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Speaker 1: Emily. We're talking about cortisol today, which people say is

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Speaker 1: a stress hormone, and yeah, we'll get there. But I've

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Speaker 1: been thinking a lot about stress this week, and one

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Speaker 1: thing I wanted to tell you is that my fitness

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Speaker 1: tracking watch, which is a Samsung watch, periodically pings me

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Speaker 1: just to be like, hey, you're feeling very stressed right now,

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Speaker 1: and this.

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Speaker 2: Is that sounds so annoying.

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Speaker 1: Not helpful, Samsung. I have no idea why. Like, it'll

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Speaker 1: come up and I as a doctor, you know, I'll

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Speaker 1: take my pulse and be like, it's something weird happening,

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Speaker 1: and I think I feel fine, But then of course

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Speaker 1: it gets in your head it's like, what, well am

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Speaker 1: I stressed? And then I decide, well, I must be stressed,

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Speaker 1: and then I'm stressed. Does this happened to you?

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Speaker 3: No, because my fitness tracker, of which I have two,

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Speaker 3: give me different kinds of inputs. But I will say

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Speaker 3: at the end of the day, every day I get

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Speaker 3: a message that's like, today you spent blah blah blah

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Speaker 3: minutes in the high stress zone. And then it tells

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Speaker 3: me whether those are like part of my actual exercise

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Speaker 3: or other things sort of like today you spent two

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Speaker 3: hours and nine minutes in the high stress zone, the

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Speaker 3: majority of which came from activities outside of strain. And

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Speaker 3: then it's like, oh, well, what else was I what

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Speaker 3: else was I doing? And then it's usually like usually

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Speaker 3: this came from sleep, and then I'll be like.

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Speaker 2: Why did you drink alcohol?

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Speaker 3: That's like it's like, so it gets a little more judgmental,

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Speaker 3: but yeah, people don't like the judgment aspects of watches.

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Speaker 3: It's like, I, do you ever do you run with

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Speaker 3: a watch?

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Speaker 2: I do exercise. Do you notice that when you start.

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Speaker 3: Running it beeps a number like plus one, plus two,

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Speaker 3: negative one?

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Speaker 2: Does your watch do this?

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Speaker 1: My watch doesn't do that.

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Speaker 2: This is the worst thing.

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Speaker 3: You're like running along and you're like I feel pretty

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Speaker 3: good and then your watch beeps and it's like negative

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Speaker 3: six and that you suck it, your bad And so

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Speaker 3: I think they should dial down the amount of information

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Speaker 3: our watches are pushing at us.

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Speaker 1: I think telling someone, hey, you your stressed man is

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Speaker 1: more or less the equivalent of me telling my sixteen

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Speaker 1: year old daughter, like, you seem like you're in a

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Speaker 1: bad mood, Like it's just just it's not going to

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Speaker 1: go well.

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Speaker 3: One step up from like are you getting your period?

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Speaker 3: But like it still pretty bad?

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Speaker 1: Okay, having three older sisters, I know not to ask

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Speaker 1: that question. You'll learn that. You learn that maybe we

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Speaker 1: need a more objective readout of stress. Maybe that objective

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Speaker 1: readout is cortisol. Maybe not. Let's figure it out, find out.

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Speaker 3: I'm Emily Aster, I'm an economist and a data expert.

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Speaker 1: And I'm Perry Wilson, I'm a medical doctor.

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Speaker 3: It's Thursday, July ninth, twenty twenty six. And this is wellness.

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Speaker 1: Actually, because you're getting a staggering amount of health and

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Speaker 1: wellness information nowadays from every source imaginable, and some of

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Speaker 1: it is awesome and some.

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Speaker 3: Of it is well actually both Fortunately we are both

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Speaker 3: people who know how to read studies, how to parse

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Speaker 3: the data, and can tell you what's worth thinking about

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Speaker 3: and what you can safely ignore.

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Speaker 1: But before we dig in, a note that this podcast

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Speaker 1: is for educational purposes and should not be construed as

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Speaker 1: medical advice. We don't know your unique situation, so talk

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Speaker 1: to your doctor for personal health decisions.

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Speaker 2: This week we're asking what's the deal with cortisol?

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Speaker 3: Perry and I will give the official smasher pass and

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Speaker 3: then we'll get to your question of the week, but

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Speaker 3: first let's do the health news roundup after the break.

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Speaker 1: And we are back with the health news of the week, Emily.

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Speaker 1: The FDA is allowing Zin pouches to market their relative

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Speaker 1: health benefits compared to other tobacco products like cigarettes. What's

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Speaker 1: going on here? What's up with zin?

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Speaker 2: So Zin is a tobacco product.

