Dr. Charles Raison on Depression, the Immune-Brain Interface & Whole-Body Hyperthermia
Posted on March 19th 2018 (10 months)
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.
Whole-body hyperthermia as a treatment for major depression."Thermal regulation is one of the royal roads into human consciousness in ways that are really profound." - Dr. Charles Raison Click To Tweet
Dr. Raison and his colleagues have demonstrated some promising evidence that a technique called whole-body hyperthermia has the potential for real-world clinical efficacy as a tool in the fight against major depression.
In Dr. Raison’s randomized, double-blind study published in JAMA in 2016, it was shown that a single session of whole-body hyperthermia (core body temperature was elevated to 38.5 C) produced a significant antidepressant effect in people with major depressive disorder compared to those who received a sham control. The improvements were apparent within a week of treatment and persisted for six weeks after treatment.
But what is responsible for this antidepressant effect? In a previous episode of the podcast, we learned that sauna use seems to share many qualities of exercise, including improvements in arterial compliance, elevations in heart rate that reach levels you might see in aerobic exercise. Moreover, sauna use has been shown to be associated with reductions in heart-related mortality, dementia and more. The impact of heat stress on the behavior of our immune system through transient alterations in the cytokines expressed by our tissues may be one more area where we can see some overlap.
The relationship between inflammation and depression."People that have higher levels of inflammation and are depressed have different functional connectivity in their brains than people that have lower levels." - Dr. Charles Raison Click To Tweet
Dr. Raison, as well as others, have found that inflammatory mediators such as IL-6 and C-Reactive protein (CRP) are higher in depressed individuals independent of other health factors like obesity and can independently predict the subsequent development of depression over a decade or more.
Moreover, the fact that chronic inflammation might not only be predictive but also induce depression is suggested by studies where injection with pro-inflammatory cytokines such as IFN-alpha have been shown to cause depressive symptoms in people. In fact, at high IFN-alpha doses, fully 50% of patients without depression will meet criteria for major depressive disorder within three months. Read Dr. Raison's review on some of this phenomena.
Recently, however, IL-6 has begun to be shown to have a slightly more nuanced role in a variety of ways. IL-6, while often associated with chronic inflammation and its associated diseases, as well as being an important part of the acute phase response to infection, can also be potently activated by exercise, even being necessary to confer some of the benefits of exercise such as improved insulin sensitivity.
In the context of exercise, IL-6 can serve an anti-inflammatory role through rapid activation of a well-known anti-inflammatory cytokine known as IL-10. It is, perhaps, for this reason, that Dr. Raison calls IL-6 Janus-faced (having two sharply contrasting characteristics).
In much the same way exercise activates IL-6, so too does heat stress. Perhaps more surprising, however, is that, according to Dr. Raison, his group found that the amount that IL-6 went up during the whole-body hyperthermia was predictive of the strength of the antidepressant effect a week later.
As Dr. Raison explains in this episode, there may be a few good reasons why this transient "hit" of inflammation that we see from things like exercise and whole-body hyperthermia may actually be helpful for depression, but one that stands out from the conversation is this: rather than the diminished neurotrophic support we see with chronic inflammation, shorter bursts of smaller or more transient inflammation seem to have beneficial neurotrophic effects.
Summary of discussion
In this nearly 2-hour episode, we discuss...
- The reason we may have evolved an immune-mediated depressive response in the first place, a hypothesis Dr. Raison calls the "Pathogen Host Defense" theory of depression or "PATHOS-D." Read Dr. Raison’s paper on PATHOS-D.
- How depression as a disease may be subdivided based on the involvement of chronic inflammation.
- The changes in functional brain connectivity that are associated with the high inflammation subtype of depression.
- The place inflammation may have in the treatment for depression, even among members of the low inflammation subgroup.
- How inflammation can play a somewhat double role where on the one hand immune cells can release beneficial growth factors in response to stimulation from cytokines, but on the other hand, how this response can become reduced from excessive and chronic stimulation over time.
- Ways to naturally elicit a transient but potentially beneficial "hit" of inflammatory cytokines.
- How higher eating frequency may help promote a low-grade inflammation due to a postprandial inflammatory response.
- The potentially therapeutic effects of whole-body hyperthermia for major depressive disorder.
- The physiological similarity of hot yoga with whole-body hyperthermia from the standpoint of potentially therapeutically boosting body temperature.
- Some of the short-term endocrine changes that happen during heat stress, especially related to the opioid pathway, which may help account for some of the anti-depressant phenomena associated with whole-body hyperthermia.
- The role of an important cytokine known as IL-6 in depression and how this cytokine which fluctuates during activities such as exercise and whole-body hyperthermia also exhibits anti-inflammatory properties through another cytokine called IL-10.
- How the anti-depressant effects of whole-body hyperthermia may actually intimately depend on the spike in IL-6.
- The role IL-6 plays as a myokine by conferring beneficial metabolic adaptations in response to exercise, including increased insulin sensitivity.
- How taking an NSAID or even certain antioxidants like vitamin C and vitamin E at the wrong time can diminish some of the benefits of exercise, such as satellite cell migration and improved insulin sensitivity.
- Heat stress as a means to sensitize pathways important to thermoregulatory cooling that also affect brain regions implicated in the regulation of mood.
- The thermoregulatory dysregulation found in other relevant psychiatric conditions outside of depression, such as schizophrenia.
- An evolutionary-biological explanation for why chronic inflammation shunts tryptophan, an important precursor of serotonin, into a neurotoxic pathway that produces a substance called kynurenine, which can become a neurotoxic NMDA agonist known as quinolinic acid that is powerfully associated with depression.
- How kynurenine can then go on to become a metabolite known as quinolinic acid which is powerfully associated with depression.
- How our muscles actually help us shift the metabolism of kynurenine away from quinolinic acid when we exercise, particularly if that exercise is endurance exercise.
- Some of the preliminary evidence that increased expression of a certain heat shock protein in the brain may influence behavior by protecting against stress-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 healing or transcendent purposes, but also potentially other practices like fasting and ultra long distance running.
- The role that heat tolerance played as a unique human adaptation enabling persistence hunting in early humans. Watch a video of persistence hunting.
- The staggering lengths that some indigenous tribes went through to induce a classical psychedelic-like experience as a rite of passage, including subjecting themselves to extensive bites or consuming them for their venom.
- 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 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 8-weeks.
- The place that some of these lifestyle interventions or hacks may increasingly have in clinical practices for the management of mood disorders.
- The dilemma clinicians face in figuring out which of their patients, around a quarter of the depressed population, will actually be made worse by the current standard of care SSRIs.
- 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.
- Dr. Raison’s perspective on so-called ancient wisdom traditions that may offer broad transformative value for creating states of mind that may be inimical to depression.
- 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.
- Andrew H. Miller
- Christine B. Whelan
- Christopher Lowry
- Daniel Lieberman
- David Mischoulon
- Hugo D. Critchley
- John H. Krystal
- Lucile Capuron
- Maren Nyer
- Michael Maes
- Rakesh Jain & Saundra Jain
- Raz Yirmiya
- Richard Davidson
- Robert Dantzer
- Roland R. Griffiths
Learn more about Dr. Charles Raison
- Raison Research Group
- The New Mind-Body Science of Depression by Vladimir Maletic & Charles Raison
- List of Publications
- Wikipedia Profile on Charles Raison, M.D.
Other relevant links
- WILD 5 program
- FoundMyFitness Episode: The Underlying Mechanisms of Depression
- FoundMyFitness Episode: Roland Griffiths, Ph.D. on Psilocybin, Psychedelic Therapies & Mystical Experiences
- FoundMyFitness Episode: Dr. Jari Laukkanen on Sauna Use for the Prevention of Cardiovascular & Alzheimer’s Disease
- Rhonda: Welcome back, my friends, to another episode of the FoundMyFitness podcast. I’m sitting here with Dr. Charles Raison who is a professor at the School of Human Ecology at the University of Wisconsin, Madison, and who is 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 FoundMyFitness podcast. So one of the reasons why I wanted to have you in, you know, 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 a sauna, it’s whole body hyperthermia, 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?
- Charles: Yeah, so it’s interesting. You know, when people began 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, right, I mean, originally, people thought the immune system was down to dealing with infection and the brain was about behavior. Now, of course, we know that they’re really one system. People thought about it in terms of immune suppression, you know. I mean, I think so many things were lost from the lives of people with depression that have 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 that get kicked up when you get the flu or something like that. Then when you looked at those sort of chemicals, they were actually elevated in depressed people. 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 alpha which was used somewhat in cancer, but a great deal for many years to treat Hepatitis C. It’s a chemical your body makes that basically turns on inflammation. You know, 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 wanna lay down. 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.
- Rhonda: At long term?
- Charles: 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 weeks of stopping it. So it really is the sort of drug, 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, you have the kind of infections that land you in the hospital, you’re significantly more likely to subsequently develop significant major depression. But significant schizophrenia and other disorders too. 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 it. 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 depression. Now we and others were some of the first suggests that it may in fact, there may be an evolutionary advantage to inflammation inducing depression. We can talk about that, but the fact that those things are linked, is pretty clear.
- Rhonda: Yeah, please do talk about the, because to me, what would be the advantage to developing depression from an evolutionary standpoint?
