strategies, unique human strategy for survival and reproduction, but then they become fascinating on her own exercise is one of them.

Another one that I'm particularly interested in involved with is psychedelics. So if you say, well, what's another thing that humans all around the world did repeatedly and for extended periods to alter consciousness? Psychedelics. It's much older than just humans. Mammals have a tropism, a craving for drugs that make them hallucinate and go crazy. You can make a list. Many mammal species have their psychedelics.

Cats have catnip. Elks have their amazing. a certain kind of moss. So there's something about mammalian brains that are drawn to substances that induce these sort of altered states of consciousness and widespread use of psychedelic medicines or psychedelic substances around the world.

And you say, well, what do these things do? Well, they tap into this interesting human-evolved capacity for transcendent states, you know, that can be induced in all sorts of other ways. And one of the most species-typical human behaviors is trying to put yourself in a whacked state, you know, the trans states, dancing. I mean, there's a whole list of these things.

And the urgency with which these were pursued in indigenous groups is really highlighted nicely by people that were indigenous in my part of the world, which is up about 200 miles from here. I grew up in Fresno in Central California. And prior to

them all being wiped out, the Yolkids that were the indigenous group in Central California, they were one of the world's great shamanistic cultures. But they didn't have good psychedelic substances. And so they felt so strongly about the need to induce these types of experiences at puberty that they would have their young people at puberty, you know, strip naked and lay on these ant hills. And their bodies would be completely covered with ants and bitten, bitten, bitten, bitten, bitten, bitten. And the ants, I don't know whether there's

formic acid. I'm not sure what it was, but there's a substance that if you get, you know, just hideously bitten, it will induce a psychedelic experience. I mean, that's the length. It's crazy. Yeah, that's the length people would go to induce these experiences because they were so integrated into certain societies. Why, puberty? Why is it like a coming of age? Yeah.

Well, in cultures that have a strong shamanistic emphasis, there's a very powerful feeling that you want to identify a spirit guide for a lifetime. So, you know, psychedelic experiences or transcendent, trans-like experiences, on a repeated basis were usually just the province of a very small group of specialists, shamans, that had very complex relationships with the rest of the population, very ambivalent. It's fascinating stuff. But most of these cultures, everybody would at least have one experience. And if that happened, it would be at puberty.

And yeah, I think basically that's the time where you sort of have a transcendent experience that orientes you to the spirit world so that you can have, you know, you're not going to have the same potency of spirit guide help that you would have if you're constantly moving, into the spirit realm like a shaman would. But it was sort of people would, you know, everybody sort of wants one of these in those sort of cultures. And so I think that's why they were used there.

Now there's some evidence that the Elysian mysteries of ancient Greeks, which we know very little about because they were all kind of hash-hush. But there's some suggestion now, I think, and I think in the last 20, 30 years some research has suggested that they may have also ingested psychedelic substances. That was sort of at the core, because these were really the core of spirituality, especially esoteric spirituality in the Greco-Roman world.

And we know so little about them because they were so secret, but they were very widespread. Another example of these things being used, not just to puberty, but for these sort of transformational purposes. And I know you would, off camera, you told me you interviewed my colleague Roland Griffiths. Yeah. And so a number of us are now involved in this work of looking really rigorously at psychedelic substances as treatments for depression.

Right. Because Roland and Steve Ross at NYU, you, Roland at Hopkins, showed that, you know, a single exposure to something like psilocybin, which is a psychedelic substance and magic mushrooms, you know, tends to induce these very unusual states of mind that often have a kind of mystical characteristic to them. And a single exposure in a couple of studies induce these powerful antidepressant responses that last for like six months, longer. I mean, I know from Steve, you know, that he's followed up at people, these are depressed, anxious people with cancer, that those are still alive two years.

years later, many of them, most of them, are still undepressed and not taking any depressed. After one experience. Yeah, profoundly life transform. Oh, it's fascinating. Yeah. I mean... Oh, it's one of the most fascinating things going in our world. I know with my discussion with Dr. Griffith, he was mentioning, again, he did say that

this mystical experience seemed to be important for the antidepressant effect. And of course, he doesn't really know the mechanism why. But parallel to that, there are also some studies. is looking at a part of the brain that's involved in rumination. I forgot what it was called. A default mode network. Yes, the default mode network. And how that was like changed also.