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Speaker 3: It is a nicotine product particular, and people like it

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Speaker 3: a lot of people like it a lot. It's become

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Speaker 3: very popular with like tech bros. Because there's this sense

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Speaker 3: that nicotine increases your focus, and people like Andrew Huberman

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Speaker 3: are kind of into the health benefits of nicotine, but

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Speaker 3: they also understand this smoking is bad for you, and

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Speaker 3: so this is like a way to get your nicotine

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Speaker 3: without smoking. And Okay, so the FDA has now allowed

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Speaker 3: Zin to make help what I would describe as health statements.

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Speaker 3: So the claim things like using Zin instead of cigarettes

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Speaker 3: puts you at a lower risk of mouth cancer, heart disease,

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Speaker 3: lung cancer, stroke emphasem, and chronic broncholitis that statement is.

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Speaker 2: I would say broadly true.

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Speaker 3: So these products are definitely safer than cigarettes. I think

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Speaker 3: what many people are concerned about is that children will

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Speaker 3: see this and be like, hey, Zen's a health food

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Speaker 3: and like I can do and this is like not

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Speaker 3: bad for me at all. And on top of an

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Speaker 3: app atmosphere in which you can also get as we

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Speaker 3: talked about an earlier episode, like fruit flavored vapes, we're

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Speaker 3: kind of entering a place where somehow we've come up

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Speaker 3: with this idea that there's health benefit opportunities to things

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Speaker 3: that are not cigarettes but still have this nicotine. And

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Speaker 3: I think that's pretty dangerous in part because if you

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Speaker 3: get addicted to nicotine and then there's no zin around,

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Speaker 3: you got to move to something else, like cigarettes, which

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Speaker 3: are bad for you.

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Speaker 1: Yeah, or just zin, I mean this is or just zin.

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Speaker 2: Is bad for you. We don't really.

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Speaker 1: I mean this is true that smoking, like lighting something

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Speaker 1: on fire and inhaling the smoke that comes out of it,

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Speaker 1: is worse for your lungs than sucking on a nicotine pouch.

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Speaker 1: This is, Yes, you're at less risk of lung cancer,

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Speaker 1: but nicotine is a highly addictive substance. It binds to

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Speaker 1: a receptor in your brain called the NMDA receptor. It

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Speaker 1: makes you feel certain good things and like all physically

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Speaker 1: addictive substances. When it's taken away from you, you feel

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Speaker 1: much worse you did at baseline. The psychological impact of

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Speaker 1: that may be substantial. Certainly the economic impact is substantial

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Speaker 1: because these things cost money. And being addicted to something

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Speaker 1: that you need to take, even if it had like

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Speaker 1: absolutely no ill health effects, if it's just like, oh man,

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Speaker 1: I've got to buy this every day and keep sucking

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Speaker 1: on it, imposes a cost. So it's an interesting shift

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Speaker 1: at the FDA where they're kind of being accurate, but

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Speaker 1: I think from a public health standpoint, they're not doing

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Speaker 1: a great job telegraphing that, like this still isn't a

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Speaker 1: good idea.

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Speaker 3: Yeah, I also think we're we're actually in terms of

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Speaker 3: the health benefits or costs of nicotine. You know, there's

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Speaker 3: some research that nicotine kind of increases focus, but I

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Speaker 3: don't know that we have anything that would tell us

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Speaker 3: about the health potential health costs of consuming quite a

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Speaker 3: lot of nicotine, which is effectively what people are doing

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Speaker 3: when they're consuming many many zinn pouches in a day.

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Speaker 3: So we're getting kind of a dose that's even a

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Speaker 3: bit different probably than we've been tested and say mice. Yeah, Anyway,

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Speaker 3: all right, something else that's going on is an outbreak

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Speaker 3: of explosive diarrhea. Cyclospora outbreak is happening throughout the US,

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Speaker 3: especially in places in the Midwest.

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Speaker 2: Perry, what can you tell.

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Speaker 3: Us about the explosive diarrhea and where it's coming next

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Speaker 3: and why?