- Charles: Well, the argument here is that depression, 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 more likely to wanna kill themselves, are a little more likely to have sort of beat 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 given 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. 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 you see in sickness. So you see more of this elevation at night. 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, you know, very, very rapidly acting powerful treatment, you treat the depressed people, you measure the body temperature again, bang, it goes right down to the level of control people. So 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 albumin, and you get an up rise in the things like CRP. You tend to also do things like lose iron, lose zinc, and you say, why, you know, when you get sick, why do you slump your iron? Well, the answer is because the microbes, especially intracellular bacteria, need the iron more than you do. They have to have that iron to replicate. You could 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 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 a 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, it’s 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 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. So, you know, a fever is an anti-pathogenesis, an antibiotic strategy, right? 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, you know. 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 why you weep and cry. And, you know, maybe it be 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. 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? 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 afflicted by other people just, you know, just get scraped, getting cut up. The things that kill you from trauma are much more likely to be extracellular 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 pre potent inflammatory activation so that your immune system kind of run to their guard stations, it’s like smoke alarm principle, you know. Stress means you’re at an increased risk of dying from a wounding-based infection. So stress becomes reliably associated with inflammation. 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 a 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 and for adaptive purposes, than it actually is in terms of mechanism. That’s interesting.
- Rhonda: 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...
- Charles: On evolution.
- Rhonda: Yeah. However, I didn’t quite read too much into that. But that is certainly, a very interesting hypothesis. I’m not sure exactly sure how you would test that, but it makes sense.
- Charles: Well, there are so many interesting ways to test it, right? Some of it, of course, is just cross-sectional. 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? That the form of the gene that’s associated with depression, does it provide any anti pathogen benefits? It turns out that almost 100% of the time it does. So if you make a list, think about something like MTHFR gene 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-inflammatory. And it’s strongly associated with increased survival in sub-Saharan Africa, because in sub-Saharan Africa, so many people innocently die of Hepatitis B, and the form of the gene that may be a risk factor for depression is actually protective against that illness.
- Rhonda: Fascinating.
- Charles: In one of our papers, we rustled up maybe 30 genes and showed that 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. There is 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. They did this fascinating study where they looked at this sort of haplotype in the 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, you know, clean water, not going to die from infection, if you have the high TNF, low IL10, the sort of the pro-inflammatory haplotype, in the parts of the country with low pathogen, you die sooner. But in high pathogen areas, you’re protected. And the protection all occurs in the early part of a lifespan, up to the age of 40, where across evolutionary time, that’s where you wanna 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 really, there’s another really interesting thing, which is, you know, you and I share, I’m sure you share with me an interest in this possibility that part of the link between sort of a metabolic immuno-disturbances and behavioral disturbances may be an evolutionary mismatch in modern times, right? So we know that there is likely to make a laundry list of factors of the modern world that are pro-inflammatory, and that are associated with depression. There is an idea, and I’ve written a lot about, 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 the sort of evolutionary mismatch between the way we live now that’s so pro-inflammatory, and how we evolve to live, right? 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 diet has become more pro-inflammatory, where we’ve been separated from a lot of the immune-regulatory 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 in people that are not living in a modern lifestyle. So one argument, and again, these are circumstantial arguments, but one argument for the fact that perhaps this link between inflammation and depression, sort of an evolutionary purpose, is that it should precede modern environments. So these folks they’re anthropologist at the University New Mexico, actually went down to this group called the Tsimane, which they’re kind of agriculturalists semi hunters gatherers down in the lowlands of Bolivia. So they actually went down there to test these ideas, and so they 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, they found, first off, they found that folks living in this completely different much closer to the way most humans lived across most of the time, depression looks 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. 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 I, particularly think that the link between inflammatory activation and depression goes way back in the mammalian phylogeny, and really, probably initially had to do with our ability to manage our relationships with the microbial world, not as much our relationships with conspecifics, although it later got usurped for conspecific stuff.
- Rhonda: 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 having this evolutionary origin, and modern day mismatch. Because...
- Charles: It’s probably a two hit.
- Rhonda: Yeah.
- Charles: Too bad.
- Rhonda: Right. And if you think about it, for example, and 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 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.
- Charles: Absolutely.
- Rhonda: Has there been any evidence to see whether or not the inflammation is driving that?
- Charles: Oh, yes. Absolutely. The best paper I know, that was done by Lucile Capuron and Andy Miller, Lucille is in Bordeaux, Andy is at Emory, where they looked at, you know, they looked at cognitive behavioral disturbance, body mass index and inflammation, and showed that the link between sort of obesity and these behavioral cognitive problems were mediated by the increased inflammation, right? Anybody in this field knows 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. I mean, there’s just a linear relationship. I just did just this huge study on like 600 people with a large pharmaceutical company where I worked with them on data looking at prediction of inflammation and response to medication. And, you know, man, it’s just a straight line. The heavier you are, especially, and unfortunately for us men, big, big production of... Because we know that fat cells are big producers of inflammation.
- Rhonda: Exactly, right. What about how they’ve 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, does their depression risk decrease? Like is there any evidence of that?
- Charles: The only data I know of on that, are people that have had these gastric bypass surgeries for weight loss. There is some data showing that they’ve been administered kind of quality of life wellbeing mood stuff, people’s moods get much better. Now it’s confound, though, of course.
- Rhonda: Yeah, of course.
- Charles: Because, you know, all of a sudden you can get into your bikinis.
- Rhonda: Look better. Yeah.
- Charles: But it would be consistent with that idea.
- Rhonda: Yeah. It certainly would be interesting to look at that, you know. In terms of some of the studies you mentioned where you’re, you know, administering pro-inflammatory cytokines, like interferon alpha, and I think...
- Charles: Endotoxin typhoid.
- Rhonda: 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 many red blood cells. 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.
- Charles: I think it’s beta.
- Rhonda: It was beta?
- Charles: I think so.
- Rhonda: But what was interesting is that he had to like leave the trial because his mood was traumatically affected. He’s usually 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 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 barrier and nothing is penetrating it, you know. Now we know these things are connected. You know, in fact the lymphatic system is...
- Charles: Absolutely.
- Rhonda: ...connected to the brain, this inflammatory mediators are crossing the blood/brain barrier, getting into the brain and, you know, disrupting neurotransmission.
- Charles: Absolutely. Yeah, cells get into the brain. This is the work of Jonathan Keith, 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 the folks in London, Hugo Critchley's group, they tended to use typhoid, and they showed that right, you know, you give normal folks a shot of typhoid which activates a sort of acute mild, it’s not going to interferon is like a sledge hammer, right? I mean this is more like a, like... But you do that and you got people report feeling more socially isolated, they feel more dysphoric, and you see changes in their brain that sort of speak to depressive brain functioning. And the folks at UCLA used the LPS endotoxin, sort of it’s all 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 is 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 Raz Yirmiya in Israel, where they took mice, and I’m pretty sure it’s mice, not rats, and subjects them with this 20-day horrible stressor. They showed that the stressor crazy activates inflammation, leads to apoptosis, death of microglia cells in the brain and, you know, huge anxious depressive behavior afterwards, right? So what’s interesting was they showed that if you block the inflammation right before the start of the stressor, sort of it starts, you block it, you can prevent the apoptosis, you can prevent the downstream behavioral effects, it’s protective. If you do nothing here and you let the little rodents go through the horrible stressor and you block the inflammation afterwards, they do worse. If you stimulate inflammation, they get antidepressant response. So there’s a little bit of a background, 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, Tumor Necrosis Factor Alpha, IL1 Beta, IL6, at lower levels in the brain, they actually have neurotrophic effects.
- Rhonda: Kinda like a hormetic stressor, where they’re active?
- Charles: We don’t know, is it stressor, or is it just that they evolved? Nature is so cheap, you know, it always wants to reuse things. That’s what makes things, evolutionary processes do this constantly, and that’s why things are, one of the reasons why biological systems are hard to understand. You know, if they’ve generated TNF knock-out mice they, can’t find their way out of a bag, they are as dumb as dirt. There’s something about lower levels of these mediators that may actually be beneficial in the CNS, at least. And then there’s sort of a you, and then all of a sudden man, very, very rapidly, they become what we think of us as counterproductive. You know, they become depressive inducing, they 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. It may be the case that the reason that you get the 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 it’s interesting, if you look at what...when inflammation gets activated in the CNS, it has a trophic effect. It doesn’t just go everywhere. It tends to go to an area called the Cingulate Cortex, and the dopamine area is down in the Ventral striatum. We and others have suggested that it may be a way 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. We now know that many of these sort of CNS organisms, like [inaudible 00:24:33], you know, the thing that, no, it will come to me, that drives crazy dopamine behavior, that a lot of times, these microorganisms will actually change behavior in ways that benefit their survival and reproduction.
- Rhonda: Toxoplasmosis.
- Charles: Yeah, toxo. Right. There’s probably an evolutionary reason for why you see the U shape 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, inflammation is elevated in depression, 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 got 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 in, day out, that’s enough to set you up for every evil thing: heart attack, strokes, dementia, I mean, because it’s a gradual wear and tear. But then 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 may be what you were looking at here was that depressed people, that they’re all in 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. This is the work of my mentor, Andy Miller, in the last five or seven years. They’ve just been world leader 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 cut off, but the people that have higher levels of inflammation and depressed, have different functional connectivity in their brains than people that have lower levels. 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 a kind of a not chronic inflammation, but a hit of inflammation. When we get around to talking about hyperthermia, I can tell you that there’s some evidence that hyperthermia does that, exercise does that. You know, 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 that 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.
- Rhonda: And with the exercise, I’ve read now several studies where exercise is, 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 hormetic effect, because exercise does elevate inflammatory processes acutely and then there’s a response. Yeah, anti-inflammatory response and anti-oxidative that, you know, 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-prandial, so after you eat a meal.