Oh, absolutely. Yes. And of course, rumination, that's a big part of depression. Huge, huge part. And it's interesting to link back. There's studies linking rumination, particularly to inflammation. Oh, really? Yeah.

So inflammation probably preferentially drives rumination. We know from interferon studies that one of the places, that inflammatory molecules most change in the brain is the rumination center in the anterior dorsal anterior cingulate, right? So there's a beautiful sort of story there. Now, why you should ruminate when you're, that's an interesting question. I don't think we know the answer to it. Why should inflammation make you ruminate? But it does. And yes, rumination is a big problem. Yeah, and that also sort of leads to this, you know, you're talking about these transformative experiences, which also, you know, are brought about by meditation. And I know you've, you know,

there seems to be at least Roland was talking about some overlap between meditative state and something that's happening with this mystical experience that's, you know, there's sort of mystical experiences are like the common denominator. Oh, yes, absolutely. It's very much like sauna versus my $50,000 fancy machine, right? It's not the machine, it's the heat, right? Uh-huh, right? I am utterly convinced it's not the psychedelic.

We know it's not psychedelic. It's the experience because we know every study pretty much just looked at this shows that the more intensely you have one of these sort of mystical type experiences. Depending how you define mystical, there's other ways. Spiritual is almost a better word because people also have these very difficult personal experiences, but that makes them feel like their life, they see their life in a different way that produces a transformation. That realm of response has just been repeatedly associated with antidepressant and anti-anxiety effects.

And not just that, but also these agents seem to have an anti-smoking effect. You can help people quit smoking. you see the same thing there right so we think that exactly there's nothing special about the psychedelics other than the fact that that they can take a wide wide range of people and and on cue induce these sorts of experiences you know just like if you want to study inflammation it's great to have interferon because I could just wait around until you got inflamed you know god forbid but I'm going to wait I'm going to wait or I could just give you the interferon shot and away you go right so in the same way I could wait around for you to have mystical experience.

And there was a wonderful study down a number of years ago that I unfortunately wasn't smart enough to put in my file. I just read about it where they did this huge sort of anonymous survey of Americans and I don't know,

crazy percent, 15, 20 percent of people have said I've had a powerful mystical experience to change my life. I just never talk about it. I was at a kitchen sink, you know, and boom, the world looked like it was interconnected in ways I'd never mentioned. So it happens, right?

But it doesn't happen predictably, Whereas, you know, believe me, if it wasn't illegal and unethical, I could give you a big dose of psilocybin right now, put you on the couch over there. And, you know, it'd be very likely you'd have a profound, you know, mystical experience, right? So, but meditation can do the same thing, absolutely. In fact, last week I was having this really, I've got a colleague named John Dunn, who's kind of one of the world's great experts on Tibetan Buddhism, a great, great scholar, talking about meditative stuff. when we were talking about it, absolutely, that we know people, you know, you can meditate your way into the same types of experience. And I suspect much more profound experiences because then you develop, you're like an athlete

of the mystical world, you know. It's not just happening to you by a drug, you're controlling it. So there's a very strong overlap. I've seen now multiple studies where, you know, first there's studies looking at the brains of long-term meditators in how they have. have various changes in brain volume in certain parts of the brain and all sorts of things going on, you know, and that taking people that are not experienced meditators and putting them apart of this like two-month program, how they can have similar changes in their

brain. So clearly, like you were saying, you're kind of like an athlete of this world where you're absolutely changing, you know, the way your brain's responding to emotional stimuli. Yeah. We did one of the studies. It's interesting. Right. Yeah. We're looking at compassion meditation and mindfulness meditation and in a kind of a health discussion

control group. Yes, absolutely. We found some very interesting results. But yes, and Ritchie Davidson, a colleague of mine, one of my sort of mentors at the University of Wisconsin has done studies showing that you can take people that are novices and get effects if you really give them like eight weeks of hardcore meditation. And of course, then there's all sorts of interesting data of these people that are just, you know, amazing long-term meditators having very different types of brain pattern activities. Yeah. And I think I even mentioned to you, I'm not a meditator in the traditional sense where I'm sitting in a quiet room with my eyes closed and but I do for for many years running has been my meditation yeah yeah and it's it's absolutely you know there there is a place I go in

