March 28, 2020
  • 3:53 pm Fun Meal Prep Idea: Yellow-Colored Lunch Box
  • 3:53 pm Gilbert’s on Main serves New York Style Deli in Bellevue – KING 5 Evening
  • 3:53 pm Keto diet Meatballs with tomato sauce ASMR cooking No talking
  • 3:53 pm John’s Texas Tenderloin Roulade
  • 2:53 pm Why You Should Try “Cook Once Eat Twice” Meal Prep | What We Ate Over a Weekend (Healthy Recipes)

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 microglial 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.

Randall Smitham