Understanding & Conquering Depression | Huberman Lab Podcast #34

00:00:00.320 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.320 | and I'm a professor of neurobiology and ophthalmology

00:00:13.040 | at Stanford School of Medicine.

00:00:15.100 | This month, we're talking all about disorders of the mind,

00:00:18.760 | things like depression, attention deficit disorders,

00:00:22.240 | eating disorders, schizophrenia, and bipolar disorder.

00:00:25.920 | During the course of this month,

00:00:28.080 | we are going to discuss the psychological

00:00:30.220 | and biological underpinnings of mood disorders of all kinds.

00:00:34.320 | You'll learn a lot of science.

00:00:35.940 | You'll also learn a lot about the various treatments

00:00:38.160 | that exist and that are in development

00:00:40.720 | for these various mood disorders.

00:00:43.120 | We will talk about behavioral tools,

00:00:45.520 | things like exercise, meditation, breath work,

00:00:49.280 | but also prescription drugs, supplements,

00:00:52.080 | and novel compounds that are now being tested

00:00:54.420 | in various clinical trials.

00:00:56.400 | Across the month, I think you'll start to realize

00:00:58.460 | that there are common pathways

00:00:59.800 | underlying many mood disorders.

00:01:02.360 | In fact, mood disorders that look quite different

00:01:05.120 | from one another often depend on the action

00:01:08.040 | of the same neurochemicals or neural circuits

00:01:10.260 | in the brain and body.

00:01:11.920 | That actually should be a point of great relief

00:01:14.420 | because what it means is that by understanding the biology

00:01:17.160 | of one mood disorder or understanding how one treatment

00:01:20.480 | or behavioral intervention can impact a mood disorder,

00:01:23.800 | we gain insight into other mood disorders as well.

00:01:26.800 | As always, we will discuss science and science-related tools

00:01:30.640 | that people could implement should they choose.

00:01:33.200 | Before we dive into today's topic,

00:01:35.660 | I'd like to discuss a very particular set

00:01:37.840 | of scientific findings that relate to today's topic

00:01:41.920 | and that are important for understanding all mood disorders

00:01:45.240 | and all states of motivation, happiness, and sadness,

00:01:50.240 | as well as depression.

00:01:52.240 | Basically, I'm going to paraphrase a brief segment

00:01:55.020 | of my discussion with Dr. Anna Lemke,

00:01:57.840 | who I sat down with to discuss addiction

00:02:00.600 | and the biological basis of addiction

00:02:02.660 | and addiction treatment.

00:02:03.920 | A very important aspect of that discussion

00:02:07.720 | was when Dr. Lemke described the pleasure-pain balance,

00:02:12.120 | literally the circuits in our brains

00:02:13.880 | that control our sense of pleasure and pain,

00:02:16.360 | and ultimately whether or not we remain happy

00:02:19.320 | in our pursuit of pleasure or not.

00:02:22.300 | This is an absolutely crucial aspect

00:02:24.440 | to the way that we function in everyday life

00:02:27.100 | and especially under conditions of mood disorders.

00:02:30.820 | The pathway that she was describing

00:02:32.460 | is the so-called pleasure system.

00:02:34.500 | However, what most people don't realize

00:02:36.460 | is that the pleasure system is also directly associated with

00:02:40.380 | and in fact is the very same system

00:02:42.500 | that modulates mental or psychological anguish and pain.

00:02:47.100 | Essentially, what she described

00:02:48.620 | is that whenever we pursue something that we think

00:02:51.620 | will bring us pleasure,

00:02:53.500 | and that could be anything that we think

00:02:55.180 | will bring us pleasure, from food to video games, to sex,

00:02:59.420 | to a particular job or goal, short-term or long-term,

00:03:03.280 | that we experience release of the neuromodulator dopamine.

00:03:09.280 | Now, dopamine is associated

00:03:11.060 | with increased levels of motivation and drive.

00:03:13.480 | It is not the molecule of reward.

00:03:15.000 | It is the molecule of craving, motivation, and drive.

00:03:18.560 | However, as Dr. Lemke pointed out,

00:03:21.480 | when we are in pursuit of something,

00:03:23.540 | there is a release of dopamine in our brain.

00:03:26.680 | That makes us feel motivated,

00:03:28.340 | and in general, it makes us feel good.

00:03:30.820 | But very shortly thereafter,

00:03:33.160 | and beneath our conscious awareness,

00:03:36.000 | there is a tilt of the pleasure-pain balance in the brain,

00:03:39.460 | literally a shift in the neural circuits

00:03:41.260 | that underlie pleasure and pain,

00:03:43.180 | such that every bit of pleasure or pleasure seeking

00:03:47.340 | that causes release of dopamine

00:03:49.480 | will be balanced out by a little bit of pain.

00:03:53.820 | And we don't experience this as physical pain,

00:03:56.320 | at least not at first.

00:03:57.460 | We experience it as craving for more

00:04:00.060 | of the thing that brought us pleasure.

00:04:02.380 | Now, that sounds pretty good.

00:04:03.740 | You get pleasure,

00:04:04.560 | and then you get a little bit of pain to balance it out.

00:04:06.820 | It's subconscious,

00:04:07.740 | and you experience it as the desire

00:04:09.340 | to seek out more pleasure.

00:04:11.300 | However, it's actually more diabolical than that,

00:04:14.580 | and we really need to keep an eye on this

00:04:16.080 | if we are to remain happy,

00:04:18.040 | if we are to remain in pursuit of our goals.

00:04:20.620 | The crucial thing to understand

00:04:22.260 | is that if we remain in constant pursuit of pleasure,

00:04:26.220 | the pain side of the balance tips

00:04:28.420 | so that each time we are in pursuit

00:04:30.940 | of that pleasureful thing, activity or substance,

00:04:34.300 | we are going to experience,

00:04:36.420 | we literally achieve less dopamine release

00:04:39.460 | each subsequent time.

00:04:41.080 | So we get less pleasure,

00:04:42.820 | and the amount of craving increases.

00:04:45.380 | Now, after a certain point or threshold,

00:04:47.020 | we call that addiction.

00:04:48.740 | And the way to reset the balance,

00:04:50.700 | and this is very important,

00:04:51.540 | the way to reset the balance

00:04:53.460 | is actually to enter into states

00:04:55.240 | in which we are not in pursuit of pleasure,

00:04:58.280 | to literally enter states in which we are bored,

00:05:01.760 | maybe even a little bored and anxious,

00:05:03.740 | and that resets the pleasure-pain balance

00:05:06.640 | so that we can return to our pursuit of pleasure

00:05:08.900 | in a way that's healthy and that in an ongoing way

00:05:11.880 | won't lead to this over-tipping

00:05:14.080 | or this increase in the amount of pain or addiction.

00:05:18.140 | So this is very important.

00:05:19.260 | And if this seemed vague, what this means is

00:05:21.420 | we should always be cautious of any state of mind or body

00:05:26.420 | or any pursuit that leads to very large increases

00:05:29.820 | in dopamine.

00:05:30.820 | And if it does, we should be very careful

00:05:33.200 | to not pursue that repeatedly over time.

00:05:35.980 | During today's episode, I'm going to give an example,

00:05:38.060 | a real-life example of a discussion that I've been in

00:05:40.820 | with a young man who's 21 years old

00:05:42.500 | who's dealing with a disruption

00:05:44.480 | in this pleasure-pain balance.

00:05:46.320 | He is essentially depressed.

00:05:49.160 | And he's depressed because of his ongoing pursuit

00:05:52.660 | of a particular activity that initially led

00:05:55.840 | to a lot of dopamine, but over time has led

00:05:57.900 | to less and less dopamine and more and more

00:06:00.360 | of this pain side of the balance.

00:06:03.380 | We could call him addicted to that particular activity.

00:06:07.140 | Whether or not he's addicted by clinical standards or not

00:06:09.700 | really isn't important.

00:06:11.100 | What is important is that he experiences this as depression,

00:06:15.540 | as low affect as it's called, or anhedonia,

00:06:18.500 | an inability to experience pleasure from that thing

00:06:21.980 | or from anything else.

00:06:23.540 | And he's currently undergoing treatment

00:06:25.180 | through a rebalancing of this pleasure-pain pathway.

00:06:28.120 | So while I can't reveal his identity to you,

00:06:29.980 | that wouldn't be appropriate.

00:06:31.220 | He did give me permission to reveal the general architecture

00:06:33.900 | of what he's coping with.

00:06:35.060 | And I spent some hours with him on the phone this week,

00:06:37.360 | talking to him, as well as to the various people

00:06:39.740 | that he's working with to really understand

00:06:41.140 | what's going on here.

00:06:42.180 | Because I think it can illustrate the relationship

00:06:44.580 | between dopamine, pleasure, and pain for sake of addiction,

00:06:48.900 | but also for understanding how to avoid depressive states,

00:06:52.620 | how to remove ourselves from depressive states.

00:06:55.500 | And as you'll see today, as we discussed depression,

00:06:57.940 | many of the molecules and neural pathways

00:07:00.420 | and biological mechanisms that we know can be used

00:07:04.460 | to counter depression,

00:07:06.860 | feed back onto this pleasure-pain balance.

00:07:09.420 | Before we begin, I'd like to say that this podcast

00:07:11.780 | is separate from my teaching and research roles at Stanford.

00:07:14.740 | It is, however, part of my desire and effort

00:07:16.860 | to bring zero cost to consumer information about science

00:07:19.620 | and science-related tools to the general public.

00:07:22.580 | In keeping with that theme,

00:07:23.720 | I'd like to thank the sponsors of today's podcast.

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00:11:16.940 | Today, we're discussing depression.

00:11:19.040 | In particular, we're going to talk about major depression.

00:11:21.760 | The phrase major depression is used to distinguish

00:11:24.380 | one form of depression from the other,

00:11:26.460 | the other one being bipolar depression.

00:11:29.720 | Bipolar depression, sometimes called bipolar disorder,

00:11:33.260 | is really characterized by manic highs,

00:11:36.940 | so where people aren't sleeping

00:11:38.960 | and they're talking very fast and they're buying things

00:11:41.900 | and pursuing resources that they can't afford.

00:11:44.540 | They're starting relationships left and right.

00:11:46.620 | They're manic, followed by periods of crashes,

00:11:50.620 | of feeling very low, lethargic, and so on.

00:11:54.340 | Bipolar depression is an absolutely crucial thing

00:11:57.520 | for us to discuss,

00:11:58.660 | and therefore, we are going to have

00:12:00.480 | an entire separate episode related to bipolar depression.

00:12:04.900 | Today, we're going to talk about major depression,

00:12:06.840 | also sometimes called unipolar depression,

00:12:09.400 | just because it doesn't have the highs and lows.

00:12:11.620 | It's more characterized by the lows.

00:12:13.980 | We're going to talk about the biology, the psychology,

00:12:18.640 | and the various treatments,

00:12:19.740 | behavioral, drugs, supplementation, diet, exercise,

00:12:22.640 | all of that.

00:12:23.480 | Before we go forward into the material,

00:12:25.360 | I just want to emphasize that any discussion

00:12:27.780 | about mood disorders carries with it

00:12:29.840 | a particular sensitivity,

00:12:32.080 | and that sensitivity is one related to self-diagnosis.

00:12:35.400 | Today's episode, and indeed in the future episodes

00:12:39.540 | for this month on mood disorders,

00:12:41.420 | you're going to hear very symptomologies

00:12:43.500 | that are used to diagnose and characterize these disorders.

00:12:48.020 | If you recognize some of these symptomologies in yourself

00:12:51.560 | or in others that you know,

00:12:53.340 | that's an important thing to take note of.

00:12:55.220 | However, accurate diagnosis really should be done

00:12:59.300 | by a qualified healthcare professional.

00:13:01.340 | So at once I'm saying, keep your eyes and your ears up

00:13:04.380 | for things that sound familiar to you

00:13:06.340 | that might be of concern.

00:13:07.460 | And at the same time, I'm saying,

00:13:09.460 | don't necessarily leap to conclusions.

00:13:11.620 | Take those flags of concern if they're there

00:13:14.100 | and bring them to a qualified healthcare professional,

00:13:16.460 | and they'll be able to properly diagnose you

00:13:19.960 | as having a particular mood disorder

00:13:21.780 | or diagnose somebody as having a particular mood disorder

00:13:24.260 | or not, and that's an essential step.

00:13:26.900 | I don't say this to protect us,

00:13:28.300 | I say this really to protect you.

00:13:30.600 | Okay, let's have a fact-based discussion about depression.

00:13:34.660 | And I promise you that where we don't know

00:13:37.720 | certain things about depression,

00:13:39.060 | I will be clear to tell you.

00:13:40.700 | In fact, we are going to talk about

00:13:41.980 | some treatments for depression

00:13:43.540 | that are looking very promising

00:13:45.060 | and that right now are actually being used more and more.

00:13:48.920 | And from my read of the mechanistic literature,

00:13:52.300 | we're still a bit in the dark as to how these work.

00:13:54.900 | That's actually a common theme of medicine.

00:13:56.540 | Many times there are treatments that seem promising

00:13:59.540 | or that look really terrific,

00:14:01.620 | and there isn't a lot of understanding about mechanism.

00:14:04.500 | However, any good discussion about neuroscience

00:14:07.360 | and in particular about mood disorders

00:14:09.060 | has to get into mechanism.

00:14:10.340 | So we're going to do that.

00:14:11.360 | And in doing that, we're going to frame the discussion

00:14:15.020 | for the tools of how to keep depression at bay

00:14:18.200 | and how to deal with it

00:14:19.420 | if you happen to find yourself depressed

00:14:21.020 | or if you know somebody else who's depressed.

00:14:23.980 | What is this thing we call depression?

00:14:26.500 | Well, as I mentioned before,

00:14:27.400 | it has two forms, bipolar depression,

00:14:29.780 | which we're not talking about today,

00:14:31.340 | and major depression,

00:14:33.020 | also called unipolar depression is the other.

00:14:36.100 | Major depression impacts 5% of the population.

00:14:41.680 | That is an enormous number.

00:14:44.140 | That means if you're in a class of 100 people,

00:14:46.800 | five of them are dealing with major depression

00:14:49.060 | or have at some point.

00:14:51.160 | Look around you in any environment

00:14:52.620 | and you can be sure that a good portion of the people

00:14:56.540 | that you're surrounded by is impacted by depression

00:14:59.880 | or will be at some point.

00:15:01.260 | So this is something we really have to take seriously

00:15:03.140 | and that we want to understand.

00:15:04.700 | It is the number four cause of disability.

00:15:09.460 | A lot of people miss work, miss school,

00:15:12.400 | and before then likely perform poorly in work or school

00:15:16.300 | due to major depression.

00:15:18.720 | Now, there's a very serious challenge

00:15:21.320 | in having a discussion about depression,

00:15:23.660 | and it relates directly to the challenges

00:15:25.480 | in diagnosing depression.

00:15:27.040 | Earlier, I did an episode with Dr. Carl Deisseroth,

00:15:30.800 | who is indeed a medical doctor and a PhD,

00:15:33.440 | he's a psychiatrist,

00:15:34.280 | and he made a very important point,

00:15:35.720 | which is that the field of psychiatry and psychology

00:15:39.880 | are confronted with a challenge,

00:15:41.320 | which is they're trying to understand what's going on

00:15:43.440 | within the stuff that's in our brains,

00:15:47.280 | that's deep to our skulls.

00:15:49.440 | We don't have access to that without brain imaging

00:15:51.640 | and electrodes and things like that.

00:15:53.520 | Someone just comes into the office

00:15:54.880 | and the dissection tool for depression, so to speak,

00:15:58.520 | is language.

00:15:59.520 | In order to determine if somebody has depression or not,

00:16:03.280 | we have to use language, how they talk about things,

00:16:05.660 | also how they carry their body,

00:16:07.280 | also some general patterns of health.

00:16:09.620 | So let's talk about depression

00:16:11.840 | the way that clinicians talk about depression,

00:16:14.520 | because one of the issues is that we use the word depression

00:16:18.560 | loosely, a lot of people say, oh, you know, I'm so depressed,

00:16:21.780 | I didn't get this job, or I'm so depressed,

00:16:24.240 | I just, I don't know, I had a really rough week,

00:16:25.920 | or I'm exhausted, I'm so depressed, or I'm so depressed,

00:16:29.240 | I thought I was going to go on vacation

00:16:30.600 | and then they canceled the flight, okay?

00:16:32.640 | That is not clinical depression,

00:16:35.240 | that's called being bummed out, being sad or disappointed.

00:16:38.320 | Now that person might be depressed,

00:16:39.760 | but clinical depression

00:16:41.040 | actually has some very specific criteria

00:16:43.880 | and those criteria are mainly characterized

00:16:48.420 | by the presence of certain things

00:16:51.160 | and the absence of a few particular things.

00:16:54.580 | So let's talk about the things that are present

00:16:57.520 | in somebody that has major depression.

00:17:00.480 | First of all, there tends to be a lot of grief,

00:17:03.900 | there tends to be a lot of sadness, that's no surprise.

00:17:06.560 | The threshold to cry is often a signature of depression.

00:17:10.140 | Now that doesn't mean that if you cry easily

00:17:12.160 | that you're depressed, some people cry more easily

00:17:14.140 | than others, but if you're somebody

00:17:15.920 | who typically didn't cry easily

00:17:17.580 | and suddenly you find yourself crying very easily,

00:17:20.240 | that could be a sign of depression,

00:17:22.440 | and I want to emphasize could.

00:17:23.940 | There's also this thing that we call anhedonia,

00:17:27.360 | a general lack of ability to enjoy things,

00:17:30.440 | things that typically or previously we enjoyed,

00:17:33.080 | things like food, things like sex, things like exercise,

00:17:36.000 | things like social gatherings,

00:17:38.000 | a kind of lack of enjoyment from those things.

00:17:41.160 | Sometimes that lack of enjoyment is sad,

00:17:44.320 | and sometimes it's just flat, it's just kind of neutral.

00:17:47.820 | It doesn't feel good because there's nothing there,

00:17:49.940 | it's like bland food, it's like these experiences

00:17:54.400 | are analogous to biting into your favorite article of food,

00:17:58.500 | and it just not tasting very good,

00:18:00.980 | it just doesn't taste like anything at all,

00:18:02.700 | and that's a common symptom of major depression.

00:18:05.960 | The other one is guilt.

00:18:08.160 | Oftentimes people with depression will feel very guilty

00:18:11.120 | about things they have done in the past

00:18:12.800 | or they'll just generally feel badly about themselves,

00:18:16.060 | and we're going to talk about this

00:18:17.480 | because it relates to some of the more serious symptomology

00:18:20.320 | seen in depression sometimes,

00:18:21.640 | things like self-harm, mutilation, or even suicide,

00:18:25.100 | but for the time being, we want to frame up anhedonia,

00:18:28.600 | this lack of ability to achieve or experience pleasure,

00:18:31.840 | a kind of a flat affect as it's called,

00:18:34.680 | sometimes even delusional thinking,

00:18:37.500 | negative delusional thinking,

00:18:39.080 | and in particular, anti-self confabulation.