- Charles: Oh, yes. That’s a big...
- Rhonda: It is. What’s interesting to me is I’ve only really, I’ve heard one other person, one of a colleague of mine who’s brilliant, his name is Mark Shigenaga. He is a gut expert, so he studies the gut, gut health, microbiome. He talks about how this postprandial inflammatory response occurs, because food is hard on the gut and...
- Charles: It’s a foreign substance, the risk. I mean, thousands of people die every year from eating out in the United States.
- Rhonda: 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 to some degree, gets compromised with every meal, you’re releasing a little bit of endotoxin in the bloodstream, because your immune system is activated.
- Charles: Leaky gut.
- Rhonda: Yeah, and so 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, that exercise had on that.
- Charles: No, I don’t think that that... But we’ve written about this phenomena.
- Rhonda: Oh, you’ve written about it? Okay.
- Charles: Well, you know, and the other thing is when you eat, it kind of gives you fever. Do you know about diet-induced thermogenesis? So every time you eat, your body temperature elevates. It’s why people sweat after they eat, you know, because it’s not a fever per se, because I don’t think it is... I don’t know whether upper regular is a thermal related 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, you know, any time 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 risk of infection and death, there’s a risk of pathogen manipulation, there’s all sorts of things. So it shouldn’t be surprising that that happens, nor should it be surprising that fasting has a powerful anti-inflammatory effect. There’s some beautiful data in animals, but also beautiful data in human too. There was a study in 19 normal volunteers, and they looked at the effect of a, like a 24-hour fast on something called the NLRP3 inflammasome. It’s the intercellular thing that connects up and it activates inflammation, turns on this thing called IL1 Beta. So you fast, and that the expression, the gene expression for that complex, just goes down, down, down, down, down. Then they let the people eat again, it goes up, up, up, up, up. And they look at sort of leaky gut, and you find that eating sort of opens the gut up to leakiness too. Which may be just a bummer, that 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 when you kind of get things kicked up in your body, you look around. I think the core idea here, and we’re talking about this in terms of the evolution of depression, is nature is really smart. It’s a compromise, it’s not perfect. But, you know, you go, “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 evolved strategy that every time you are exposed to death by an infection, the body responds with a little bit of pre potent 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 a smoke alarm principle. That little bit of damage is more than outweighed for the one time you don’t do it then you die.
- Rhonda: Yeah, right. So it totally makes sense, because the gut is what is exposed, the internal environment, I mean. So that’s...
- Charles: I mean, when you think about it, that’s the big one, right?
- Rhonda: Right.
- Charles: I mean, the skin is a much more robust protector against... Any membrane that’s wet, it’s just bad news in that way. But it has to be for us to survive to eat, and it’s sort of the compromise that we’ve evolved.
- Rhonda: I’m pretty interested when you’re mentioning this hyperthermia in terms of, you know, 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 hyperthermia 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 it is?
- Charles: Oh yeah, yeah. It’s just the heat.
- Rhonda: Okay.
- Charles: I mean, the machine is 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 know, you’re getting that heat on your skin. It’s hard, right?
- Rhonda: It’s definitely hot.
- Charles: 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. I’ve never been so... So to back up, yes, you’re right, we did do a study, and we treat people to a core body temperature of 38.5 centigrade, which is 101 point something or other, which is unbelievably hot if you don’t wanna be that hot. I mean, I’d 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 desert summer, you know. It’s really hot. It’s mild hyperthermia, but it’s hot. Now we have colleagues, David Mischoulon and Maren Nyer at Harvard that have joined us in hyperthermia work, and she especially is interested, and has a grant to study hot yoga, and convincing people to wear a rectal probe when they’re doing hot yoga. And hot yoga, which also, you know, makes people sweat like pigs, elevates core body temperature too, interestingly, exactly the same place, 38.5.
- Rhonda: Oh, wow.
- Charles: Right. You know, a lot of people when I talk about hyperthermia, and I give talks to folks. A lot of people, if it’s a crowd, will come up afterwards and say well, “You know, hot yoga.” And like, a lot of people are hooked on hot yoga, and it’s because, I’m convinced it’s because it’s an anti-depression strategy. That they are 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 and their core body need to be elevated for at least another hour. So even the timing of hot yoga is probably consistent with sort of our hyperthermia machine.
- Rhonda: So the hot yoga, sauna, I mean, maybe a hot bath, like if you say, so basically anything that’s...
- Charles: It’s the heat.
- Rhonda: Yeah.
- Charles: Yeah, that’s true. There’s some interesting data on hot baths improving autistic symptoms, right? There’s people looking at this in New York, right? So yeah, there’s a story there.
- Rhonda: Yeah. There’s a personal story for me 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 the YMCA, and they had a sauna there and so I was just, you know, using the sauna. I’d go into this, I’d use the sauna before I would go into the lab and do my experiments for the day.
- Charles: Yeah.
- Rhonda: And, you know, as you know, graduate school is extremely stressful, failed experiments sometimes setting you back six months, and lots of stress.
- Charles: Your career going up in smoke.
- Rhonda: Yeah. I mean, just 16-hour experiments you have to do, and you’ve got to publish and they’re new, and you’ve got to publish... Well, 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...
- Charles: More chilled out.
- Rhonda: Yeah. It’s so much easier for me to deal with all the stress. And it was extremely noticeable, enough for me, you know, to start to go, “Something’s going on here.” So I started looking at the literature. Of course, my husband, Dan, was doing the same thing, and he had definitely noticed the same thing. So what was really interesting, I looked in the literature and found, you know, that using, that heat stress in general, increases...you dump a bunch of beta endorphins. Well, that’s obvious. That happens with exercise. I think part of the, like you mentioned, you know, you’re 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 kappa opioid pathway, so mu opioid receptors bind endorphins, and kappa opioid are sort of the opposite of endorphins, is sort of the dysphoric.
- Charles: The kind of depressorgens.
- Rhonda: Yeah, dysphoric feeling. You don’t feel great. And he was telling me about some research with if you agonize that receptor, the kappa opioid receptor, what ends up happening is the 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 dynorphin, is up regulated when you’re exposed to heat, because it cools your body down. So I started to go, “Wow, I wonder...” You know, so for example, there are studies where you expose rats to heat stress and they increased their dynorphin. I thought, “Well, what if the dynorphin binding to the kappa opioid receptor does actually sensitize mu opioid receptors to beta endorphins?” 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, you know, weeks later, I’d still feel really good.” So that’s sort of an interesting personal story for me. I’m not sure if you’ve ever looked into the dynorphin or beta-endorphin.
- Charles: Well, so this is a fascinating thing. Yes, indeed. So it turns out, you know, that almost certainly, within the next, sort of in 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 kappa receptor, so it’s exactly opposite. Now interestingly though, and I have an interest in psychedelic medicines, something called ‘Salvinorin A’ is a kappa agonist, and is also of some significant interest at lower doses as an antidepressant, right? So here’s an example of this phenomenon. It’s a meta issue, and I don’t mean like meta like the Buddhist meditation, but meta, M-E-T-A, that opposites sometimes do the same thing. It’s interesting, there’s thing called an enantiodromia, goes all way back to Heraclitus, back in the... That right, sometimes you can get the same effect by doing opposite things. So right, the fact that hyperthermia stimulates kappa receptors, and the fact that blocking them could maybe also have an antidepressant effect, it’s fascinating but it’s consistent with this sort weird, again maybe kind of U-shape 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 looked at a bunch of immune stuff.
- Rhonda: And what did you find with the hyperthermia?
- Charles: Well, we found that hyperthermia does exactly same thing that exercise does.
- Rhonda: Okay.
- Charles: Which is not so surprising, right, but which is quite interesting. So to kind of want 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 one beta and the tumor necrosis factor, so IL1 Beta and TNF. They get activated, they do all sorts of stuff. They’re really pro inflammatory. They secondarily activate another cytokine called interleukin 6, or IL6. Now, IL6 is a bad guy, I think. 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’re going to get strokes, you’re going to get cancer, you’re going to get... You know, it’s a bad deal to have your IL6. It’s going to shrink your hippocampus. We know a lot of stuff about that. So it’s a bad boy. It’s activated by IL1, but it’s a sort of secondary. We’ve also known for years that, I see it sometimes as a Janus-faced cytokine. It faces two directions, because it also has anti-inflammatory effects, it activates IL10. So what you see with bad infection, IL1, TNF, they shoot up, IL6 goes up and you’re sick and that’s how it is, right? What exercise seems to do is it activates IL6 like crazy, but it doesn’t activate IL1 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 horrible 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. That’s anti-inflammatory thing you’re talking about, right? So you get this IL6 response, and then you get the sort of IL10 coming along, which is powerful anti-inflammatory. That’s what we see with hyperthermia.
- Rhonda: That’s so cool.
- Charles: Yeah. So in this study, you know, the challenge...we did a first small, open, sort of clinical study in Switzerland with these colleagues of mine. Found an old hyperthermia machine in the basement of this crazy alternative treatment psychiatric kind of castle, hospital. One of the guys is an engineer, he rebuilt the thing and we started just sticking people in it. We saw this powerful antidepressant response that we only looked to people five days later, but clearly, five days later their scores were generally cut in half, right? 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 make it everybody is sitting in the box, you get hot and you go, “Oh my God, you’re doing something for me.”
- Rhonda: Right.
