- Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a Professor of
Neurobiology and Ophthalmology at Stanford School of Medicine. This month, we're talking all
about disorders of the mind, things like depression,
attention deficit disorders, eating disorders, schizophrenia,
and bipolar disorder. During the course of this month, we are going to discuss the psychological and biological underpinnings
of mood disorders of all kinds. You'll learn a lot of science. You'll also learn a lot
about the various treatments that exist and that are in development for these various mood disorders. We will talk about behavioral
tools, things like exercise, meditation, breath work,
but also prescription drugs, supplements and novel compounds
that are now being tested in various clinical trials. Across the month, I think
you'll start to realize that there are common pathways underlying many mood disorders. In fact, mood disorders
that look quite different from one another often
depend on the action of the same neurochemicals
or neural circuits in the brain and body. That actually should be
a point of great relief because what it means is that
by understanding the biology of one mood disorder or
understanding how one treatment or behavioral intervention
can impact a mood disorder, we gain insight into other
mood disorders as well. As always, we will discuss
science and science related tools that people could implement
should they choose. Before we dive into today's topic, I'd like to discuss a very particular set of scientific findings
that relate to today's topic, and that are important for
understanding all mood disorders and all states of motivation,
happiness, and sadness, as well as depression. Basically, I'm going to
paraphrase a brief segment of my discussion with Dr. Anna Lembke, who I sat down with to discuss addiction and the biological basis of addiction and addiction treatment. A very important aspect of that discussion was when Dr. Lembke described
the pleasure pain balance, literally the circuits in our brains that control our sense
of pleasure and pain, and ultimately whether
or not we remain happy in our pursuit of pleasure or not. This is an absolutely crucial aspect to the way that we
function in everyday life, and especially under
conditions of mood disorders. The pathway that she was describing is the so-called pleasure system. However, what most people don't realize is that the pleasure system is also directly associated with, and in fact is the very same system that modulates mental or
psychological anguish and pain. Essentially what she described is that whenever we pursue something that we think will bring us pleasure, and that could be anything that we think will bring us pleasure from
food, to video games, to sex, to a particular job or goal,
short-term or long-term, that we experience release of
the neuromodulator dopamine. Now, dopamine is associated
with increased levels of motivation and drive. It is not the molecule of reward, it is the molecule of
craving motivation and drive. However, as Dr. Lembke pointed out, when we are in pursuit of something, there is a release of
dopamine in our brain that makes us feel motivated, and in general, it makes us feel good. But very shortly thereafter and beneath our conscious awareness, there is a tilt of the pleasure
pain balance in the brain, literally a shift in the neural circuits that underlie pleasure and pain, such that every bit of
pleasure or pleasure seeking that causes release of dopamine will be balanced out by
a little bit of pain. And we don't experience
this as physical pain, at least not at first, we experience it as craving for more of the thing that brought us pleasure. Now, that sounds pretty good. You get pleasure and then
you get a little bit of pain to balance it out. It's subconscious and you experience it as the desire to seek out more pleasure. However, it's actually
more diabolical than that. And we really need to keep an eye on this if we are to remain happy, if we are to remain in
pursuit of our goals. The crucial thing to
understand is that if we remain in constant pursuit of pleasure, the pain side of the balance tips so that each time we are in pursuit of that pleasureful thing,
activity, or substance, we are going to experience, we literally achieve less dopamine release each subsequent time. So we get less pleasure and the
amount of craving increases. Now, after a certain point or threshold, we call that addiction. And the way to reset the balance, and this is very important, the way to reset the balance is actually to enter into states in which we are not in
pursuit of pleasure, to literally enter states
in which we are bored, maybe even a little bored and anxious, and that resets the pleasure pain balance so that we can return to
our pursuit of pleasure in a way that's healthy,
and then in an ongoing way, won't lead to this over
tipping or this increase in the amount of pain or addiction. So this is very important. And if this seemed vague, what this means is we
should always be cautious of any state of mind
or body or any pursuit that leads to very large
increases in dopamine. And if it does, we should be very careful to not pursue that repeatedly over time. During today's episode, I'm
going to give an example, a real life example of a
discussion that I've been in with a young man who's 21 years old who's dealing with a disruption in this pleasure pain balance. He is essentially depressed
and he's depressed because of his ongoing pursuit
of a particular activity that initially led to a lot of dopamine, but over time has led to
less and less dopamine and more and more of this
pain side of the balance. We could call him addicted
to that particular activity. Whether or not he's addicted
by clinical standards or not, really, isn't important. What is important is that he
experiences this as depression, as low affect as it's called or anhedonia, an inability to experience
pleasure from that thing or from anything else. And he's currently undergoing treatment through a rebalancing of
his pleasure pain pathway. So while I can't reveal
his identity to you, that wouldn't be appropriate. He did give me permission to reveal the general architecture
of what he's coping with. And I spent some hours with
him on the phone this week, talking to him as well
as to the various people that he's working with
to really understand what's going on here 'cause
I think it can illustrate the relationship between
dopamine, pleasure, and pain for sake of addiction, but also for understanding how
to avoid depressive states, how to remove ourselves
from depressive states. And as you'll see today,
as we discussed depression, many of the molecules and neural pathways and biological mechanisms
that we know can be used to counter depression, feed back onto this pleasure pain balance. Before we begin, I'd like
to say that this podcast is separate from my teaching
and research roles at Stanford. It is however, part of
my desire and effort to bring zero cost to consumer
information about science and science related tools
to the general public. In keeping with that theme, I'd like to thank the
sponsors of today's podcast. Our first sponsor is InsideTracker. InsideTracker is a
personalized nutrition platform that analyzes data from blood and DNA to help you better understand your body and help you reach your health goals. I've long been a believer in
getting regular blood work done for the simple reason
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of your brain, your mood, various aspects of brain inflammation or limiting brain
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brought to us by Belcampo. Belcampo is a regenerative
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grass fed, and finished certified humane meats. I don't need a lot of meat. Typically my diet regime
is one in which I fast until about noon, and then I have a lunch
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Belcampo, first-time customers can get 20% off by going
to belcampo.com/huberman and using the code "Huberman" at checkout. That's belcampo.com/huberman for 20% off and use the code "Huberman" at checkout. Today we're discussing depression. In particular, we're going to
talk about major depression. The phrase major depression
is used to distinguish one form of depression from the other, the other one being bipolar depression. Bipolar depression, sometimes
called bipolar disorder, is really characterized by manic highs. So where people aren't sleeping and they're talking very fast, and they're buying things
and pursuing resources that they can't afford, they're starting
relationships left and right, they're manic, followed by periods of
crashes of feeling very low, lethargic, and so on. Bipolar depression is an
absolutely crucial thing for us to discuss. And therefore we are
going to have an entire separate episode related
to bipolar depression. Today, we're going to talk
about major depression, also sometimes called unipolar depression, just because it doesn't
have the highs and lows. It's more characterized by the lows. We're going to talk about the biology, the psychology, and
the various treatments, behavioral, drug,
supplementation, diet, exercise, all of that. Before we go forward into the material, I just want to emphasize
that any discussion about mood disorders carries with it a particular sensitivity, and that sensitivity is one
related to self-diagnosis. Today's episode, and indeed
in the future episodes for this month on mood disorders, you're going to hear various
symptomologies that are used to diagnose and characterize
these disorders. If you recognize some of these
symptomologies in yourself or in others that you know, that's an important thing to take note of. However, accurate diagnosis
really should be done by a qualified healthcare professional. So at once I'm saying, keep
your eyes and your ears up for things that sound familiar to you that might be of concern. And at the same time, I'm saying don't necessarily
leap to conclusions. Take those flags of
concern if they're there and bring them to a qualified
healthcare professional, and they'll be able to
properly diagnose you as having a particular mood
disorder or diagnose somebody as having a particular
mood disorder or not. And that's an essential step. I don't say this to protect us, I said this really to protect you. Okay, let's have a fact-based
discussion about depression. And I promise you that where
we don't know certain things about depression, I will
be clear to tell you. In fact, we are going to
talk about some treatments for depression that are
looking very promising, and that right now are actually
being used more and more. And from my read of the
mechanistic literature, we're still a bit in the
dark as to how these work. That's actually a common
theme of medicine. Many times there are
treatments that seem promising or that look really terrific. And there isn't a lot of
understanding about mechanism. However, any good discussion
about neuroscience and in particular about mood disorders, has to get into mechanisms. So we're going to do that. And in doing that, we're
going to frame the discussion for the tools of how to
keep depression at bay and how to deal with it if you happen to find yourself depressed, or if you know somebody
else who's depressed. What is this thing we call depression? Was I mentioned before, it has two forms, bipolar depression, which
we're not talking about today, and major depression, also
called unipolar depression is the other. Major depression impacts
5% of the population. That is any enormous number. That means if you're in
a class of 100 people, five of them are dealing
with major depression or have at some point. Look around you in any environment and you can be sure that a
good portion of the people that you're surrounded by
is impacted by depression, or will be at some point. So this is something we
really have to take seriously and that we want to understand. It is the number four cause of disability. A lot of people miss work, miss school, and before then likely perform
poorly in work or school due to major depression. Now there's a very serious
challenge in having a discussion about depression and it relates
directly to the challenges in diagnosing depression. Earlier, I did an episode
with Dr. Karl Deisseroth, who is indeed a medical doctor and a PhD. He's a psychiatrist. And he made a very important point, which is that the field of
psychiatry and psychology are confronted with a challenge, which is they're trying to
understand what's going on within the stuff that's in our brains that's deep to our skulls. We don't have access to
that without brain imaging and electrodes and things like that. Someone just comes into the
office and the dissection tool for depression so to speak is language. In order to determine if
somebody has depression or not, we have to use language,
how they talk about things, also how they carry their body. Also some general patterns of health. So let's talk about depression the way that clinicians
talk about depression, because one of the issues is that we use the word depression loosely. A lot of people say,
"Oh, I'm so depressed. "I didn't get this job
or I'm so depressed. "I just don't know, I
had a really rough week "or I'm exhausted. "I'm so depressed or I'm so depressed "I thought I was going to go on vacation "and then they canceled the flight." Okay. That is not clinical depression. That's called being bummed
out, being sad or disappointed. Now that person might be depressed, but clinical depression actually has some very specific criteria. And those criteria are
mainly characterized by the presence of certain things and the absence of a
few particular things. So let's talk about the
things that are present in somebody that has major depression. First of all, there tends
to be a lot of grief. There tends to be a lot of sadness. That's no surprise. The threshold to cry is often
a signature of depression. Now that doesn't mean
that if you cry easily, that you're depressed. Some people cry more easily than others, but if you're somebody who