00:18:43.080 | What is anti-self confabulation?

00:18:44.680 | Well, first of all, confabulation is an incredible aspect

00:18:48.160 | of our mind and our nervous system.

00:18:50.220 | You sometimes see other forms of confabulation

00:18:53.480 | in people who have memory deficits,

00:18:55.440 | either because they have brain damage

00:18:57.240 | or they have age-related dementia.

00:19:00.200 | A good example of this would be

00:19:01.700 | someone with age-related dementia

00:19:03.760 | sometimes will find themselves in a location in the house

00:19:07.800 | and not know how they got there.

00:19:09.620 | And if you ask them, oh, what are you doing here?

00:19:12.320 | They will create these elaborate stories.

00:19:14.280 | Oh, you know, I was thinking about going to shopping today,

00:19:16.860 | and I was going to take the bus, and then I was going to do,

00:19:19.640 | they create these elaborate stories, they confabulate,

00:19:23.000 | and yet that person hasn't left the house in weeks,

00:19:25.080 | and that person doesn't have a driver's license.

00:19:26.740 | And so they're really just creating this stuff.

00:19:28.640 | They're not lying to get out of anything.

00:19:30.720 | They're confabulating.

00:19:31.560 | It's as if a brain circuit that writes stories

00:19:34.360 | just starts generating content.

00:19:37.720 | In major depression,

00:19:38.740 | there's often a state of delusional anti-self confabulation

00:19:42.600 | where the confabulations are not directly

00:19:45.900 | or completely linked to reality,

00:19:48.160 | but they are ones that make the self,

00:19:50.840 | the person describing them,

00:19:52.520 | seem sick or in some way not well.

00:19:56.920 | A good example would be somebody

00:19:58.200 | who experiences a physical injury, perhaps.

00:20:00.780 | Maybe they break their ankle, maybe it's an athlete,

00:20:02.900 | and they also happen to become depressed.

00:20:06.240 | And you'll talk to them.

00:20:07.080 | You'll say, how are things going?

00:20:08.040 | How's your rehab?

00:20:08.880 | And they'll go, oh, it's okay.

00:20:09.720 | And I don't know, I'm just,

00:20:11.140 | I feel like I'm getting weaker and weaker by the day.

00:20:13.560 | I'm just not performing well.

00:20:14.880 | And then you'll talk to the person that they're working with,

00:20:17.720 | their kinesiologist or whoever the physical therapist is,

00:20:21.120 | and they'll say, no, they're actually really improving.

00:20:23.040 | And I tell them they're improving,

00:20:24.120 | but somehow they're not.

00:20:25.420 | They're not seeing that improvement.

00:20:26.800 | They're not registering that improvement.

00:20:28.620 | You notice that sometimes it's subtle

00:20:30.480 | and sometimes it's severe, but they'll start confabulating.

00:20:33.720 | You'll say, I actually heard you're doing much better.

00:20:36.400 | You're getting better.

00:20:37.440 | You're taking multiple trips around the building now

00:20:40.320 | before you could barely get out of bed.

00:20:42.080 | And they'll say, yeah, well, basically,

00:20:44.760 | they changed some things about the parking lot

00:20:47.520 | that make it easier to move around, so it's not really me.

00:20:50.040 | And these aren't people that are just explaining away

00:20:52.400 | their accomplishments

00:20:54.400 | 'cause they're trying to brush off praise.

00:20:57.000 | They are viewing themselves and they're confabulating

00:21:00.740 | according to a view that is very self-deprecating

00:21:04.760 | to the point where it doesn't match up with reality.

00:21:07.500 | It's not what other people see,

00:21:08.920 | and it's actually not matched up with reality.

00:21:11.500 | And that's a symptom of depression

00:21:13.780 | that I think we don't often think about

00:21:16.080 | or conceptualize enough.

00:21:18.000 | So it's not just telling people, oh yeah,

00:21:20.640 | it's not as good as it seems, everything's bad.

00:21:22.760 | These people really believe that

00:21:24.200 | and it becomes disconnected from reality.

00:21:26.320 | So it's as if they're sort of sinking into a pit

00:21:28.380 | and they're losing touch with the realities of the world,

00:21:30.980 | including data about themselves,

00:21:32.960 | their ability to move and get around.

00:21:35.380 | For example, in the particular instance

00:21:37.920 | that I used as an example, but there are others as well.

00:21:40.960 | The other common symptomology of major depression

00:21:45.360 | is what they call vegetative symptoms, okay?

00:21:48.680 | So vegetative symptoms are symptoms that occur

00:21:52.240 | without any thinking, without any doing,

00:21:55.040 | or without any confabulation.

00:21:56.440 | These are things that are related to our core physiology.

00:21:59.080 | The word vegetative, you might know it sounds like vegetable,

00:22:02.080 | it actually relates to a system in the body

00:22:04.520 | that nowadays is more commonly called

00:22:06.160 | the autonomic nervous system.

00:22:08.480 | The vegetative nervous system

00:22:10.600 | and the autonomic nervous system,

00:22:12.320 | historically were considered sort of one in the same.

00:22:15.040 | And it relates to things like the stress response

00:22:17.840 | or to our ability to sleep.

00:22:19.720 | So vegetative symptoms be things like

00:22:22.480 | constantly being exhausted.

00:22:24.400 | The person just feels exhausted.

00:22:26.720 | It's not because they exercise too much.

00:22:28.400 | It's not necessarily because of a life event, it could be,

00:22:31.640 | but they're just worn out.

00:22:33.440 | They don't have the energy they once had.

00:22:36.080 | So it's not in their heads.

00:22:38.180 | It's probably, and now I think we have good data

00:22:40.840 | to support the fact that there's something off.

00:22:43.480 | Something is disrupted in the autonomic

00:22:45.540 | or so-called vegetative nervous system.

00:22:47.560 | And one of the most common symptoms

00:22:49.400 | of people with major depression,

00:22:51.220 | one of the signs of major depression is early waking

00:22:55.560 | and not being able to fall back asleep

00:22:57.560 | despite being exhausted.

00:22:59.820 | So waking up at 3 a.m. or 4 a.m. or 5 a.m.

00:23:03.220 | just spontaneously and not being able to go back to sleep.

00:23:06.220 | I want to emphasize that that could happen

00:23:07.900 | for other reasons as well,

00:23:09.860 | but it is a common symptom or warning sign

00:23:12.900 | of major depression.

00:23:14.520 | So let's talk more about sleep and depression.

00:23:16.960 | It's well known that the architecture of sleep

00:23:21.460 | is disrupted in depression.

00:23:23.320 | What's the architecture of sleep?

00:23:24.660 | I've done entire episodes about this,

00:23:26.100 | but very briefly in two sentences,

00:23:28.340 | although they'll probably be run on sentences,

00:23:31.140 | early in the night, you tend to have slow wave sleep

00:23:34.320 | more than REM sleep or rapid eye movement sleep.

00:23:36.620 | As the night goes on,

00:23:37.500 | you tend to have more rapid eye movement sleep.

00:23:39.860 | That architecture of slow wave sleep

00:23:42.380 | preceding rapid eye movement sleep

00:23:44.840 | is radically disrupted in major depression.

00:23:49.840 | In addition, the pattern of activity in the brain

00:23:52.220 | during particular phases of sleep is disrupted.

00:23:55.180 | Now this is during sleep.

00:23:56.420 | So this can't be that people are creating

00:23:58.460 | this situation for themselves.

00:23:59.640 | These are real physiological signs

00:24:01.940 | that something is off in this so-called autonomic

00:24:04.780 | or vegetative nervous system.

00:24:06.880 | And then there are some other things

00:24:08.160 | that relate to the autonomic nervous system,

00:24:10.780 | but that we normally think of as more voluntary in nature.

00:24:14.560 | And these are things like decreased appetite.

00:24:17.180 | So you could imagine that one could have decreased appetite

00:24:21.180 | because of the anhedonia, the lack of pleasure from food.

00:24:24.660 | If you don't enjoy food, then you might be less motivated

00:24:27.620 | to eat it, that makes sense.

00:24:29.660 | As well, because of these disruptions

00:24:31.500 | in the autonomic nervous system,

00:24:33.260 | these vegetative symptoms as they're called,

00:24:35.540 | you can imagine that someone would have decreased appetite

00:24:37.740 | because some of the hormones associated with appetite,

00:24:40.320 | hypocretinorexin and things of that sort,

00:24:42.820 | ghrelin, that those will be disrupted.

00:24:45.460 | And if those names of hypocretinorexin and ghrelin

00:24:47.660 | don't make any sense to you, don't worry about it.

00:24:49.820 | What those are just hormones that impact when we eat,

00:24:53.180 | when we feel hungry and when we crave food more,

00:24:57.140 | as well as when we feel full,

00:24:58.620 | we have enough so-called satiety.

00:25:00.460 | If you want to learn more about those,

00:25:01.700 | we did entire episodes on eating and metabolism.

00:25:04.700 | So you can see that the symptomology of major depression

00:25:07.940 | impacts us at multiple levels.

00:25:09.800 | There's the conscious level of how excited we are generally.

00:25:14.160 | Well, that's reduced.

00:25:15.340 | There's grief, there's guilt, there's crying,

00:25:18.580 | but then there's also these vegetative things.

00:25:20.640 | There's disruptions in sleep,

00:25:21.860 | which of course make everything more challenging

00:25:23.860 | when we're awake, we know that.

00:25:25.260 | Sleep is so vital for resetting.

00:25:27.020 | You're waking up early, you can't get back to sleep.

00:25:28.940 | That's going to adjust your affect,

00:25:32.860 | your emotions in negative ways, we know this.

00:25:35.540 | And appetite is off.

00:25:36.940 | And there are hormones that get disrupted.

00:25:39.500 | So cortisol levels are increased.

00:25:41.660 | In particular, there's a signature pattern of depression

00:25:44.620 | whereby cortisol, the stress hormone that normally

00:25:48.060 | is released in a healthy way

00:25:49.740 | only in the early part of the day

00:25:51.900 | is shifted to late in the day.

00:25:54.740 | In fact, a 9 p.m. peak in cortisol

00:25:57.500 | is one of the physiological signatures

00:26:00.980 | of depressive like states.

00:26:02.820 | It's not the only one, but it is an important one.

00:26:06.440 | So there are a lot of things going on in major depression.

00:26:08.520 | And by now you're probably thinking,

00:26:10.000 | oh goodness, this is dreadful.

00:26:11.180 | Like there's all this terrible stuff.

00:26:12.500 | And indeed it is terrible.

00:26:14.480 | It is a terrible thing to find oneself

00:26:17.420 | in a mode where things feel sad, you feel guilty,

00:26:20.660 | you're exhausted.

00:26:22.020 | And oftentimes there's also an association

00:26:24.480 | with the anxiety system.

00:26:26.620 | So just because people are exhausted and lethargic

00:26:29.160 | and they don't enjoy things doesn't necessarily mean

00:26:31.320 | that there's an absence of anxiety.

00:26:33.320 | There can also be a lot of anxiety

00:26:34.660 | about what's going to happen to me.

00:26:35.940 | Am I going to be able to achieve my goals in life?

00:26:38.140 | Will I ever get out of this state?

00:26:40.540 | And so things really start to layer on.

00:26:42.420 | And as if this sounds depressing to you,

00:26:44.580 | it is indeed depressing.

00:26:46.380 | This is really the place that many people find themselves.

00:26:49.700 | And it's a pit that they just don't know

00:26:51.520 | how to climb out of.

00:26:52.940 | So let's just take a few minutes

00:26:54.700 | and talk about some of the underlying biology

00:26:57.380 | that creates this cloud

00:27:00.020 | or this constellation of symptomology.

00:27:02.940 | I think that's really important to do

00:27:04.380 | because if we want to understand the various treatments,

00:27:08.180 | how they work and why they work and how to implement them,

00:27:10.660 | we have to understand some of the underlying biology.

00:27:13.260 | So let's spend a few minutes talking

00:27:14.700 | about the biology of depression.

00:27:16.740 | What's known, what's not known.

00:27:18.460 | Because in doing that,

00:27:19.800 | I think you'll get a much clearer picture

00:27:21.860 | about why certain tools work to relieve depression

00:27:25.020 | and why others might not.

00:27:26.700 | So one of the most important early findings

00:27:31.040 | in the search for a biological basis of depression

00:27:35.180 | was this finding that there are drugs

00:27:37.960 | that relieve some of the symptoms of depression.

00:27:41.960 | Those drugs generally fall into three major categories,

00:27:45.520 | but the first set of ones that were discovered

00:27:48.320 | were the so-called tricyclic antidepressants

00:27:51.780 | and the MAO inhibitors, the monoamine oxidase inhibitors.

00:27:56.780 | You don't need to understand that nomenclature,

00:27:59.040 | but I'm going to give you a little bit of detail

00:28:00.600 | so that if you want to understand it, you can.

00:28:03.480 | Most of this work took place in the late 1950s

00:28:06.920 | and in the 1960s and continued well until the 1980s

00:28:11.320 | when new classes of drugs were discovered.

00:28:13.880 | And these tricyclic antidepressants and the MAO inhibitors

00:28:17.780 | largely worked by increasing levels of norepinephrine

00:28:23.440 | in the brain, as well as in the body in some cases.

00:28:27.100 | And they were discovered

00:28:28.440 | through a kind of odd set of circumstances.

00:28:30.320 | We don't have time to go into all the history,

00:28:31.820 | but suffice to say that they were discovered

00:28:34.120 | because of the exploration for drugs

00:28:36.760 | that alter blood pressure.

00:28:39.320 | Norepinephrine impacts blood pressure

00:28:41.920 | and drugs that lower blood pressure,

00:28:45.200 | reduce levels of norepinephrine.

00:28:47.440 | And that in many cases was shown to lead to depression

00:28:51.280 | or depressive-like symptoms.

00:28:53.240 | And so these drugs, these tricyclic drugs

00:28:55.720 | and the MAO inhibitors actually increase norepinephrine.

00:28:59.740 | And frankly, they do quite a good job of relieving some,

00:29:03.800 | if not all of the symptoms of major depression.

00:29:07.360 | However, they carry with them many side effects.

00:29:10.160 | Some of those side effects are side effects

00:29:12.540 | related to blood pressure itself.

00:29:13.960 | By increasing noradrenaline, norepinephrine as it's called,

00:29:17.600 | you raise blood pressure.

00:29:18.680 | That can be dangerous.

00:29:20.060 | That can be uncomfortable.

00:29:21.600 | But they also have a lot of other side effects.

00:29:25.000 | The reason they have other side effects

00:29:26.680 | is because they impact systems in the brain and in the body

00:29:30.180 | that impact things like libido, appetite, digestion,

00:29:35.040 | and others, and we'll talk about each of those in sequence.

00:29:38.280 | Okay, so the experience that clinicians had

00:29:41.160 | of observing some relief for depression

00:29:44.140 | with the tricyclic antidepressants

00:29:46.120 | and with MAO inhibitors was terrific,

00:29:48.780 | but there were all these side effects,

00:29:50.400 | side effects that people really did not like.

00:29:52.440 | They didn't like these drugs at all.

00:29:54.360 | A lot of people would get dry mouth.

00:29:55.920 | I mentioned the low libido.

00:29:57.120 | They'd have sleep issues, appetite issues, weight gain.

00:30:00.000 | They made some people so uncomfortable

00:30:01.480 | that they preferred not to take them,

00:30:02.980 | even though when they didn't take them,

00:30:04.840 | they had a worsening or a maintenance

00:30:06.720 | of their depressive symptoms.

00:30:08.160 | A decade or so later, there was the discovery

00:30:12.840 | of the so-called pleasure pathways in the brain.

00:30:15.480 | These are pathways, literally groups of neurons

00:30:18.380 | that reside in different locations in the brain,

00:30:20.520 | but connect to one another.

00:30:21.580 | So it's a circuit.

00:30:22.880 | And when you stimulate these neurons with certain behaviors

00:30:27.880 | or with electrical stimulation in an experiment,

00:30:30.680 | believe it or not, that's been done

00:30:31.640 | in both animals and humans.

00:30:33.620 | Animals and humans become very, very motivated

00:30:36.660 | to get more stimulation of these pathways.

00:30:39.680 | So this pleasure pathway or these circuits for pleasure

00:30:42.280 | are very what we call reinforcing.

00:30:45.320 | In fact, animals and humans will work hard

00:30:51.600 | to get stimulation of these brain areas

00:30:54.040 | even more than they will work to obtain sex, drugs,

00:30:58.600 | or even if they are addicted to a particular drug

00:31:01.200 | and they are in a state of withdrawal,

00:31:02.840 | the ultimate state of craving, if given a choice,

00:31:06.140 | a person or an animal will select to have stimulation

00:31:10.620 | of this pleasure pathway instead of the drug itself.

00:31:14.060 | And that is a major and significant finding.

00:31:17.060 | This pleasure pathway, as it's sometimes called,

00:31:19.820 | involves areas like the nucleus accumbens

00:31:22.060 | and the ventral tegmental area.

00:31:23.920 | These are areas of the brain that are rich with neurons

00:31:26.660 | that make dopamine.

00:31:28.360 | And if you think to the symptoms of depression,

00:31:31.000 | of anhedonia, lack of pleasure,

00:31:32.760 | a lack of ability to experience pleasure,

00:31:35.340 | well, that was a smoking gun that there's something wrong

00:31:39.440 | with the dopamine pathway in depression.

00:31:42.300 | And indeed that's the case.

00:31:43.260 | So it's not just norepinephrine,

00:31:44.640 | it's also the dopamine or pleasure pathway

00:31:46.960 | is somehow disrupted.

00:31:48.640 | And then in the 1980s,

00:31:50.360 | there was the discovery of the so-called SSRIs.

00:31:53.000 | Most people are now familiar with the SSRIs,

00:31:55.240 | the selective serotonin reuptake inhibitors.

00:31:58.400 | The SSRIs worked by distinct mechanisms

00:32:01.980 | from the tricyclic antidepressants and the MAO inhibitors.

00:32:06.060 | As their name suggests, SSRI,

00:32:08.160 | selective serotonin reuptake inhibitors,

00:32:11.020 | prevent serotonin from being wiped up from the synapse

00:32:16.020 | after two neurons talk to one another.

00:32:18.340 | What do I mean by that?

00:32:19.200 | Well, here's some very basic neurobiology 101.

00:32:21.920 | If you don't know any neurobiology,

00:32:23.560 | you're going to know some in about 15 seconds.

00:32:26.480 | Neurons communicate with one another

00:32:28.560 | by spitting out chemicals into the little gap between them.

00:32:32.520 | The little gap between them is called the synapse

00:32:34.700 | or by the Brits, the synapse.

00:32:37.320 | Those chemicals bind to the neuron on the opposite side

00:32:40.840 | and cause changes in the electrical activity

00:32:43.200 | of that neuron on the other side of the synapse.