my brain when I am running that you know is I am I am sometimes I'm in the present sometimes I do daydreams sometimes you know but it's it's always a very like I just feel so good I feel so good after and it helps calm me and if I'm anxious about something and I go for a run, I mean, it's immediately therapeutic for me. Absolutely. So, I mean, what do you think, you know, right now I would say that, you know, if a person was depressed or anxious, if they, if they, if it has some sort of life event that, you know, maybe induce that, you know, a divorce or something like that, they go and see a psychiatrist

and they get prescribed. A medicine. A medicine. typically, you know, SSRI or something like that, which aren't necessarily always effective and could have side effects. And, you know, there's so many of these different, you know, lifestyle interventions, the weight loss, the exercise, the whole body hypothermia via your favorite method, sauna, hot yoga,

or hot bath. There's meditation, there's these, you know, psychedelics, which, of course, that would be something that you can't really, It's not legal yet. But, you know, for the ones that are, you know, do you think there's any hope that, you know, the medical community will embrace them, that will start to have, you know, treatment centers that people are now, you know, can go and meditate or do hot yoga or sauna or they can at least be told by their physician, you know, try this, you know. Oh, yes, yes, yes, yes. No, I, yes, the science is going to go this way. So it's very interesting.

So, I mean, I, you know, I specialize in depression. That's, you know, that's kind of what I do. And it's a very, and I actually, my colleague Christine Wheeler and I are writing a book about these ancient practices we're talking about and looking at it in relationship to the pluses and minuses of antidepressants, right? So there's an interesting truth, or there's an interesting thing about antidepressants is not widely known, which is, and it's a lot like a lot of things. So, you know, if you look at, there's these studies showing that, you know, if you start out depressed here and you do eight weeks with an antidepressant or a sugar pill, you know, the antidepressant gets you down less depressed. Here's the antidepressant, you know, also get you undepress, but lesser, right? So you think, well, you know, antidepressants seem to work pretty well for everybody.

You know, they seem to work better than a sugar pill for people, but that's not the truth. Yeah. John Crystal Yale did this great study where they were able to, I won't bore you with the details, but what really happens is, about 70% of people in the United States will do much better in terms of short term with an antidepressant than they will with a placebo. I mean, they really feel better. So there's a group of people that really do well with antidepressants. And by well here, what I mean is the day we're really coming apart with depression. And now, you know, a couple of three weeks later, they feel like they've got their life back.

They feel better. They feel fantastic. 25% of people that are depressed will do much worse with an antidepress. than they would with a sugar pill. And that's what's not widely known. We've seen a very similar pattern in some of our immune intervention studies. It seems like all interventions or many interventions may share this, that if they help some people, they may actually hurt others.

So the first thing I say to people is, you know, if you're depressed and anxious, and if it is impairing your life, I mean, where you're really having trouble, you know, where you just, you really have it, you know, there is some very good chance that if you take a regular am, antidepressant, you will feel considerably better. And there's some chance you'll feel like way better, right? And that could be very useful. And so let's just bracket that, right?

I mean, these agents are very powerful for a not insignificant subset of the population is depressed. It's also possible if you take one of those agents that, in fact, it's not going to help you. That happens a lot. Now, what you don't know, in fact, is that by it not helping you, you know. So if you look at these studies where, you know, what happens is if you don't respond to an antidepressant, most of the time, if down is good, you stay the same. But if I'd given you a sugar pill, you would have done much better, right? So you come to me and say, you're just not responsive antidepressants.

What's actually happening is that those antidepressants are a absolutely non-optimal intervention for you, right? So there's a whole bunch of people that antidepressants are not optional for, or not optimal for. So that's the first thing. And so if you're one of those people, then what do you do? And that's where these other things become very, very interesting, right? But the problem with antidepressants, as I sometimes say, and I'm a psychopharmacologist, I have seen antidepressants save many lives, and I've seen many people benefit from them. But they are a bit of an unearned grace.

They take you from a state when they work. They take you from a state where you just feel horrible about yourself, you feel horrible about the world, you're anxious, you're miserable, you're not eating, you're not sleeping, you're eating too much. And, you know, you're downing yourself. Everything's dark. You can barely get out of bed. You know, you're scared of your shadow.

You can't make decisions, right? They can take you from that. And in a month, you can become like super yourself when they work. You know, now you're confident. You feel better. All that stuff that is bothering you. You're like, yeah, what's the big deal? You know, sue me, right?