- Charles: So we had to invent a placebo, or some kind of compared, you know, 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 with my colleague Walter Johnson, 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, kinda comfy, toasty but not like you’re going to die of the heat. And so we put people in the box, we turned on the fake lights, we turned on the heating coils down there and the fan. More than 70% of 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 the vast bulk says, “Oh, we got to the real.” Because they were warm, and you know. Not everybody who got the real thought they got the real, it’s interesting. I mean, their sweat is pouring off the body, but kinda masochistic if you’re going, “There must be something worse than this,” right? So the fact we saw this massive difference between the two suggests that it has to do with the heat. In effect, we, just recently we’ve now realized that in fact, the fake group, the sham group, they got more heat than we probably should have given them. Some of them actually went up, and those people had the same kind of antidepressant response as the other people. 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 that got the real treatment, IL6 shoots up. Now, we measured it beforehand, after. And like Dum-Dums. We should have measured it like six hours later, but we measured a week later. By a week later and four weeks later, all the immune measures were back to normal, there was huge IL6. We looked at maybe 12 of these cytokines, and none of the other ones moved. So it’s just IL6. Now, what’s interesting is the higher the IL6 went up, if you look at the whole population, the higher the IL6 went up, the more un-depressed you were a week later. There 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 which you noticed from taking a sauna, it nicely correlates with increased IL6. If you had an increased IL6 response, you’re going to be happier. Now this just flies in the face of this idea that inflammation is just depressogenic. It really suggests that it depends. It depends on how long it is. It depends what context it happens, and it depends on how you think about something like IL6, right? So then, you know, 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 Dantzer, down in Houston. I said, you know, “How could this be?” and he said, “Well, measure something called Neopterin.” Neopterin is a chemical that’s really only made by activated immune cells, by monocytes, these innate, immune pro-inflammatory cells. So we measure neopterin, neopterin also went up, and it correlated very strongly with the IL6. 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: Simmie Foster and the folks I’ve mention Dave Mischoulon and Maren Nyer. I think what’s going on is that IL6 is not just activated by immune cells that we were talking about earlier. It’s activated by fat cells, but it’s really activated by muscle cells in the context of exercise, or in the context of heat. There’s animal data showing that if you induce heat shock, so if you really heat up a road, you get massive IL6 production from the muscle cells that spills in 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, so, you know, you talk about the immune system, and the brain being one unified organ. Really of course, so are the muscles. IL6, which we think of it as mostly inflammatory cytokine in the context of sickness, is a myokine in the context of exercise. 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 IL-6 in a row that exercises, you block all the beneficial metabolic effects.
- Rhonda: Oh, wow.
- Charles: 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 humans. If you exercise and take a non-steroidal anti-inflammatory agent, you get rid of all those good effects.
- Rhonda: Right. Right. Yeah.
- Charles: You’ve seen that, right?
- Rhonda: I think I’ve seen that. Also, there was another study very similar to the anti-inflammatory, where they’re saying the NSAIDs. So there’s another study that showed taking high dose, alpha-tocopherol, no, vitamin c, so antioxidants, also suppressed the insulin sensitivity effects of exercise, possibly through, because you’re not activating that whole inflammatory.
- Charles: Well, exactly. What you really would like to do is sometimes activate these compensatory systems, right?
- Rhonda: Right.
- Charles: If you can activate your inflammation in a way...You know, if you think about exercise, right, we were talking off camera, I think we were off camera, about the fact that I’m going to go run around Mission Bay here and I’m going to get an increase in my inflammation. Well, with these caveats, that it’s a certain pattern, but you get certain your IL6 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 kinda 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 weakens. You’ve been using this with hormesis right?
- Rhonda: Exactly.
- Charles: Exactly, this idea. Doing this weakens the system’s own sort of internal capacity, so what you get is a dependence on that external element to keep the system in that state. 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, it sort of drives the system into that other state. We have some evidence from this hyperthermia, 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 is true. So in the European study, we actually very successfully measured core body temperature the day before they got to treatment, and five days after. What we found was that the hotter you were before you got into the box, the better antidepressant response you got.
- Rhonda: I was going to ask you about.
- Charles: Right. What we found from five days after being in the 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.
- Rhonda: Long term, you mean?
- Charles: Longer term.
- Rhonda: Which would be like a, almost like a hormetic effect.
- Charles: Yeah, it is. We toughened the system. We toughened up the system. We recalibrated. And this is really the work of my colleague, Christopher Lowry, at UC Boulder, in Colorado. What we think we’ve done, is sensitized thermal regulatory cooling pathways so that the heat actually exercised them in some way, or shocked them into being more sensitive. There is a giant literature on this fact that thermoregulation is impaired as we said in depression. Depressed people can’t cool off. They can’t sweat. They can’t cool off. So what we think we’ve done is sensitized the pathways of 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-depressants levels.
- Rhonda: It’d be interesting to look at dynorphin, that whole system. Because that is involved in this.
- Charles: I know. Because it’s also, what do they call it, a cryogen, it cools.
- Rhonda: Yeah. Don’t schizophrenics also have a similar problem in terms of thermal regulation?
- Charles: They do. They’ve got really, really crazy thermal regulatory challenges, right? So that means when you see folks out, you know, it’s a tragedy, when you see them out on the street, one of the things you notice about schizophrenics is it can be hot, and they’re wearing three or four coats. So they really, really have thermal regulatory problems. If I think about it for a minute, I’ll be able to tell you there’s a study where they found that they do better...so what do they do better? 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.
- Rhonda: The thermal regulation. Yeah.
- Charles: But their thermal regulation is absolutely whacked, right.
- Rhonda: Yeah.
- Charles: I mean, you see these guys, you know, and women, right? So it’s not just depression.
- Rhonda: I was making a mental note when you’re talking about IL6 being a myokine in the muscle. Because, you know, a very interesting, there’s a few interesting studies that have 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 kynurenine pathway. I guess, you know, for people that aren’t familiar with kynurenine, it’s basically a byproduct of tryptophan metabolism. When your immune system is activated in the case of chronic inflammation, for example, you’re not converting tryptophan into serotonin, you’re actually converting into something else called kynurenine, which activates immune cells. But the problem is that kynurenine can form is it quinolinic acid?
- Charles: You can find kynurenic acid and quinolinic acid, that’s right. Quinolinic acid is definitely a neurotoxic agent.
- Rhonda: Okay. It’s evolved into depression, somehow?
- Charles: Yeah, it is. We actually did the study, again, this is Andy Miller and I, years ago in the interferon alpha work. We had the good sense to do spinal taps on people, right? So we drew up the fluid around their brain spinal fluid, and looked to see does chronic inflammation delivered by interferon-alpha change serotonin metabolism? So Michael Moss and Lucile Capuron, and a number of people in the early 2000s, began to show that chronic inflammation activated an enzyme called Indoleamine 2,3-Dioxygenase. This is an enzyme that basically, as you said, takes tryptophan and shunts it away from serotonin into kynurenine. 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. I can’t remember, I used to know all this stuff, but there are certain infections where they’re just lethal.
- Rhonda: Wow.
- Charles: I think Leishmaniasis is one of them. I think, but I’m not sure about that. So anyway, yes, you get everything is shunted to kynurenine. 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 kynurenine to tryptophan, and that tells you how active enzyme is. We got spinal fluid and showed that indeed, and this is really interesting, that the interferon definitely jacks up kynurenine. Kynurenine 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 kynurenic acid. Setting aside the kynurenic acid, which is interesting. It’s an NMDA antagonist. Quinolinic acid is an NMDA agonist. It causes neurotoxic effects. Quino linic acid skyrocketed under interferon treatment. That’s what’s associated with depression, powerfully. Now, on the other hand, we actually measured tryptophan in the blood and the spinal fluid around the brain, and there was no effect if tryptophan falls in the periphery, but it’s maintained in the brain. So there’s a, I can’t remember the name of it, but there’s, it’s an amino acid pump, it’s got a fancy name, that basically actively transports amino acids. So although we never really followed up on this, the suggestion is that when you’re under chronic inflammation or some sort of, what’s the word I wanna use, accommodation that’s made so that your tryptophan, you preferentially shunt tryptophan into the central nervous system, probably because you’ve got to have serotonin in there.
- Rhonda: Rights. 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 that exercise, so the transport system that transports tryptophan in the brain also transports branching amino acid like isoleucine, which unfortunately, outcompete tryptophan. However, exercise causes this branching amino acid to be taken up in the muscle cells, and it sort of alleviates the competition of tryptophan.
- Charles: So you get more tryptophan.
- Rhonda: You get more serotonin.
- Charles: Right, that’s interesting. So inflammation has hit upon sort of the same thing. So really, it looks like exactly is that kynurenine and its metabolites almost, I mean, those are results that have been replicated. But they’re probably more relevant bad actors through that pathway in terms of the depression genesis in the context of inflammation than is the drop in serotonin.
- Rhonda: Right.
- Charles: Right.
- Rhonda: Yeah. So the studies that I was wanting to talk about, or tell you about, you probably have seen them, but where exercise, this has been shown now, it first was shown in animal studies and then more recently in the past, I think it was 2017, it’s been shown in humans where it causes muscle cells take up kynurenine so they can’t form quinolinic acid, which then means you’re not getting that.
- Charles: Exactly, so you’re not getting all that, that’s right.
- Rhonda: So there is another mechanism that was...
- Charles: It’s fascinating.
- Rhonda: Yeah. And I’m not exactly sure why that happens, or all the logistics, but that’s another very interesting way, this exercise inducing the hyperthermic effect and the anti-inflammatory effect after the inflammation is generated, this hormetic effect, the increased serotonin getting in the brain, because the trypto... There’s so many different mechanisms by which exercise seems to affect 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.