00:32:46.280 | Serotonin is one such neurotransmitter

00:32:49.040 | or more specifically, it's a neuromodulator.

00:32:51.720 | It can change the activity of large groups of neurons

00:32:54.520 | in very meaningful ways.

00:32:55.900 | Selective serotonin reuptake inhibitor means

00:32:59.400 | when a person takes this drug,

00:33:02.040 | some of those drugs include things like Prozac or Zoloft,

00:33:05.160 | the more typical names or more generic names

00:33:07.320 | are things like fluoxetine.

00:33:09.100 | When people take those,

00:33:10.640 | more serotonin hangs out in the synapse

00:33:13.640 | and is able to be taken up by the neuron

00:33:15.880 | on the opposite side

00:33:17.540 | because of this selective reuptake inhibition.

00:33:22.320 | It prevents the clearance of serotonin from the synapse

00:33:26.700 | and thereby more serotonin can have an effect.

00:33:29.500 | So SSRIs don't increase the total amount of serotonin

00:33:33.240 | in the brain.

00:33:34.180 | They change how effective the serotonin

00:33:37.900 | that's already in the brain is

00:33:40.020 | at changing the activity of neurons, okay?

00:33:43.860 | So they don't increase serotonin.

00:33:45.760 | They increase the efficacy or the function of serotonin

00:33:49.560 | in the way that I just described.

00:33:51.540 | So that was more than 15 seconds,

00:33:53.000 | but now you understand how SSRIs work.

00:33:55.860 | And I wouldn't be talking about SSRIs

00:33:58.200 | if they didn't in fact work.

00:34:00.100 | Yes, there are many problems with SSRIs.

00:34:03.820 | They do carry certain side effects in many individuals.

00:34:06.900 | Also about a third of people that take SSRIs

00:34:11.240 | don't derive any benefit.

00:34:13.020 | It doesn't relieve their symptoms of depression.

00:34:15.300 | However, for the other two thirds,

00:34:17.080 | there's often a relief of some,

00:34:18.860 | if not all of the symptoms of major depression.

00:34:21.480 | The problem is the side effects that accompany those SSRIs.

00:34:25.500 | And so these days, SSRIs are a complicated topic.

00:34:28.740 | It's sort of what I would call a barbed wire topic

00:34:30.780 | because we often hear about all the problems with them,

00:34:33.860 | but these drugs also have saved a lot of lives.

00:34:36.300 | They've also improved a lot of lives.

00:34:39.280 | The issue is that they tend to have varying effects

00:34:42.660 | on different individuals

00:34:43.580 | and sometimes varying effects over time.

00:34:45.820 | So they'll work for a while,

00:34:47.160 | then they won't work for a while.

00:34:48.240 | There are also a lot of mysteries about the SSRIs

00:34:51.620 | and those mysteries bother people.

00:34:53.700 | What mysteries am I referring to?

00:34:55.100 | Well, SSRIs increase the amount of serotonin

00:34:59.300 | or more specifically,

00:35:00.540 | they increase the efficacy of serotonin at the synapse.

00:35:04.220 | That happens immediately

00:35:05.860 | or very soon after people start taking SSRIs,

00:35:08.980 | but people generally don't start experiencing any relief

00:35:11.700 | from their symptoms of depression

00:35:13.300 | if they're going to experience them at all

00:35:16.060 | until about two weeks after they start taking these drugs.

00:35:19.000 | So there's something going on there that's not clear.

00:35:21.380 | One idea is that the SSRIs

00:35:23.780 | actually can improve symptoms of depression

00:35:27.620 | or even remove symptoms of depression

00:35:30.340 | through so-called neuroplasticity

00:35:32.820 | by changing the way that neural circuits function.

00:35:35.900 | And there are many studies on this,

00:35:37.820 | but the main categories of studies on SSRIs

00:35:40.200 | that relate to neuroplasticity fall into two camps.

00:35:43.020 | One is the ways in which SSRIs might,

00:35:46.400 | and I want to emphasize might,

00:35:47.760 | be able to trigger the production of more neurons

00:35:50.180 | in the brain, in particular areas of the hippocampus

00:35:53.200 | called the dentate gyrus and others that impact memory.

00:35:57.460 | This is important and we're going to come back to memory.

00:35:59.460 | The other is that the SSRIs have been shown

00:36:02.540 | in various scientific studies

00:36:04.900 | to reopen critical periods of plasticity.

00:36:08.500 | I'll just briefly describe one of those studies.

00:36:10.500 | It was a study done by Lumberto Maffei's group in Pisa

00:36:14.380 | that explored brain plasticity

00:36:16.820 | that's known to be present in young animals

00:36:18.960 | and disappear in older animals.

00:36:21.440 | And this is also true in humans.

00:36:23.140 | Younger humans have a far more plastic brain.

00:36:25.980 | It can change in many more ways,

00:36:27.740 | more easily than can the older brain.

00:36:30.180 | And what they showed was that fluoxetine, Prozac,

00:36:33.340 | given to adult animals,

00:36:35.980 | can reopen this incredible period of plasticity.

00:36:39.860 | It can allow more plasticity to occur.

00:36:42.580 | That was interesting.

00:36:43.420 | I mean, it's purely through increases

00:36:44.820 | in serotonin transmission.

00:36:46.900 | And there are other studies showing

00:36:48.700 | that fluoxetine can increase the number of new neurons

00:36:51.000 | that are born into the adult brain, so-called neurogenesis,

00:36:54.220 | the production of new neurons.

00:36:56.300 | So it's very clear that there are at least

00:36:59.340 | three major chemical systems in the brain,

00:37:01.700 | norepinephrine, dopamine, and serotonin

00:37:04.620 | that relate to and can adjust the symptoms of depression.

00:37:08.980 | And those actually can be divided into separate categories.

00:37:12.120 | So for instance, epinephrine or norepinephrine

00:37:15.940 | is thought to relate to the so-called psychomotor defects,

00:37:19.300 | sometimes called psychomotor retardation.

00:37:21.380 | This is the lethargy.

00:37:22.680 | This is the exhaustion.

00:37:24.060 | This is the inability to get out of bed in the morning.

00:37:26.740 | Dopamine is thought to relate to the anhedonia,

00:37:30.300 | or I should say lack of dopamine in depressive patients

00:37:33.700 | is thought to lead to the anhedonia,

00:37:35.920 | the lack of ability to experience pleasure.

00:37:39.360 | And serotonin is thought to relate to the grief, the guilt,

00:37:44.360 | some of the more cognitive

00:37:45.820 | or more emotional aspects of depression.

00:37:49.140 | So we've got the norepinephrine system

00:37:50.740 | related to activity and alertness,

00:37:52.920 | the dopamine system relating to motivation, pleasure,

00:37:56.100 | and the ability to seek and experience pleasure,

00:37:58.520 | and then the serotonin system that's related to grief.

00:38:02.340 | And unfortunately, brains and organisms don't work

00:38:05.640 | in a simple mathematical way where you just say,

00:38:08.380 | "Oh, well, this person's experiencing a lot of grief,

00:38:10.760 | but they don't have any problems with lethargy,

00:38:14.460 | and so let's just boost up their serotonin."

00:38:16.300 | On paper, it works,

00:38:17.300 | but oftentimes it doesn't work clinically.

00:38:19.580 | And in another patient,

00:38:21.320 | you might get somebody who can't experience pleasure,

00:38:23.260 | but they're kind of anxious.

00:38:24.540 | They don't have any trouble sleeping,

00:38:27.220 | but they're just much more anxious

00:38:28.820 | and frustrated than they normally are,

00:38:31.140 | and they meet the symptoms of depression.

00:38:33.260 | Well, you might think, "Oh, well, do you just give

00:38:35.600 | that person some drug to increase dopamine

00:38:37.800 | and everything will be better?"

00:38:38.760 | And indeed, in some cases, that's true.

00:38:40.740 | There are drugs like wellbutrin,

00:38:43.100 | which function more specifically on the dopamine system

00:38:46.660 | to increase dopamine, and they also increase norepinephrine.

00:38:49.480 | Many people get great relief from things like wellbutrin.

00:38:53.540 | They don't really impact the serotonin system so much,

00:38:56.460 | and therefore you don't get a lot of the serotoninergic

00:38:58.860 | or serotonin-related side effects.

00:39:00.920 | However, some people feel far too anxious on those drugs.

00:39:04.460 | Some people get addicted to those drugs in a way,

00:39:07.420 | because a lot of those drugs that increase dopamine

00:39:09.940 | make you want more of those drugs.

00:39:11.620 | So you start to realize that what makes sense on paper

00:39:13.900 | doesn't always make sense clinically,

00:39:15.300 | and this is why it's complicated,

00:39:16.480 | and a really good psychologist

00:39:18.060 | and a really good psychiatrist will work with someone

00:39:19.840 | to try and pull and push on these various systems

00:39:22.400 | to find the combination of drugs

00:39:24.540 | that may be or may not be correct for them.

00:39:27.940 | There's a fourth aspect of the chemistry of depression

00:39:31.180 | that's really important to understand, and that's pain.

00:39:34.500 | We've talked about pain on this podcast before,

00:39:36.480 | but even if you didn't hear the episode

00:39:37.920 | on pleasure and pain, I just want to emphasize

00:39:39.900 | that pain is something that we experience in our body,

00:39:42.400 | no surprise there, an injury, a cut, et cetera,

00:39:45.100 | but that we also experience emotional pain,

00:39:47.280 | and those systems are linked in very intricate ways.

00:39:50.320 | There's actually some data showing that pain relievers,

00:39:55.120 | Tylenol, aspirin, these sorts of things

00:39:56.880 | can help certain people with emotional pain.

00:40:00.000 | Now, I'm not recommending people run out

00:40:01.360 | and take those things for emotional pain,

00:40:03.200 | but actually, if you think about that,

00:40:04.220 | it shouldn't come as any surprise,

00:40:05.620 | given the enormous number of people that take painkillers,

00:40:09.040 | opioids and things like them,

00:40:10.360 | to try and relieve their psychological pain,

00:40:12.240 | and as we know, those drugs are very, very problematic

00:40:16.380 | for many individuals.

00:40:18.080 | They can help certain individuals,

00:40:19.320 | but they are very prone to abuse,

00:40:21.720 | and they can induce addiction very easily

00:40:24.040 | in a number of people.

00:40:25.320 | There's a substance that's literally called substance P,

00:40:29.460 | the letter P, that's manufactured by neurons

00:40:32.880 | in our brain and body,

00:40:33.720 | which underlies our sensation of pain,

00:40:35.360 | and indeed, substance P inhibitors have been used

00:40:38.800 | to treat depression, and in some cases, works.

00:40:41.360 | A lot of people with depression are hypersensitive to pain,

00:40:44.920 | and of course, they could have multiple things going on.

00:40:46.880 | They could have chronic pain or chronic injury

00:40:48.880 | and major depression, so you start to get the constellation

00:40:51.720 | of the many things that could happen.

00:40:53.880 | So that's all I want to say today

00:40:55.960 | about the chemistry underlying depression

00:40:59.840 | or major depression.

00:41:01.160 | There's a lot more there,

00:41:02.160 | but I think if you understand the norepinephrine system

00:41:04.600 | and that it relates to some of these things like lethargy,

00:41:08.560 | the psychomotor defects, as they're called,

00:41:11.560 | dopamine and how it relates to motivation

00:41:13.960 | and lack of motivation and lack of dopamine and depression,

00:41:16.960 | and serotonin and its relationship to grief,

00:41:20.280 | and that low serotonin can lead to extreme grief and shame

00:41:23.480 | and higher serotonin levels can sometimes restore

00:41:25.960 | a sense of wellbeing and safety

00:41:27.880 | and feeling good about oneself.

00:41:29.680 | If you understand that and you understand

00:41:31.040 | that physical pain is somehow involved in certain cases,

00:41:34.400 | I think you will know more about depression

00:41:37.280 | and its underlying chemistry than most all people out there,

00:41:39.840 | and if you'd like to learn more,

00:41:40.840 | I invite you to pursue searching those terms further

00:41:44.520 | on the internet, and we'll certainly go into them

00:41:46.440 | in more depth, but that really sets the stage

00:41:48.720 | for where we're headed next.

00:41:50.140 | So next, I'd like to talk about hormones

00:41:51.780 | and how they relate to depression,

00:41:53.920 | and I'd also like to talk about stress

00:41:55.740 | and how it relates to depression,

00:41:57.380 | as well as talk about some of the genetics

00:41:59.440 | or the predispositions to depression,

00:42:02.740 | and for those of you that are thinking,

00:42:03.940 | hey, I want the tools, I want to know how to fix depression,

00:42:07.080 | I understand the desire for that.

00:42:09.740 | I will just ask if you hang in here with me

00:42:11.760 | a little bit longer, not only will you learn a lot more

00:42:14.060 | about how this complicated mood disorder works,

00:42:17.980 | some of the more interesting things about it,

00:42:20.240 | but it will also position you to get a lot more out

00:42:22.740 | of the tools that we will describe.

00:42:24.480 | You always have the option to skip forward, of course,

00:42:26.400 | but I think it's important to understand some

00:42:28.440 | of the hormonal and stress-related aspects of depression.

00:42:31.540 | So let's talk about hormones.

00:42:33.100 | 20% of people that have major depression

00:42:37.180 | have low thyroid hormone.

00:42:39.340 | Thyroid hormone is related to metabolism.

00:42:42.100 | Oftentimes we think about thyroid as only related

00:42:44.460 | to having a fast metabolism,

00:42:47.240 | but thyroid is related to all forms of metabolism,

00:42:50.340 | including our ability to synthesize new tissues

00:42:52.800 | like protein and repair injuries.

00:42:55.420 | I did a whole episode on thyroid and growth hormone.

00:42:58.460 | If you want to check that out,

00:42:59.500 | all of that is archived at Hubermanlab.com.

00:43:02.340 | It's all timestamped, et cetera.

00:43:03.700 | You can find it on YouTube, Apple, Spotify,

00:43:05.140 | all those places.

00:43:06.340 | So if you're curious about thyroid hormone

00:43:07.900 | and growth hormone, and you want to do the deep dive

00:43:10.000 | on those, and you want to learn how to alter their levels

00:43:13.000 | using various approaches, check that out.

00:43:15.640 | But 20% of people with major depression are hypothyroidal.

00:43:20.340 | They don't make enough thyroid.

00:43:22.240 | And that leads to low energy,

00:43:24.240 | low metabolism in the brain and body.

00:43:27.300 | And there's a condition called Hashimoto's,

00:43:30.060 | which is essentially low thyroid output.

00:43:33.520 | And again, I don't want to get

00:43:34.660 | into all the tools related to thyroid.

00:43:36.140 | Sometimes a psychiatrist will prescribe thyroid medication

00:43:39.980 | to increase thyroid output in people that are depressed,

00:43:42.500 | and that will work to relieve the symptoms.

00:43:44.520 | So there isn't necessarily a direct problem

00:43:46.900 | with serotonin, dopamine, and norepinephrine,

00:43:49.000 | or substance B.

00:43:49.840 | Sometimes it's a thyroid problem.

00:43:51.620 | So there are certain situations or conditions

00:43:54.140 | that can impact the thyroid hormone system

00:43:57.120 | and make people more susceptible to depression

00:43:59.660 | or make a preexisting depression worse.

00:44:01.860 | And those are things like childbirth.

00:44:04.340 | So it's well known that women who give birth

00:44:06.780 | can often undergo what's called postpartum depression.

00:44:09.660 | It actually comes from the word postpartuition depression.

00:44:13.780 | They give birth, what's happier,

00:44:16.660 | what's more joyful than the birth of a new healthy child,

00:44:19.320 | and they will lapse into a depression.

00:44:20.900 | And that's thought to be hormonally related,

00:44:23.360 | either directly to the thyroid system

00:44:25.960 | or perhaps to the cortisol system as well.

00:44:27.760 | We'll talk about cortisol in a moment.

00:44:29.460 | As well, certain women during certain phases

00:44:31.940 | of their menstrual cycle experience symptoms

00:44:34.940 | that are very much like clinical depression

00:44:37.760 | and oftentimes are diagnosed

00:44:39.760 | with clinical depression appropriately.

00:44:42.100 | And of course, the menstrual cycle is associated

00:44:43.700 | with shifts in hormone levels.

00:44:45.040 | As well, menopause and postmenopausal women

00:44:48.620 | are more susceptible to major depression,

00:44:51.480 | regardless of whether or not they've had

00:44:52.780 | that major depression earlier in their life.

00:44:54.380 | So these are things to be on the lookout for

00:44:56.160 | and to definitely talk to a doctor and get a blood panel

00:44:59.180 | that hopefully includes measures of thyroid hormone

00:45:01.700 | and cortisol hormone.

00:45:02.660 | Why cortisol hormone?

00:45:03.780 | Well, more stress is correlated with more bouts

00:45:07.220 | of major depression across the lifespan.

00:45:09.820 | How many bouts?

00:45:10.660 | Well, it turns out that as you go from having one

00:45:14.380 | to two to three, well, when you hit four to five bouts

00:45:17.620 | of really intense stressful episodes in life,

00:45:20.700 | these tend to be long-term stressful episodes,

00:45:23.260 | your risk for major depression goes way up.

00:45:26.300 | So whether or not you have a genetic predisposition

00:45:28.860 | to depression or not, one of the best things you can do

00:45:32.980 | to try and avoid getting depressed

00:45:34.500 | is to learn to control your stress system,

00:45:37.460 | to not go from short-term stress,

00:45:39.880 | which everybody experiences,

00:45:41.140 | we all have short-term stressors,

00:45:43.220 | to medium-term stress, to long-term stress,

00:45:45.380 | and to not have too many bouts of long-term stress

00:45:47.780 | because that probability of getting depressed

00:45:50.180 | goes way, way up.

00:45:51.380 | And this is something I've seen over and over again,

00:45:54.360 | not just in my scientific career, but just throughout life,

00:45:56.900 | people in all sorts of domains, young and old,

00:45:59.520 | I've seen that people will go

00:46:01.260 | through a very intense relationship, a breakup,

00:46:05.460 | sometimes it's the staying together that's stressful,

00:46:07.460 | sometimes it's a graduate school that can be stressful,

00:46:10.880 | sometimes it's some other event,

00:46:12.860 | and then some months later, they become depressed.

00:46:15.580 | And that's because the stress system

00:46:17.220 | is associated with the release of cortisol.

00:46:19.240 | The cortisol system can dramatically impact

00:46:21.720 | the way that these different neuromodulators,

00:46:23.880 | dopamine, norepinephrine, and serotonin function.

00:46:26.260 | And so there's this kind of latent or longer lasting impact

00:46:30.420 | on the systems that impact mood and wellbeing.

00:46:33.940 | So learning how to control your stress is really key

00:46:36.400 | if you're not depressed,

00:46:37.940 | or you're somebody that has not lapsed

00:46:39.980 | into a depression recently,

00:46:42.020 | take control of your stress system.