And all of a sudden, the world responds better. They go, oh, I'm so happy to see you. This is the Listening to Prozac, that famous book for the 90s. That's a real phenomenon. But the problem is, and it goes back to what I say about the spring versus the thing where you become dependent on, you're only that person when you're taking the antidepressant. You take away the antidepressant and it fades. And so that's problem number one, which you'd really like to do, is find a treatment that

whatever it does, it induces something that's less dependent on something external for your sense of well-being. And the other thing about antidepressants is there is some data, there are some data that the longer you take them, you may become more and more reliant, your body and brain, you may need them to feel good. There's some evidence that they may induce a vulnerability so that you have to make a decision in your life, you know. Are you going to be Rhonda alone, or are you going to be Rhonda plus Prozac?

Right. And that's a weird thing. Yeah. I think I've even seen some evidence where there's changes. in, there's downregulation of like serotonin receptors, for example, when you're constantly, when you have like serotonin, the synapses that's not, you know, being re-uptake like it should, it's staying around, and so the receptors are like, oh, there's more serotonin here, and so you start to downregulate.

So again, if you were to take that away, all of a sudden you have downregulation receptors and your baseline's now even, you know. So relapse rates, so you can take people, and there's a lot of studies now, you can take people who have been in full remission taking an antidepressant for two years, you take it away and 60, 80% of them will have relapsed within a month. I mean, especially if you stop it quickly, right? Whereas interestingly, if you take away placebo, that people do pretty well. So placebo responses are more stable and more long-lasting than antidepressant responses. And that is a shockeroo, man. I mean, for those of us in the field. So it really speaks to the fact that the strategy of dealing with the adversities of life.

and dealing with depression, which is really sort of an involved response to adversity. I think it's mostly an involved response to microbial diversity, adversity like we were talking about. But it's been just now that's what it is. It's all around the world. You know, if you're sick, if you're stressed, if things are going badly and you're vulnerable to it, that's what sets you off into depression. Well, you know, it's much better to take an antidepressant than to kill yourself or to have your life come apart or to just fall apart.

Of course. Right. But it would be even better if you can, you can't. could find something that would allow that that antidepressant response to become endogenous to your own brain body system and that's where these alternative practices and I think some of these ancient practices have promise I don't think any of them are antidepressants the way an antidepressant is an antidepressant I think all these things what they do is that they they they set you on a path

or they open a door for you to begin to transform yourself in ways that are going to protect you from depression right because one of One of the things that when you live with depression for a long time and you watch it, what you see is that the things that tend to make people depressed are those things in their life that are the sort of challenges that emerge out of who they are in terms of their behavior, their thoughts, their feelings, right? So you know, you think of a lot of examples, but you know, like a lot of times people become depressed when they, you know, the person who always chooses the wrong partner, right?

You know, no matter what they do, they always end up with somebody that's abusive to them, something like that, right? So, you know, what they need to do is transcend that pattern. And if they could transcend that pattern, then a huge driver of their depression goes away. But, you know, when they get depressed, it's because they're approaching it again, or they give up, or they lie to themselves about it, or they, whatever. You know, when you can't, life is like, I believe this deeply, actually, that life is like a series of challenges to perfect sort of the functioning of who I am,

who you are as a being, right? the sort of behavioral and biological organization of yourself as an entity. This is a bit of mystical mumbo-jumbo, but I do think that for reasons I don't fully understand that this is the challenge of human beings is to sort of perfect it. And if you do that, that is the ultimate antidepressant strategy. Dalai Lama doesn't get depressed, as far as I can tell, you know. Because what he's done, it seems to me, and I know him somewhat,

is that he's transformed the, he's transformed the way his brain-body complex works, so he's in states of mind that are just, they're just inimical to depression, right? And so I think that that, in fact, is the ultimate antidepressant strategy. But the problem is that it's a lifetime's worth of work and it's extremely difficult. But I think that these alternative things are more likely to drive you that direction than our modern pharmacology. You make yourself more resilient, right, to, to, I think when they work, you make yourself more resilient, and you begin to develop perspectives

that line up very strongly with many ancient wisdom traditions about the truths of what it means to be alive in this particular universe with its challenges, which are, there's myriad challenges, right? And so I think that that is the ultimate way forward. How that works is interesting, because there's not, it's very hard to monetize that, and that's an interesting challenge, right?

because these other ways are far more easy to make, you know, billions of dollars off of. Now, how you combine standard pharmacology with this pursuit for this sort of, what I call sort of personal transformation view of antidepressant, you know, thing, that's another really challenging thing, you know, and, you know, when are antidepressants a, you know, sometimes people take antidepressants as an excuse not to face what's going on in their lives. Like I've known many people in patients, you know, that, you know, that, you know, You know, they knew, take an example, they knew they're in a marriage and they know that it's just they need to get out, right? But there's a famous saying that many marriages are saved by, usually the women, because the guys are such adults, you know, but like that many American marriages have been saved by the woman just being put on Prozac, right?