typically didn't cry easily and suddenly you find
yourself crying very easily, that could be a sign of depression. And I want to emphasize, could. There's also this thing
that we call anhedonia, a general lack of ability to enjoy things, things that typically or
previously we enjoyed. Things like food, things like
sex, things like exercise, things like social gatherings, a kind of lack of enjoyment
from those things. Sometimes that lack of enjoyment is sad, and sometimes it's just flat,
it's just kind of neutral. It doesn't feel good
because nothing there. It's like bland food. It's like these experiences are analogous to biting into your
favorite article of food and it just not tasting very good. It just doesn't taste
like anything at all. And that's a common symptom
of major depression. The other one is guilt. Oftentimes people with
depression will feel very guilty about things they have done in the past, or they'll just generally
feel badly about themselves. And we're going to talk
about this because it relates to some of the more serious symptomology seen in depression sometimes, things like self harm,
mutilation, or even suicide. But for the time being, we
want to frame up anhedonia, this lack of ability to
achieve or experience pleasure, or kind of a flat affect as it's called. Sometimes even delusional thinking, negative delusional thinking, and in particular anti-self confabulation. What is anti-self confabulation? Well, first of all, confabulation
is an incredible aspect of our mind and our nervous system. You sometimes see other
forms of confabulation in people who have memory deficits either because they have brain damage or they have age-related dementia. A good example of this would be someone with age related dementia
sometimes will find themselves in a location in the house and
not know how they got there. And if you ask them, "Oh,
what are you doing here?" They will create these elaborate stories. "Oh, I was thinking about
going to the shopping today, "and I was going to take the bus, "and then I was going to do this." They create these elaborate
stories, they confabulate. And yet that person hasn't
left the house in weeks and that person doesn't
have a driver's license. And so they're really
just creating this stuff. They're not lying to get out of anything, they're confabulating. It's as if a brain circuit
that writes stories, just starts generating content. In major depression, there's often a state of
delusional anti-self confabulation, where the confabulation are not directly or completely linked to reality, but they are ones that make the self, the person describing them, seem sick or in some way not well. A good example would be somebody who experiences a physical injury perhaps. Maybe they break their
ankle, maybe it's an athlete, and they also happen to become depressed. And you'll talk to them and
say, "How are things going? "How's your rehab though?" And they go, "Oh, it's
okay. And I don't know. "I feel like I'm getting
weaker and weaker by the day. "I'm just not performing well." And then you'll talk to the person that they're working with, their kinesiologist or whoever
the physical therapist is. And they'll say, "No, they're
actually really improving. "And I tell them they're improving, "but somehow they're not
seeing that improvement, "they're not registering
that improvement." You notice that sometimes it's subtle and sometimes it's severe, but
they'll start confabulating. You'll say, "I actually heard
you're doing much better. "You're getting better,
you're taking multiple trips "around the building now "before you could barely get out of bed." And they'll say, "Yeah, well basically,
they changed some things "about the parking lot that
make it easier to move around. "So it's not really me." And these aren't people that
are just explaining away their accomplishments 'cause they're trying to brush off praise. They are viewing themselves and they're confabulating
according to a view that is very self-deprecating to the point where it doesn't
match up with reality. It's not what other people see and it's actually not
matched up with reality. And that's a symptom of depression that I think we don't often think about or conceptualize enough. So it's not just telling people, "oh yeah, it's not as good as
it seems. Everything's bad." These people really believe that and it becomes disconnected from reality. So it's if they're sort
of sinking into a pit and they're losing touch with
the realities of the world, including data about themselves, their ability to move and get around it, for example, in that particular instance that I used as an example,
but there are others as well. The other common symptomology
of major depression is what they call
vegetative symptoms, okay? So vegetative symptoms
are symptoms that occur without any thinking, without any doing, or without any confabulation. These are things that are
related to our core physiology. The word vegetative, you might know it sounds like vegetable. It actually relates to
a system in the body that nowadays is more commonly called the autonomic nervous system. The vegetative nervous system and the autonomic nervous system, historically were considered
sort of one in the same. And it relates to things
like the stress response or to our ability to sleep. So vegetative symptoms be things like constantly being exhausted. The person just feels exhausted. It's not because they exercise too much, it's not necessarily because
of a life event, it could be, but they're just worn out. They don't have the energy they once had. So it's not in their heads, it's probably, and now I think we have good
data to support the fact that there's something off, something is disrupted in the autonomic or so-called vegetative nervous system. And one of the most common symptoms of people with major depression, one of the signs of major
depression is early waking and not being able to fall back asleep despite being exhausted. So waking up at 3:00 AM
or 4:00 AM or 5:00 AM just spontaneously and not
being able to go back to sleep. I want to emphasize that that could happen for other reasons as well,
but it is a common symptom or warning sign of major depression. So let's talk more about
sleep and depression. It's well-known that the
architecture of sleep is disrupted in depression. What's the architecture of sleep? I've done entire episodes about this, but very briefly in two sentences, although they're probably
be run on sentences, early in the night, you tend to have slow wave
sleep more than REM sleep or Rapid Eye Movement sleep. As the night goes on, you tend to have more
Rapid Eye Movement sleep. That architecture of slow wave sleep preceding Rapid Eye Movement sleep is radically disrupted
in major depression. In addition, the pattern
of activity in the brain during particular phases
of sleep is disrupted. Now this is during sleep. So this can't be that people are creating this
situation for themselves. These are real physiological
signs that something is off in this so-called autonomic
or vegetative nervous system. And then there are some
other things that relate to the autonomic nervous system, but that we normally think of
as more voluntary in nature. And these are things
like decreased appetite. So you can imagine that one
could have decreased appetite because of the anhedonia, the lack of pleasure from food, right? If you don't enjoy food, then you might be less
motivated to eat it. That makes sense. As well because of these disruptions in the autonomic nervous system, these vegetative symptoms,
as they're called, you can imagine that someone
would have decreased appetite because some of the hormones
associated with appetite, hypocretin orexin and things
of that sort, ghrelin, that those will be disrupted. And if those names of
hypocretin orexin and ghrelin don't make any sense to
you, don't worry about it. What those are just hormones
that impact when we eat, when we feel hungry, and
when we crave food more, as well as when we feel full, we have enough so-called satiety. If you want to learn more about those, we did entire episodes
on eating and metabolism. So you can see that the
symptomology of major depression impacts us at multiple levels. There's the conscious level of
how excited we are generally. Well, that's reduced. There's grief, there's
guilt, there's crying, but then there's also
these vegetative things. There's disruptions in sleep, which of course make
everything more challenging when we're awake. We know that sleep is
so vital for resetting. You're waking up early, you
can't get back to sleep. That's going to adjust your affect, your emotions in negative ways. We know this. And appetite is off. And there are hormones that get disrupted. So cortisol levels are increased. In particular, there's a
signature pattern of depression whereby cortisol, the
stress hormone that normally is released in a healthy way only in the early part of the day is shifted to late in the day. In fact, a 9:00 PM peak in cortisol is one of the physiological signatures of depressive like states. It's not the only one, but
it is an important one. So there are a lot of things
going on in major depression. And by now you're probably thinking, goodness, this is dreadful. Like there's all this terrible stuff. And indeed it is terrible. It is a terrible thing to find oneself in a mode where things
feel sad, you feel guilty, you're exhausted. And oftentimes there's also an association with the anxiety system. So just because people are exhausted and lethargic and they don't enjoy things, doesn't necessarily mean that
there's an absence of anxiety. There can also be a lot of anxiety about what's going to happen to me. Am I going to be able to
achieve my goals in life? Will I ever get out of this state? And so things really start to layer on. And if this sounds depressing to you, it is indeed depressing. This is really the place that
many people find themselves. And it's a pit that they just don't know how to climb out of. So let's just take a few minutes and talk about some of
the underlying biology that creates this cloud
or this constellation of symptomology. I think that's really important to do because if we want to understand
the various treatments, how they work and why they
work and how to implement them, we have to understand some
of the underlying biology. So let's spend a few minutes talking about the biology of depression, what's known and what's not known. Because in doing that, I think you'll get a much clearer picture about why certain tools
work to relieve depression and why others might not. So one of the most
important early findings in the search for a
biological basis of depression was this finding that there are drugs that relieve some of the
symptoms of depression. Those drugs generally fall
into three major categories, but the first set of
ones that were discovered were the so-called
tricyclic antidepressants, and the MAO inhibitors, the
monoamine oxidase inhibitors. You don't need to understand
that nomenclature, but I'm going to give you
a little bit of detail so that if you want to
understand it, you can. Most of this work took
place in the late 1950s and in the 1960s, and
continued well until the 1980s when new classes of drugs were discovered. And these tricyclic antidepressants
and the MAO inhibitors largely worked by increasing
levels of norepinephrine in the brain, as well as
in the body, in some cases. And they were discovered through a kind of odd
set of circumstances. We don't have time to
go into all the history, but suffice to say that
they were discovered because of the exploration for drugs that alter blood pressure. Norepinephrine impacts blood pressure, and drugs that lower blood pressure reduce levels of norepinephrine. And that in many cases, was
shown to lead to depression or depressive like symptoms. And so these drugs, these tricyclic drugs, and the MAO inhibitors actually
increase norepinephrine. And frankly, they do quite a
good job of relieving some, if not all of the symptoms
of major depression. However, they carry with
the many side effects. Some of those side
effects are side effects related to blood pressure itself, by increasing noradrenaline,
norepinephrine as it's called, you raise blood pressure. That can be dangerous,
that can be uncomfortable. But they also have a lot
of other side effects. The reason they have other side effects is because they impact systems
in the brain and in the body that impact things like
libido, appetite, digestion, and others. And we'll talk about each
of those in sequence. Okay, so the experience
that clinicians had of observing some relief for depression with the tricyclic antidepressants
and with MAO inhibitors was terrific, but there
were all these side effects, side effects that people
really did not like, they didn't like these drugs at all. A lot of people get dry mouth,
I mentioned the low libido, they'd have sleep issues,
appetite issues, weight gain. They made some people so uncomfortable that they preferred not to take them, even though when they didn't take them, they had a worsening or a maintenance of their depressive symptoms. A decade or so later,
there was the discovery of the so-called pleasure
pathways in the brain. These are pathways,
literally groups of neurons that reside in different
locations in the brain but connect to one another. So it's a circuit. And when you stimulate these
neurons with certain behaviors or with electrical
stimulation in an experiment, believe it or not, that's been done in
both animals and humans, animals and humans become
very, very motivated to get more stimulation of these pathways. So this pleasure pathway or
these circuits for pleasure are very what we call reinforcing. In fact, animals and humans will work hard to get stimulation of these brain areas even more than they will
work to obtain sex, drugs, or even if they are addicted
to a particular drug and they are in a state of withdrawal, the ultimate state of craving, if given a choice, a person or an animal will select to have stimulation