- Charles: These things do interdigitate with each other in really interesting ways, don’t they?
- Rhonda: Yeah, they do. Are you familiar with heat shock proteins?
- Charles: Well, that’s what we’re looking at with the Harvard folks.
- Rhonda: Oh, really? Take a look at, if you’re not familiar with this study, I may have sent it to you, “Heat Shock Protein 105.” There was a study in mice where, I’m not sure, I didn’t read the whole method section, how they induced the heat shock 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 had increased heat shock protein 105 were protected from these depressive symptoms, you know, after their, whatever stress tests 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, like an inflammation.
- Charles: What we think now is actually the heat is probably activating the heat shock proteins, which is then, you know, contributing to the IL6 being released properly from the muscles, which is then...we haven’t done the study yet, so I don’t know. But we’re going to dump some IL6 on immune cells to see if it can produce neopterin. Because then it’d be sweet, then we’d know well, you know, it wasn’t the immune cells that were making the IL6, it’s the IL6 then is maybe driving secondary immune effects, right? Please, do send me that, because I, you know, I’m trying to bone up on... 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 I like, you know, pop stars. Their songs all sound similar, 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 up at UCLA, you know, I mean, and somehow over the last 20 years, I’m now having to teach myself about heat shock proteins.
- Rhonda: Right.
- Charles: How did this happen? You know, I was just an immune system guy just trying to mind my own business. The subtlety of evolved natural processes take you places.
- Rhonda: Isn’t it the best?
- Charles: It’s the best. It’s just the greatest damn thing.
- Rhonda: I mean, if the same thing happens with me, you know, coming from a biochemistry background and studying metabolism, and cancer, and all this, and I’m like into the brain and autism, and I just getting serotonin. You know, I love it. You know, it’s absolutely true that it takes you to very interesting places. Certainly, biology is always surprising you, you know. It’s never like you predict.
- Charles: Yeah, that’s right.
- Rhonda: But we were talking a little bit like off camera, about some of the, you know, you were talking about these, some societies, that were doing these running long term, running as a sort of possible treatment for depression, or?
- Charles: Well, not treatment for depression, these are spiritual practices.
- Rhonda: Okay.
- Charles: So one of my interests, and this is what we were talking about off camera, was... It’s complex how I came to this, but, you know. So I was a clinician, saw thousands and 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. One thing led to another, and it’s interesting to trace the steps, but I began to realize, you know, we begin to look at interventions based on these things. I begin 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, like I said, I’m not 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, probably a couple of million years of hominid evolution that reliably signaled either wellbeing and sort of evolutionary success, or danger and failure. We sort of need those signals to orient ourselves rightly in time, space and behavior. A lot of them have been just profoundly disrupted by the modern world, and so what you get in the modern world this is wonderful opportunity to do things you never could have done in any sort of hunter and gatherers 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, bring back some of, ways to bring back these ancient wellbeing inputs, and integrate them more into our lives so that we get the foundation of a felt mind, body sense of stability and wellbeing, right? 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, you know, probably in Paleolithic times, but certainly in the last 10,000 years. You can make a list of them. It turns out that there are a lot of things we were talking about. So 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 a 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, auto immune problems we have, but I also think a lot of depressive problems.
- Rhonda: You’re talking about the gut microbiome?
- Charles: Microbiome, but also not just in the gut, but there’s a lot of pseudo-commensal. So we existed in a world where trillions of environmental organisms pass 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. Of course, things that pass through us also then marginally, they want to live within us, that they form kind of a home in. So in that way, there’s an immunological story around ancient associations, around the fact that really we would do well to sort of recalibrate ourselves. We don’t wanna be hanging out with, you know, we don’t wanna go back to the times when 50% of everybody born was dead by 15 from infection, but we don’t wanna throw the baby out with the bathwater. We want to reintegrate the sort of beneficial bacteria, and not just bacteria, but viruses and fungus, and the whole...We wanna 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? It’s astounding, the number of cultures in the world that use phasic exposure to high heat for healing purposes, or for transcendent purposes. I mean, we’re sitting in the new world, and certainly, the use of things like sweat lodges, and Temazcals were just were rampant in new world indigenous cultures, but across the old world too, you know. If you look at the healing rites in the ancient world, you know, hot baths were just a huge part. So it’s a widespread human thing. 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? I mean, why would you repeatedly stuff yourself in a smoky, hideous, dark, miserable, sweat lodge, right? Answer, because that’s what sort of face heated exposure induces profound states of positive wellbeing that have antidepressants effects, right? There is one. Fasting. You know, almost every religion worth its salt, both indigenous and the sort of world religions, have fasting is 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 that looking at fasting for related things like pain. And the many studies have given mood questionnaires, fasting has powerful mood elevating effects, and it almost certainly has antidepressant 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. 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 those things that exist in those communities. And it’s been very successful, it’s interesting. There’s community for instance, in Navajo land, they’ve got some great things going on where they’re re-exposing kids to long distance running. I have a long connection with Tibetan Buddhism, and that was very much a practice there. In Buddhism, and we were talking about this off camera, but there’s 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. Only 48 people have successfully done it since the 1850s. But why would you do this? Well, you do this because it’s believed to be a massive inducer of transcendent states. It’s a way to achieve Buddhahood 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 wanna know as you wander around in your life, what are the states where you come closest to the mind of the Buddha, one of them is running to the point of exhaustion. Now, others are sneezing, urinating, defecating. There’s a whole list of them. It turns out that from a tantric Buddhist perspective, rapid shifts in autonomic nervous system functioning seem to be the sort of simulacrum for, you know, the mind of enlightenment, but running to the point of exhaustion being one of them. So running especially, because you think about across evolutionary time, they didn’t have bicycles, they didn’t have the things we have now so it’s not so surprising. Now, of course, you know, this ties in, because I’m kind of a reductionist. I’m always interested in how these sort of spiritual practices were exacted out of behaviors that were necessary for survival and reproduction. You know, there’s this really interesting, Dan Lieberman is kind of the famous guy at Harvard, but there’s this idea that human brains may have evolved largely in response to long distance running, do you know that? Like persistence hunting.
- Rhonda: Yeah, I know. I didn’t know about this theory.
- Charles: Oh, yeah, yeah. So this is really, really interesting stuff. You ever wanna go do it, I can hook you up with the guys who do this. Humans are the greatest thermal regulators in the animal world, right? 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 a human being for 100 miles in a hot environment. 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, there 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 of our body was that we were first able to stand upright and thermal regulate, that we were able to sweat, that we were able to cool off. And remember we were talking about thermal regulation being abnormal depression. Thermal regulation 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, essentially, humans can outrun them. And outrun them meaning that the animal develops heat stroke and dies, right?
- Rhonda: Wow.
- Charles: There’s some great footage, you can just on Google. If you just type in “Persistent Hunting,” David Attenborough, back now I think 30-40 years ago, went out with a group of song bushman and showed that they could run an eland to death. Astounding, they ran this huge animal. The animal runs but it just, keep it moving enough that it can’t cool off, and then finally just stands there and it goes...
- Rhonda: Because it can’t sweat?
- Charles: It can’t sweat. It’s dying of heat. It’s heat shock. The guy just goes up, kills it, hauls it back and eats it, right? So humans, you know, I think many of these ancient practices that induce heightened states of awareness, evolved out of strategies, unique human strategies for survival and reproduction. But then they become fascinating on their own. Exercise is one of them. Another one that I’m particularly interested and involved with is psychedelics. If you say, “What’s another thing that humans all around the world did repeatedly and for extended periods to alter consciousness?” It’s psychedelics. It’s much older than just humans. You know, 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 a certain kind of moss. So there’s something about mammalian brains that are drawn to substances that induce the sort of altered states of consciousness, and widespread use of psychedelic medicines, psychedelic substances around the world. You know, you say, “Well, what do these things do?” Well, they tap into this interesting human evolved capacity for transcendent states. You know, they can be induced in all sort of other ways. One of the most species typical human behaviors is trying to put yourself in a whacked state, you know, a trance state. Dancing, I mean, there’s a whole list of these things. 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. Prior to them all being wiped out, the Yokuts, that were the indigenous groups 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. Their bodies would be completely covered with ants and bitten, bitten, bitten, bitten. And the ants, I don’t know whether 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...
- Rhonda: That’s crazy.
- Charles: Yeah, that’s the length people would go to induce these experiences, because they were so integrated into certain societies.
- Rhonda: Why puberty? Was it like a coming of age?
- Charles: 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 trance-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 points you to the spirit world so that you can have, you know, you’re not going to have the same potency of the 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. So I think that’s why they were used there. Now there’s some evidence that “The Eleusinian Mysteries” of ancient Greece, which we know very little about because they were all kind of hush-hush. But there’s some suggestion now, I think in the last 20-30 years, some researchers suggest 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 a Greco-Roman world, you know. And we know so little about because it was so secret, but they were very widespread. Another example of these things being used, not just at puberty, but for these sort of transformational purposes, and I know you would, off camera you told me you interviewed my colleague, Roland Griffiths.
- Rhonda: Yeah.
- Charles: And so a number of us are now involved in this work of looking really rigorously at psychedelic substances as treatment for depression, because Roland and Steve Ross at NYU, Roland at Hopkins, showed that, you know, a single exposure to something like psilocybin, which is a psychedelic substance in magic mushrooms, you know, tends to induce you to very unusual states of mind, that often have a kind of mystical characteristic to them. A single exposure in a couple of studies induce these powerful anti-depressive responses that last for like six months, longer. I mean, I know from Steve, you know, that he’s followed up on people, these are depressed, anxious people with cancer, that those who are still alive two years, later many of them, most of them are still un-depressed and not taking...