Because when it works, she goes, you know, I can play bridge, I can play golf, he's not so bad. You know, you basically just medicate yourself away from the truth of what you know on a deeper level to be true for you, right? So in that way, you know, the antidepressant is actually working against what I would see is this more optimal way of sort of transforming into sort of coming into full ownership of who you are. So. But on the other hand, you know, you can imagine somebody that gets up to a wall and they know they need to do this, whatever it is, but it's overwhelming. They can't do it. You know, you put them on an end depressant for a while and it gives them the sort of chops to hop the wall. then maybe the antidepressant has become sort of a tool for transformation, right? And I've never seen anybody talk much about this, and I've only been thinking about it for the last six months or so. But it's an interesting question. So there's a lot of complexities around this dance.

Are there optimal ways of combining these things, too? But yes, there's many people that are interested in trying to invoke these sort of, many of them, older ways of transformation. So I'll make a plug for one of my closest colleagues, two of my closest colleagues, Rakesh and Sondra Jen, J-A-I-N. They have developed a program called The Wild Five, which is this fascinating online-based resource that basically combines exercise, diet, sleep, social connectivity, and what an idiot, I can't think of the fifth one since I'm involved in all this stuff.

Let's see. Diet, exercise, sleep, social connectivity, and meditation. Yeah, mindfulness. And it's a beautiful program because it's all, you know, it's completely sort of user-friendly and not overwhelming and doable. And it uses a lot of sort of things like tracking your behavior that sort of make people get kind of feedback. So I've been involved in this work with them because we do so much medical education together and we do some research together. And the results are really striking. Man, people do it for 30 days and they feel way, way better. So Rakesh is one of the great psychiatric leaders at the interface of pharma, the guy. The guy is very deeply involved in sort of, he's a pharmacologist like me, but, you know, way up there. But over the last 10 years, while not abandoning that, he's become utterly convinced that that is not the final way forward, that we really need to move into these sort of transformative wellness practices. And so, you know, the king of pharma goes into this, and he brings some of that expertise into it. But it's a classic example. I mean, they and I, many of us are now talking about, well, how can we develop, you know, various levels of, of, of,

programs that that interdigitate these sort of wellness practices. What was the name of the program again? The Wild Five. The Wild Five. And do they like give you advice on like protocols to follow for a diet? Oh, yes, absolutely. Oh no, it's all kind of protocol manualized. Oh yeah, they've got to publish a book.

Yeah, if you just Google Wild Five together. Oh yeah, yeah, you definitely will find it. It's kind of like the, you know, those five things are so incredibly important. I mean, sleep, of course, you know, sleep deprivation. All that's been shown to be associated with depression or cause depressive symptoms. Inflammation, weight, inflammation. All right, all that. And then another thing we didn't talk about was, and you kind of mentioned, you alluded to it with this evolutionary mismatch.

You mentioned, you know, the world that we live in today is much different. We've got all these artificial lights, you know, where our light exposure is totally changed. Some of us are in offices all day and we're not exposed to bright light during the day. Then we go home at night with all these lights on. And, you know, so it's kind of, there's a mismatch there. And I do know that there's, I think I sent you a couple of studies. And one was showing that bright light exposure was able to even help treat people with non-seasonal depressive. Oh, absolutely.

Yeah, there's some nice data on that. Yeah. Absolutely. And what I was kind of trying to make was the link between cortisol and the bright light exposure. Oh, yeah, absolutely. Because, of course, you know, that's what entranes to a large degree of cortisol rhythms and probably cytokine rhythms, too. They also have it. Yeah.