of this pleasure pathway instead of the drug itself. And that is a major and
significant finding. This pleasure pathway,
as it's sometimes called, involves areas like the nucleus accumbens and the ventral tegmental area. These are areas of the brain that are rich with neurons
that make dopamine. And if you think to the
symptoms of depression, of anhedonia, lack of pleasure, a lack of ability to experience pleasure, well, that was a smoking gun
that there's something wrong with the dopamine pathway in depression. And indeed that's the case. So it's not just norepinephrine, it's also the dopamine or pleasure pathway is somehow disrupted. And then in the 1980s, there was the discovery
of the so-called SSRIs Most people are now
familiar with the SSRIs, the Selective Serotonin
Re-Uptake Inhibitors. The SSRIs worked by distinct mechanisms from the tricyclic antidepressants
and the MAO inhibitors. As their name suggests, SSRI, Selective Serotonin Re-Uptake Inhibitors prevent serotonin from being
wiped up from the synapse after two neurons talk to one another. What do I mean by that? Well, here's some very
basic Neurobiology 101. If you don't know any neurobiology, you're going to know
some in about 15 seconds. Neurons communicate with one another by spitting out chemicals into
the little gap between them. The little gap between
them is called the synapse or by the Brits, the synapse. Those chemicals bind to the
neuron on the opposite side and cause changes in the
electrical activity of that neuron on the other side of the synapse. Serotonin is one such neurotransmitter or more specifically,
it's a neuromodulator, can change the activity
of large groups of neurons in very meaningful ways. Selective serotonin re-uptake inhibitor means when a person takes this drug, some of those drugs include
things like Prozac or Zoloft, the more typical names
or more generic names are things like fluoxetine, when people take those,
more serotonin hangs out in the synapse and is able to be taken up by the neuron on the opposite side because of this selective
re-uptake inhibition. It prevents the clearance of
serotonin from the synapse and thereby more serotonin
can have an effect. So SSRIs don't increase the
total amount of serotonin in the brain. They change how effective the serotonin that's already in the brain is at changing the activity of neurons, okay? So they don't increase serotonin, they increase the efficacy
or the function of serotonin in the way that I just described. So that was more than 15 seconds, but now you understand how SSRIs work. And I wouldn't be talking about SSRIs if they didn't in fact work. Yes, there are many problems with SSRIs. They do carry certain side
effects in many individuals. Also, about a third of
people that take SSRIs don't derive any benefit, it doesn't relieve their
symptoms of depression. However, for the other two thirds, there's often a relief of some, if not all of the symptoms
of major depression. The problem is the side effects
that accompany those SSRIs. And so these days SSRIs
are a complicated topic. It's sort of what I would
call a barbed wire topic because we often hear about
all the problems with them, but these drugs also have
saved a lot of lives. They've also improved a lot of lives. The issue is that they tend
to have varying effects on different individuals, and sometimes varying effects over time. So they'll work for awhile then
they won't work for a while. There are also a lot of
mysteries about the SSRIs, and those mysteries bother people. What mysteries am I referring to? Well, SSRIs increase
the amount of serotonin or more specifically,
they increase the efficacy of serotonin at the synapse,
that happens immediately, or very soon after people
start taking SSRIs. But people generally don't
start experiencing any relief from their symptoms of depression if they're going to
experience them at all, until about two weeks after
they start taking these drugs. So there's something going
on there that's not clear. One idea is that the SSRIs
actually can improve symptoms of depression or even remove
symptoms of depression through so-called neuro-plasticity by changing the way that
neural circuits function. And there are many on this, but the main categories
of studies on SSRIs that relate to neuroplasticity
fall into two camps. One is that the ways in which SSRIs might, and I want to emphasize,
might be able to trigger the production of more
neurons in the brain, in particular areas of the hippocampus called the dentate gyrus and
others, that impact memory. This is important. We're
going to come back to memory. The other is that the
SSRIs have been shown in various scientific studies to reopen critical periods of plasticity. I'll just briefly describe
one of those studies. There was a study done by
Lamberto Maffei's group in Pisa, that explored brain plasticity that's known to be
present in young animals and disappear in older animals. And this is also true in
humans that younger humans have a far more plastic
brain that can change in many more ways more easily
than can the older brain. And what they showed was
that fluoxetine, Prozac, given to adult animals can reopen this incredible period of plasticity, can allow more plasticity to occur. That was interesting. I mean, it's purely through increases in serotonin transmission. And there are other studies
showing that fluoxetine can increase the number of new neurons that are born into the adult brain, so called neurogenesis, the
production of new neurons. So it's very clear that there are at least three major chemical systems in the brain; norepinephrine, dopamine,
and serotonin that relate to and can adjust the symptoms of depression. And those actually can be
divided into separate categories. So for instance, epinephrin
or norepinephrine is thought to relate to the
so-called psychomotor defects, sometimes called psychomotor retardation. This is the lethargy,
this is the exhaustion, this is the inability to get
out of bed in the morning. Dopamine is thought to
relate to the anhedonia, or I should say lack of
dopamine in depressive patients is thought to lead to the anhedonia. The lack of ability to
experience pleasure. And serotonin is thought to
relate to the grief, the guilt, some of the more cognitive
or more emotional aspects of depression. So we've got the norepinephrine system related to activity and alertness, the dopamine system
relating to motivation, pleasure, and the ability to
seek and experience pleasure, and then the serotonin system
that's related to grief. And unfortunately, brains and organisms don't work in a simple mathematical way where you just say, oh, well, this person's experiencing a lot of grief, but they don't have any
problems with lethargy. And so let's just boost
up their serotonin. On paper it works, but oftentimes it doesn't work clinically. And another patient,
you might get somebody who can't experience pleasure,
but they're kind of anxious. They don't have any trouble sleeping, but they're just much more
anxious and frustrated than they normally are, and they meet the symptoms of depression. Well, you might think, oh, well, do you just give that person
some drugs increase dopamine and everything will be better? And indeed, in some cases that's true. There are drugs like Wellbutrin, which function more specifically
on the dopamine system to increase dopamine and they
also increase norepinephrine. Many people get great relief
from things like Wellbutrin. They don't really impact the
serotonin system so much. And therefore you don't get
a lot of the serotonergic or serotonin related side effects. However, some people feel far
too anxious on those drugs, some people get addicted
to those drugs in a way, because a lot of those
drugs that increase dopamine make you want more of those drugs. So you start to realize that
what makes sense on paper doesn't always make sense clinically. And this is why it's complicated. And a really good psychologist and a really good psychiatrist
will work with someone to try and pull and push
on these various systems to find the combination
of drugs that may be or may not be correct for them. There's a fourth aspect of
the chemistry of depression that's really important to understand. And that's pain. We've talked about pain
on this podcast before, but even if you didn't hear
the episode on pleasure and pain, just want to
emphasize that pain is something that we experience in our
body, no surprise there, an injury, a cut, et cetera, but that we also
experience emotional pain. And those systems are linked
in very intricate ways. There's actually some data
showing that pain relievers, Tylenol, Aspirin, these sorts of things, can help certain people
with emotional pain. Now I'm not recommending people run out and take those things for emotional pain. But actually, if you think about it, that shouldn't come as any surprise. given the enormous number of
people that take painkillers, opioids and things like
them to try and relieve their psychological pain. And as we know, those drugs
are very, very problematic for many individuals. They can help certain individuals, but they are very prone to abuse and they can induce addiction very easily in a number of people. There's a substance that's
literally called substance P, the letter P, that's manufactured
by neurons in our brain and body, which underlies
our sensation of pain. And indeed substance P
inhibitors have been used to treat depression,
and in some cases works. A lot of people with depression
are hypersensitive to pain, and of course they could have
multiple things going on. They could have chronic
pain or chronic injury and major depression. So you start to get the constellation of the many things that could happen. So that's all I want to say
today about the chemistry underlying depression or major depression. There's a lot more there, but I think if you understand
the norepinephrine system and that it relates to some
of these things like lethargy, the psychomotor defects,
as they're called, dopamine and how it relates to motivation and lack of motivation and lack
of dopamine and depression, and serotonin and its
relationship to grief, and that low serotonin can
lead to extreme grief and shame and higher serotonin levels
can sometimes restore a sense of wellbeing and safety and feeling good about oneself. If you understand that and you
understand that physical pain is somehow involved in certain cases, I think you will know
more about depression and its underlying chemistry
than most all people out there. And if you'd like to learn more, I invite you to pursue
searching those terms further on the internet. And we'll certainly go
into them in more depth. But that really sets the stage
for where we're headed next. So next I'd like to talk about hormones and how they relate to depression. And I'd also like to talk about stress and how it relates to depression, as well as talk about some of the genetics or the predispositions to depression. And for those of you that are thinking, hey, I want the tools. I want to know how to fix depression. I understand the desire for that. I will just ask if you
hang in here with me a little bit longer, not only
will you learn a lot more about how this complicated
mood disorder works, some of the more
interesting things about it, but it will also position
you to get a lot more out of the tools that we will describe. You always have the option
to skip forward of course, but I think it's important to understand some of the hormonal and stress-related aspects of depression. So let's talk about hormones. 20% of people that have major depression have low thyroid hormone. Thyroid hormone is related to metabolism. Oftentimes we think about
thyroid is only related to having a fast metabolism, but thyroid is related to
all forms of metabolism, including our ability to
synthesize new tissues like protein and repair injuries. I did a whole episode on
thyroid and growth hormone. If you want to check that out, all of that is archived
at hubermanlab.com. It's all timestamped, et cetera. You can find on YouTube, Apple,
Spotify, all those places. So if you're curious about thyroid hormone and growth hormone, and you want
to do the deep dive on those, and you want to learn
how to alter their levels using various approaches, check that out. But 20% of people with major
depression are hypo thyroidal. They don't make enough thyroid. And that leads to low energy, low metabolism in the brain and body. And there's a condition
called Hashimoto's, which is essentially low thyroid output. And again, I don't want
to get into all the tools related to thyroid. Sometimes a psychiatrists will
prescribe thyroid medication to increase thyroid output
in people that are depressed and that will work to
relieve the symptoms. So there isn't necessarily
a direct problem with serotonin, dopamine,
and norepinephrine or substance abuse. Sometimes it's a thyroid problem. So there are certain
situations or conditions that can impact the thyroid hormone system and make people more
susceptible to depression or make a pre-existing depression worse. And those are things like childbirth. So it's well-known that
women who give birth can often undergo what's
called postpartum depression. It actually comes from the word
post parturition depression. They give birth, what's happier, what's
more joyful than the birth of a new healthy child, and they will lapse into a depression. And that's thought to
be hormonally related, either directly to the thyroid system or perhaps to the cortisol system as well. We'll talk about cortisol in a moment. As well, certain women
during certain phases of their menstrual cycle
experience symptoms that are very much like
clinical depression, and oftentimes are diagnosed with clinical depression appropriately. And of course the menstrual
cycle is associated with shifts in hormone levels. As well, menopausal and
post-menopausal women are more susceptible to major depression, regardless of whether or not they've had that major depression
earlier in their life. So these are things to
be on the lookout for and to definitely talk to a