00:46:43.660 | And we did an entire episode on how to conquer stress,

00:46:46.560 | and that involves dealing with stress in the short-term,

00:46:48.860 | the medium-term, and in the long-term,

00:46:50.420 | and there are a lot of different ways to do that.

00:46:52.620 | One of the more important reasons

00:46:54.620 | for learning how to counter stress

00:46:56.160 | in order to offset depression

00:46:59.000 | is that there is a genetic predisposition

00:47:01.940 | that certain people carry to become depressed.

00:47:04.540 | There are these studies now of many,

00:47:06.680 | many thousands of individuals.

00:47:08.260 | These were mainly done in New Zealand,

00:47:09.860 | but these studies have now been done elsewhere,

00:47:12.160 | looking at many tens of thousands of individuals

00:47:15.460 | who carry particular copies of genes,

00:47:18.680 | what they call polymorphisms,

00:47:20.560 | in particular of a gene called 5-HTTLPR,

00:47:24.980 | which is a serotonin transporter.

00:47:27.320 | So this is a gene that controls or regulates

00:47:29.880 | how much serotonin is available in the brain.

00:47:32.620 | If you have this gene, this polymorphism,

00:47:36.100 | it doesn't necessarily mean that you will be depressed,

00:47:38.460 | but it greatly shifts your susceptibility

00:47:42.560 | to depression under conditions of stress.

00:47:45.180 | So I realize some people are listening to this

00:47:47.240 | and some people are watching it on YouTube,

00:47:48.660 | so I'm going to describe this in a way

00:47:49.840 | that doesn't require looking at any graphs.

00:47:51.980 | What I want you to imagine is a very shallow hill,

00:47:56.200 | like a very mellow hill.

00:47:58.100 | It's just a ramp set at about 10 or 15 degrees, okay?

00:48:02.580 | What we're plotting there in your mind

00:48:04.640 | is that with each bout of serious stress,

00:48:09.640 | so that could be trying to finish a degree

00:48:11.540 | or a relationship breakup or a family member that's sick

00:48:14.980 | or the loss of a loved one or a pet,

00:48:16.740 | with each bout of stress,

00:48:18.960 | the probability that you will experience

00:48:20.700 | a major depression goes up.

00:48:23.060 | However, if you carry this gene, this HTTLPR gene,

00:48:29.820 | the steepness of that curve goes way, way up,

00:48:33.380 | or it's actually more like a line,

00:48:35.040 | such that you need far fewer bouts of stress

00:48:39.460 | in order to lapse into a major depression, okay?

00:48:42.380 | So if the typical person who doesn't carry this polymorphism

00:48:46.020 | has to experience two or three or four or five bouts of stress

00:48:49.380 | before they lapse into a depression,

00:48:51.940 | somebody with this gene is susceptible

00:48:54.540 | to getting depression after just one bout

00:48:56.640 | or two bouts of intense stress, okay?

00:48:59.200 | So that's how these genes work.

00:49:01.160 | They don't preordain or determine you to be depressed.

00:49:05.800 | They raise a susceptibility.

00:49:07.460 | And many genes, many things related to heritability

00:49:10.740 | in general work in that way.

00:49:13.100 | And we know there's a strong genetic component

00:49:15.320 | to depression.

00:49:16.160 | How do we know?

00:49:16.980 | Well, in what are called concordant monozygotic twins.

00:49:21.060 | So these would be identical twins,

00:49:23.580 | and they can either be in one biological sac

00:49:26.780 | or two biological sacs while in utero,

00:49:30.080 | what's called a monochorionic or dichorionic.

00:49:32.780 | Well, typically it's monochorionic and identical twins

00:49:37.780 | for which one of those twins goes on

00:49:39.940 | to have major depression.

00:49:41.020 | There's a 50% probability that the other one

00:49:43.440 | will have major depression.

00:49:44.580 | So it's not 100%.

00:49:45.640 | It's not 100% inherited.

00:49:48.140 | It's not 100% genetic, as you might say,

00:49:50.860 | but there's a much higher predisposition for depression.

00:49:55.660 | Whereas in fraternal twins, that number drops.

00:49:59.500 | And in siblings, that number drops to about 25%.

00:50:02.620 | And in half siblings, it's about 10%.

00:50:05.380 | The numbers vary from study to study.

00:50:07.100 | But basically the more closely related you are

00:50:09.220 | to somebody who has major depression,

00:50:11.460 | the more likely it is that you will also

00:50:13.700 | get major depression.

00:50:14.540 | And therefore, if you haven't gotten major depression,

00:50:17.100 | the more likely it is that you should take steps

00:50:20.600 | to learn to mitigate stress,

00:50:22.660 | because stress is the major factor

00:50:24.140 | that can trigger one of these depressive episodes.

00:50:27.140 | Okay, so we've covered a lot related to the stress

00:50:32.140 | and the hormones and the neurochemistry of depression.

00:50:35.860 | In fact, I think this is probably the deepest

00:50:37.560 | I've ever gone into the biology of any topic

00:50:40.280 | on this podcast before getting to any specific tools.

00:50:43.700 | I mentioned that learning how to mitigate stress

00:50:45.640 | and deal with stress, learning how to measure

00:50:47.740 | and adjust your thyroid hormone, those might be useful.

00:50:50.460 | But next I'd like to turn to some very specific tools

00:50:53.780 | that people who both have depression

00:50:57.100 | or who are prone to depression,

00:50:58.580 | as well as people who don't have depression

00:51:00.020 | and simply want to maintain a good mood,

00:51:02.540 | who want to maintain a positive affect

00:51:04.320 | and pursuit of things in life.

00:51:05.900 | What are the things that you can do?

00:51:07.340 | It turns out there are things that you can do.

00:51:08.940 | And all of the biology that underlies

00:51:11.880 | the utility of those things,

00:51:14.180 | meaning the reasons those things work

00:51:16.420 | will now make sense to you,

00:51:17.640 | because they adjust things like serotonin and dopamine,

00:51:20.620 | and they adjust them through very specific pathways.

00:51:24.180 | I know for many people,

00:51:25.680 | learning about mechanism is kind of grueling.

00:51:27.780 | I realize this podcast isn't necessarily one

00:51:29.840 | that you can listen to passively while doing other things,

00:51:32.300 | although I would hope that you could do that

00:51:34.740 | and still enjoy it and extract the information.

00:51:37.220 | Why mechanism?

00:51:38.140 | Mechanism is so key,

00:51:39.940 | because mechanism is a little bit like understanding

00:51:42.920 | some of the chemistry of cooking.

00:51:44.580 | If you read a recipe and you can follow a recipe,

00:51:48.820 | you often hear people say, "Oh, I can follow a recipe."

00:51:52.440 | That means that if you have every ingredient in that recipe,

00:51:55.420 | you're good.

00:51:56.260 | You likely can make that dish.

00:51:58.020 | You can make that meal.

00:51:59.700 | However, if you understand a little bit of the chemistry

00:52:02.340 | of why salt has to be added third and not first,

00:52:06.820 | or why the heat has to be adjusted at a particular time,

00:52:09.820 | well, then not only can you follow a recipe,

00:52:12.140 | but that also gives you flexibility

00:52:13.660 | for when salt isn't available,

00:52:15.540 | or when you want to adjust the flavor of the dish,

00:52:18.340 | or when you want to try a new dish,

00:52:20.480 | or you want to get experimental.

00:52:21.640 | So when you understand mechanism,

00:52:23.100 | it puts you in a tremendous place of power

00:52:25.780 | to work with your system.

00:52:27.500 | So it's not just plug and chug,

00:52:28.880 | like take 12 milligrams of this,

00:52:31.660 | you either feel better or you don't.

00:52:33.260 | You can really start to understand how prescription drugs,

00:52:37.060 | supplements, nutrition, behavioral tools,

00:52:41.500 | how those things weave together

00:52:43.020 | to either work for you or not work for you,

00:52:44.980 | and get you to paths of healthy mind and body.

00:52:49.180 | So let's think about why any tool would work

00:52:51.980 | to relieve depression.

00:52:53.520 | We've talked about how some of the drugs

00:52:54.900 | that impact these different chemical systems might work,

00:52:57.280 | and why they create some of the problems they create.

00:53:00.200 | The problems are mainly created by the fact

00:53:01.740 | that they impact lots of systems in the brain and body.

00:53:04.520 | So you take a drug to increase serotonin,

00:53:06.840 | but that serotonin is also related not just to mood,

00:53:10.220 | but to things related to libido and appetite,

00:53:12.480 | and so you start disrupting multiple systems.

00:53:15.040 | The same could be said for behavioral tools, right?

00:53:18.960 | That any behavioral tool that adjusts the levels

00:53:22.180 | of a particular chemical ought to perhaps provide

00:53:25.860 | some relief for some of the symptoms of major depression.

00:53:28.720 | Let's take an example that I've talked about before

00:53:31.600 | on the podcast, which is if you get into a very cold shower,

00:53:34.220 | you take an ice bath, you will release norepinephrine

00:53:37.260 | and epinephrine in your brain and body.

00:53:38.900 | There's no question about that.

00:53:40.900 | I don't think anyone can really escape that.

00:53:43.020 | It's a kind of a universal response to being in cold water.

00:53:46.680 | Well, if some aspects of depression are related

00:53:50.160 | to low levels of norepinephrine,

00:53:52.220 | will taking cold showers relieve your depression?

00:53:55.660 | Perhaps.

00:53:56.500 | It might even relieve certain aspects of that depression.

00:53:58.920 | Is it a cure?

00:53:59.760 | Well, that's going to depend on the individual.

00:54:02.000 | Will exercise help?

00:54:04.000 | Well, if you go out for a run,

00:54:05.680 | you're going to increase the amount of norepinephrine

00:54:07.920 | in your body.

00:54:09.080 | If you enjoy that run,

00:54:10.980 | it's likely that you'll increase the levels of dopamine

00:54:13.760 | and probably serotonin in your brain and body as well.

00:54:16.840 | Will that cure your depression?

00:54:18.000 | Well, there are a lot of studies exploring how exercise

00:54:21.040 | can impact depression and indeed regular exercise

00:54:23.940 | is known to be a protective behavior against depression,

00:54:28.000 | but it also can help relieve

00:54:30.480 | some of the symptoms of depression.

00:54:32.460 | So you may ask yourself, why would you need drugs at all?

00:54:35.400 | Why would there be prescription drugs

00:54:37.520 | or the need for supplementation or other things

00:54:39.580 | to alleviate the symptoms of depression?

00:54:41.600 | Ah, well, that's the diabolical nature of depression,

00:54:44.880 | which is if people are far enough along in this thing,

00:54:49.880 | this sometimes called disease, sometimes called disorder,

00:54:52.520 | but major depression,

00:54:54.600 | oftentimes they can't get the energy to even get up

00:54:58.480 | and take a bath or a shower.

00:55:00.800 | They have no motivation to do it.

00:55:03.100 | They have no desire to go for a run.

00:55:05.160 | So you say, come on, let's go, you'll feel better.

00:55:06.880 | I know you feel better.

00:55:07.720 | It generates all these chemicals.

00:55:08.920 | I heard on the whatever podcast, Huberman Lab podcast

00:55:12.000 | or another podcast that getting into action

00:55:14.240 | does all these things and they just don't want to do it.

00:55:16.640 | And to you, a person who's not experiencing depression

00:55:20.160 | that perhaps could just seem like the most frustrating

00:55:22.040 | and confusing thing in the world,

00:55:23.660 | but it's very important to highlight the fact

00:55:25.440 | that these circuits that are accessible to some of us,

00:55:29.040 | the circuits for happiness, for pursuit of pleasure,

00:55:31.660 | for exercise, for getting in a cold shower,

00:55:36.360 | if that's your thing, that those circuits are present

00:55:39.740 | in all people, but for certain people

00:55:42.520 | that are experiencing major depression

00:55:44.160 | and are really in the depths of their depression,

00:55:46.960 | they can't really access those circuits in the same way

00:55:50.600 | that people who are not suffering from depression can.

00:55:54.200 | So I hope that makes it clear.

00:55:55.180 | It's not offering any excuses for them.

00:55:57.360 | And indeed, I think those behaviors would help

00:56:00.440 | jolt them out of some of the symptomology of depression,

00:56:04.380 | but they're just not accessible to everybody.

00:56:07.200 | So let's talk about the things that people can do

00:56:10.700 | to deal with depression.

00:56:12.180 | And again, anytime you add a behavior or a tool

00:56:15.660 | or a supplement or subtract a behavior tool,

00:56:18.860 | supplement, drug, et cetera,

00:56:19.940 | you absolutely should talk to your physician,

00:56:21.680 | especially if you're somebody

00:56:23.100 | that's dealing with major depression.

00:56:25.180 | I want to focus on the stress system.

00:56:27.860 | And I'm not just going to tell you

00:56:29.820 | to get sunlight in your eyes and to get a good night's sleep,

00:56:32.380 | although I think everybody should do that

00:56:33.940 | on a regular basis, ideally every day.

00:56:36.640 | Talked about those ad nauseum on this podcast.

00:56:38.960 | They will help your sleep.

00:56:40.140 | They will help you alleviate stress.

00:56:41.660 | I think you should have tools to deal with stress

00:56:43.320 | in real time, et cetera.

00:56:45.100 | But let's look at depression from the standpoint

00:56:47.340 | of a deeper biological phenomenon,

00:56:49.440 | which is inflammation and the immune system.

00:56:52.500 | There's growing evidence now

00:56:54.360 | that many forms of major depression,

00:56:56.460 | if not all of them, relate to excessive inflammation.

00:57:01.560 | Now, inflammation plays an important role in wound healing

00:57:04.100 | is that it is a positive aspect of our immune system,

00:57:07.580 | our ability to combat wounds, combat illnesses, et cetera,

00:57:12.580 | but inflammation gone unchecked,

00:57:15.640 | inflammation that lasts too long or is of too high amplitude,

00:57:19.140 | meaning too many anti-inflammatory or inflammatory cytokines

00:57:23.340 | and things of that sort in the body is bad.

00:57:25.920 | And there's decent evidence now

00:57:27.940 | that inflammation can lead to or exacerbate depression.

00:57:32.340 | And that if we want to control depression

00:57:34.380 | or limit or eliminate depression,

00:57:36.740 | that focusing on reducing inflammation

00:57:40.180 | and its associated pathways is a really good thing to do.

00:57:42.840 | And I think this is a really good thing

00:57:44.860 | for everybody to do, regardless of whether or not

00:57:47.300 | you suffer from depression or not.

00:57:48.660 | And today we're going to talk about exactly how depression

00:57:52.140 | comes about through the inflammation pathway.

00:57:55.540 | So first of all, who are the major players

00:57:59.340 | in creating chronic inflammation in the brain and body?

00:58:02.620 | They are the inflammatory cytokines,

00:58:04.980 | things like IL-6, interleukin-6,

00:58:07.420 | things like tumor necrosis alpha, TNF alpha,

00:58:11.660 | things like C-reactive protein, all right?

00:58:15.340 | Not all of these are cytokines, you have interferons

00:58:18.060 | and your prostaglandins and a lot of these things,

00:58:20.580 | but when we are stressed, chronically stressed,

00:58:23.580 | we get inflamed, our brain and various locations

00:58:26.620 | in the brain become inflamed because certain classes

00:58:28.740 | of cells in particular, those glial cells,

00:58:31.380 | the cells that are typically thought

00:58:33.140 | to just be support cells, those cells and their biochemistry

00:58:36.460 | and their dialogue with the neurons of the brain and body

00:58:39.140 | starts to become disrupted.

00:58:40.580 | I may have mentioned it earlier, I don't recall,

00:58:44.100 | but I certainly mentioned it in an earlier podcast

00:58:46.540 | that adrenaline, epinephrine, when it's released in the body

00:58:50.260 | it doesn't cross the brain barrier,

00:58:51.860 | but there are certain things that are able

00:58:55.140 | to cross the blood-brain barrier when we are stressed,

00:58:56.960 | things like the E2 prostaglandins,

00:58:58.980 | those cross the blood-brain barrier

00:59:01.100 | and our blood and our brain,

00:59:03.520 | therefore our brain and our body can communicate

00:59:06.140 | because certain things can pass through this barrier

00:59:09.400 | we call the BBB or the blood-brain barrier

00:59:11.240 | and also we have something called the glymphatic system,

00:59:13.380 | which is really a plumbing system

00:59:14.700 | that links the brain and body,

00:59:15.820 | it's the link between the immune system and the brain.

00:59:19.540 | Well, there is a set of actions that we can take

00:59:23.940 | in order to limit inflammation

00:59:26.400 | and this has been shown in several quality

00:59:29.420 | peer-reviewed studies now to reduce inflammation

00:59:32.620 | and to relieve some, and in some cases,

00:59:35.280 | all of the symptoms of major depression.

00:59:37.700 | One of those approaches is to increase our intake

00:59:41.660 | of so-called EPAs or essential fatty acids.

00:59:45.320 | There's now a very long list of papers in quality

00:59:49.720 | peer-reviewed journals showing that when people ingest

00:59:53.640 | a certain level of EPA omega-3 fatty acids,

00:59:58.640 | the relief from depressive symptoms matches the SSRIs.

01:00:03.780 | That's incredible, right?

01:00:05.880 | That essential fatty acids could relieve symptoms

01:00:08.280 | of depression as well as some

01:00:09.580 | of the prescription antidepressants.

01:00:11.800 | Now this doesn't necessarily mean you run off

01:00:13.880 | and stop taking your antidepressants

01:00:15.680 | if you've been prescribed them.

01:00:16.560 | Please don't do that.

01:00:17.400 | Please talk to your physician.

01:00:18.640 | And I should mention that some of these same studies

01:00:22.480 | have shown that increasing our intake

01:00:24.560 | of these essential fatty acids,

01:00:25.980 | in particular the EPA variety of omega-3s,

01:00:30.840 | can lower the effective dose of things like SSRIs,

01:00:35.680 | meaning if we required a 50 milligram

01:00:37.820 | or 40 milligram dose of fluoxetine,

01:00:40.560 | that one can get by on a lower dose

01:00:42.840 | and thereby perhaps not experience as many

01:00:46.360 | or as severe side effects by taking

01:00:48.800 | or supplementing with EPAs.

01:00:51.240 | Now the threshold level seems to be about one gram,

01:00:54.980 | a thousand milligrams of EPA.

01:00:57.140 | So you will sometimes see on a bottle of krill oil

01:01:00.360 | or fish oil or any other source,

01:01:02.320 | even plant source or other source of EPA,

01:01:07.280 | that it's a thousand milligrams or 1200 milligrams.

01:01:10.360 | But what's really important to look at is

01:01:12.640 | whether or not there's more than a thousand milligrams

01:01:15.400 | of EPA, because the EPA in particular

01:01:18.160 | is what's important here.

01:01:19.280 | And actually in exploring some of the literature

01:01:22.280 | on the effects of EPAs on cardiovascular health,

01:01:26.120 | as well as their effects on depression,

01:01:28.700 | there's some interesting dose dependent responses

01:01:31.960 | such that people who took anywhere from 400 milligrams

01:01:36.000 | to 5,000 milligrams of EPAs achieved a variety

01:01:40.320 | of different benefits.