Absolutely. There's another example of this idea that humans evolved to, if not need, to function optimally with certain types of inputs. And if you say, well, why do they function optimally with those inputs? It's because across a couple million years, that's what they got. And so they evolved to function optimally with those inputs. You know, the reason that we, the reason we like bright light in the morning and dark at night is because for like until fairly recently since the creation of the world, morning for bright

and nights were black. And so we, you know, we marry ourselves to those conditions because evolution is always trying to optimize the organism to the environment. That's the challenge, right? So we optimize to that mixture of light. But then we also have a sort of an evolutionary mandate to compete with each other, to be productive. And so all of a sudden you invent things like lights,

and now you can stay up all day and night and work. And work, because that's also a, human mandate, right? I mean, we're these ultimately social creatures, and so we get ourselves in these double binds. Where these mandates, you know, one mandate is if you see something sweet, eat it immediately as much as you can because it's rare

and it's huge calories and that's great. So if that's true, then maybe we should just invent nothing but sweet stuff, and that's so awesome, but now we're killing ourselves. We're sweet stuff, so now we need to, you know, renounce. So it's always like you get these sort of things where, you know, one mandate

in the human world interacts, you know, problematically with another. And light is a classic example of that. Yeah, it is. And the fact that, you know, the circadian rhythm is regulated largely by light, also by food intake as well. But the cortisol take on it, you know, cortisol is a hormone that changes like 25% of the human genome. Many of those genes involved in inflammation, like you said. Absolutely. It's a huge inflammatory. Yeah, exactly. So totally, you know, makes sense that these two are interconnected. And, you know, having just bright light exposure, there was one. study were exposing humans to like 10,000 lux bright light for seven hours a day, lowered their

cortisol response during the rising phase when it's usually like the highest. And so, you know, so obviously was an anti-inflammatory sort of, you know, or depressive, I guess, immunosuppressive effect as well because you're not having as high of a cortisol response. Yeah. But another thing that just so many humans don't realize that that could also be playing a role in their, you know, in their depression, their way that they're responding to emotional stimuli and all these things, you know, so I personally, we, my husband and I have optimized, tried to optimize to the best for our ability, our light exposure. So we have these lights in our, in our house called Philippeux, which basically they, they change, you can change color. So blue light is what, you know.

That's what you want early in the day and not what you want at night. So at night, we have our setup, you can time them so that it shuts off the blue light and it turns on red light. So we have all these red lights around our house that come on. Oh, wow, cool. Yeah, and it really, really makes a difference. I mean, you get tired, you know, because you start making melatonin. And so the sleep onset is much earlier than if you were to have, you know, regular blue lights.

Yeah. And then we have, you know, apps on our phone and our computer called flux, flux, sorry, flux, which then also tones down the blue light. So your computer screen isn't emitting the blue light. Yeah. But the lights around the house are really cool. They're kind of expensive, but really worth it. And you have them all around the house.

We have them in every room. Yeah. What do they call? In the kitchen. Phillips Hugh. H-U. I'll send you. Okay.

H-E. I will. But yeah, it's really cool. They do all sorts of colors. They do purple, blue, orange. But we go from the bright blue to red. Yeah. So that's what we're using them for.

And then the bright light exposure, early in the morning, you know, like having, you know, going outside for 30 minutes or making sure you have light in your house. Even on the cloudiest day. Yeah. You get like 5,000 lux on a cloudy day. You cannot, yeah. It's just, so even on a cloudy day, you get like. Oh, yeah, you get a lot compared to just sitting in your average room. And do you know how long, like, can people just do 30 minutes or an hour? Like, because it's hard. It is. Going to work. I took people 30 minutes. And, and I mean, yeah, and there's no doubt that the light boxes really help a lot of people, and not just seasonal people.

So there's another example. There's an interesting example of a simple technology recapitulating natural conditions that optimize human emotional well-being. Now, the other thing that I'm convinced is really important is dark. There's a whole biology of dark. Like during the time when it's supposed to be dark, like even.

Yeah, yeah. Because even a little bit of light absolutely screws up melatonin release. You know, blue light mostly. I mean, that's where it's really smart to do this. But, you know, I mean, we cannot now. The first academic paper ever wrote was called The Moon and Madness reconsidered about why the moon was associated with madness in ancient times,

making an argument that the moon was essentially a light source that activated manic episodes because, you know, sleep deprivation is such a powerful driver of mania. But as part of that work, I did this massive research on the history of lighting. And it is so interesting, you know. Like, for instance, in ancient Rome, Rome was so dark at night that you could go out into the biggest street in Rome and you wouldn't see your hand in front of your face unless the moon was out.