- Rhonda: After one experience?
- Charles: Profoundly life transforming.
- Rhonda: That is phenomenal.
- Charles: Oh, it’s fascinating.
- Rhonda: Yeah, I mean...
- Charles: It’s one of the most fascinating things going in our world right now.
- Rhonda: I know with my discussion with Dr. Griffiths, he was mentioning, again, he did say that this mystical experience seemed to be important for the antidepressant effect. Of course, he doesn’t really know the mechanism why, but parallel to that, there are also some studies looking at a part of the brain that’s involved in like rumination, forgot what it was called.
- Charles: The default mode.
- Rhonda: Yeah, the default mode network. And how that was changed also.
- Charles: Oh, absolutely, yes.
- Rhonda: Of course rumination, that’s a big part of depression.
- Charles: Huge, huge part. And it’s interesting to link back, there are studies linking rumination particularly to inflammation.
- Rhonda: Oh, really?
- Charles: 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 that I don’t think we know the answer to, why should inflammation make you ruminate? But it does. And yes, rumination is a big problem.
- Rhonda: Yeah. And that also sort of leads to this, you know, you’re talking about these transformative experiences which also 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 there is something that’s happening with this mystical experience. You know, there are sort of mystical experiences that are like calming to nerves.
- Charles: Absolutely. It’s very much like sauna versus my $50,000 fancy machine, right? It’s not the machine, it’s the heat.
- Rhonda: Uh, huh. Right.
- Charles: 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 that’s looked 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 the better word, because people also have these very difficult personal experiences but that it makes them feel like their life, they see their life in a different way that produces a transformation. You know, that realm of response, it’s just been repeatedly associated with antidepressant and anti-anxiety effects. And not just that, but also these agents seem to have anti-smoking effect, they 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 they can take a wide, wide range of people and on cue, induce these sorts of experiences. You know, just like if you wanna study inflammation, it’s great to have interferon because I can just wait around until you get inflamed, you know, God forbid, but I’m going to wait. I’m going to wait, you know. Or I can just give you interferon shot and away you go, right? So in the same way, I could wait around for you to have mystical experience. There was a wonderful study done 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, you know, anonymous survey of Americans. And I don’t know, some crazy percent, 15%, 20% of people said, “I’ve had a powerful mystical experience that changed my life, I just never talk about it. I was at the kitchen sink, you know, and I boom, the world looked like it was interconnected in ways I had never mentioned.” So it happens, but it doesn’t happen predictably. Whereas believe me, if it wasn’t illegal and unethical, I could give you a big old dose of psilocybin right now, put you on the couch over there, and it would be very likely you’d have a profound mystical experience, right? But meditation would 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. We were talking about 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.
- Rhonda: I’ve seen multiple studies where first there’s studies looking at the brains of long term meditators, and how they various changes in brain volume in some parts of the brain, and all sorts of things going on. 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’re 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.
- Charles: Yeah. We did one of those studies, it’s interesting.
- Rhonda: Right. Yeah, so you did the study?
- Charles: Yeah, looking at compassion meditation and mindfulness meditation, and then that kind of health discussion with two groups. Yes, absolutely, we found some very interesting results. And Ricky 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 hard core meditation. 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.
- Rhonda: Yeah. 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, but I do, for many years, running has been my meditation.
- Charles: Me too.
- Rhonda: Yeah. There’s a place I go in my brain when I am running that I am, sometimes I’m in the present, sometimes I do daydream, sometimes, you know, but it’s a very, like I just feel so good, it feels so good after, and it helps calm me. If I’m anxious about something and I go for a run, I mean, it’s immediately therapeutic for me.
- Charles: Absolutely.
- Rhonda: So I mean, what do you think? Right now I would say that if a person was depressed or anxious, if it hasn’t sort of life event that may be induced that, a divorce or something like that, they go and see a psychiatrist and they get prescribed...
- Charles: A medicine.
- Rhonda: A medicine, typically you know.
- Charles: SSRI.
- Rhonda: SSRI, or something like that. Which aren’t necessarily always effective and could have side effects. There are many of these different lifestyle interventions: the weight loss, the exercise, the whole body hyperthermia 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 for the ones that are, do you think there’s any hope that the medical community will embrace them, that we’ll start to have a treatment centers that people are now can, they can go and meditate, or do hot yoga or sauna, or they can at least be told by their physician, “Try this?”
- Charles: Oh, yes. Oh, yes, yes. Yes, the science is going to go this way. So it’s very interesting. I mean, I specialize in depression, that’s kind of what I do. And it’s a very, and actually my colleague, Christine Whelan 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 that’s 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 if you start out depressed here, and you do eight weeks with an antidepressant or a sugar pill, the antidepressant gets you down, less depressed. Here’s the antidepressant. Sugar pill, you know, will also get you un-depressed but lesser, right? So you say, “Antidepressants seemed to work pretty well for everybody. You know, they seemed to work better than a sugar pill for people,” but that’s not the truth.
- Rhonda: Yeah.
- Charles: John Krystal at Yale did this great study where they were able... I won’t bore you with the details, but what really happens is about 70% of people will do much better 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 that they were really coming apart with depression and now, you know, couple or three weeks later, they feel like they’ve got their life back. They feel better. They feel fantastic. Twenty five percent of people that are depressed will do much worse with an antidepressant 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 interventions 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, there is some very good chance that if you take a regular antidepressant, you will feel considerably better, and there’s some chance that you’ll feel like way better, right? That could be very useful, and so it’s just bracket that. I mean, that these agents are very powerful for a not insignificant subset of the population that’s 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 what happens is if you don’t respond to an antidepressant, most the time if down is good, you just stay the same. But if I’d given a sugar pill, you would have done much better, right? So you come to me and you say, “I’m just not responsive to 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 are not optimal for. So that’s the first thing. So if you’re one of those people, then what do you do? And that’s where these other things become very, very interesting. But the problem with antidepressants, as I sometimes say, and I, you know, I’m a psycho-pharmacologist. 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, feel horrible at the world, you’re anxious, you’re miserable, you’re not eating, you’re not sleeping, or eating too much and, you know, you’re just, you’re down yourself. Everything is dark. You can barely get out of bed. You know, you’re scared of your shadow. You can’t make decisions. They can take from that and in a month, you can become like super yourself, when they work. Now you’re confident, you feel better, all that stuff that was bothering, you’re like, “Yeah, what’s the big deal? You know, sue me.” All of a sudden the world responds better. They go, “Oh, I’m so happy to see you.” This is “Listening to Prozac,” that famous book from the 90s, that’s a real phenomenon. But the problem is, and it goes back to what I said 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. So that’s problem number one. What you would 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 wellbeing. The other thing about antidepressants is there’s some data, there are some data that the longer you take them, you may become more and more reliant. You may need them to feel good. There’s some evidence that they may induce a vulnerability, so you have to make a decision in your life, you know, are you going to to be Rhonda alone, or are you going to be Rhonda plus Prozac? And that’s a weird thing.
- Rhonda: Yeah. I think I’ve even seen some evidence where there’s changes in, there’s down regulation of serotonin receptors, for example, and you’re constantly, you have serotonin synapses that’s not, you know, being the reuptake like it should. It’s staying around, and so the receptors are like, “Oh, there’s more serotonin and so we should down regulate.” So again, if you were to take that away, all of a sudden you have down regulation receptors and it, your baseline is now even, you know.
- Charles: So relapse rate, so you can take people, and there’s a lot of studies now. You can take people that have been in full remission, taking an antidepressant for two years, you take it away and 60% to 80% of them will have relapsed within a month. I mean, especially if stop it quickly, right?
- Rhonda: Yeah.
- Charles: Whereas initially, if you take away a placebo, a lot of people do pretty well. So placebo responses are more stable and more long lasting than antidepressant responses. And that is a shocker real, 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 involved response to microbial adversity, like we were talking about. Just now, that’s what it is, 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.
- Rhonda: Of course.
- Charles: But it would be even better if you could find something that would allow that antidepressant response to become endogenous to your own brain-body system. 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 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. Because 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 they have a lot of examples, but like a lot of times, people become depressed when they, the person who always chooses the wrong partner. No matter what they do, they always end up with somebody that’s abusive to them, or somebody that, yeah. So what they need to do is transcend that pattern, and if they can 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. 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, the sort of behavioral and biological organization of yourself as an entity. This is 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. 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 way his brain-body complex works. So he’s in states of mind that are just, they’re just inimical to depression, right? 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.
- Rhonda: You make yourself more resilient, right?
- Charles: 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 a myriad challenges. 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 the sort of, what I call personal transformation view of antidepressant, you know, thing, that’s another really challenging thing. Sometimes people take antidepressants as an excuse not to face what’s going on in their lives. Like I’ve known many people, and patients that they knew, take an example, 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 the, usually the women, because the guys are dolts, you know. Like many American marriages have been saved by the woman just being put on Prozac, because when it works, she goes, “Yeah, 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 at a deeper level to be true for you. 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 to coming into full ownership of who you are. 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 antidepressants 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. 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 of, are their 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 Saundra Jain, J-A-I-N. They have developed a program called “The Wild 5,” 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, and I’m involved in all this stuff. Let’s see: diet, exercise, sleep, social connectivity, and meditation.
- Rhonda: Meditation.