doctor and get a blood panel that hopefully includes
measures of thyroid hormone and cortisol hormone. Why cortisol hormone? Well more stress is
correlated with more bouts of major depression across the lifespan. How many bouts? Well, it turns out that as you go from having one to two to three, well, when you hit four to five bouts of really intense,
stressful episodes in life, these tend to be long-term
stressful episodes, your risk for major
depression goes way up. So whether or not you have
a genetic predisposition to depression or not, one of the best things you can do to try and avoid getting depressed is to learn to control your stress system, to not go from short-term stress, which everybody experiences, we all have short-term stressors, to medium term stress to long-term stress, and to not have too many
bouts of long-term stress because that probability
of getting depressed goes way, way up. And this is something I've
seen over and over again, not just in my scientific
career, but just throughout life. People in all sorts of
domains, young and old, I've seen that people will go through a very intense relationship, a breakup, sometimes it's the staying
together that stressful, sometimes it's a graduate
school that can be stressful, sometimes it's some other event. And then some months later
they become depressed. And that's because the stress system is associated with the
release of cortisol. The cortisol system
can dramatically impact the way that these
different neuromodulators, dopamine, norepinephrine
and serotonin function. And so there's this kind of
latent or longer lasting impact on the systems that
impact mood and wellbeing. So learning how to control
your stress is really key. If you're not depressed or you're somebody that has not lapsed into
a depression recently, take control of your stress system. And we did an entire episode
on how to conquer stress, and that involves dealing
with stress in the short term, the medium term, and in the long-term. And there are a lot of
different ways to do that. One of the more important reasons for learning how to counter stress in order to offset depression is that there is a genetic predisposition that certain people carry
to become depressed. There are these studies now of many, many thousands of individuals, these were mainly done in New Zealand, but these studies have
now been done elsewhere, looking at many tens of
thousands of individuals who carry particular copies of genes, what they call polymorphisms, in particular of a gene called 5HTTLPR, which is a serotonin transporter. So this is a gene that
controls or regulates how much serotonin is
available in the brain. If you have this gene, this polymorphism, it doesn't necessarily mean
that you will be depressed, but it greatly shifts your
susceptibility to depression under conditions of stress. So I realize some people
are listening to this and some people are
watching it on YouTube. So I'm going to describe this in a way that doesn't require
looking at any graphs. What I want you to imagine
is a very, shallow hill, like a very mellow hill. It's just a ramp set at
about 10 or 15 degrees, okay. What we're plotting there in your mind is that with each about of serious stress, so that could be trying to finish a degree or a relationship breakup, or
a family member that's sick, or the loss of a loved one or a pet, with each about of stress, the probability that you will experience a
major depression goes up. However, if you carry this
gene, this HTTLPR gene, the steepness of that
curve goes way, way up where it's actually more like a line such that you need far
fewer bouts of stress in order to lapse into a
major depression, okay? So if the typical person who
doesn't carry this polymorphism has to experience two or
three or four or five bouts of stress before they
lapse into a depression, somebody with this gene is
susceptible to getting depression after just one about or two
bouts of intense stress, okay? So that's how these genes work. They don't preordain or
determine you to be depressed. They raise a susceptibility. And many genes, many things related to
heritability in general, work in that way. And we know there's a
strong genetic component to depression. How do we know? Well, in what are called
concordant monozygotic twins. So these will be identical twins. And they can either be
in one biological sack or two biological sacks while in utero, what's called monochorionic
or dichorionic. Well, typically it's monochorionic. And identical twins, for
which one of those twins goes on to have major depression, there's a 50% probability
that the other one will have major depression. So it's not 100%, it's not 100% inherited, it's not 100% generic, as you might say, but there's a much higher
predisposition for depression. Whereas in fraternal
twins, that number drops, and in siblings, that
number drops to about 25%, and in half siblings, it's about 10%. The numbers vary from study to study, but basically the more
closely related you are to somebody who has major
depression, the more likely it is that you will also get major depression. And therefore, if you haven't
gotten major depression, the more likely it is
that you should take steps to learn to mitigate stress because stress is the major factor that can trigger one of
these depressive episodes. So we've covered a lot
related to the stress and the hormones and the
neurochemistry of depression. In fact, I think this is probably
the deepest I've ever gone into the biology of any
topic on this podcast before getting to any specific tools. I mentioned that learning
how to mitigate stress and deal with stress, learning how to measure and
adjust your thyroid hormone, those might be useful. But next I'd like to turn
to some very specific tools that people who both have depression or who are prone to depression, as well as people who
don't have depression and simply want to maintain a good mood, who want to maintain a positive affect and pursuit of things in life, what are the things that you can do? It turns out there are
things that you can do and all of the biology that underlies the utility of those things. Meaning the reasons those things work will now make sense to you
because they adjust things like serotonin and dopamine, and they adjust them through
very specific pathways. I know for many people
learning about mechanism is kind of grueling. I realized this podcast
isn't necessarily one that you can listen to passively
while doing other things. Although I would hope
that you could do that and still enjoy it and
extract the information. Why mechanism? Mechanism is so key because mechanism is a
little bit like understanding some of the chemistry of cooking. If you read a recipe and
you can follow a recipe, you often hear people say,
oh, I can follow a recipe. That means that if you have
every ingredient in that recipe, you're good. You likely can make that
dish. You can make that meal. However, if you understand a
little bit of the chemistry of why salt has to be
added third and not first, or why the heat has to be
adjusted at a particular time, well then not only can
you follow a recipe, but that also gives you flexibility for when salt isn't available, or when you want to adjust
the flavor of the dish, or when you want to try a new dish, or you want to get experimental. So when you understand mechanism, it puts you in a tremendous place of power to work with your system. So it's not just plug and chug, like take 12 milligrams of this, you either feel better or you don't. You can really start to
understand how prescription drugs, supplements, nutrition, behavioral tools, how those things weave
together to either work for you or not work for you and get you to paths of healthy mind and body. So let's think about
why any tool would work to relieve depression. We've talked about how some of the drugs that impact these different
chemical systems might work and why they create some of
the problems they create. Problems are mainly created
by the fact that they impact lots of systems in the brain and body. So you take a drug to increase serotonin, but that serotonin is also
related, not just to mood, but to things related
to libido and appetite. And so you start disrupting
multiple systems. The same could be said for
behavioral tools, right? That any behavioral tool
that adjusts the levels of a particular chemical ought to perhaps, provide some relief for
some of the symptoms of major depression. Let's take an example that
I've talked about before on the podcast, which is, if you get into a very cold
shower, you take an ice bath, you will release
norepinephrine and epinephrine in your brain and body. There's no question about that. I don't think anyone
can really escape that. It's a kind of a universal
response to being in cold water. Well, if some aspects of depression are related to low
levels of norepinephrine, will taking cold showers
relieve your depression? Perhaps it might even
relieve certain aspects of that depression. Is it a cure? Well, that's going
to depend on the individual. Will exercise help? Well, if you go out for a run, you're going to increase
the amount of norepinephrine in your body. If you enjoy that run, it's
likely that you'll increase the levels of dopamine
and probably serotonin in your brain and body as well. Will that cure your depression? Well, there are a lot of studies exploring how exercise can impact depression. And indeed, regular
exercise is known to be a protective behavior against depression, but it also can help relieve some of the symptoms of depression. So you may ask yourself, why
would you need drugs at all? Why would there be prescription drugs or the need for
supplementation or other things to alleviate the symptoms of depression? Ah, well, that's the diabolical
nature of depression, which is if people are far
enough along in this thing, this sometimes called disease,
sometimes called disorder, but major depression, oftentimes
they can't get the energy to even get up and take
a bath or a shower. They have no motivation to do it, they have no desire to go for a run. So you say, "Come on, let's
go, you'll feel better. "I know you feel better, it
generates all these chemicals "I heard on the whatever
podcast, Huberman Lab podcast, "or another podcast
that getting into action "does all these things." And they just don't want to do it. And to you, a person who's
not experiencing depression, that perhaps could just seem
like the most frustrating and confusing thing in the world. But it's very important to highlight the fact that these circuits that are accessible to some of us, the circuits for happiness,
for pursuit of pleasure, for exercise, for
getting in a cold shower, if that's your thing, that those circuits are
present in all people, but for certain people that are experiencing major depression and are really in the
depths of their depression, they can't really access
those circuits in the same way that people who are not
suffering from depression can. So I hope that makes it clear. It's not offering any excuses for them. And indeed, I think those
behaviors would help jolt them out of some of the
symptomology of depression, but they're just not
accessible to everybody. So let's talk about the
things that people can do to deal with depression. And again, anytime you add a behavior or a tool or a supplement, or subtract a behavior, tool,
supplement, drug, et cetera, you absolutely should
talk to your physician, especially if you're somebody that's dealing with major depression. I want to focus on the stress system. And I'm not just going to tell you to get sunlight in your eyes and to get a good night's sleep, although I think everybody should do that on a regular basis, ideally every day, talked about those ad
nauseum on this podcast. They will help your sleep, they will help you alleviate stress. I think you should have
tools to deal with stress in real time, et cetera. But let's look at depression
from the standpoint of a deeper biological phenomenon, which is inflammation
and the immune system. There's growing evidence now that many forms of major depression, if not all of them, relate
to excessive inflammation. Now inflammation plays an
important role in wound healing. It is a positive aspect
of our immune system. Our ability to combat wounds,
combat illnesses, et cetera, but inflammation gone unchecked, inflammation that lasts too long, or is of too high amplitude, meaning too many anti-inflammatory or inflammatory cytokines
and things of that sort in the body is bad. And there's decent evidence
now that inflammation can lead to or exacerbate depression. And that if we want to control depression, or limit or eliminate depression, that focusing on reducing inflammation and its associated pathways
is a really good thing to do. And I think this is a really
good thing for everybody to do regardless of whether or not
you suffer from depression or not. And today we're going to talk
about exactly how depression comes about through the
inflammation pathway. So, first of all, who
are the major players in creating chronic inflammation
in the brain and body? They are the inflammatory cytokines. Things like IL-6, interleukin-6, things like Tumor
Necrosis Alpha, TNF alpha, things like C reactive protein, alright? Not all of these are cytokines. You have interferons and prostoglandins and a lot of these things. But when we are stressed,
chronically stressed, we get inflamed, our brain
and various locations of the brain become inflamed
because certain classes of cells, in particular,
those glial cells, the cells that are typically thought to just be support cells, those cells and their biochemistry and their dialogue with the neurons of the brain and body
starts to become disrupted. I may have mentioned it
earlier, I don't recall. But I certainly mentioned
it in an earlier podcast that adrenaline epinephrin,
when it's released in the body, it doesn't cross the blood brain barrier, but there are certain things that are able to cross
the blood-brain barrier when we are stressed. Things like the E2 prostoglandins, those cross the blood brain barrier. And our blood and our brain, therefore our brain and