I mean, it was just pitch black. People take everything in because it's just total blackness. London was pitch black. You know, there was a massive prostitution business that was run on the London Bridge. We know this good Boswell, you know, Boswell, the guy that wrote the biography on Samuel Johnson, recorded all of his dalliances,

and, you know, he'd be out there doing it on the bridge. I actually went back and matched the dates of his prostitute things with the phases of the moon in the 1760s, and he was always doing it at dark of the moon. It's fascinating, right? So, I mean, London, the greatest city on Earth in that time was so dark that you could do that. This is in the 1760s.

So, you know, we just, and there's a guy named Tom Ware, he's retired now, but he was sort of the king of the circadian stuff for many years at NIMH, the National Institute of Mental Health. And he actually took, he did this great study where he, in particular, he took this one just impossibly bipolar person, stuck him to dark for 12 hours every day for a year or so and just profoundly fix the guy, right? So darkness.

Now, darkness is another example, actually, of an ancient spiritual practice. So one of the most bizarre of sort of tantric, heavy-duty Tibetan Buddhist practice is something called the Dark Retreat, where people go into utter complete darkness for 49 days straight. 49 days, wow.

That's the length of time that they believe. That's the maximum length of time between reincarnations. Now they also in silence as well? Silence and dark. Silence except for a couple times a day when people slip, they've got some mechanism now for slipping food under the door. But they're not talking to anyone.

No, no. And they start hallucinating like mad. And the point of that is utter sensory deprivation, right? The point of that then is to, from their perspective, the point of that is to recognize that the whole world can arise from the creation of their mind. And so they realize that this world is also sort of insubstantial. I mean, at least that's my understanding of the spiritual.

But isn't it amazing that something like dark can also be appropriated for spiritual practices? Now, whether it would have any therapeutic potential is kind of unknown, but it's on my bucket list, not to do 49 days, but to go. And I've got an invitation to go check it out. Wow. Very famous, very famous television journalist is going to come with me. It's hardcore. Are you familiar with some of the gene polymorphisms, the SNPs, and there's one gene, that I think it's N-pass too.

Yes. That is involved in circadian rhythm, but also there's susceptibility to bipolar disorder, like when it's dysregulated. So again, sort of this... Yes. Well, especially bipolar disorder. You know, if depression,

if regular depression is sort of involved human response to the adversity of relationship, bipolar disorder is response to the adversity of time. What do you mean by that? Well, what you see with bipolar disorder, disorder is that a many, so folks with bipolar disorder are also, they can be set off into either manias or depressions by stress, right? But they're also exquisitely sensitive to, to fluctuations in circadian patterns, right? So the great way to induce a manic episode is to just keep people

awake. So there's wonderful data for the 1980s for the national institute mental health where they'd keep really very ill bipolar patients in psychiatric wards for years and study every, you every episode and always depressive, but especially manic episodes would be triggered by a night of sleep deprivation, right? And you see this clinically, right? So time, time is, time is an adversity because it's, you know, it's constantly threatening homeostasis, right? So, you know, the things we're talking about, the sun comes up, the sun goes down, this happens, that happens, this happened, and your body goes up and down. Anytime things move, there's always a risk of things coming off the way. rails and breaking, right? And so bipolar folks are so profoundly vulnerable to disruptions

in their circadian sleep-wake cycles, in their activity cycles. Ellen Frank was one of the originators of this called chronotherapy, came out of the University of Pittsburgh, where they actually, you know, as a therapeutic thing for bipolar disorder, part of it was education about you always go to sleep at the same time, you get up at the same time, you know, you'd be careful about air travel, right? There's a beautiful study from Heathrow showing that, you know, that there's a hugely increased risk of people showing up at Heathrow with a psychotic mania. If they come from America to Heathrow, then if they come from Asia to Heathrow, and the reason is because it's a sleep deprivation thing. If you're coming from here, that's why you're always exhausted. When you land in Europe,

you've missed a night of sleep. Oh, so many manic patients I saw in my years running the emergency psychiatrist at UCLA, many of them were activated by getting on a plane. Wow. I was normal until I got on a plane, and I got off the plane, and the world looked different, and then they're off and gone, right? That's what patients would say. Oh, yeah. Wow. And first episodes were often induced. I mean, people really develop these lifelong psychotic disorders in response.