01:01:41.520 | And in some cases, some side effects,

01:01:43.260 | we'll talk about those.

01:01:44.360 | And it does seem that this thousand milligrams

01:01:47.280 | is the critical threshold for benefiting

01:01:50.460 | or getting some relief from depressive symptoms.

01:01:52.720 | But people who took two grams seem to do better.

01:01:55.360 | And in the cardiovascular health realm,

01:01:57.680 | there it's a little more complicated.

01:01:59.680 | Some studies point to a very positive effect

01:02:03.080 | on cardiovascular health by taking increasing amounts

01:02:05.920 | of EPA, others not so much.

01:02:08.160 | The current data point to the fact

01:02:11.240 | that for every gram of EPA that one ingest,

01:02:13.880 | there's about a 9% improvement in cardiovascular health.

01:02:17.220 | The same dose dependent improvement on psychological health

01:02:21.560 | in combating depression can't really be stated.

01:02:25.600 | I wouldn't say that the more EPA you take,

01:02:28.200 | the better you're going to feel, so to speak.

01:02:30.220 | I don't think the data point to that.

01:02:32.760 | However, it does seem that if you take a gram,

01:02:35.200 | a thousand milligrams or 2000 milligrams of EPA,

01:02:38.420 | there does seem to be some substantial relief

01:02:40.840 | for many people, which I emphasize many, not all,

01:02:43.500 | for many people in major depressive symptoms.

01:02:47.800 | So how would this work?

01:02:49.240 | Well, it turns out that these inflammatory cytokines,

01:02:52.020 | they impact neurons and the circuits of the brain

01:02:56.600 | that relate to things like serotonin,

01:02:58.360 | dopamine, and norepinephrine.

01:03:00.560 | These inflammatory cytokines act in a variety

01:03:03.280 | of different ways, but they mainly act to inhibit

01:03:06.000 | the release of serotonin, norepinephrine, and dopamine,

01:03:09.160 | or the synthesis of serotonin, norepinephrine, and dopamine.

01:03:13.320 | And I'll give you one example of how EPAs

01:03:16.120 | can positively impact this process.

01:03:18.080 | And then it points to a second tool,

01:03:19.860 | which is the proper utilization of exercise

01:03:22.760 | to offset the effects of depression.

01:03:26.900 | So now you should understand why having healthy levels

01:03:29.420 | of serotonin is important for maintaining healthy mood.

01:03:32.760 | It's not responsible for all the aspects

01:03:35.840 | of having a healthy mood.

01:03:37.980 | There's also dopamine and norepinephrine,

01:03:39.560 | but it is a very important one.

01:03:41.800 | Dopamine, also called 5-HT,

01:03:44.000 | essentially derives from a precursor called tryptophan.

01:03:50.560 | Tryptophan arrives into our system through our diet, okay?

01:03:54.800 | Tryptophan is an amino acid.

01:03:56.800 | Tryptophan is found in turkey.

01:03:59.600 | It's found in carbohydrates.

01:04:01.640 | And that should therefore raise the idea of,

01:04:04.000 | hmm, I wonder if one of the reasons why people

01:04:06.080 | who are depressed have such an appetite for carbohydrate

01:04:08.540 | laden foods is because they're trying to get more tryptophan

01:04:12.180 | and therefore more serotonin.

01:04:13.960 | And indeed that's the case.

01:04:15.520 | Tryptophan is eventually converted into serotonin.

01:04:19.820 | However, if there's excessive amounts of inflammation,

01:04:23.380 | these inflammatory cytokines cause tryptophan

01:04:28.500 | to not be converted so much into serotonin,

01:04:31.640 | but to be diverted down a different pathway.

01:04:35.460 | The pathway involves something called IDO, indolamine,

01:04:38.760 | which converts tryptophan into kynuren, okay?

01:04:43.260 | Kynuren actually acts as a neurotoxin

01:04:46.020 | by way of converting into something called quinolinic acid,

01:04:50.720 | okay?

01:04:51.560 | And quinolinic acid is pro-depressive.

01:04:53.500 | So if that seems like a complicated biochemical pathway,

01:04:55.920 | what's basically happening here is that the tryptophan

01:04:58.220 | that normally would be made into serotonin

01:05:00.420 | under conditions of inflammation

01:05:02.900 | is being diverted into a neurotoxic pathway.

01:05:06.260 | And ingestion of EPAs,

01:05:08.040 | because it limits these inflammatory cytokines,

01:05:11.140 | things like IL-6, C-reactive protein, et cetera,

01:05:13.840 | can cause more of the tryptophan that one ingests

01:05:19.900 | or has in their body to be diverted

01:05:21.940 | towards the serotonergic pathway.

01:05:23.800 | Exercise, it turns out, also has a positive effect

01:05:29.980 | on the tryptophan to serotonin conversion pathway.

01:05:34.060 | And the way it does it is really interesting.

01:05:35.860 | You now know that tryptophan

01:05:37.340 | can either be converted into serotonin

01:05:39.340 | or it can be converted into this neurotoxin,

01:05:41.300 | which is a bad thing.

01:05:42.580 | Exercise, the activation of the muscles

01:05:46.260 | through rhythmic repeated use,

01:05:47.880 | in particular aerobic exercise,

01:05:49.180 | but also resistance training

01:05:51.020 | has been shown to do this to some extent,

01:05:53.460 | tends to sequester or shuttle the kynuren into the muscle

01:05:58.340 | so that it isn't converted into this neurotoxin

01:06:01.300 | that is pro-depression, okay?

01:06:03.860 | There are a lot of steps in the pathway

01:06:05.100 | leading to depression.

01:06:06.620 | But what this essentially means

01:06:08.100 | is that hitting a certain threshold level of EPA intake,

01:06:12.380 | whether by supplementation with fish oil or krill oil

01:06:15.500 | or through some plant source,

01:06:16.900 | if you're not into ingesting fish or krill,

01:06:19.700 | or trying to get up above that 1,000 milligram threshold

01:06:23.860 | for EPA by ingesting particular food sources,

01:06:25.940 | you certainly can do it through food,

01:06:27.060 | you don't have to supplement,

01:06:28.540 | but it's easier to do with supplements,

01:06:31.380 | that doing that will limit the inflammation

01:06:33.620 | that diverts tryptophan into this neurotoxic pathway.

01:06:36.740 | And exercise as well augments this conversion

01:06:41.480 | of tryptophan into serotonin

01:06:44.380 | because it takes this thing

01:06:45.900 | that would potentially be a neurotoxin

01:06:48.780 | and it sequesters it, it pulls it away

01:06:51.120 | so that it can't actually go have its pro-depressive effects.

01:06:54.540 | So you've got multiple steps here.

01:06:57.000 | We're describing two tools, increasing EPA

01:07:00.240 | and regular exercise as a way of increasing serotonin

01:07:03.960 | somewhat indirectly, right?

01:07:05.580 | It's by limiting this bad pathway

01:07:07.480 | to promote the activity of a good pathway.

01:07:10.200 | But from the data that are published

01:07:12.460 | in quality peer review journals,

01:07:13.820 | it really appears that this inflammation pathway

01:07:15.700 | does function to increase depression through these pathways.

01:07:19.220 | And so knowing that there are behavioral steps

01:07:21.380 | and supplementation-based steps,

01:07:22.980 | or if you prefer getting your EPAs from typical food,

01:07:26.940 | from nutritional approaches,

01:07:29.580 | I find that very reassuring that the mechanisms

01:07:32.580 | all converge on a common pathway, serotonin.

01:07:35.360 | That gives me great peace of mind

01:07:37.820 | that when people say, hey, go out for a run

01:07:40.840 | or you should get outdoors, exercise,

01:07:42.580 | or you should take fish oil,

01:07:44.480 | or like the Scandinavians do,

01:07:45.540 | I have Scandinavian family members,

01:07:46.900 | and they are known to,

01:07:49.840 | or I should say they are quite open about the fact

01:07:52.260 | that during the winter months in particular

01:07:54.060 | when depression is more likely,

01:07:55.920 | but throughout the year, really,

01:07:57.400 | they make an effort to regularly ingest high levels of EPA,

01:08:01.920 | either through ingesting fatty fish and its skin.

01:08:06.180 | I'm not a particular fan of ingesting the skin of fatty fish

01:08:08.520 | or by supplementing with cod liver oil

01:08:10.740 | or other types of fish oil,

01:08:11.900 | sardines and things of that sort, sardine oils.

01:08:14.540 | There are a number of different things out there

01:08:15.800 | that one could use.

01:08:17.220 | So I find it very reassuring

01:08:19.580 | that there's a common biochemical pathway

01:08:21.660 | that can explain why these things not just work,

01:08:24.820 | but why they should work.

01:08:26.520 | They should work because they operate

01:08:28.060 | in the very same biochemical pathways

01:08:30.540 | that antidepressants that are prescribed to people do.

01:08:34.680 | So what does this mean for you?

01:08:35.760 | Well, if you're somebody who suffers from major depression,

01:08:38.720 | again, don't stop taking your prescribed medication,

01:08:41.040 | talk to your doctor,

01:08:41.880 | but talk to them perhaps about the EPAs and exercise

01:08:46.880 | and how these things can impinge

01:08:48.360 | on the same biochemical pathways.

01:08:50.160 | If you're somebody who's not suffering

01:08:51.380 | from major depression,

01:08:52.500 | I still think these pathways are really important

01:08:54.480 | to understand and actually knowing these pathways

01:08:57.180 | is additional motivation to get regular exercise.

01:09:01.100 | I think we all know that we should be getting anywhere

01:09:02.980 | from 150 minutes to 180 minutes per week

01:09:05.820 | of so-called zone two cardio for cardiovascular effects.

01:09:08.820 | Zone two is the kind of mellowish cardio

01:09:10.740 | where you can sort of hold a conversation

01:09:12.740 | if you needed to, but it's a little bit tough.

01:09:14.300 | You're kind of sucking for air a little bit

01:09:16.540 | and that's going to limit these depressive like symptoms.

01:09:20.080 | I think in all of us,

01:09:20.940 | I don't think that we should think of depression

01:09:22.700 | as a strict threshold.

01:09:24.740 | I'm somebody who personally has made the choice

01:09:27.220 | to take a thousand milligrams of EPA per day.

01:09:30.740 | I do that by supplementing fish oil.

01:09:33.020 | There's debate out there as to whether or not

01:09:35.120 | it's better to take EPA and DHA in particular ratios

01:09:39.860 | and whether or not DHA can impact the LDL,

01:09:43.340 | which is the so-called bad cholesterol.

01:09:45.260 | That's getting really down into the weeds

01:09:46.980 | and we can talk about that in a future episode.

01:09:49.160 | But for myself, I notice a pretty substantial

01:09:53.400 | positive effect of taking anywhere

01:09:55.360 | from a thousand milligrams to 2000 milligrams

01:09:57.400 | of EPA per day.

01:09:58.440 | I do that through supplementation

01:09:59.740 | and I do strive to try and eat some fish,

01:10:02.080 | even though frankly, I've never liked the taste of fish.

01:10:04.680 | For those of you that would like a little more detail

01:10:06.740 | or perhaps a lot more detail into the effects

01:10:09.640 | of EPA on depression and in relieving depressive symptoms,

01:10:14.220 | and if you want to get into the nitty gritty of it,

01:10:17.120 | I invite you to go to examine.com, put in depression, EPA.

01:10:20.780 | They list off and have links to 28 studies

01:10:24.900 | on the effects of EPA on major depression.

01:10:27.120 | If you go to PubMed, there are many, many studies on this

01:10:30.940 | now that date back several decades, really.

01:10:34.000 | If you're interested in the specific effects of EPA

01:10:39.300 | as opposed to DHA, I want to point you towards

01:10:42.460 | a particular study entitled, not surprisingly,

01:10:45.180 | EPA but not DHA appears to be responsible

01:10:48.240 | for the efficacy of omega-3 long chain polyunsaturated

01:10:51.000 | fatty acid supplementation and depression,

01:10:53.200 | evidence from a meta analysis of randomized control trials.

01:10:55.960 | This is a really wonderful paper.

01:10:58.080 | The author is Julian Martins, M-A-R-T-I-N-S.

01:11:02.240 | It was published in 2009.

01:11:04.760 | We will provide a link to this study in the caption.

01:11:08.080 | And that study is really the one that at least to me

01:11:10.400 | points to why EPA in particular is what's effective.

01:11:15.080 | And that whether or not DHA is problematic or not

01:11:19.260 | is a separate issue, but it's really the EPA

01:11:22.200 | that one wants to hit a certain threshold level of

01:11:25.160 | if one's goal is to get relief from depression

01:11:28.160 | or to keep depression at bay by keeping mood elevated,

01:11:31.600 | which is why I take a high dose EPA.

01:11:35.000 | So we've got EPA, we've got exercise.

01:11:37.240 | Now you understand how they work to adjust mood.

01:11:40.580 | Now I want to talk about something that at least for me

01:11:44.620 | was quite surprising when I first learned about it

01:11:47.400 | for sake of treatment of mood disorders

01:11:50.400 | and that's creatine.

01:11:52.160 | Creatine has a number of very important functions

01:11:54.900 | throughout the body.

01:11:56.220 | For those of you that are into resistance training

01:11:59.620 | and actually for those of you

01:12:00.680 | that are into endurance training as well,

01:12:02.800 | creatine has achieved a lot of popularity in recent years

01:12:07.360 | because supplementation with creatine

01:12:09.960 | can draw more water into muscles

01:12:11.960 | and can increase power output from muscles.

01:12:14.820 | So it's something that does indeed work.

01:12:18.260 | There have been debates about whether or not

01:12:20.460 | it's unhealthy for the kidneys

01:12:21.700 | to take long-term creatine supplementation at high doses.

01:12:24.480 | And I invite you to go down that rabbit hole.

01:12:26.760 | I think most people now accept the idea

01:12:29.300 | that for most people, not all, but for most people,

01:12:31.740 | low dose creatine supplementation

01:12:33.300 | of anywhere from one gram to five grams per day

01:12:36.640 | can have a number of positive effects

01:12:39.380 | on physical performance.

01:12:41.380 | People with kidney issues, et cetera,

01:12:43.000 | need to be especially cautious,

01:12:44.280 | but creatine is interesting for that purpose.

01:12:46.960 | However, there's also a so-called phosphocreatine system

01:12:50.520 | in the brain and that phosphocreatine system

01:12:53.820 | has everything to do with the dialogue

01:12:55.460 | between neurons and these other cell types called glia

01:12:58.700 | and glia comprise several cell types,

01:13:01.600 | microglia, astrocytes, et cetera.

01:13:04.260 | But the phosphocreatine system in the forebrain in particular

01:13:08.340 | in the front of our brain has been shown to be involved

01:13:11.220 | in regulation of mood and some of the reward pathways,

01:13:15.460 | as well as in depression.

01:13:17.940 | And there are now several studies, at least three,

01:13:22.260 | although there are probably more by time this comes out

01:13:25.980 | because they're coming out very quickly now,

01:13:27.980 | at least three quality studies pointing to the fact

01:13:30.540 | that creatine supplementation

01:13:32.980 | doesn't just have these positive effects

01:13:35.300 | on physical performance,

01:13:36.280 | but can also be used as a way to increase mood

01:13:40.980 | and to improve the symptoms of major depression.

01:13:44.100 | This has been now done in several double-blind,

01:13:49.100 | placebo-controlled studies.

01:13:50.540 | These studies have looked at women, have looked at men,

01:13:55.540 | have looked at adolescents, some of whom were taking SSRIs,

01:13:59.540 | some of whom were not.

01:14:01.420 | They've done magnetic resonance spectroscopy.

01:14:05.860 | So spectroscopy is a way that you can look at

01:14:09.520 | the concentrations of particular compounds in the brain

01:14:12.200 | in real time in humans.

01:14:13.960 | It can be used for other things as well, of course.

01:14:15.660 | And basically what's been observed is that

01:14:18.920 | increasing the activity of the phosphocreatine system

01:14:21.840 | in the forebrain can be beneficial,

01:14:23.940 | or at least as correlated with improvements in mood.

01:14:27.140 | So let's just talk for a moment about what's involved

01:14:29.740 | with using or supplementing creatine

01:14:32.400 | in order to improve mood and perhaps even treat depression.

01:14:36.000 | First of all, when I talk about creatine,

01:14:39.140 | I'm talking about creatine monohydrate.

01:14:42.700 | There are a number of different forms of creatine.

01:14:44.300 | Here I'm talking about creatine monohydrate.

01:14:47.260 | The American Journal of Psychiatry in 2012 published a study

01:14:52.260 | which was a randomized double-blind placebo-controlled trial

01:14:54.740 | of oral creatine monohydrate.

01:14:56.860 | And what it found is that it could augment

01:14:59.440 | or enhance the response to a selective serotonin

01:15:01.920 | reuptake inhibitor, in particular in women

01:15:04.460 | with major depressive disorder.

01:15:07.320 | So like EPA, creatine supplementation

01:15:10.940 | seems to either lower the required dose of SSRI

01:15:14.680 | that's required to treat depression,

01:15:16.540 | or can improve the effectiveness of a given dose of SSRI.

01:15:21.540 | However, there are other studies that have looked directly

01:15:25.240 | at creatine supplementation in the absence of SSRIs,

01:15:27.940 | and those are interesting as well.

01:15:29.360 | There's a wonderful and very comprehensive review

01:15:32.780 | on creatine for the treatment of major depression

01:15:35.760 | that includes beautiful tables of all the subjects

01:15:39.340 | and the dosages, et cetera.

01:15:40.560 | I'm not going to read off every line

01:15:42.480 | and every column in that review,

01:15:46.160 | but we will provide a link to that review as well.

01:15:48.660 | One of the things that's really striking

01:15:51.960 | about the lists of studies that they include

01:15:54.820 | is that most of them used dosages

01:15:58.080 | that are pretty reasonable for most people,

01:16:00.960 | anywhere from three grams to five grams,

01:16:04.800 | sometimes up to as many 10 grams per day of creatine.

01:16:08.960 | Many of these also were shown to increase activity

01:16:12.980 | of this phosphocreatine system in the forebrain,

01:16:16.040 | and some show a relationship

01:16:18.600 | between that phosphocreatine system

01:16:21.240 | and a particular category of receptors in the brain

01:16:24.480 | called the NMDA receptor, N-methyl-D-aspartate receptor.

01:16:31.000 | The NMDA receptor is one of the first things

01:16:35.080 | that every budding neuroscientist learns about

01:16:38.000 | because it is the receptor

01:16:40.340 | that has particular electrical and chemical properties

01:16:43.520 | that make it a critical gate for so-called neuroplasticity.

01:16:48.520 | So it's not a receptor that's activated in the brain

01:16:52.360 | typically for just the functioning of the brain

01:16:56.320 | on a day-to-day basis.