our body can communicate because certain things can
pass through this barrier we call the BBB or the
Blood Brain Barrier. And also we have something
called the glymphatic system, which is really a plumbing system that links the brain and body. It's the link between the
immune system and the brain. Well, there is a set of
actions that we can take in order to limit inflammation. And this has been shown in several quality peer
reviewed studies now to reduce inflammation
and to relieve some, and in some cases, all of the
symptoms of major depression. One of those approaches
is to increase our intake of so-called EPAs or
Essential Fatty Acids. There's now a very long list of papers in quality peer review journals showing that when people ingest a certain level of EPA
omega-3 fatty acids, the relief from depressive
symptoms matches the SSRIs. That's incredible, right? That essential fatty acids could relieve symptoms of depression, as well as some of the
prescription antidepressants. Now, this doesn't
necessarily mean you run off and stop taking your antidepressants if you've been prescribed
them, please don't do that. Please talk to your physician. And I should mention that
some of the same studies have shown that increasing our intake of these essential fatty acids, in particular, the EPA
variety of omega-3s, can lower the effective
dose of things like SSRIs. Meaning if we required a 50
milligram or 40 milligram dose of fluoxetine, that one
can get by on a lower dose and thereby perhaps not experience as many or as severe side effects by taking or supplementing with EPAs. Now, the threshold level
seems to be about one gram, 1000 milligrams of EPA. So you will sometimes see
on a bottle of krill oil or fish oil or any other
source, even plant source or other source of EPA
that it's 1000 milligrams or 1200 milligrams. But what's really important to look at is whether or not there's more
than 1000 milligrams of EPA, because the EPA in particular
is what's important here. And actually in exploring
some of the literature on the effects of EPAs on
cardiovascular health, excuse me, as well as their effects on depression, there's some interesting
dose dependent responses, such that people who took
anywhere from 400 milligrams to 5,000 milligrams of EPAs, achieved a variety of different benefits. And in some cases, some side effects, we'll talk about those. And it does seem that this 1000 milligrams is the critical threshold for benefiting or getting some relief
from depressive symptoms. But people who took two
grams seem to do better. And in the cardiovascular health realm, there it's a little more complicated. Some studies point to
a very positive effect on cardiovascular health by taking increasing amounts
of EPA, others, not so much. The current data point to the fact that for every gram of
EPA that one ingest, there's about a 9% improvement
in cardiovascular health, the same dose dependent
improvement on psychological health in combating depression
can't really be stated. I wouldn't say that the more EPA you take, the better you're going
to feel so to speak. I don't think the data point to that. However, it does seem
that if you take a gram, 1000 milligrams or 2000 milligrams of EPA, there does seem to be
some substantial relief for many people, should
emphasize many, not all, for many people in major
depressive symptoms. So how would this work? Well, turns out that these
inflammatory cytokines, they impact neurons and
the circuits of the brain that relate to things like serotonin, dopamine, and norepinephrine. These inflammatory cytokines act in a variety of different ways, but they mainly act to inhibit
the release of serotonin, norepinephrine, and dopamine,
or the synthesis of serotonin, norepinephrine and dopamine. And I'll give you one example of how EPAs can positively impact this process. And then it points to a second tool, which is the proper
utilization of exercise to offset the effects of depression. So now you should understand
why having healthy levels of serotonin is important
for maintaining healthy mood. It's not responsible for all the aspects of having a healthy mood, there's also dopamine and norepinephrine, but it is a very important one. Dopamine also called 5HT, essentially derives from a
precursor called tryptophan. Tryptophan arrives into our
system through our diet, okay, tryptophan is an amino acid. Tryptophan is found in Turkey,
it's found in carbohydrates. And that should therefore raise the idea, hmm, I wonder if one of
the reasons why people who are depressed have such an appetite for carbohydrate late in foods is because they're trying
to get more tryptophan, and therefore more serotonin. And indeed that's the case. Tryptophan is eventually
converted into serotonin. However, if there's excessive
amounts of inflammation, these inflammatory
cytokines cause tryptophan to not be converted so
much into serotonin, but to be diverted down
a different pathway. The pathway involves something
called IDO, Indoleamine, which converts tryptophan into kynurenine. Kynurenine actually acts as a neurotoxin by way of converting into
something called quinolinic acid. And quinolinic acid is pro depressive. So if that seems like a
complicated biochemical pathway, what's basically happening
here is that the tryptophan that normally would be
made into serotonin, under conditions of
inflammation is being diverted into a neurotoxic pathway. And ingestion of EPAs, because it limits these
inflammatory cytokines, things like IL-6, C-reactive
protein, et cetera, can cause more of the
tryptophan that one ingests or has in their body to be diverted towards the serotoninergic pathway. Exercise, it turns out,
also has a positive effect on the tryptophan to
serotonin conversion pathway. And the way it does it
is really interesting. You now know that tryptophan
can either be converted into serotonin or it can be
converted into this neurotoxin, which is a bad thing. Exercise, the activation of the muscles through rhythmic repeated use, in particular aerobic exercise,
but also resistance training has been shown to do this to some extent, tends to sequester or shuttle
the contouring into the muscle so that it isn't converted
into this neurotoxin that is pro depression, okay? There are a lot of steps in the pathway leading to depression, but what this essentially means is that hitting a certain
threshold level of EPA intake, whether by supplementation
with fish oil or krill oil or through some plant source if you're not into
ingesting fish or krill, or trying to get up above
that 1000 milligram threshold for EPA by ingesting
particular food sources, you certainly can do it through food, you don't have to supplement, but it's easier to do with supplements, that doing that will
limit the inflammation that diverts tryptophan into
this neurotoxic pathway. And exercise as well, augments
this conversion of tryptophan into serotonin because it takes this thing that would potentially be a
neurotoxin and it sequesters it, it pulls it away so that it can't actually go have its pro depressive effects. So you've got multiple steps here. We're describing two tools, increasing EPA and regular exercise as a way of increasing serotonin, somewhat indirectly, right? It's by limiting this bad pathway to promote the activity of a good pathway. But from the data that are published in Quality Peer Review journals, it really appears that
this inflammation pathway does function to increase
depression through these pathways. And so knowing that there
are behavioral steps and supplementation based steps, or if you prefer getting
your EPAs from typical food, from nutritional approaches, I find that very reassuring
that the mechanisms all converge on a common
pathway, serotonin. That gives me great peace of
mind that when people say, hey, go out for a run, or you should get outdoors exercise, or you should take fish oil
like the Scandinavians do, I have Scandinavian family
members and they are known to, or I should say they are
quite open about the fact that during the winter
months in particular when depression is more likely, but throughout the year, really, they make an effort to regularly
ingest high levels of EPA, either through ingesting
fatty fish and its skin, I'm not a particular fan of ingesting the skin of fatty fish, or by supplementing with Cod liver oil or other types of fish oil, sardines, and things of that sort, sardine oils. There are a number of
different things out there that one could use. So I find it very reassuring that there's a common biochemical pathway that can explain why these
things not just work, but why they should work. They should work because they operate in the very same biochemical pathways that antidepressants that
are prescribed to people do. So what does this mean for you? Well, if you're somebody who
suffers from major depression, again, don't stop taking
your prescribed medication. Talk to your doctor, but talk to them perhaps
about the EPAs and exercise and how these things can impinge on the same biochemical pathways. If you're somebody who is not suffering from major depression, I
still think these pathways are really important to understand. And actually knowing these
pathways is additional motivation to get regular exercise. I think we all know that
we should be getting anywhere from 150 minutes
to 180 minutes per week of so-called zone two cardio
for cardiovascular effects. Zone two is the kind of melowish cardio where you can sort of hold a
conversation if you needed to. But it's a little bit tough, you're kind of sucking
for air a little bit. And that's going to limit
these depressive like symptoms, I think in all of us. I don't think that we
should think of depression as a strict threshold. I'm somebody who personally
has made the choice to take 1000 milligrams of EPA per day. I do that by supplementing fish oil. There's debate out there
as to whether or not it's better to take EPA
NDHA in particular ratios, and whether or not DHA can impact the LDL, which is the so-called bad cholesterol. That's getting really down into the weeds. And we can talk about
that in a future episode. But for myself, I notice
a pretty substantial positive effect of taking anywhere from 1000 milligrams to 2000
milligrams of EPA per day. I do that through supplementation and I do strive to try and eat some fish, even though frankly, I've
never liked the taste of fish. For those of you that would
like a little more detail or perhaps a lot more detail
into the effects of EPA on depression and in
relieving depressive symptoms, and if you want to get into
the nitty gritty of it, I invite you to go to examine.com,
put in depression, EPA, they list off and have links to 28 studies on the effects of EPA on major depression. If you go to pub med, there are many, many studies on this now that date back several decades, really. If you're interested in the
specific effects of EPA, as opposed to DHA, I want to point you towards
a particular study entitled, not surprisingly EPA, but not
DHA appears to be responsible for the efficacy of omega-3
long chain polyunsaturated fatty acids supplementation
and depression, evidence from a meta analysis
of randomized control trials. This is a really wonderful paper. The author is Julian
Martins, M-A-R-T-I-N-S. It was published in 2009. We will provide a link to
this study in the caption. And that study is really
the one that at least to me, points to why EPA in
particular is what's effective, and that whether or not
DHA is problematic or not as a separate issue,
but it's really the EPA that one wants to hit a
certain threshold level of if one's goal is to get
relief from depression or to keep depression at bay
by keeping mood elevated, which is why I take a high-dose EPA. So we've got EPA, we got exercise, now you understand how
they work to adjust mood. Now, I want to talk about
something that at least for me, was quite surprising when
I first learned about it for sake of treatment of mood disorders, and that's creatine. Creatine has a number of
very important functions throughout the body. For those of you that are
into resistance training, and actually for those of you that are into endurance training as well, creatine has achieved a lot
of popularity in recent years because supplementation with
creatine can draw more water into muscles and can increase
power output from muscles. So it's something that does indeed work. There have been debates
about whether or not it's unhealthy for the kidneys
to take long-term creatine, supplementation at high doses. And I invite you to go
down that rabbit hole. I think most people now accept the idea that for most people, not
all, but for most people, low dose creatine
supplementation of anywhere from one gram to five grams per day can have a number of positive effects on physical performance. People with kidney issues, et cetera, need to be especially cautious, but creatine is interesting
for that purpose. However, there's also a
so-called phosphocreatine system in the brain, and that
phosphocreatine system has everything to do with
the dialogue between neurons and these other cell types called, glial, and glial comprise several cell types, microglia, astrocytes, et cetera, but the foster creatine system in the forebrain in particular,
in the front of our brain, has been shown to be involved
in regulation of mood and some of the reward pathways
as well as in depression. And there are now several
studies, at least three, although they're probably more
by the time this comes out because they're coming
out very quickly now, at least three quality
studies pointing to the fact that creatine supplementation doesn't just have these positive effects on physical performance, but can also be used as
a way to increase mood and to improve the symptoms
of major depression. This has been now done
in several double blind placebo controlled studies. The studies have looked at women, have it looked at men,
have looked at adolescents, some of whom were taking
SSRIs, some of whom were not, they've done magnetic