- Charles: Yeah, mindfulness. it’s a beautiful program because it’s all, you know, it’s completely sort of user-friendly, and not overwhelming, and doable. It uses a lot of things like tracking your behavior that make people get the kind of feedback. 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 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.
- Rhonda: Wow.
- Charles: 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 programs that interdigitate these wellness practices?”
- Rhonda: What was the name of the program?
- Charles: “The Wild 5.”
- Rhonda: “The Wild 5?”
- Charles: Yeah.
- Rhonda: Do they give you advice on protocols to follow for diet?
- Charles: Oh, yes. Absolutely.
- Rhonda: Oh, wow.
- Charles: I don’t know, it’s all kind of protocol, manualized. Oh yeah, they’ve published a book, if you just Google “Wild 5,” to get there, yeah, you definitely will find.
- Rhonda: It’s kind of like the, you know, those five things are so incredibly important. I mean, sleep, of course, sleep deprivation, all that’s been shown to be, especially with depression or it caused depression symptoms.
- Charles: Yeah, inflammation, weight gain, metabolic, all that.
- Rhonda: All of it. And the other thing we didn’t talk about was, and you kind of mentioned, you alluded to it with this evolutionary mismatch, you mentioned, you know, that the world that we live in today is much different. We’ve got all these artificial lights, you know, we’re...
- Charles: It’s a big thing.
- Rhonda: Yeah, our light exposure has totally changing. You know, 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. 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 depression or.
- Charles: Oh, absolutely. Yeah, there is some nice data on that.
- Rhonda: Yeah.
- Charles: Absolutely.
- Rhonda: What I was kind of trying to make was the link between cortisol and the bright light exposure.
- Charles: Oh, yeah, absolutely. Because of course, you know, that’s what entrains to a large degree of cortisol rhythm, and probably cytokine rhythms too. They also...
- Rhonda: Right. Yeah.
- Charles: Absolutely. There’s another example of this idea that humans evolved to, if not need to function optimally with certain types of inputs. If you say, “Why do they function optimally with those inputs?” It’s because across a couple of million years that’s what they got, and so they evolved to function optimally with those inputs. You know, 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, mornings were 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.
- Rhonda: And work.
- Charles: 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 somebody’s 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. That’s so awesome, but now we’re killing ourselves with sweet stuff, so now we need to, you know, renounce. So you always like you get these sort of things where one mandate in the human world interacts problematically with another, and light is a classic example of that.
- Rhonda: 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...
- Charles: Absolutely, that’s a huge inflammatory.
- Rhonda: Yeah, exactly. So it totally makes sense that these two are, they’re interconnected. You know, having just bright light exposure there is one study where exposing humans to like 10,000 lux of bright light for seven hours a day lowered their cortisol response during the rising phase when it’s usually the highest. So obviously, it was a anti-inflammatory sort of, 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 could also be playing a role in their depression, the way that they’re responding to emotional stimuli, and all these things. So I personally, we, my husband and I have optimized, try to optimize to the best of our ability our light exposure. So we have these lights in our house called Philip Hue, which basically, they can change color. So blue light is what, you know...
- Charles: It’s what you want early in the day, and not what you want at night.
- Rhonda: Not at night. So at night we have it all set where you can time them so that the shuts off the blue light and it turns on red light. So we have all these red lights around our house that come on.
- Charles: Oh, cool.
- Rhonda: 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 regular, old blue lights. Yeah. And then we have, you know, apps on our phone and our computer called lux, sorry, f.lux, 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.
- Charles: And you have them all around the house?
- Rhonda: We have them in every room, yeah.
- Charles: What are they called?
- Rhonda: In the kitchen. Philips Hue.
- Charles: H-U...
- Rhonda: I’ll send you, H-U-E.
- Charles: Okay, send that after.
- Rhonda: I will, 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, like having, going outside for 30 minutes, or just making sure you have to light in the house.
- Charles: Even on the cloudiest day?
- Rhonda: Yeah.
- Charles: You get like 5,000 lux on a cloudy day. You cannot, yeah, it’s just this...
- Rhonda: So, you know, on a cloudy day you get like...
- Charles: Oh, you get a lot, compared to just sitting in your average room.
- Rhonda: And do you know how long, like can people just use 30 minutes or an hour? Because it’s hard.
- Charles: It is. I tell people 30 minutes.
- Rhonda: Thirty minutes.
- Charles: I mean, yeah, 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 wellbeing. Now, the other thing that I’m convinced is really important is dark. There’s a whole biology on dark.
- Rhonda: Like during the time when it’s supposed to be dark?
- Charles: Yeah. Because even a little bit of light absolutely screws up melatonin release, you know, blue light, mostly. I mean, that’s why it’s really smart to do this. But, you know, I mean, we cannot now, the first academic paper I ever 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, and it was 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 because Boswell, you know, Boswell, the guy that wrote the biography of Samuel Johnson, recorded all those 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 the dark of the moon. It was fascinating. I mean, London, the greatest city on earth in that time, was so dark that you could do that. This is in the 1760s. There’s a guy named Tom Ware, he’s retired now, but he was sort of the king of the circadian stuff. I mean, he was at NIMH, the National Institute of Mental Health, and he actually took... He did this great study, and in particular he took this one just impossibly bipolar person, stuck him in the dark for 12 hours every day for a year or so, and just profoundly fixed the guy. Now, darkness is another example actually, of an ancient spiritual practice. So one of the first bizarre 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.
- Rhonda: Forty nine days, wow.
- Charles: That’s the length of time that they believe, that’s the maximum length of time between reincarnation.
- Rhonda: And are they also in silence as well? Silence and dark.
- Charles: Silence, except for a couple of times a day when people slip, they’ve got some mechanism now for slipping food under the door, people checking them.
- Rhonda: But they’re not talking to anyone?
- Charles: No. And they start hallucinating like mad.
- Rhonda: Wow.
- Charles: The point of that is utter sensory deprivation. 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 that 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. I’ve got an invitation to go check it out, yeah.
- Rhonda: Wow.
- Charles: Very famous television journalist is going to come.
- Rhonda: It’s hardcore.
- Charles: It’s hardcore.
- Rhonda: Are you familiar with some of the gene polymorphisms, the snps in... There’s one gene that, I think it’s NPAS2, I think, that is involved in circadian rhythm, but also there is susceptibility to bipolar disorder when it’s dis-regulated. So again, sort of this...
- Charles: Yes. Well, especially bipolar disorder. You know, if depression, if regular depression is sort of an evolved human response to the adversity of a relationship, bipolar disorder is a response to the adversity of time.
- Rhonda: What do you mean by that?
- Charles: Well, what you see with bipolar disorder is that the 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 fluctuations in circadian patterns. So the great way to induce a manic episode is to just keep people awake. There’s wonderful data from the 1980s from the National Institute of Mental Health where they’d keep really very ill bipolar patients in psychiatric wards for years and study every, you know, every episode. And always, depressive but especially, manic episodes would be triggered by a night of sleep deprivation. You see this clinically. So time is an adversity because it’s, you know, it’s constantly threatening homeostasis. So, you know, the things we’re talking about, the sun comes up, the sun goes down, this happens, that happened, this happened, and your body went up and down. Any time things move, there’s always a risk of things coming off the rails and breaking, right? So bipolar folks are so profoundly vulnerable to disruptions in their circadian sleep/wake cycles, in their activity cycles. Helen Frank was one of the originators of this, called “Chronotherapy.” It came out of University of Pittsburgh, where they actually, you know, as a therapeutic thing for bipolar sort of, part of it was education about, you always go to sleep at the same time, you get up at the same time. You know, be careful about air travel. There is 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, than 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 psychiatry at UCLA. Many of them were activated by getting on a plane.
- Rhonda: Wow.
- Charles: “I was normal till I got on the plane. I got off the plane, and the world looked different.” And then they’re off and gone.
- Rhonda: That’s what patients would say?
- Charles: Oh, yeah.
- Rhonda: Wow.
- Charles: And the first episodes were often induced. I mean, people really developed life-long psychotic disorders in response to...
- Rhonda: Do you think those people that are having that are a little more sensitive to the, like their circadian, they maybe have some snp and...?
- Charles: Yeah, that’s probably NPAS, which is one of the great kind of drivers or regulators of the circadian things, is a particular bipolar disorders, 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 disorder.
- Rhonda: Yeah. And probably lots of genes are not being regulated properly, right?
- Charles: That’s right.
- Rhonda: And 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 activate, you know?
- Charles: Yeah. Whereas, you know, it’s interesting is, if you don’t have that bipolar risk, most of us do not end up in the psych hospital because we missed a night of sleep, right?
- Rhonda: Yeah, right.
- Charles: 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...
- Rhonda: When I’m missing out in sleep, like if I’m traveling abroad, I certainly feel strange when I land in Heathrow, or any other airport in Europe, or even Asia. But I certainly don’t feel...
- Charles: You’re not.
- Rhonda: Yeah. It feels kind of weird.
- Charles: Right. But you’re not psychotic.
- Rhonda: No. I don’t actually have that snp so.
- Charles: Yeah.
- Rhonda: 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?
- Charles: The book, I published it with one of my other closest colleagues, Vladmir Maletic. It’s called “The New Mind-Body, Science of Depression.”
- Rhonda: “The New Mind-Body, Science of Depression.”
- Charles: Seven hundred pages, it’s a monster.
- Rhonda: Wow.
- Charles: Oh, yeah.
- Rhonda: And so if people are more interested in sort of learning more about some of the stuff...
- Charles: So a lot of the stuff we’ve talk 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 wanna 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 that are 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 cases that had a, like a miracle cure to hyperthermia. So it’s interesting, yeah, a lot of it is in the book.