01:16:57.680 | It's a receptor that's activated

01:16:59.240 | when circuits are going to change,

01:17:01.900 | when they are inspired to change

01:17:03.780 | by some very strong stimulus, meaning some experience,

01:17:07.440 | or in some cases a drug, or in some cases something else.

01:17:11.420 | But the NMDA receptor is a kind of a key node

01:17:15.760 | for shifting brain circuitry.

01:17:17.340 | And so while the details aren't entirely clear,

01:17:20.100 | it seems that creatine supplementation

01:17:23.180 | leads to increases in the phosphocreatine system

01:17:26.280 | in the forebrain,

01:17:27.560 | and that increases in the activity

01:17:30.520 | of the forebrain phosphocreatine system

01:17:32.980 | relate to changes in the way the NMDA receptors function

01:17:36.960 | and may lead to some of the plasticity,

01:17:38.840 | the changes in neural circuits that underlie the shift

01:17:42.120 | from negative mood and affect to positive mood.

01:17:44.940 | Now, there are a lot of gaps.

01:17:46.040 | Those are, you know, there are a lot of little boxes

01:17:48.560 | or bins in the diagram I just laid out for you,

01:17:50.880 | and some of them are still truly black boxes, as we say,

01:17:53.640 | meaning we don't really know what's in them yet,

01:17:55.680 | and more mechanistic data are coming.

01:17:57.400 | However, when you look over the data in this review,

01:17:59.600 | or when I look over the data in this review,

01:18:01.900 | what you find is that

01:18:03.060 | they're pretty striking positive effects of creatine.

01:18:07.400 | And one of the more interesting effects

01:18:10.180 | is that creatine has actually been shown

01:18:12.960 | to increase mania in people that are already manic.

01:18:17.960 | And that's interesting.

01:18:19.740 | We're not talking about bipolar depression today,

01:18:22.000 | but it seems that creatine elevates levels of activation

01:18:25.480 | and kind of mood overall.

01:18:26.620 | And you could see why that would be a problem for somebody

01:18:28.620 | that's already in a manic phase,

01:18:29.960 | but it actually might be beneficial for somebody

01:18:32.520 | who is very low affect and has major depression.

01:18:37.200 | So should you supplement with creatine?

01:18:39.180 | Well, as always, talk to your healthcare provider.

01:18:42.560 | But if you're somebody who is thinking about things

01:18:45.760 | that you can do and things that you can take

01:18:48.000 | in order to improve your mood, keep depression at bay,

01:18:50.680 | maybe even support other treatments for major depression,

01:18:56.040 | the creatine system seems like a logical one.

01:18:58.700 | There's at least strong studies

01:19:01.680 | and a good number of them to look to

01:19:03.800 | to determine whether or not that's right for you.

01:19:06.240 | I personally take five grams of creatine for other reasons.

01:19:10.500 | I take it for the physical performance enhancing effects,

01:19:15.500 | but it's kind of nice to think that perhaps

01:19:17.700 | it's also helping me improve my mood.

01:19:19.780 | That's a choice that I've made for me

01:19:21.140 | as in within the margins of safety for me in my life.

01:19:24.120 | I don't know that it's right for everybody,

01:19:26.040 | but I find it very interesting.

01:19:27.860 | And again, I find it particularly interesting

01:19:29.900 | because there's a logical biochemical pathway

01:19:32.800 | to support the finding that it improves mood

01:19:35.200 | and can offset the effects of major depression

01:19:37.640 | in some cases, or can improve the effects

01:19:40.120 | of antidepressant medication in many cases.

01:19:44.000 | When I see mechanism and I see effectiveness

01:19:47.240 | and the mechanism and the effectiveness map

01:19:49.580 | to a lot of the same mechanisms

01:19:51.200 | that are involved in prescription drugs,

01:19:52.720 | that gives me great reassurance

01:19:54.400 | that this isn't just some sort of mysterious pathway

01:19:58.240 | or mysterious compound by which creatine might be working.

01:20:01.580 | So now we've clustered together EPA's exercise

01:20:06.040 | and their relationship to inflammation,

01:20:07.880 | creatine and its relationship to forebrain function

01:20:11.320 | and the phosphocreatine system and this NMDA receptor.

01:20:15.920 | And as you'll see in a few minutes,

01:20:17.080 | that NMDA receptor turns out to be vitally important

01:20:20.520 | and is actually one of the main nodes of action

01:20:23.600 | for some of the more novel and exciting therapeutics

01:20:26.160 | that are being explored now in psychiatric clinics.

01:20:29.800 | So let's talk a little bit more about this NMDA receptor

01:20:33.200 | and how it relates to some of the more experimental

01:20:36.720 | or novel therapeutic compounds

01:20:38.600 | for the treatment of major depression.

01:20:40.200 | And the compounds that we're going to be talking about,

01:20:43.620 | you may have heard of before, one is ketamine,

01:20:46.980 | which is getting increasing interest in psychiatric clinics

01:20:50.620 | and in various experimental and clinical studies.

01:20:53.460 | And the other is PCP.

01:20:55.840 | Both ketamine and PCP are known drugs of abuse.

01:20:59.940 | For many years, people have abused these drugs,

01:21:02.540 | go by the street name Special K, et cetera,

01:21:05.440 | and they create dissociative anesthetic states.

01:21:08.860 | So dissociative states where people don't feel

01:21:12.060 | as closely meshed with their emotions

01:21:15.180 | and their perceptions, it's an odd state I hear,

01:21:20.180 | and it's an odd state that clinicians are now leveraging

01:21:24.080 | for the treatment of depression.

01:21:25.380 | We'll talk about why that is,

01:21:26.680 | but let's talk a little bit about this NMDA receptor

01:21:29.580 | and why ketamine and PCP might work

01:21:32.760 | for the treatment of depression or how they even could work.

01:21:35.840 | I want to be very direct that this is an area

01:21:40.160 | that still needs a lot of data.

01:21:42.960 | There are however, some excellent papers

01:21:44.900 | from really terrific groups.

01:21:46.940 | One of them is a paper that was published

01:21:49.560 | in "Nature" last year, 2020.

01:21:52.100 | First author is Vesuna, Sam Vesuna, V-E-S-U-N-A,

01:21:56.060 | and the last author and the lead on the study

01:21:57.780 | was Dr. Karl Deisseroth, who was a guest

01:22:02.420 | on the Huberman Lab podcast a few months ago.

01:22:05.620 | He's a world expert in neuroscience.

01:22:07.560 | He's a psychiatrist.

01:22:09.200 | And this paper from Sam Vesuna and Karl

01:22:13.260 | and colleagues explored how these dissociative states

01:22:16.560 | come about.

01:22:17.400 | And they looked at this both in animals and in humans

01:22:20.400 | and found that there was essentially a common mechanism

01:22:23.800 | whereby a particular layer of cortex.

01:22:27.360 | So your brain has this outer shell of tissue

01:22:31.480 | that is called the neocortex.

01:22:33.160 | It's where our perceptions lie.

01:22:35.360 | It's where our associations lie.

01:22:37.160 | It's a very important area for processing,

01:22:39.760 | decision-making and planning, et cetera.

01:22:43.080 | It's literally stacks of cells.

01:22:45.220 | And one of those layers in the stack of cells is layer five.

01:22:48.940 | And the layer five neurons in particular

01:22:50.940 | went into a particular rhythm of electrical activity,

01:22:54.040 | this one to three Hertz rhythm,

01:22:56.400 | after mice or humans were administered ketamine or PCP.

01:23:01.400 | There was activation of a particular area of the brain,

01:23:07.020 | this retrosplenial cortex, as it's called,

01:23:10.540 | and the dissociative state that emerged

01:23:14.140 | was an interesting one.

01:23:15.860 | And clinically what's described in the trials for ketamine

01:23:20.180 | and things like it,

01:23:21.480 | that people who are depressed will take ketamine,

01:23:25.180 | will experience a kind of separateness from their grief

01:23:28.980 | and from their emotions.

01:23:31.020 | And that possibly there's plasticity.

01:23:33.660 | There are actually shifts in the neural circuitry

01:23:35.660 | such that their emotions don't weigh on them so heavily.

01:23:39.600 | I'm using very loose language here,

01:23:41.780 | but that they don't feel as over ridden

01:23:45.660 | or as burdened by their own emotions

01:23:48.360 | as they did previously to the ketamine therapy.

01:23:50.760 | Now, absolutely in no way, shape or form,

01:23:53.140 | in my suggestion that people run out and take ketamine

01:23:55.180 | in order to treat their own depression.

01:23:56.980 | These drugs are still very much experimental,

01:24:00.540 | although they are approved in certain contexts,

01:24:04.020 | at least in the US by prescription

01:24:06.740 | for the treatment of depression.

01:24:09.220 | What's interesting to me is that these dissociative states

01:24:13.360 | sound, at least at the outset,

01:24:15.780 | to be more of a separateness from everything.

01:24:20.120 | It sounds a little bit like depression itself.

01:24:22.360 | It's sort of like anhedonia,

01:24:24.560 | an inability to experience pleasure.

01:24:27.320 | And then one takes a dissociative anesthetic

01:24:30.500 | and somehow is able to get relief

01:24:32.940 | by getting even further away from an experience.

01:24:36.000 | To me, that doesn't make sense,

01:24:37.620 | but that just speaks to the fact that these drugs

01:24:40.740 | and these receptors and these pack pathways

01:24:43.620 | operate through very cryptic means.

01:24:46.660 | And we really don't understand all the pathways in the brain

01:24:49.060 | that relate to motivation and mood and so forth.

01:24:51.740 | And the results with these ketamine trials

01:24:53.500 | are looking very promising.

01:24:55.600 | In fact, there are a number of trials that show that

01:24:59.380 | a fair number of people that take ketamine

01:25:01.260 | in a therapeutic setting legally

01:25:03.060 | with a psychiatrist guiding the experience

01:25:05.920 | are able to get relief from their symptoms

01:25:08.520 | without the need for many, many treatments with the drug.

01:25:12.080 | Just how many treatments varies

01:25:14.640 | from individual to individual,

01:25:15.900 | but it's not like people have to take this stuff ongoing.

01:25:18.440 | This is really an attempt to tap into this NMDA receptor

01:25:22.380 | that is related to neuroplasticity.

01:25:24.920 | Both ketamine and PCP essentially act as antagonists,

01:25:30.560 | which means they block the NMDA receptor.

01:25:34.640 | They do it through different methods,

01:25:36.680 | non-competitive and competitive

01:25:38.080 | for you chemists and pharmacologists out there.

01:25:40.380 | You can look it up if you like.

01:25:42.260 | But what's therefore even more surprising

01:25:45.140 | is that every neuroscientist learns

01:25:47.420 | that activation of the NMDA receptor,

01:25:50.380 | not antagonism or blocking of the NMDA receptor,

01:25:53.660 | leads to changes in neural circuitry in very profound ways.

01:25:56.440 | In fact, experimentally,

01:25:57.900 | and I've done these experiments myself,

01:25:59.180 | if you want to prevent plasticity,

01:26:01.400 | you want to prevent an experience

01:26:03.660 | from reshaping neural circuitry,

01:26:05.180 | you give an NMDA receptor blocker.

01:26:08.020 | I've done that many times

01:26:09.200 | in the course of my experimental neuroscience career,

01:26:11.760 | not to myself, obviously,

01:26:12.880 | but in the course of doing experiments.

01:26:15.940 | So it's still a bit mysterious to me how this could work.

01:26:21.300 | A couple of things,

01:26:22.140 | one is this layer five activation is pretty interesting.

01:26:26.720 | We're going to come back to layer five

01:26:28.280 | when we talk about yet another emerging treatment

01:26:31.480 | for depression, which is psilocybin, so-called magic mushrooms

01:26:34.660 | and the effects of psilocybin

01:26:38.460 | on layer five neurons in the cortex.

01:26:41.000 | So there's a common theme emerging here,

01:26:42.600 | which is that layer five activity in the cortex

01:26:45.360 | may be important for rewiring the brain in certain ways

01:26:48.200 | that can lead to recovery or to an alleviation

01:26:53.200 | of some of the symptoms of major depression.

01:26:56.400 | So if this is sounding a little bit vague to you,

01:26:59.420 | it's because this is still truly experimental and new

01:27:03.380 | and still very much on the cutting edge

01:27:05.600 | of what's happening now, we don't have all the answers.

01:27:08.440 | So if it sounds like I'm moving slowly through this

01:27:10.520 | and I'm being extra careful about what I say,

01:27:12.780 | you are correct, your antennae are correct in this case.

01:27:17.780 | I never want to misstep and say something that's not true,

01:27:21.760 | but that's especially the case

01:27:23.960 | when we're talking about experimental therapies and drugs,

01:27:26.240 | which formerly were taken as drugs of abuse,

01:27:28.220 | which are now being used as drugs

01:27:29.920 | for therapeutic treatment in the clinic.

01:27:31.960 | There is a very interesting study.

01:27:35.840 | This was published in Science in 2019.

01:27:38.640 | So these are very recent studies.

01:27:41.120 | The last author on this is Liston, L-I-S-T-O-N.

01:27:44.440 | The title of the paper is "Sustained Rescue

01:27:47.040 | of Prefrontal Circuit Dysfunction

01:27:49.340 | by Antidepressant-Induced Spine Formation."

01:27:52.200 | And here, when we hear spine,

01:27:54.160 | we're not referring to spine as in your vertebrae

01:27:57.360 | running down your spinal column.

01:27:59.940 | We're talking about the spines,

01:28:01.100 | which are these little protrusions on neurons.

01:28:04.180 | Neurons are not smooth by any stretch.

01:28:07.380 | If you zoom in on a neuron,

01:28:09.380 | if you were to come to my lab

01:28:10.440 | and look down the microscope at a neuron and zoom in on it,

01:28:13.120 | you'd find that some neurons are smooth,

01:28:14.440 | but most neurons have these little protrusions,

01:28:16.340 | and those little protrusions are called spines.

01:28:18.420 | And those little spiny protrusions are little sites

01:28:22.000 | where neurons can reach out and form and receive

01:28:24.900 | new synapses from neighboring neurons.

01:28:27.760 | So they increase the surface area of a neuron

01:28:29.880 | and allow new connections to be formed.

01:28:31.980 | And so spine formation is synonymous with neuroplasticity,

01:28:36.340 | which is synonymous with changes in circuit function,

01:28:38.800 | which is synonymous with changes in the ways that we think,

01:28:42.520 | we feel, and we behave.

01:28:45.160 | And what was shown in this study is really interesting.

01:28:47.920 | What they showed is that ketamine

01:28:49.880 | can relieve depressive symptoms rapidly

01:28:53.400 | by changing or increasing, in this case,

01:28:56.920 | the spines on these neurons in the prefrontal cortex.

01:29:00.660 | And if that word prefrontal rings a bell,

01:29:02.740 | well, now you remember the phosphocreatine system,

01:29:05.680 | the ingestion of creatine monohydrate,

01:29:08.580 | and the forebrain, activation of the forebrain,

01:29:12.340 | were related to, in some way or another,

01:29:15.180 | to relief or improvement of major depressive symptoms.

01:29:19.380 | So we're starting to converge on a picture here

01:29:21.820 | whereby these drugs, ketamine, PCP,

01:29:25.400 | used in a therapeutic context,

01:29:27.360 | may be increasing neuroplasticity,

01:29:30.540 | literally the changing of neural circuits in the forebrain,

01:29:33.640 | somehow through dissociative states.

01:29:36.540 | And I don't want to speculate too much

01:29:38.640 | about how that might come about,

01:29:40.600 | but one of the things that's such a resounding

01:29:44.720 | or repeating theme of major depression

01:29:47.600 | is that when you talk to somebody who has major depression,

01:29:50.060 | it is a real downer,

01:29:52.000 | and I'm not being disparaging of those people,

01:29:54.200 | but if you've ever had a conversation

01:29:55.380 | with someone who's depressed,

01:29:56.960 | they're always talking about how exhausted they are,

01:29:59.180 | or in really severe cases,

01:30:01.140 | they are not even responsive at all.

01:30:02.820 | They just kind of stare at you blankly or they fall asleep.

01:30:06.480 | I mean, they're truly depressed.

01:30:08.160 | Their system is lowered in terms of its activation state.

01:30:12.120 | So I think that it's interesting

01:30:14.900 | that the application of drugs

01:30:18.020 | that allow people to separate from that state

01:30:20.660 | of not caring or being uninterested

01:30:22.820 | or unwilling to do anything

01:30:24.700 | is actually one of the paths to treatment.

01:30:26.680 | It's not always about just getting people peppy

01:30:29.260 | and excited and happy.

01:30:31.440 | There also seems to be a requirement

01:30:32.900 | for getting them distanced from their own grief.

01:30:36.320 | And this brings us back to something that we talked about

01:30:38.680 | way back at the beginning of this episode,

01:30:40.840 | which was this particular feature

01:30:43.920 | of the anti-self confabulation,

01:30:46.760 | that everything that happens is a reflection

01:30:49.300 | that I should say for the depressed person,

01:30:50.940 | that everything that happens is a reflection

01:30:52.740 | of how life is bad and their experiences

01:30:54.940 | just point to the fact that nothing is going to get better.

01:30:58.100 | This is the common language of depression.

01:31:00.060 | If this is very depressing to hear me talk about,

01:31:02.660 | it is heavy.

01:31:04.020 | And that's what it's like to hear these things.

01:31:06.340 | It's even heavier, of course,

01:31:07.420 | for somebody to experience them.

01:31:09.460 | And those beliefs, those patterns of guilt and grief

01:31:14.780 | and anhedonia and delusional anti-self confabulations,

01:31:18.840 | those are the things that eventually,

01:31:20.500 | if they get severe enough,

01:31:22.120 | start to convert into things like self-harm, mutilation,

01:31:26.180 | and in the most tragic of cases, of course, suicide.

01:31:29.640 | And so I think we can look to these treatments

01:31:33.400 | such as ketamine and PCP,

01:31:35.660 | but in particular ketamine and its use in the clinic

01:31:38.640 | as ways for people to get distanced

01:31:41.080 | from the negative affect that they feel

01:31:43.700 | isn't just inside them or overwhelms them,

01:31:46.600 | but that for the very severely depressed person,

01:31:49.300 | they feel is them.

01:31:51.420 | And we hear this sometimes, you are not your emotions.

01:31:54.020 | That's a statement that I've always been

01:31:55.340 | a little bit challenged by.

01:31:56.180 | I mean, yes, indeed, emotions are not who we are.

01:32:01.140 | They are states that we go into and out of,

01:32:03.100 | including happiness and sadness,

01:32:04.940 | but they are very much a part of us when we experience them.

01:32:08.940 | We don't experience them as next to us or behind us

01:32:11.200 | or across the room from us.

01:32:12.840 | We experience them as our emotions.

01:32:14.900 | They are so much part and parcel

01:32:17.680 | with our experience of ourself

01:32:19.760 | that a statement like we aren't our emotions

01:32:22.300 | is a very hard statement to digest,

01:32:24.120 | especially for the depressed person.