resonance spectroscopy. So spectroscopy is a way that you can look at the concentrations of
particular in the brain in real time in humans, it can be used for other
things as well, of course. And basically what's been
observed is that increasing the activity of the phosphocreatine
system in the forebrain can be beneficial or
at least is correlated with improvements in mood. So let's just talk for a
moment about what's involved with using or supplementing creatine in order to improve mood and
perhaps even treat depression. First of all, when I talk about creatine, I'm talking about creatine monohydrate, there are a number of
different forms of creatine. Here I'm talking about
creatine monohydrate. The American Journal
of Psychiatry in 2012, published a study, which was a randomized, double blind placebo controlled trial of oral creatine monohydrate. And what it found is that it could augment or enhance the response
to a selective serotonin re-uptake inhibitor, in particular, in women with
major depressive disorder. So like EPA, creatine supplementation seems to either lower the required dose of SSRI that's required
to treat depression, or can improve the effectiveness
of a given dose of SSRI. However, there are other studies
that have looked directly at creating supplementation
in the absence of SSRIs. And those are interesting as well. There's a wonderful and
very comprehensive review on creatine for the
treatment of major depression that includes beautiful
tables of all the subjects and the dosages, et cetera. I'm not going to read off every line and every column in that review, but we will provide a link
to that review as well. One of the things that's really striking about the lists of
studies that they include is that most of them used dosages that are pretty reasonable
for most people, anywhere from three grams to five grams, sometimes up to as many 10
grams per day of creatine. Many of these also were shown to increase activity of this phosphocreatine
system in the forebrain, and some show a relationship between that phosphocreatine system and a particular category
of receptors in the brain called the NMDA receptor,
N-methyl D-aspartate receptor. The NMDA receptor is
one of the first things that every budding
neuroscientists learns about because it is the receptor
that has particular electrical and chemical properties
that make it a critical gate for so-called neuroplasticity. So it's not a receptor that's
activated in the brain, typically for just the
functioning of the brain on a day-to-day basis. It's a receptor that's activated when circuits are going to change, when they are inspired to change by some very strong stimulus,
meaning some experience, or in some cases a drug, or
in some cases something else. But the NMDA receptor
is a kind of a key node for shifting brain circuitry. And so while the details
aren't entirely clear, it seems that creatine supplementation leads to increases in the
phosphocreatine system in the forebrain. And that increases in the
activity of the forebrain phosphocreatine system relate to changes in the way the NMDA receptors function and may lead to some of the plasticity, the changes in neural
circuits that underlie the shift from negative mood
and affect to positive mood. Now, there are a lot of gaps. There are a lot of little
boxes or bins in the diagram I just laid out for you. And some of them are still
truly black boxes, as we say, meaning, we don't really
know what's in them yet. And more mechanistic data are coming. However, when you look over
the data in this review, or when I look over the
data in this review, what you find is that
they're pretty striking positive effects of creatine. And one of the more interesting effects is that creatine has actually been shown to increase mania in people
that are already manic. And that's interesting, we're not talking about
bipolar depression today, but it seems that creatine
elevates levels of activation and kind of mood overall. And you could see why
that would be a problem for somebody that's
already in a manic phase, but it actually might be
beneficial for somebody who is very low affect
and has major depression. So should you supplement with creatine? Well, as always, talk to
your healthcare provider, but if you're somebody who
is thinking about things that you can do and
things that you can take in order to improve your
mood, keep depression at bay, maybe even support other
treatments for major depression. the creatine system
seems like a logical one. There's at least strong studies
and a good number of them to look to, to determine whether or not that's right for you. I personally take five grams
of creatine for other reasons. I take it for the physical
performance, enhancing effects, but it's kind of nice
to think that perhaps it's also helping me improve my mood. That's a choice that I've made for me is in within the margins of
safety for me in my life. I don't know that it's
right for everybody, but I find it very interesting. And again, I find it
particularly interesting because there's a logical
biochemical pathway to support the finding
that it improves mood and can offset the effects
of major depression in some cases, or can improve the effects of antidepressant
medication in many cases. When I see mechanism
and I see effectiveness, and the mechanism and
the effectiveness map to a lot of the same mechanisms that are involved in prescription drugs, that gives me great reassurance
that this isn't just some sort of mysterious
pathway or mysterious compound by which a creatine might be working. So now we've kind of
clustered together EPAs, exercise, and their
relationship to inflammation, creatine and its relationship
to forebrain function, and the phosphocreatine
system, and this NMDA receptor. And as you'll see in a few minutes, that NMDA receptor turns
out to be vitally important and is actually one of
the main nodes of action for some of the more novel
and exciting therapeutics that are being explored
now in psychiatric clinics. So let's talk a little bit
more about this NMDA receptor and how it relates to some
of the more experimental or novel therapeutic
compounds for the treatment of major depression. And the compounds that we're
going to be talking about, you may have heard of
before, one is ketamine, which is getting increasing
interest in psychiatric clinics and in various experimental
and clinical studies, and the other is PCP. Both ketamine and PCP
are known drugs of abuse. For many years, people
have abused these drugs, go by the street name,
special K, et cetera. And they create dissociative
anesthetic states. So dissociative states
where people don't feel as closely meshed with their
emotions and their perceptions. It's an odd state, I hear. And it's an odd state that clinicians are now leveraging for the
treatment of depression. And we'll talk about why that is, but let's talk a little bit
about this NMDA receptor and why ketamine and PCP
might work for the treatment of depression or how they even could work. I want to be very direct
that this is an area that still needs a lot of data. There are however, some excellent papers from really terrific groups. One of them is a paper that
was published in nature last year, 2020. First author is Vesuna,
Sam Vesuna, V-E-S-U-N-A, and the last author and
the lead on the study, who was Dr. Karl Deisseroth, who was a guest on the
Huberman Lab podcast a few months ago. He's world expert in
neuroscience, he's a psychiatrist. And this paper from Sam
Vesuna and Karl and colleagues explored how these
dissociative states come about. And they looked at this both
in animals and in humans and found that there was a, essentially a common mechanism whereby a particular layer of cortex, so your brain has this
outer shell of tissue that is called the neocortex. It's where our perceptions lie, it's where our associations lie, it's a very important area for processing decision-making and planning, et cetera. It's literally stacks of cells, and one of those layers in the
stack of cells is layer five. And the layer five neurons in particular, went into a particular rhythm
of electrical activity, this one to three Hertz
rhythm after mice or humans were administered ketamine or PCP. There was activation of a
particular area of the brain, this retro splenium cortex as it's called. And the dissociative state that emerged was an interesting one. And clinically what's
described in the trials for ketamine and things like it, that people who are
depressed will take ketamine, will experience a kind of separateness from their grief and from their emotions. And that possibly there's plasticity, there actually shifts
in the neural circuitry, such that their emotions don't
weigh on them so heavily, I'm using very loose language here, but that they don't feel as over written or as burdened by their own emotions as they did previously
to the ketamine therapy. Now, absolutely in no way, shape or form am I suggesting that people
run out and take ketamine in order to treat their own depression. These drugs are still
very much experimental, although they are approved
in certain contexts, at least in the U S, by prescription for the
treatment of depression. What's interesting to me is
that these dissociative states sound at least at the outset
to be more of a separateness from everything. It sounds a little bit
like depression itself. That's sort of like
anhedonia and an inability to experience pleasure. And then one takes a
dissociative anesthetic and somehow is able to get relief by getting even further
away from an experience. To me, that doesn't make sense, but that just speaks to
the fact that these drugs and these receptors and these pathways operate through very cryptic means. And we really don't understand
all the pathways in the brain that relate to motivation
and mood and so forth. And the results with these ketamine trials are looking very promising. In fact, there are a number of trials that show that a fair number
of people that take ketamine in a therapeutic setting
legally with a psychiatrist guiding the experience are able to get relief from their symptoms without the need for many,
many treatments with the drug. Just how many treatments varies from individual to individual, but it's not like people have
to take this stuff ongoing. This is really an attempt to
tap into this NMDA receptor that is related to neuroplasticity. Both ketamine and PCP
essentially act as antagonists, which means they block the NMDA receptor. They do it through different methods, non-competitive and competitive for you chemists and pharmacologists out there. You can look it up if you like. But what's therefore even more surprising is that every neuroscientist
learns that activation of the NMDA receptor, not antagonism or blocking
of the NMDA receptor leads to changes in neural
circuitry in very profound ways. In fact experimentally, and I've done these experiments myself, if you want to prevent plasticity, you want to prevent an experience from reshaping neural circuitry, you give an MDA receptor blocker. I've done that many times in the course of my experimental
neuroscience career, not to myself, obviously, but in the course of doing experiments. So it's still a bit mysterious
to me how this could work. A couple things. One is this layer five
activation is pretty interesting. We're going to come back to layer five when we talk about yet another emerging treatment for depression,
which has psilocybin, so-called magic mushrooms, and the effects of psilocybin
on layer five neurons in the cortex. So there's a common theme emerging here, which is that layer five
activity in the cortex may be important for rewiring
the brain in certain ways that can lead to recovery
or to an alleviation of some of the symptoms
of major depression. So if this is sounding a
little bit vague to you, it's because this is still
truly experimental and new, and still very much on the cutting edge of what's happening now. We don't have all the answers. So if it sounds like I'm
moving slowly through this, and I'm being extra
careful about what I say, you are correct. Your antenna are correct in this case. I never want to misstep and
say something that's not true, but that's especially the case when we're talking about
experimental therapies and drugs, which formerly were
taken as drugs of abuse, which are now being used as
drugs for therapeutic treatment in the clinic. There is a very interesting study. This was published in science in 2019. So these are very recent studies. The last author on this
is Liston, L-I-S-T-O-N. The title of the paper is "Sustained Rescue of
Prefrontal Circuit Dysfunction "by Antidepressant
Induced Spine Formation." And here, when we hear spine, we're not referring to
spine as in your vertebrae, running down your spinal column, we're talking about the spines, which are these little
protrusions on neurons. Neurons are not smooth by any stretch. If you zoom in on a neuron,
if you were to come to my lab and look down the microscope
at a neuron and zoom in on it, you'd find that some neurons are smooth, but most neurons have
these little protrusions. And those little protrusions
are called spines. And those little spiny
protrusions are little sites where neurons can reach
out and form and receive new synapses from neighboring neurons. So they increase the
surface area of a neuron and allow new connections to be formed. And so spine formation is
synonymous with neuroplasticity, which is synonymous with
changes in circuit function, which is synonymous with changes
in the ways that we think, we feel, and we behave. And what was shown in the
study is really interesting. What they showed is that ketamine can relieve depressive symptoms rapidly by changing or increasing in this case, the spines on these neurons
in the prefrontal cortex. And if that word prefrontal rings a bell, well, now you remember the
phosphocreatine system, the ingestion of creatine
monohydrate, and the forebrain, activation of the
forebrain were related to, in some way or another,
to relief or improvement of major depressive symptoms. So we're starting to