Do you think those people that are having that are a little more sensitive to the, like, they're circadian, they're, they maybe have some snip and. Yeah, this is probably the impasse. Which is one of the great kind of drivers or regulators of the circadian things is a particular bipolar disorder is because, you know, it's a condition where time, the changes of time, the recurrent changes of time are just a big stressor for that. order. Yeah, and probably lots of genes are not being regulated properly, right? That's right. It's like a transcription factor regulating a whole host of genes. And so their response to things are very different because they're not activating all those pathways that you're supposed to act, activate, you know? Whereas, you know, what's interesting is, if you don't have that bipolar risk, you know, most of us are not, most of us do not end up in the

psych hospital because we missed a night of sleep. Yeah, right? We end up in a psych hospital because the person we cared about dumped us or somebody died or we lost or we were shamed or, you know, it's just the things, when something tees it off, it's a different register of things that tee it off, which is so interesting. It's one of the main differences between. When I miss Anette's sleep, like if I'm traveling abroad, I certainly feel strange when I land in Hithrow or any other airport in Europe or even Asia. But I certainly don't feel. Yeah, you're not. Yeah, I'm just kind of like, it feels kind of weird. Right. You're not psychotic. No. Yeah. No. I don't actually have that SNIP. But fascinating conversation that we've had. We've talked about so many different things.

Really, you just published a book. What's the name of the book? I published it with one of my other closest colleagues, Vladimir Malatech. It's called The New Mind, Body, Science of Depression. The New Mind Body Science of Depression. 700 pages. It's a monster. Wow.

Oh, yeah. And so people are more interested in sort of learning more about. So a lot of the stuff we've talked about, right? So all the inflammation stuff we've talked about is in there. All the evolutionary stuff we've talked about is in there. A lot of stuff about the risk factors for depression is in there. And then if you want to take just a very deep dive into the neurobiology of depression, a lot about, you know, kind of wide-scale brain abnormalities and depression,

molecular abnormalities and depression. And then a few cases, too, that people seem to enjoy their sort of a little bit easier sledding around sort of how these things apply. I discuss hyperthermia, so I actually talk about one of my hyperthermia that had like a miracle cure to hypothermia. So it's interesting, yeah, a lot of it's in the book. Cool. And the book, so it's available, is it like on Amazon?

Published by Norton, it's available. Awesome. Yeah, it's available sometimes in Barnes & Noble and it's available in Amazon, yeah. Great. Yeah. Really, really happy to have this discussion with you. Definitely want to stay in touch and I'll send you studies whenever I come across them. but thanks so much for taking time to speak with me today.

Oh, thank you. This is great. Yeah, really cool. You made it. Thanks for sticking around. A huge thanks to Dr. Charles Raison for this enormously engaging and fascinating conversation. I knew I was in for a good sit-down from just having read through his publications. But to be honest, this one really exceeded my expectations.

I hope you guys enjoyed it as much as I did. Chuck really does bring some extremely profound perspectives that will be so very important as research continues to unravel the various mysteries surrounding the effective treatment of some of these conditions. A few quick things before we wrap up. Chuck discusses a very large body of scholarly work in this episode, and believe it or not, my team actually managed to track down many of those publications and add them to this episode's video. How cool is that? So if you're interested in seeing figures, quotes from the literature, and of course citations, definitions, a transcript, and much more, head over to the episode page which you can find at foundmyfitness.com forward slash episodes.

That's foundmyfitness.com forward slash epi-s-odd-es episodes. Remember that little bit of conversation where we talk about genetic polymorphisms in an important circadian gene called N-PASS-2 and how it's associated with an increased risk for bipolar disorder? Well, if you have your genetic data from a service like 23 and me, you can actually learn about whether or not you have this specific polymorphism, as well as a variety of other circadian-related polymorphisms. Learn more about that by heading over to foundmyfitness.com forward slash genetics. That's found my fitness.com forward slash genetics, G-E-N-E-T-I-C-S. You'll find these polymorphisms

tucked away in a report named, you might have guessed it, the circadian report. So make sure to check that out. It's some cool stuff. And as always, if you enjoyed this episode and our hungry For More, this episode and all episodes of the podcast exist through a generous pay-what-you-can support from listeners, just like you. To learn more about how you can join the community nurturing the existence of this podcast, head over to foundmyfitness.com forward slash crowdsponsor. That's foundmyfitness.com forward slash C-R-O-W-D-S-P-O-N-S-O-R crowd-sponsor. Thanks for listening. Until next time.