01:32:26.020 | And so I think that the NMDA receptor

01:32:28.940 | and its capacity to induce neuroplasticity circuit changes,

01:32:32.500 | the fact that PCP and ketamine

01:32:33.880 | are both showing activation of neural circuits

01:32:37.420 | by way of suppressing activity of the NMDA receptor

01:32:40.140 | and some of the positive or exciting therapeutic outcomes

01:32:43.440 | that are coming from this

01:32:44.640 | really point to the fact that ketamine and PCP

01:32:47.640 | and removal of negative experiences

01:32:51.200 | or the experience of a negative experience,

01:32:53.680 | it's sort of getting meta there,

01:32:55.080 | but the experience of a negative experience

01:32:56.900 | may be an important path

01:32:58.380 | by which people treat their depression,

01:33:00.720 | especially in its most severe forms

01:33:02.600 | where people are veering towards

01:33:04.560 | self-harm, mutilation, and suicide.

01:33:07.480 | So you may have noticed a theme,

01:33:08.880 | which is that certain categories of approaches

01:33:11.080 | that we've been discussing

01:33:12.040 | for offsetting the symptoms of depression,

01:33:14.680 | such as exercise, ingesting EPAs, reducing inflammation,

01:33:19.680 | or even the SSRIs for increasing serotonin,

01:33:22.700 | focus on changing some core biological function,

01:33:27.440 | like raising the amount of a chemical, serotonin,

01:33:29.700 | or reducing the amount of inflammatory cytokines

01:33:33.360 | in the brain and body.

01:33:35.740 | And yet things like ketamine focus more

01:33:38.920 | on rewiring circuitry, changing neural circuitry

01:33:42.060 | so that it functions better in the immediate

01:33:44.760 | and hopefully in the long-term as well,

01:33:46.380 | and keep people with major depression

01:33:48.040 | in what they call remission, away from major depression.

01:33:52.100 | Another category of treatments

01:33:53.780 | that's being actively explored now in laboratories

01:33:57.040 | and in the psychiatry realm are the psychedelics.

01:34:00.780 | And that's a huge category of compounds.

01:34:04.820 | However, one in particular, psilocybin,

01:34:07.400 | is one that's being most intensely and actively pursued

01:34:11.180 | for its capacity to treat major depressive disorder.

01:34:14.240 | I want to be very clear that the work

01:34:16.280 | that I'm going to describe is work that's being done

01:34:18.860 | in university settings, university hospitals,

01:34:21.840 | by scientists and psychiatrists.

01:34:25.820 | And these are clinical studies, clinical trials,

01:34:28.240 | leading to peer-reviewed data.

01:34:30.360 | And those are the data that we'll be discussing.

01:34:33.200 | Some of the major luminaries in this area include,

01:34:36.480 | of course, aren't limited to,

01:34:37.360 | but include people like Matthew Johnson,

01:34:38.940 | who's at Johns Hopkins.

01:34:40.320 | We'll discuss some of his work now.

01:34:41.660 | And fortunate to say that he will be coming on the podcast

01:34:44.460 | as a guest to describe the studies

01:34:47.120 | in a variety of laboratories,

01:34:49.320 | working on a variety of different psychedelic compounds.

01:34:52.700 | But let's focus on psilocybin for its capacity

01:34:55.660 | to rewire neural circuits and alleviate depression.

01:35:00.200 | There have been anecdotal data or evidence over the years

01:35:04.500 | that psilocybin has this capacity.

01:35:06.600 | How does psilocybin work?

01:35:07.680 | Well, psilocybin magic mushrooms, as it's sometimes called,

01:35:11.580 | mainly works on what's called the serotonin 5-H2-A receptor

01:35:16.580 | with some affinity for the 5-HT1 receptor.

01:35:19.980 | What does that mean?

01:35:20.820 | Well, basically you've got a lot of different kinds

01:35:22.840 | of serotonin receptors,

01:35:24.000 | just as you have a lot of different kinds

01:35:25.400 | of dopamine receptors or other types of receptors.

01:35:28.200 | The advantage of having different receptors

01:35:30.280 | expressed in different parts of the brain and body,

01:35:33.000 | even on different parts of individual cells

01:35:35.540 | in the brain and body,

01:35:36.760 | is that the same compound serotonin

01:35:38.640 | can have a diverse set of effects

01:35:40.920 | on different cells and tissues.

01:35:42.540 | This is also the basis of some of the side effect profiles

01:35:45.680 | of SSRIs, because maybe, for instance,

01:35:50.040 | we know that taking Prozac fluoxetine

01:35:52.480 | will increase serotonin in one area,

01:35:54.040 | but also in another area,

01:35:55.280 | and then they will go have diverse effects

01:35:57.500 | on different brain circuits

01:35:58.780 | because of the variety of receptors.

01:36:00.860 | Receptors are just like parking slots

01:36:02.840 | where the molecule serotonin parks

01:36:05.000 | and has different effects.

01:36:06.500 | Well, psilocybin engages or increases serotonin transmission,

01:36:11.500 | meaning it increases the amount of serotonin,

01:36:15.400 | mainly by acting at these 5-H2-A receptors,

01:36:18.980 | but where in the brain does it happen

01:36:21.200 | and what are the major effects?

01:36:22.400 | First, let's talk about the major effects,

01:36:23.840 | 'cause I think that's what people are interested in.

01:36:26.100 | The study that I'd like to highlight

01:36:27.600 | is a fairly recent one.

01:36:28.940 | It was published in May of 2021 in Journal of the American

01:36:34.920 | Medical Association Psychiatry, so JAMA Psychiatry,

01:36:39.440 | and it's entitled "Effects of Psilocybin-Assisted Therapy

01:36:42.360 | "on Major Depressive Disorder, a Randomized Clinical Trial."

01:36:45.800 | It's an absolutely beautiful study, a very important study.

01:36:49.040 | It includes some of the luminaries in this area,

01:36:51.120 | like Matthew Johnson, Patrick Finnan, Roland Griffiths,

01:36:54.440 | and others, we will provide a link to this study.

01:36:57.140 | It is available in its full form at zero cost

01:37:02.080 | if you want to read it.

01:37:02.920 | It's got a lot of details,

01:37:03.840 | so I'm just going to summarize a few things,

01:37:05.360 | but basically what they did was they screened for patients

01:37:09.460 | to come into the clinic.

01:37:10.380 | These were people that suffered

01:37:11.420 | from major depressive disorder

01:37:13.820 | and administered either one or two rounds of psilocybin.

01:37:18.820 | They used particular dosages.

01:37:21.620 | They're listed in the study, so you can look it up

01:37:23.260 | if you're really interested in that level of detail.

01:37:25.680 | Typically, it was 20 milligrams per kilogram of body weight,

01:37:29.260 | so it depends on body weight,

01:37:30.780 | or 30 milligrams of psilocybin

01:37:33.380 | per 70 kilograms of body weight.

01:37:36.940 | They were given in capsule form,

01:37:38.120 | so people weren't eating the mushrooms.

01:37:39.600 | This is obviously a very controlled study,

01:37:42.400 | and they want to control the dosages appropriately.

01:37:46.180 | They were randomized to begin the treatment immediately

01:37:48.600 | or after an eight-week delay.

01:37:50.760 | They had all the appropriate control groups

01:37:52.440 | that one would like to see.

01:37:53.980 | What's really striking about this study

01:37:56.380 | is that there was a very significant improvement

01:38:00.720 | in mood and affect and relief from depressive symptoms

01:38:04.340 | in anywhere from 50 to 70% of the people

01:38:09.160 | that were subjects in the study

01:38:11.100 | who received the psilocybin treatment,

01:38:16.100 | and whether or not it was 50 or whether or not it was 71%

01:38:19.840 | varied according to how long after the study

01:38:23.060 | they maintained these antidepressant effects,

01:38:25.380 | whether or not they stayed in remission from the depression,

01:38:27.660 | but these are really enormous and significant effects,

01:38:31.140 | very exciting, and are pointing in the direction

01:38:35.620 | of psilocybin very soon becoming a treatment

01:38:39.620 | for various forms of depression,

01:38:41.720 | including major depression.

01:38:43.800 | Now, of course, this is limited to the laboratory at present.

01:38:48.160 | There are a number of elements of these studies

01:38:50.140 | that are important to take into consideration, too,

01:38:51.980 | which is that there are highly trained guides,

01:38:55.340 | meaning people to direct people through the experience.

01:38:58.620 | As Matthew Johnson has told me,

01:39:00.660 | there is the occurrence from time to time

01:39:03.600 | of people having so-called bad trips,

01:39:05.360 | of having anxiety attacks during the hallucinations

01:39:07.940 | and all that, and they have ways to mitigate that

01:39:10.260 | and deal with that because the guides are trained.

01:39:12.780 | They have all the sorts of medical monitoring devices

01:39:16.680 | for heart rate and temperature and things

01:39:18.260 | that one would like to see for a study like this,

01:39:21.960 | because these are very powerful compounds.

01:39:24.300 | I don't want to give away any elements of the discussion

01:39:26.800 | with Matthew Johnson because it will be released

01:39:29.460 | in podcast form reasonably soon here,

01:39:32.260 | the Huberman Lab podcast,

01:39:33.740 | but one of the things that came up

01:39:35.540 | and is a fundamental question that I had

01:39:37.140 | that I think probably many of you are asking is,

01:39:39.760 | does the experience that one has on these compounds

01:39:43.780 | make a difference for whether or not somebody gains relief

01:39:46.480 | from depression from these psilocybin journeys or not?

01:39:50.780 | In other words, does it matter what they talk about?

01:39:52.780 | Does it matter what they think about?

01:39:53.900 | Does it matter if they have a good trip or a bad trip?

01:39:55.980 | And I don't want to hold you in too much suspense.

01:39:58.700 | I'll let Matthew provide the more thorough answer,

01:40:00.960 | but what's really interesting is there are some common themes

01:40:05.300 | to psilocybin administration and experience

01:40:09.140 | that lead to relief from depressive symptoms,

01:40:11.420 | but they are subjectively, excuse me,

01:40:14.740 | subjectively very varied, meaning that whether or not

01:40:19.740 | people feel they had a good experience or a bad experience,

01:40:22.520 | whether or not people thought about their parents

01:40:24.620 | or thought about the color of the ceiling

01:40:27.420 | doesn't seem to have too much of an impact

01:40:30.140 | on whether or not they receive relief during these studies,

01:40:34.780 | in these clinical studies.

01:40:36.280 | It seems like different people

01:40:38.580 | can have lots of different experiences

01:40:40.160 | and still receive benefit.

01:40:42.780 | And that points to something deeper.

01:40:45.420 | It points to the fact that these drugs,

01:40:48.180 | which is really what they are,

01:40:49.800 | are rewiring neural circuitry in a common way

01:40:53.780 | despite a diversity of experience while on the drug.

01:40:56.980 | And that itself is really interesting.

01:40:58.700 | And it takes us back to a place that we've been before

01:41:01.100 | in this discussion, which is layer five of the cortex,

01:41:04.060 | this area that ketamine seems to impact as well

01:41:06.520 | by generating rhythms of the,

01:41:08.180 | I mentioned one to three Hertz activity in layer five

01:41:10.960 | of certain areas of the cortex.

01:41:13.240 | Well, the 5-HT1A receptor is known to be enriched

01:41:17.480 | in layer five of the cortex.

01:41:19.800 | And layer five of the cortex is a very interesting area

01:41:23.540 | because it's an area in which

01:41:25.100 | there's a lot of lateral connectivity.

01:41:27.300 | So connections between different brain areas laterally

01:41:30.640 | generally is what allows us to merge different senses.

01:41:34.560 | So for instance, when we hear a sound off to our right,

01:41:37.020 | over here, we turned our right,

01:41:39.200 | there's a very hardwired response.

01:41:41.000 | And typically we hear something off to our right,

01:41:42.680 | we don't look to our left.

01:41:44.140 | That's how hardwired some of these circuits are.

01:41:46.700 | What appears to be happening is that the activation

01:41:49.340 | of the serotonin system in 5-HT1A receptor in layer five

01:41:53.580 | is offering up or providing an experience

01:41:57.440 | whereby the lateral connections are able to engage

01:42:01.260 | much more broadly than they would normally.

01:42:03.820 | Now that also could be a bad thing.

01:42:07.100 | When I asked Matt about this, that sounds kind of spooky.

01:42:10.480 | I don't know that when I hear something off to my right

01:42:12.620 | that I want to look off to my left,

01:42:13.820 | that could be highly maladaptive,

01:42:15.440 | especially if it's a car coming at me from my right.

01:42:18.460 | That doesn't seem to be what's happening.

01:42:19.980 | It's not really rewiring these deeply reflexive circuits.

01:42:24.040 | It's somehow rewiring associations between events,

01:42:27.680 | emotional events, past events, current events,

01:42:30.240 | and future events in ways that allow people

01:42:33.100 | to get some sort of relief or distance

01:42:35.720 | from these narratives, these depressive stories

01:42:39.140 | about their past and present,

01:42:40.780 | and allow them to see new opportunity

01:42:42.900 | and optimism in the future.

01:42:44.460 | That's really a fascinating thing

01:42:46.980 | if you really think about it,

01:42:48.380 | because I would have thought that simply

01:42:51.220 | by ramping up laterality of connections,

01:42:53.880 | meaning the cross associations,

01:42:56.060 | that things could either be rewired randomly

01:42:59.660 | in ways that don't serve us

01:43:01.260 | or would perhaps just cause no effect at all.

01:43:04.860 | So it's either going to be bad or neutral,

01:43:06.480 | but that's not really the way things are turning out.

01:43:08.680 | Again, these are highly controlled studies.

01:43:10.600 | I do want to emphasize that ketamine, psilocybin,

01:43:13.140 | these things are still illegal, most all places.

01:43:16.460 | There are some regions and cities in the United States

01:43:19.160 | where they are locally decriminalized,

01:43:21.420 | but they are not legal.

01:43:22.560 | They're still illegal.

01:43:23.540 | So what we're referring to here are indeed clinical studies

01:43:26.500 | in which people are taking them legally.

01:43:29.780 | I think it's very likely we will see a shift

01:43:32.880 | in the legislature around psychedelics

01:43:35.380 | and in particular psilocybin in the not too distant future.

01:43:39.700 | And I think that for now,

01:43:41.420 | what we should know is what Matt told me

01:43:44.820 | and what you'll hear far more about,

01:43:47.080 | which is that psilocybin, this one,

01:43:51.420 | or in most cases, two dose treatments done

01:43:54.380 | in a highly clinical setting, controlled setting

01:43:57.580 | with patients that are carefully selected,

01:44:00.320 | can in many cases, the majority of people receive

01:44:03.620 | and maintain relief from their depressive symptoms

01:44:07.100 | simply through the experience of this psychedelic journey.

01:44:11.500 | I did ask him about microdosing.

01:44:13.580 | I made it sound as if I had never heard about it before.

01:44:16.760 | Microdosing, not microdosing, microdosing.

01:44:19.780 | And his answer was interesting.

01:44:22.660 | His answer was that the microdosing effects

01:44:25.500 | don't seem to be nearly as impactful as some of these,

01:44:29.820 | let's just call them what they are,

01:44:31.320 | these kind of high amplitude sessions

01:44:34.500 | that there are just one or two.

01:44:37.820 | There are some studies ongoing where there's more than two,

01:44:40.720 | but that the microdosing doesn't seem to compare

01:44:43.120 | to these macrodosing, I mentioned the dosages before,

01:44:47.600 | this 20 milligrams per 70 kilograms

01:44:49.640 | or 30 milligrams per 70 kilograms,

01:44:51.760 | dosages given several weeks apart.

01:44:55.960 | So you'll hear more about microdosing

01:44:58.220 | and other psychedelics and their impact

01:45:00.440 | on depressive states and major depression

01:45:04.200 | in the episode with Matt.

01:45:05.640 | But for the time being, it really seems as if,

01:45:07.880 | again, we're looking at neuroplasticity,

01:45:09.560 | we're coming back to layer five,

01:45:11.040 | just like with ketamine and PCP,

01:45:13.060 | we're hearing about layer five,

01:45:14.320 | we're hearing about rewiring of circuitry,

01:45:15.940 | we're hearing about a dissociation

01:45:17.800 | or a distancing of oneself from these negative moods

01:45:22.680 | and affects and narratives.

01:45:24.000 | But there's a key distinction between the ketamine work

01:45:28.860 | and the psilocybin work, which is that in the ketamine work,

01:45:31.500 | it really is about dissociating from experience

01:45:34.580 | during the session with the psychiatrist.

01:45:36.820 | Whereas during the psilocybin journey,

01:45:38.760 | it's really about immersing oneself in the experience

01:45:41.740 | and being fully present to that experience.

01:45:43.860 | That does seem to be an important component.

01:45:45.700 | And what the difference is there

01:45:47.460 | and why they both seem to provide some relief

01:45:50.580 | from major depression isn't clear.

01:45:53.460 | I think most likely it takes us back to the fact

01:45:56.400 | that this thing we call major depression

01:45:59.260 | clearly involves serotonin, dopamine, and norepinephrine.

01:46:03.520 | And in some individuals,

01:46:04.520 | they may be more deficient in one or several of those

01:46:07.900 | or all of those, whereas in other individuals,

01:46:09.740 | it might be a different collection of chemicals.

01:46:12.200 | And of course, there are a tremendous number

01:46:14.380 | of other psychedelic compounds that people are exploring

01:46:18.580 | for treatment of major depression,

01:46:21.240 | but really psilocybin is the one

01:46:22.600 | that we have the most data on.

01:46:24.540 | MDMA has mainly been explored in the clinical realm

01:46:29.060 | for treatment of trauma.

01:46:30.260 | There are some trials ongoing for treatment of depression,

01:46:34.420 | but the big breakthroughs seem to be happening

01:46:38.140 | in the realm of trauma treatment,

01:46:40.380 | the so-called MAPS group that's doing this,

01:46:42.500 | again, legally in a clinical setting.

01:46:44.820 | And there are other groups

01:46:45.860 | that are starting to do it as well.

01:46:47.260 | We are going to do an entire podcast episode about MDMA

01:46:50.740 | and some related compounds.

01:46:52.180 | So I'll save that discussion for then.

01:46:54.560 | One of the most common questions I get for this podcast

01:46:57.320 | is about different diets, different regimes,

01:47:00.720 | different nutritional plans, things like keto,

01:47:03.460 | ketogenic diet, or vegan diets, or intermittent fasting,

01:47:07.980 | or the all meat diet, the so-called lion diet, et cetera.

01:47:11.760 | There are actually really interesting data

01:47:14.360 | relating nutrition and diet to major depressive disorder.

01:47:18.720 | And I think we just need to frame this

01:47:21.660 | by returning to something that was said earlier,

01:47:23.560 | which is that the ingestion of carbohydrates,

01:47:26.700 | in particular carbohydrates and some meats like turkey

01:47:29.660 | that are rich in tryptophan, this precursor to serotonin,

01:47:34.660 | are in many ways the self-medicating version

01:47:39.660 | of depression treatment.