converge on a picture here whereby these drugs, ketamine, PCP, used in a therapeutic context, may be increasing neuroplasticity. Literally the changing of
neurocircuits in the forebrain somehow through dissociative states. And I don't want to speculate too much about how that might come about, but one of the things
that's such a resounding or repeating theme of major depression is that when you talk to somebody
who has major depression, it is a real downer. And I'm not being
disparaging of those people. But if you've ever had a conversation with someone who's depressed, they're always talking about
how exhausted they are, or in really severe cases, they are not even responsive at all. They just kind of stare at you
blankly, or they fall asleep. I mean, they're truly depressed. Their system is lowered in
terms of its activation state. So I think that it's
interesting that the application of drugs that allow people
to separate from that state of not caring or being
uninterested or unwilling to do anything is actually
one of the paths to treatment. It's not always about
just getting people peppy and excited and happy. There also seems to be requirement for getting them distanced
from their own grief. And this brings us back to
something that we talked about way back at the beginning of this episode, which was this particular feature of the anti self confabulation, that everything that
happens is a reflection that I should say for
the depressed person, that everything that
happens is a reflection of how life is bad and their experiences just point to the fact that
nothing is going to get better. This is the common language of depression. If this is very depressing
to hear me talk about it, it is heavy. And that's what it's like
to hear these things, it's even heavier, of course, for somebody to experience them. And those beliefs, those
patterns of guilt and grief and anhedonia and delusional
anti self confabulation, those are the things that eventually, if they get severe enough, start to convert into things
like self harm mutilation, and in the most tragic of
cases, of course, suicide. And so I think we can
look to these treatments such as ketamine and PCP, but in particular ketamine
and its use in the clinic, as ways for people to get
distanced from the negative affect that they feel isn't just
inside them or overwhelms them, but that for the very
severely depressed person, they feel is them. And we hear this sometimes,
you are not your emotions. That's a statement that I've
always been a little bit challenged by. I mean, yes, indeed
emotions are not who we are. They are states that
we go into and out of, including happiness and sadness, but they are very much a part
of us when we experience them. We don't experience them
as next to us or behind us or across the room from us. We experienced them as our emotions. They are so much part and
parcel with our experience of ourself that a statement
like we aren't our emotions is a very hard statement to digest, especially for the depressed person. And so I think that the NMDA
receptor and its capacity to induce neuroplasticity,
circuit changes, the fact that PCP and
ketamine are both showing activation of neural circuits
by way of suppressing activity of the NMDA receptor, and some of the positive or
exciting therapeutic outcomes that are coming from this
really point to the fact that ketamine and PCP and
removal of negative experiences or the experience of
a negative experience, sort of getting meta there. But the experience of
a negative experience may be an important path by which people treat their depression, especially
in its most severe forms where people are veering
towards self-harm, mutilation, and suicide. So you may have noticed a theme, which is that certain
categories of approaches that we've been discussing for offsetting the symptoms of depression,
such as exercise, ingesting EPAs, reducing inflammation, or even the SSRIs for
increasing serotonin, focus on changing some
core biological function, like raising the amount
of a chemical, serotonin, or reducing the amount
of inflammatory cytokines in the brain and body. And yet things like ketamine focus more on rewiring circuitry, changing neural circuitry
so that it functions better in the immediate and hopefully
in the long-term as well, and keep people with major depression in what they call, remission,
away from major depression. Another category of treatments that's being actively
explored now in laboratories and in the psychiatry
realm are the psychedelics. And that's a huge category of compounds. However, one in particular, psilocybin is one that's
being most intensely and actively pursued for its capacity to treat major depressive disorder. I want to be very clear that the work that I'm going to describe
as work that's being done in university settings,
university hospitals, by scientists and psychiatrists, and these are clinical
studies, clinical trials, leading to peer reviewed data. And those are the data
that we'll be discussing. Some of the major luminaries
in this area include, of course aren't limited to, but include people like Matthew Johnson who's at Johns Hopkins. We'll discuss some of his
work now, and fortunate to say that he will be coming
on the podcast as a guest to just scribe the studies
in a variety of laboratories, working on a variety of
different psychedelic compounds, but let's focus on
psilocybin for its capacity to rewire neural circuits
and alleviate depression. There have been anecdotal data
or evidence over the years that psilocybin has this capacity,
how does psilocybin work? Well, psilocybin, magic mushrooms,
as it's sometimes called, mainly works on what's called
the serotonin 5H2A receptor with some affinity for the 5HT1 receptor. What does that mean? Well, basically, you've
got a lot of different kinds of serotonin
receptors just as you have a lot of different kinds
of dopamine receptors or other types of receptors. The advantage of having
different receptors expressed in different
parts of the brain and body, even on different parts
of individual cells in the brain and body is that
the same compound, serotonin, can have a diverse set of effects on different cells and tissues. This is also the basis of some
of the side effect profiles of SSRIs, because maybe for instance, we know that taking Prozac fluoxetine will increase serotonin in one area, but also in another area. And then they will go have diverse effects on different brain circuits because of the variety of receptors. Receptors are just like parking slots where the molecule serotonin parks and has different effects. Well psilocybin engages or increases serotonin transmission, meaning it increases
the amount of serotonin, mainly by acting at these 5H2A receptors, but where in the brain does it happen and what are the major effects? First, let's talk about the major effects 'cause I think that's what
people are interested in. The study that I'd like to
highlight is a fairly recent one. It was published in may of 2021 in Journal of the American Medical
Association Psychiatry, so JAMA Psychiatry, and it's entitled, "Effects of Psilocybin Assisted Therapy "on Major Depressive Disorder,
a Randomized Clinical Trial." It's an absolutely beautiful
study, a very important study. It includes some of the
luminaries in this area like Matthew Johnson, Patrick Finan, Roland Griffiths, and others. We will provide a link to this study. It is available in its
full form at zero cost if you want to read it. It's got a lot of detail. So I'm just going to
summarize a few things, but basically what they did
was they screened for patients to come into the clinic. These were people that suffered from major depressive disorder, and administered either one
or two rounds of psilocybin. They used particular dosages
that are listed in the study. So you can look it up if
you're really interested in that level of detail. Typically it was 20 milligrams
per kilogram of body weight. So it depends on body weight. Or 30 milligrams of
psilocybin per 70 kilograms of body weight. They were given in capsule form. So people weren't eating the mushrooms. This is obviously a very controlled study and they wanted to control
the dosages appropriately. They were randomized to begin
the treatment immediately or after an eight week delay. They had all the
appropriate control groups that one would like to see. What's really striking this study is that there was a very
significant improvement in mood and affect and relief
from depressive symptoms in anywhere from 50 to 70% of the people that were subjects in
the study who received the psilocybin treatment. And whether or not it was 50
or whether or not it was 71%, varied according to how
long after the study they maintain these
antidepressive effects, whether or not they stayed in
remission from the depression, but these are really enormous
insignificant effects, and very exciting and are
pointing in the direction of psilocybin very soon,
becoming a treatment for various forms of depression,
including major depression. Now, of course, this is
limited to the laboratory at present. There are a number of
elements of these studies that are important to take
into consideration too, which is that there are
highly trained guides, meaning people to direct
people through the experience. As Matthew Johnson has told me, there is the occurrence from time to time of people having so-called bad trips of having anxiety attacks
during the hallucinations and all that. And they have ways to mitigate
that and deal with that because the guides are trained. They have all the sorts of
medical monitoring devices for heart rate and temperature and things that one would like to
see for a study like this, because these are very powerful compounds. I don't want to give away any
elements of the discussion with Matthew Johnson, because it will be
released in podcast form reasonably soon here,
the Huberman Lab podcast. But one of the things that came up and is a fundamental question that I had, that I think probably
many of you are asking, is does the experience that
one has on these compounds make a difference for whether
or not somebody gains relief from depression, from these
psilocybin journeys or not? In other words, does it
matter what they talk about? Does it matter what they think about? Does it matter if they have
a good trip or a bad trip? And I don't want to hold
you in too much suspense, I'll let Matthew provide
the more thorough answer. But what's really interesting is there are some common themes
to psilocybin administration and experience that lead to
relief from depressive symptoms, but they are subjectively very varied, meaning that whether or not people feel they had a good experience
or a bad experience, whether or not people
thought about their parents or thought about the color of the ceiling, doesn't seem to have too much of an impact on whether or not they receive relief during these studies in
these clinical studies. It seems like different people can have lots of different experiences
and still receive benefit. And that points to something deeper. It points to the fact that these drugs, which is really what they are, are rewiring neural
circuitry in a common way despite a diversity of
experience while on the drug. And that itself is really interesting. And it takes us back to a
place that we've been before in this discussion, which
is layer five of the cortex. This area that ketamine
seems to impact as well by generating rhythms of the, I mentioned one to three Hertz activity in layer five of certain
areas of the cortex. Well, the 5HT1A receptor
is known to be enriched in layer five of the cortex, and layer five of the cortex
is a very interesting area because it's an area in which there's a lot of lateral connectivity. So connections between
different brain areas laterally, generally is what allows us
to merge different senses. So for instance, when we
hear a sound off to our right over here, we turn to our right. There's a very hardwired response. And typically we hear
something off to our right, we don't look to our left. That's how hardwired some
of these circuits are. What appears to be happening
is that the activation of the serotonin system and
5HT1A receptor in layer five is offering up or providing an experience whereby the lateral
connections are able to engage much more broadly than
they would normally. Now that also could be a bad thing. And I asked Matt about this,
that sounds kind of spooky. I don't know that when I hear
something off to my right, that I want to look off to my left. That could be highly maladaptive, especially if it's a car
coming at me from my right. That doesn't seem to be what's happening. It's not really rewiring these
deeply reflexive circuits. It's somehow rewiring
associations between events, emotional events, past
events, current events, and future events in
ways that allow people to get some sort of relief or distance from these narratives,
these depressive stories about their past and
present and allow them to see new opportunity and
optimism in the future. It's really a fascinating thing if you really think about it, because I would have thought that simply by ramping up
laterality of connections, meaning that cross associations, that things could either
be rewired randomly in ways that don't serve us, or would perhaps just
cause no effect at all. So it's either going to be bad or neutral, but that's not really the
way things are turning out. Again, these are highly
controlled studies. I do want to emphasize
that ketamine, psilocybin, these things are still illegal. Most all places. There are some regions and
cities in the United States where they are locally decriminalized, but they are not legal. They're still illegal. So what we're referring to here
are indeed clinical studies in which people are taking them legally. I think it's very likely
we will see a shift in the legislature around psychedelics, and in particular, psilocybin
in the not too distant future. And I think that for
now, what we should know is what Matt told me and what
you'll hear far more about, which is that psilocybin.