- Rhonda: Cool. And the book so, it’s available? Is it like on Amazon?
- Charles: Yeah. Published by Norton. It’s available.
- Rhonda: Awesome.
- Charles: It’s available sometimes in Barnes and Noble and it’s available in Amazon now.
- Rhonda: Great. Really, really happy to have this discussion with you. Definitely, let’s stay in touch, and I’ll send you studies whenever I come across some.
- Charles: Yeah.
- Rhonda: But thanks so much for taking time to speak today.
- Charles: Oh, thank you. This was great, yeah. Really cool.
- Rhonda: Yeah.
Acute tryptophan depletion (ATD)
A method of lowering brain tryptophan and, thus, serotonin (5-HT). Administration of a bolus, usually a drink, containing large neutral amino acids (LNAA), but lacking tryptophan, limits the transport of endogenous tryptophan across the blood-brain barrier through competition with other LNAAs undergoing active transport. This is able to subsequently decrease serotonergic neurotransmission and is a useful way for scientists to study the effects of this type of neurotransmission.
Serum albumin is the main protein of human blood plasma. It binds water, cations (such as Ca2+, Na+, and K+), fatty acids, hormones, bilirubin, thyroxine (T4) and pharmaceuticals (including barbiturates): _its main function is to regulate the oncotic pressure of blood_. **Oncotic pressure**, or colloid osmotic pressure, is a form of osmotic pressure exerted by proteins, notably albumin, in a blood vessel's plasma (blood/liquid) that usually tends to pull water into the circulatory system
Autonomic Nervous System
A division of the peripheral nervous system that influences the function of internal organs, and acts largely unconsciously to regulate bodily functions such as the heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal. **It is also the primary mechanism in control of the fight-or-flight response and the freeze-and-dissociate response.**
A member of the same species.
A steroid hormone that participates in the body’s stress response. Cortisol is a glucocorticoid hormone produced in humans by the adrenal gland. It is released in response to stress and low blood glucose. Chronic elevated cortisol is associated with accelerated aging because it can damage the hippocampus and impair hippocampus-dependent learning and memory in humans.
A broad category of small proteins (~5-20 kDa) that are important in cell signaling. Cytokines are short-lived proteins that are released by cells to regulate the function of other cells. Sources of cytokines include macrophages, B lymphocytes, mast cells, endothelial cells, fibroblasts, and various stromal cells. Types of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
Default Mode Network
The default mode network is most commonly shown to be active when a person is not focused on the outside world and the brain is at wakeful rest, such as during daydreaming and mind-wandering. Functions include autobiographical information, self-reference, emotions of one's self and others, theory of mind, moral reasoning, social evaluations, social categories, remembering past, imagining future, and story comprehension.
The annual rites performed by the ancient Greeks at the village of Eleusis near Athens in honor of Demeter and Persephone. They've been referred to as "the most famous of the secret religious rites of ancient Greece" by the Encyclopedia Britannica. The rites, ceremonies, and beliefs were kept secret and consistently preserved from antiquity.
The tendency of things to change into their opposites, especially as a supposed governing principle of natural cycles and of psychological development.
Relating to or characterized by pleasure. Hedonism is a school of thought that argues that pleasure and happiness are the primary or most important intrinsic goods and the aim of human life.
The infection specificity of certain pathogens to particular hosts and host tissues. This type of tropism explains why most pathogens are only capable of infecting a limited range of host organisms. Pathogens that can infect a wide range of hosts and tissues are said to be **amphotropic**, while **ecotropic** pathogens, on the other hand, are only capable of infecting a _narrow_ range of hosts and host tissue.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
Insulin is a peptide hormone secreted by the beta cells of the pancreatic islets cells and maintains normal blood glucose levels by facilitating the uptake of glucose into cells, regulating carbohydrate, lipid and protein metabolism and promoting cell division and growth. Insulin resistance, characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response and lead to high blood glucose levels.
(of two or more things) interlock like the fingers of two clasped hands.
Interleukin 10 (IL-10)
IL-10, also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine with multiple, pleiotropic, effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. A study in mice has shown that IL-10 is also produced by mast cells, counteracting the inflammatory effect that these cells have at the site of an allergic reaction. IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such as IFN-γ, IL-2, IL-3, TNFα and GM-CSF made by cells such as macrophages and Th1 T cells.
Interleukin 6 (IL-6)
A pro-inflammatory cytokine that plays an important role as a mediator of fever and the acute-phase response. IL-6 is rapidly induced in the context of infection, autoimmunity, or cancer and is produced by almost all stromal and immune cells. Many central homeostatic processes and immunological processes are influenced by IL-6, including the acute-phase response, glucose metabolism, hematopoiesis, regulation of the neuroendocrine system, hyperthermia, fatigue, and loss of appetite. IL-6 also plays a role as an anti-inflammatory cytokine through inhibition of TNF-alpha and IL-1 and activation of IL-1ra and IL-10.
The kaihōgyō (回峰行) ("circling the mountain") is an ascetic practice performed by Tendai Buddhist monks. The practice involves walking a route on Mount Hiei (the location of the Tendai school headquarters) while offering prayers at halls, shrines and other sacred places. There are two versions: • 100 days (hyaku-nichi kaihōgyō) • 1,000 days (sennichi kaihōgyō)
A hormone found in animals (and conserved in plants, fungi, and bacteria) that is critical in regulating our relationship with the light-dark circadian cycle down to a cellular level and also functions as an antioxidant. Melatonin regulates over 500 genes, and, interestingly, has been shown to be elevated in the blind and may play a part in their decreased cancer risk.  Feychting, Maria, Bill Österlund, and Anders Ahlbom. "Reduced cancer incidence among the blind."_ Epidemiology_ (1998): 490-494.
Cytokines and other small proteins, including brain-derived neurotrophic factor (BDNF) and various interleukins, such as IL-6, which are produced and released by muscle cells in response to muscular contractions. Myokines have autocrine, paracrine and/or endocrine effects and are involved in exercise-associated metabolic changes and adaptations and also participate in tissue regeneration and repair, maintenance of healthy bodily functioning, immunomodulation, cell signaling, expression, and differentiation.
A catabolic product of GTP (the purine nucleotide) synthesized by human macrophages upon stimulation with interferon-gamma. High neopterin production is associated with increased production of reactive oxygen species and serves as an estimate of the extent of oxidative stress elicited by the immune system.
A disease state in which the hematocrit (the volume percentage of red blood cells in the blood) is elevated. It can be due to an increase in the number of red blood cells ("absolute polycythemia") or to a decrease in the volume of plasma ("relative polycythemia").
Organisms that, although not reproducing and residing permanently in the gut, maintain a persistent presence through continual re-introduction via our environment, including through the food we eat and the water we drink.
A class of hallucinogenic substances whose primary action is to alter cognition and perception, typically as serotonin receptor agonists, causing thought and visual/auditory changes, and "heightened state of consciousness." Major psychedelic drugs include mescaline, LSD, psilocybin, and DMT. Psychedelics have a long history of traditional use in medicine and religion, for their perceived ability to promote physical and mental healing.
Quinolinic acid behaves as an excitatory neurotoxin through its agonism of the NMDA receptor. Reduction of the excitotoxic effects of quinolinic acid is the subject of on-going research. Shifting metabolism to produce the alternative metabolite, kynurenic acid, can help reduce the dangerous activity of the NMDA receptor by acting as an antagonist and, thus, a neuroprotectant. Aerobic endurance exercise has been shown to preferentially shift metabolism to the production of more kynurenic acid over quinolinic acid and may have relevance for patients with major depression as an increased serum QUIN/KYNA ratio has been linked to patients with depressive disorder.  Guillemin, Gilles J. "Quinolinic acid, the inescapable neurotoxin." The FEBS journal 279.8 (2012): 1356-1365.  Kalonia, Harikesh, Puneet Kumar, and Anil Kumar. "Licofelone attenuates quinolinic acid induced Huntington like symptoms: possible behavioral, biochemical and cellular alterations." Progress in Neuro-Psychopharmacology and Biological Psychiatry 35.2 (2011): 607-615.  Schlittler, Maja, et al. "Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans." American Journal of Physiology-Cell Physiology 310.10 (2016): C836-C840.
Single Nucleotide Gene Polymorphism (SNP)
A change in one nucleotide DNA sequence in a gene that may or may not alter the function of the gene. SNPs can affect phenotype such as hair and eye color, but they can also affect our disease risk, the way we absorb and metabolize micronutrients, macronutrients, and much more.
A type of sweat lodge which originated with pre-Hispanic Indigenous peoples in Mesoamerica. The word temazcal comes from the Nahuatl word temāzcalli ("house of heat"), or possibly from the Aztec teme (to bathe) and calli (house).
A pathogen that has been shown to alter the behavior of infected rodents in ways that increase their chances of being preyed upon by felids. Support for this "manipulation hypothesis" stems from studies showing T. gondii-infected rats have a decreased aversion to cat urine. Because cats are the only hosts within which T. gondii can sexually reproduce to complete and begin its lifecycle (a "definitive host"), such behavioral manipulations are thought to be evolutionary adaptations that increase the parasite's reproductive success. Though humans and other mammals are not definitive hosts of T. gondii, infection is thought to be widespread with estimates in countries like France as high as 84%.
The Yokuts (previously known as Mariposas) are an ethnic group of Native Americans native to central California. Before European contact, the Yokuts consisted of up to 60 tribes speaking the same language. "Yokuts" means "People."
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