01:47:41.700 | Now, to be clear, I'm not saying that people should use food

01:47:44.300 | to medicate their depression.

01:47:46.100 | Many people do that reflexively, however,

01:47:48.300 | they reach for carbohydrate-rich foods

01:47:50.240 | to blunt their cortisol, because that's indeed what it does.

01:47:53.420 | It blunts cortisol when you ingest high carbohydrate foods,

01:47:56.080 | in particular starchy foods.

01:47:57.720 | And it does increase serotonin, in particular,

01:48:01.760 | if those foods rather are rich in the amino acid tryptophan.

01:48:06.760 | Now, ingesting food is wonderful and important and great,

01:48:10.320 | but ingesting excessive foods of any kinds,

01:48:12.380 | carbohydrate or otherwise is not healthy, of course.

01:48:16.420 | There have been some explorations

01:48:19.200 | of whether or not a vegan diet

01:48:20.660 | can improve symptoms of depression.

01:48:23.100 | Not a lot of data, not impressive data.

01:48:25.460 | There have been very few controlled studies

01:48:27.700 | looking at the carnivore all-meat diet.

01:48:31.100 | On that, I think there are now some

01:48:32.700 | that are starting to spin up,

01:48:34.020 | meaning the studies are starting to spin up.

01:48:35.540 | However, the ketogenic diet has been explored

01:48:39.140 | for its ability to relieve certain symptoms of depression,

01:48:44.140 | in particular to what's called maintained euthymia,

01:48:49.140 | Euthymia is the kind of state of equilibrium

01:48:51.820 | between a manic episode and a depressive episode

01:48:55.020 | in a manic bipolar person.

01:48:56.340 | We'll return to this more in a future episode.

01:48:58.200 | But basically, manics have highs and they have lows.

01:49:01.680 | Bipolars either cycle back and forth really quickly,

01:49:04.320 | so rapid cycling, bipolars or slope, some people.

01:49:07.360 | So really quickly can be day-to-day.

01:49:09.200 | Other people, it's month-to-month or week-to-week,

01:49:11.100 | they're going highs and lows.

01:49:13.460 | And you hear about mania and you hear about dysphoria.

01:49:16.040 | Euthymia is that kind of place in the middle

01:49:19.160 | where people feel neither too high nor too low.

01:49:22.840 | And there are some interesting studies

01:49:25.180 | looking at the ketogenic diet

01:49:26.840 | for maintaining euthymia in manic depressives,

01:49:29.720 | but also in people with major depressive disorder.

01:49:32.520 | Why would this work?

01:49:33.600 | Well, we have to remember that the ketogenic diet

01:49:36.600 | wasn't discovered so that self-appointed nutrition gurus

01:49:41.420 | could talk about it online

01:49:43.160 | or so that people could make money selling anything

01:49:46.440 | related to ketosis.

01:49:48.000 | And here I'm not disparaging of the ketogenic diets,

01:49:50.000 | helped a lot of people.

01:49:51.320 | The ketogenic diet was actually shown to be medically

01:49:55.180 | relevant for its use to treat epilepsy.

01:49:58.860 | It turns out that in epilepsy

01:50:02.800 | or in particular pediatric epilepsy,

01:50:05.280 | that a ketogenic diet and the shift of brain metabolism

01:50:09.580 | to predominantly one in which ketones are being metabolized

01:50:12.840 | rather than more standard glucose type metabolism

01:50:17.680 | can greatly reduce the number of epileptic seizures

01:50:20.780 | that these children experience.

01:50:22.720 | It's not always the case, but it's often the case.

01:50:24.560 | And so you talk to a neurologist or a neurosurgeon

01:50:27.320 | who's specialized in epilepsy

01:50:31.320 | and particular pediatric epilepsy,

01:50:32.880 | and they'll tell you this,

01:50:34.140 | oh yeah, the ketogenic diet in many cases,

01:50:36.480 | not all can be very effective for this treatment.

01:50:38.740 | How, how is it that a ketogenic diet reduces seizures?

01:50:43.600 | Well, the way it reduces seizures

01:50:46.380 | is by increasing what's called GABA transmission.

01:50:49.940 | GABA is a substance that is naturally released in our brain.

01:50:54.260 | It's an inhibitory neurotransmitter,

01:50:56.380 | meaning that when it's released into the synapse,

01:50:58.980 | it has the tendency to reduce the firing,

01:51:01.700 | to reduce the electrical activity of the next neuron

01:51:04.700 | or sets of neurons.

01:51:06.940 | There are various compounds that increase GABA,

01:51:09.500 | in particular, GABA in the forebrain.

01:51:10.900 | One common example would be something like alcohol.

01:51:14.540 | Drinking alcoholic drink or two

01:51:16.900 | will increase GABA transmission will ironically,

01:51:20.380 | will lower your social inhibitions

01:51:22.980 | by increasing your neurochemical inhibition.

01:51:25.980 | It basically suppresses the self-monitoring pathways.

01:51:30.020 | And if people drink enough, it will suppress all pathways

01:51:32.440 | and people will urinate themselves and fall over.

01:51:34.840 | It will eventually inhibit all sorts of pathways.

01:51:37.480 | So the GABA system has a rich array of effects

01:51:41.240 | all over the brain and body,

01:51:42.920 | but alcohol tends to activate the release of GABA.

01:51:47.160 | You might say, well, then why not just take alcohol

01:51:49.520 | to suppress seizures?

01:51:50.360 | Well, that would be a terrible idea

01:51:51.500 | because there tends to be a rebound excitability

01:51:54.040 | after alcohol stops having its effects

01:51:57.680 | on the GABA receptors.

01:51:58.880 | And so then there's an excitability

01:52:00.680 | for which an epilepsy would be terrible.

01:52:03.120 | The reason why the epileptic diet is useful for epilepsy

01:52:07.120 | is that increases the, what we call the tonic level,

01:52:09.720 | the sort of the tide, the level of GABA in the brain.

01:52:13.840 | And that suppresses some of the hyperexcitability

01:52:16.580 | that is the characteristic feature of epilepsy.

01:52:20.160 | And there are other drugs, for instance,

01:52:21.880 | the benzodiazepines and things of the Xanax variety,

01:52:26.600 | Valium and so forth, those increase GABA transmission.

01:52:30.080 | Those drugs also have a lot of potential

01:52:32.100 | for abuse and addiction, et cetera.

01:52:34.000 | And they're problematic for other reasons.

01:52:35.960 | But the ketogenic diet,

01:52:38.620 | by way of increasing ketone metabolism

01:52:40.900 | or shifting brain's metabolism over to ketones,

01:52:44.560 | tends to modulate GABA such that GABA is more active

01:52:49.560 | and adjust the so-called GABA glutamate balance.

01:52:54.000 | This is getting technical,

01:52:55.000 | but glutamate is an excitatory neurotransmitter,

01:52:58.060 | GABA is inhibitory neurotransmitter,

01:52:59.760 | and their balance is vital for neuroplasticity,

01:53:02.480 | for maintaining healthy levels of activity

01:53:04.640 | in the brain, et cetera.

01:53:06.800 | And so there is decent evidence

01:53:10.120 | that people with major depressive disorders,

01:53:13.340 | in particular, the people with major depressive disorders

01:53:17.160 | that are refractory, meaning they don't respond

01:53:20.760 | to classical antidepressants, can benefit, it seems,

01:53:25.600 | from the ketogenic diet.

01:53:28.820 | Now, this is not always the case,

01:53:30.240 | but for those of you out there

01:53:31.600 | who are struggling with major depression

01:53:33.840 | and for which drugs have not worked,

01:53:35.080 | please talk to your psychiatrist.

01:53:36.380 | I don't know how many of them are up on the literature

01:53:38.360 | about the ketogenic diet or the EPAs and the rest.

01:53:42.840 | Psychiatrists vary in terms of how involved

01:53:45.480 | in the current literature they tend to be,

01:53:47.420 | but there are many excellent psychiatrists out there.

01:53:49.880 | Most of them, in my experience,

01:53:51.320 | are actually quite avid learners about what's happening

01:53:55.840 | and what's new in this realm that they call psychiatry.

01:53:59.260 | So it's really interesting that eating in a particular way,

01:54:02.980 | lowering carbohydrates to the point where you rely

01:54:06.520 | on ketogenic metabolism in the brain increases GABA

01:54:10.480 | and can provide some relief for depressive symptoms.

01:54:13.780 | And that in particular, that seems to have positive effects

01:54:16.860 | in people that are refractory

01:54:18.100 | or don't respond to classic antidepressants.

01:54:21.040 | And that would include things like fluoxetine, et cetera.

01:54:24.060 | I'll make one final point about ketogenic diets

01:54:26.700 | and GABA and depression,

01:54:27.920 | which is that it's also been shown that for people

01:54:31.720 | that respond well to these drugs

01:54:34.800 | that impact the serotonin system, dopamine system,

01:54:37.260 | or norepinephrine, the ketogenic diet there

01:54:40.460 | may improve the ability for those drugs

01:54:44.380 | to work at lower dosages,

01:54:45.580 | which is reminiscent of what we saw

01:54:47.040 | with the EPA supplementation.

01:54:49.120 | So today we've covered what at least feels to me

01:54:51.820 | like a tremendous amount of material.

01:54:53.820 | This topic of depression is indeed an enormous topic

01:54:56.540 | to try and get our arms around.

01:54:58.160 | We talked about the symptomology,

01:54:59.500 | we talked about some of the underlying neurochemistry

01:55:01.420 | and biology, and then we talked about approaches

01:55:04.120 | to deal with it that are really grounded

01:55:06.200 | in the neurochemistry and biology.

01:55:08.700 | I just want to recap a few of those tools

01:55:11.480 | and what those things are.

01:55:12.780 | First of all, we talked about making the effort

01:55:16.340 | to not overwhelm the pleasure system.

01:55:19.080 | That might seem counterintuitive,

01:55:20.620 | to not overly seek out pleasure

01:55:22.660 | or else one can find themselves in a place of depression.

01:55:26.500 | I mentioned way back at the beginning of the episode,

01:55:29.020 | a young man who I know to be really struggling

01:55:32.720 | with depression and it is thought,

01:55:36.020 | and we don't know for sure,

01:55:37.460 | but it is thought that some of that depression

01:55:39.220 | was probably triggered by an overindulgence in video games

01:55:42.620 | and other highly dopaminergic activities

01:55:45.380 | to the point where those activities

01:55:47.100 | eventually were countered by the pain balance

01:55:50.440 | that Dr. Analemke described.

01:55:52.680 | And he now has to do those activities repeatedly

01:55:57.140 | and for many, many hours each day just to feel okay,

01:56:00.040 | not even to derive pleasure from them.

01:56:02.400 | And worse, many other activities,

01:56:05.960 | practically all other activities have lost their zest,

01:56:09.520 | they've lost their excitement

01:56:10.700 | and his sense of pleasure for them.

01:56:13.040 | And so there's a really active campaign now

01:56:15.920 | to reset that system.

01:56:17.820 | So number one, don't overwhelm your pleasure centers

01:56:22.020 | either through activities or compounds.

01:56:24.060 | It might seem counterintuitive,

01:56:25.400 | but you're setting yourself up for anhedonia and depression

01:56:28.540 | if you do that.

01:56:29.380 | It's not just about addiction, that too,

01:56:31.000 | but it's also about setting yourself

01:56:32.280 | for anhedonia and depression.

01:56:35.160 | How often can you engage in these activities?

01:56:37.460 | Well, that's going to differ from person to person,

01:56:39.400 | everyone's slightly different,

01:56:40.880 | but you should really mind your extreme highs

01:56:43.480 | and your extreme lows and be cautious about those.

01:56:46.260 | We'll probably have Dr. Lemke on again in a future time

01:56:49.200 | to try and get some more specifics about that.

01:56:51.300 | But if you do feel like you need to reset that system,

01:56:54.640 | it really does seem like a 30-day complete detox

01:56:58.940 | from whatever activity or substance that is,

01:57:01.120 | and ideally it doesn't continue after that 30 days,

01:57:03.840 | especially in conditions of drugs of abuse.

01:57:06.880 | Second of all, talked about the norepinephrine system

01:57:10.080 | and how the norepinephrine system is really deficient

01:57:12.880 | in many forms of major depression and in depression.

01:57:17.740 | There is now more deliberate pursuit

01:57:20.540 | of norepinephrine-inducing activities that are healthy,

01:57:23.080 | that aren't adrenaline-seeking per se,

01:57:26.260 | things like cold showers,

01:57:27.500 | things like particular patterns of breathing

01:57:31.520 | that engage and tend to make us more alert,

01:57:35.260 | things like exercise that will increase

01:57:37.580 | our levels of noradrenaline.

01:57:39.140 | I'd be remiss if I said that these activities

01:57:42.040 | could completely eliminate depressive symptoms

01:57:45.340 | in people with major depressive disorder.

01:57:46.860 | I don't think that's the case.

01:57:47.860 | And again, I want to acknowledge

01:57:48.860 | that people with major depressive symptoms

01:57:50.900 | often don't have the energy, the willingness,

01:57:53.960 | or the capacity to engage in some of these activities,

01:57:57.120 | but things like cold showers, deliberate cold showers,

01:58:00.020 | things like regular exercise,

01:58:02.300 | they aren't just feel-good activities.

01:58:05.140 | They actually engage the norepinephrine system

01:58:07.460 | and keep that system tuned up

01:58:09.140 | and allow us to increase our norepinephrine levels at will

01:58:11.740 | on a regular basis.

01:58:13.020 | And their mood-enhancing effects are real effects

01:58:15.420 | that at the level of neurochemistry.

01:58:17.840 | Then we talked about EPAs, these essential fatty acids,

01:58:20.200 | and it's clear that for most people,

01:58:23.080 | getting above 1,000 milligrams

01:58:24.880 | and probably even closer to 2,000 milligrams per day of EPAs

01:58:28.280 | can be beneficial for mood,

01:58:29.500 | especially in attempts to treat

01:58:31.840 | or offset major depressive disorder.

01:58:34.640 | Are there side effects?

01:58:35.600 | Well, you need to explore those for yourself

01:58:37.820 | and with your doctor.

01:58:38.640 | Everyone has a different health background.

01:58:41.340 | You know, for the margins of safety for most people

01:58:43.860 | will probably be quite large,

01:58:45.880 | but for some people that might not be the case.

01:58:48.500 | So definitely check with your physician.

01:58:50.960 | We also talked about exercise

01:58:52.360 | and how EPA and exercise on a regular basis

01:58:54.820 | can offset these inflammatory pathways.

01:58:57.140 | I want to mention something I've mentioned

01:58:58.580 | on a previous podcast,

01:58:59.680 | but in terms of keeping the inflammatome,

01:59:02.100 | all these molecules that create inflammation

01:59:04.300 | and then the inflammation can limit the amount of serotonin

01:59:07.020 | through the pathways we described.

01:59:08.640 | In order to do that, it's also very, very useful

01:59:12.720 | to ingest two to four servings of fermented foods

01:59:16.040 | on a daily basis or near daily basis.

01:59:17.920 | These are data that were published by the Sonnenberg Lab

01:59:19.920 | at Stanford recently in the journal Cell,

01:59:22.040 | Cell Press Journal, excellent journal,

01:59:24.240 | that ingestion of these fermented foods

01:59:27.600 | really keeps the gut microbiome tuned up, so to speak,

01:59:31.360 | well in order to offset these inflammatory cytokines,

01:59:34.160 | keeping inflammation at bay.

01:59:35.780 | It just turns out to be a really good thing

01:59:38.040 | in order to keep our mood in a good place.

01:59:40.760 | So EPA, exercise, fermented foods,

01:59:42.640 | creatine as a potential source of relief from depression

01:59:45.860 | or offsetting or keeping us away from major depression

01:59:49.320 | or relapse into depression.

01:59:50.840 | And then we talked about the prescription compounds

01:59:53.600 | and the compounds that are being used

01:59:55.080 | mainly in the course of studies

01:59:56.540 | and of psychiatry and depression,

01:59:58.500 | things like ketamine, PCP, psilocybin and related compounds.

02:00:01.680 | And then lastly, we talked about ketosis,

02:00:03.480 | which may not be right for everybody,

02:00:04.940 | but might be right for certain individuals out there

02:00:08.060 | who are grappling with this.

02:00:09.460 | If you're learning from this podcast

02:00:11.940 | and hopefully enjoying it

02:00:12.900 | and applying some of the tools that we describe,

02:00:15.640 | please subscribe to the podcast on YouTube.

02:00:17.940 | That really helps us.

02:00:19.400 | As well, please leave us a comment and some feedback

02:00:22.140 | for future episodes and topics

02:00:23.840 | that you'd like to see us cover.

02:00:25.160 | You can do that on YouTube in the comment section.

02:00:28.340 | As well, please follow us on Instagram.

02:00:30.260 | It's Huberman Lab on Instagram there.

02:00:32.380 | I provide some recaps of some of this material.

02:00:34.700 | I also provide some original material

02:00:36.940 | that doesn't show up in the podcast.

02:00:38.820 | Please also subscribe on Apple and Spotify

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02:00:46.000 | as well as a comment and some feedback.

02:00:48.960 | Please also check out the sponsors

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02:00:52.660 | So that's a terrific way to support what we're doing.

02:00:55.340 | We also have a Patreon.

02:00:56.500 | It's patreon.com/andrewhuberman.

02:01:00.020 | And there you can support the podcast

02:01:01.840 | at any level that you like.

02:01:03.800 | Throughout the course of today's episode

02:01:05.420 | and in previous episodes, I mentioned supplements

02:01:08.260 | that may be appropriate for you.

02:01:10.540 | If you want to check out the supplements that I take,

02:01:12.860 | you can go to thorn.com/u/huberman.

02:01:17.360 | That's T-H-O-R-N-E.com/u/huberman.

02:01:22.360 | There, you can see the supplements I take.

02:01:25.220 | If you want to try any of those supplements,

02:01:27.220 | you can get 20% off any of those supplements.

02:01:29.160 | And if you navigate from that location in the website

02:01:32.000 | to any other locations in the Thorne site,

02:01:33.960 | you will also get 20% off any of the other supplements

02:01:36.640 | that Thorne makes.

02:01:37.820 | We partnered with Thorne

02:01:38.860 | because they have the absolutely highest levels

02:01:41.100 | of stringency in terms of the quality and quantity

02:01:43.940 | of the supplements that they put in their formulations.

02:01:47.380 | And last but not least,

02:01:48.540 | I want to thank you for embarking on this journey

02:01:50.940 | of trying to understand what is depression,

02:01:53.140 | how does it work, and how to treat it.

02:01:55.460 | And thank you for your interest in science.

02:01:57.460 | [upbeat music]

02:02:00.040 | (upbeat music)

Understanding & Conquering Depression | Huberman Lab Podcast #34

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