this one where in most cases, two dose treatments done in
a highly clinical setting, controlled setting with patients that are carefully
selected, can in many cases, the majority of people
receive and maintain relief from their depressive symptoms, simply through the experience
of this psychedelic journey. I did ask them about micro dosing. I made it sound as if I'd
never heard about it before. Microdosing, not micro dosing. Microdosing, and his
answer was interesting. His answer was that
the microdosing effects don't seem to be nearly as
impactful as some of these, well, let's just call them what they are. These kind of high amplitude sessions that there are just one or two, there are some studies ongoing
where there's more than two, but that the microdosing
doesn't seem to compare to these macrodosing, I
mentioned the dosages before, this 20 milligrams per 70 kilograms or 30 milligrams per 70 kilograms dosages given several weeks apart. So you'll hear more about microdosing and other psychedelics and their impact on depressive states and major depression in the episode with Matt. But for the time being, it
really seems as if, again, we're looking at neuroplasticity, we're coming back to layer five, just like with ketamine and PCP. We're hearing about layer five, we're hearing about rewiring of circuitry, we're hearing about a
dissociation or a distancing of oneself from these
negative moods and affects and narratives, but
there's a key distinction between the ketamine work
and the psilocybin work, which is that in the ketamine work, it really is about
dissociating from experience during the session with the psychiatrist, whereas during the psilocybin journey, it's really about immersing
oneself in the experience and being fully present
to that experience. That does seem to be
an important component and what the difference is there and why they both seem
to provide some relief from major depression isn't clear. I think most likely it
takes us back to the fact that this thing we call major depression clearly involves serotonin,
dopamine, and norepinephrine. And in some individuals,
they may be more deficient in one or several of
those or all of those, whereas in other individuals, it might be a different
collection of chemicals. And of course there
are a tremendous number of other psychedelic compounds
that people are exploring for treatment of major depression. But really psilocybin is the one that we have the most data on. MDMA has mainly been explored
in the clinical realm for treatment of trauma. There are some trials ongoing
for treatment of depression, but the big breakthrough
seemed to be happening in the realm of trauma treatment, the so-called maps
group that's doing this, again, legally in a clinical setting. And there are other groups that are starting to do it as well. We are going to do an
entire podcast about MDMA and some related compounds. So I'll save that discussion for then. One of the most common
questions I get for this podcast is about different
diets, different regimes, different nutritional
plans, things like keto, ketogenic diet, or vegan
diets, or intermittent fasting, or the all meat diet, the
so-called lion diet, et cetera. There are actually really interesting data relating nutrition and diet
to major depressive disorder. And I think we just need to frame this by returning to something
that was said earlier, which is that the
ingestion of carbohydrates, in particular carbohydrates
and some meats like turkey, that are rich in tryptophan,
this precursor to serotonin, are in many ways the
self-medicating version of depression treatment. Now, to be clear, I'm not saying that people should use food
to medicate their depression. Many people do that reflexively however, they reach for carbohydrate rich foods to blunt their cortisol, because
that's indeed what it does. It blunts cortisol when you
ingest high carbohydrate foods, in particular starchy foods, and it does increase serotonin, in particular, if those
foods rather are rich in the amino acid tryptophan. Now ingesting food is wonderful
and important and great, but ingesting excessive
foods of any kinds, carbohydrate or otherwise
it's not healthy, of course. There have been some explorations of whether or not a vegan diet can improve symptoms of depression. Not a lot of data, not impressive data. There have been very
few controlled studies looking at the carnivore or all meat diet. On that, I think there are now some that are starting to spin up, meaning those studies
are starting to spin up. However, the ketogenic
diet has been explored for its ability to relieve
certain symptoms of depression, in particular to what's
called maintain euthymia. Euthymia is the kind
of state of equilibrium between a manic episode
and a depressive episode in a manic bipolar person. We'll return to this
more in a future episode, but it basically, maniacs
have highs and they have lows, bipolars, either cycle back
and forth really quickly. So rapid cycling bipolars
or slow, some people So really quickly can be day to day, other people it's month
to month or week to week, they're going highs and lows. And you hear about mania and
you hear about dysphoria, euthymia is that kind
of place in the middle where people feel neither
too high nor too low. And there are some interesting studies looking at the ketogenic
diet for maintaining euthymia in manic depressives, but also in people with
major depressive disorder. Why would this work? Well, we have to remember
that the ketogenic diet wasn't discovered so that
self appointed nutrition gurus could talk about it
online or so that people could make money selling
anything related to ketosis. And here I'm not disparaging
of the ketogenic diet. It's helped a lot of people. The ketogenic diet was actually shown to be medically relevant for
its use to treat epilepsy. It turns out that in epilepsy, or in particular pediatric epilepsy, that a ketogenic diet and
the shift of brain metabolism to predominantly one in which
ketones are being metabolized rather than more standard
glucose tight metabolism, can greatly reduce the
number of epileptic seizures that these children experience. It's not always the case,
but it's often the case. And so you talk to a
neurologist or a neurosurgeon who's specialized in epilepsy, in particular pediatric epilepsy,
and they'll tell you this, "Oh yeah, the ketogenic
diet, in many cases, not all, "can be very effective
for this treatment." How? How is it that a ketogenic
diet reduces seizures? Well, the way it reduces seizures is by increasing what's
called GABA transmission. GABA is a substance that is
naturally released in our brain. It's an inhibitory neurotransmitter, meaning that when it's
released into the synapse, it has the tendency to reduce the firing, to reduce the electrical
activity of the next neuron or sets of neurons. There are various compounds
that increase GABA, in particular, GABA in the forebrain. One common example would
be something like alcohol, drinking alcoholic drink or two will increase GABA transmission, ironically will lower
your social inhibitions by increasing your
neurochemical inhibition. It basically suppresses the
self-monitoring pathways. And if people drink enough, it will suppress all pathways and people will urinate
themselves and fall over. It will eventually inhibit
all sorts of pathways. So the GABA system has
a rich array of effects all over the brain and body. But alcohol tends to
activate the release of GABA. You might say, well then
why not just take alcohol to suppress seizures? Well, that be a terrible idea because there tends to
be a rebound excitability after alcohol stops having its effects on the GABA receptors. And so then there's an excitability for which an epilepsy would be terrible. The reason why the epileptic
diet is useful for epilepsy is that increases what
we call the tonic level, the sort of the ti, the
level of GABA in the brain, and that suppresses some
of the hyperexcitability, that is the characteristic
feature of epilepsy. And there are other drugs, for instance, the benzodiazepines and
things of the Xanax, variety, Valium, and so forth. Those increased GABA transmission. Those drugs also have a
lot of potential for abuse and addiction, et cetera, and they're problematic for other reasons. But the ketogenic diet, by way of increasing ketone metabolism or shifting brain's
metabolism over to ketones tends to modulate GABA such
that GABA is more active and adjust the so-called
GABA glutamate balance. This is getting technical, but glutamate is an
excitatory neurotransmitter, GABA is inhibitory neurotransmitter, and their balance is
vital for neuroplasticity, for maintaining healthy levels
of activity in the brain, et cetera. And so there is decent evidence that people with major
depressive disorders, in particular, the people with
major depressive disorders that are refractory,
meaning they don't respond to classical antidepressants, can benefit, it seems,
from the ketogenic diet. Now this is not always the case, but for those of you out
there who are struggling with major depression, and for
which drugs have not worked, please talk to your psychiatrist. I don't know how many of
them are up on the literature about the ketogenic diet
or the EPAs and the rest. Psychiatrists vary in
terms of how involved in the current literature they tend to be, but there are many excellent
psychiatrists out there. Most of them in my experience, are actually quite avid
learners about what's happening and what's new in this realm
that they call psychiatry. So it's really interesting that
eating in a particular way, lowering carbohydrates to
the point where you rely on ketogenic metabolism in the brain, increases GABA and can provide some relief for depressive symptoms. And that in particular, that
seems to have positive effects in people that are
refractory or don't respond to classic antidepressants. And that would include things
like fluoxetine, et cetera. I'll make one final point
about ketogenic diets and GABA and depression, which is that it's also been shown that for people that
respond well to these drugs that impact the serotonin
system, dopamine system, or norepinephrine, the ketogenic diet, there may improve the ability for those drugs to work at lower dosages, which is reminiscent of
what we saw with the EPA supplementation. So today we've covered
what at least feels to me, like a tremendous amount of material. This topic of depression
is indeed an enormous topic to try and get our arms around. We talked about the symptomology, we talked about some of the
underlying neurochemistry and biology, and then we talked about
approaches to deal with it that are really grounded in
the neurochemistry in biology. I just want to recap a few of those tools and what those things are. First of all, we talked about making the
effort to not overwhelm the pleasure system. That might seem counterintuitive. To not overly seek out pleasure, or else one can find themselves
in a place of depression. I mentioned way back at the
beginning of the episode, a young man who I know
to be really struggling with depression, and it is thought, and we don't know for sure, but is thought that some of that depression
was probably triggered by an overindulgence in video games and other highly dopaminergic activities to the point where those
activities eventually were countered by the pain balance that Dr. Anna Lembke described. And he now has to do those
activities repeatedly and for many, many hours
each day, just to feel okay, not even to derive pleasure from them. And worse, many other activities, practically all other
activities have lost their zest, they've lost their excitement
and his sense of pleasure for them. And so there's a really
active campaign now to reset that system. So, number one, don't
overwhelm your pleasure centers either through activities or compounds. Might seem counterintuitive, but you're setting yourself up
for anhedonia and depression if you do that. It's not just about addiction that too, but it's also about setting
yourself for anhedonia and depression. How often can you engage
in these activities? Well, that's going to differ
from person to person, everyone's slightly different, but you should really
mind your extreme highs and your extreme lows and
be cautious about those. We'll probably have a Dr.
Lembke on again at a future time to try and get some more
specifics about that. But if you do feel like you
need to reset that system, it really does seem like
a 30 day complete detox from whatever activity
or substance that is. And ideally it doesn't
continue after that 30 days, especially in conditions
of drugs of abuse. Second of all, talks about
the norepinephrine system and how the norepinephrine
system is really deficient in many forms of major depression. And in depression, there is
now more deliberate pursuit of nor epinephrin inducing
activities that are healthy, that aren't adrenaline seeking per se, things like cold showers, things like particular
patterns of breathing that engage and tend
to make us more alert, things like exercise that
will increase our levels of noradrenaline. I'd be remiss if I said
that these activities could completely eliminate
depressive symptoms in people with major depressive disorder. I don't think that's the case. And again, I want to acknowledge that people with major depressive symptoms often don't have the
energy, the willingness, or the capacity to engage
in some of these activities, but things like cold shower,
deliberate cold showers, things like regular exercise, they aren't just feel good activities. They actually engage the
norepinephrine system and keep that system tuned
up and allow us to increase our norepinephrine levels
at will on a regular basis. And their mood enhancing
effects are real effects at the level of neurochemistry, then we talked about EPAs,
Essential Fatty Acids, and it's clear that for most people, getting above 1000 milligrams and probably even closer to
2000 milligrams per day of EPAs can be beneficial for mood,
especially in attempts to treat or offset major depressive disorder. Are there side effects? Well, you need to explore
those for yourself and with your doctor, everyone has a different
health background. For the margins of safety, for most people would
probably be quite large, but for some people that
might not be the case. So definitely check with your physician. We also talked about exercise
and how EPA and exercise on a regular basis can offset
these inflammatory pathways. I want to mention something I've mentioned on a previous podcast, but in terms of keeping the Inflammatone, all these molecules that
create inflammation, and then the inflammation can
limit the amount of serotonin through the pathways we described. In order to do that, it's
also very, very useful to ingest two to four
servings of fermented foods on a daily basis or near daily basis. These are data that were
published by the Sonnenberg Lab at Stanford recently in the journal Cell, Cell Press Journal, excellent journal that ingestion of these fermented foods really keeps the gut microbiome
tuned up, so to speak, well in order to offset
these inflammatory cytokines, keeping inflammation at bay, it just turns out to
be a really good thing in order to keep our mood in a good place. So EPA, exercise, fermented foods, creatine as a potential source
of relief from depression or offsetting, or keeping us
away from major depression or relapse into depression. And then we talked about
the prescription compounds and the compounds that are being used mainly in the course of
studies and of psychiatry and depression, things like
ketamine, PCP, psilocybin, and related compounds. And then lastly, we talked about ketosis, which may not be right for everybody, but might be right for
certain individuals out there who are grappling with this. If you're learning from this podcast and hopefully enjoying it and
applying some of the tools that we describe, please subscribe to
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of trying to understand what is depression, how does
it work, and how to treat it. And thank you for your
interest in science. [upbeat music]