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Speaker 1: Uh okay. Cyclospora is a parasitic amiba that causes a

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Speaker 1: really bad gastro intestinal illness voluminous, watery, non bloody. For

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Speaker 1: what it's worth, diarrhea people are going dozens of times

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Speaker 1: per day, can lead to pretty severe dehydration, including the

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Speaker 1: need for ivy fluids, et cetera. Current numbers, there are

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Speaker 1: seven hundred reported cases. This is a one of the

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Speaker 1: reportable outbreak, So like if you get a positive test,

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Speaker 1: and if you run a clinical lab and a positive

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Speaker 1: test comes through, you're required to report it, so we

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Speaker 1: catch those, But there are likely people who are suffering

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Speaker 1: in silence at home and their gatorade and not getting

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Speaker 1: officially tested for this. It's predominantly in the Midwest. The

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Speaker 1: concern is that we actually don't know the source. So

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Speaker 1: it's clear that you know where a cyclist bora usually

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Speaker 1: lives is on produce and particularly like mint and parsley,

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Speaker 1: like the sort of garnishy produce, as well as berries,

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Speaker 1: which gets into my head because the berries are so

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Speaker 1: good right now, and I like am getting blueberries and

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Speaker 1: strawberries and raspberries and blackberries all the time at my

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Speaker 1: grocery store. But so far testing has not revealed a

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Speaker 1: particular source. It is certainly out there.

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Speaker 3: It's I should say, it's actually a hard thing to

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Speaker 3: test exact sources for because it takes The incubation period

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Speaker 3: is not immediate. So if there's something which makes you

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Speaker 3: sick in you know, three hours, it's actually quite easy

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Speaker 3: to say, Okay, you know a group of people got

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Speaker 3: sick within three hours, we know exactly what they ate

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Speaker 3: three hours ago. Okay it was spinach or whatever. Here

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Speaker 3: it takes a while. People don't remember what they eight.

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Speaker 3: They ate a lot of different things. It's been hard

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Speaker 3: to pinpoint.

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Speaker 2: Yeah.

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Speaker 1: One thing I was looking into about this because my

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Speaker 1: daughter gave me a hard time the other day because

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Speaker 1: I made her a hamburger and she said it was

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Speaker 1: undercooked and she's very afraid of gastrointestinal illnesses. And you sure,

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Speaker 1: but you know, yes, I guess you should cook your

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Speaker 1: meat adequately, but like, come on, a rare hamburger is

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Speaker 1: just the best thing in July. So I did dig

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Speaker 1: into this to see, like gastro intestinal illnesses in the

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Speaker 1: United States, what percent come from meat and poultry versus produce?

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Speaker 1: And actually forty six percent of the food born illnesses

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Speaker 1: come from produce and thirty one percent from meat and poultry,

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Speaker 1: which leaves I don't know whatever percent. I'm not sure

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Speaker 1: what else, but more often, more often from produce. Yeah,

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Speaker 1: could be things like that, but produce is the most

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Speaker 1: common source for food born illnesses in the US. You

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Speaker 1: should wash your produce, and guys, it's watermelon season, like

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Speaker 1: you should be washing the outside of your watermelon. I

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Speaker 1: know you think that you're cutting into it, but you

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Speaker 1: know you cut through the skin and it goes through.

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Speaker 1: That's my own that you can suffer.

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Speaker 2: Your safety perries here for ruining everything.

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Speaker 1: Washa, I'm not ruining it. Just wash it and then

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Speaker 1: it's delicious. All right. Let's talk about a new secret

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Speaker 1: shopper study of these GLP one websites. So, as you know,

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Speaker 1: there are multiple websites online that market GLP ones, and

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Speaker 1: a new study actually out of Yale. Although I wasn't

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Speaker 1: affiliated with it, set up a fake persona and called

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Speaker 1: forty nine of these websites and was able to get

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Speaker 1: a prescription from forty five of the forty nine, and

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Speaker 1: two of them issued a prescription in under five minutes. Emily,

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Speaker 1: problem or solution, I.

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Speaker 3: Would say problem. I mean, look, we've talked about this before.

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Speaker 3: I'm a smashed broadly on GLP ones as a treatment

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Speaker 3: for many things, and I think this is an incredible technology. However,

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Speaker 3: it is a medication, injectable, medication or now oral, but

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Speaker 3: like it's a medication that has significant effects on people

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Speaker 3: and should ideally be prescribed by a doctor who has

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Speaker 3: had some interaction with the patient. And I do worry

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Speaker 3: about people who are really don't need this or for

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Speaker 3: whom maybe it's even kind of damaging in the sense that,

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Speaker 3: you know, we have seen some concerning at least anecdotal

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Speaker 3: evidence about me people have suffered from meeting disorders in

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Speaker 3: the past, this kind of this environment reupping those and

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Speaker 3: I would worry about people in that category calling an

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Speaker 3: online pharmacy and saying, hey, I feel like I need

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Speaker 3: a JLP one similar to an article I saw come

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Speaker 3: across my Instagram feeds. Just a clip of someone saying

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Speaker 3: that the way that she got a JLP one was

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Speaker 3: by wearing twenty pound ankle weights to the doctor so

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Speaker 3: she could weigh the like required one hundred and sixtys

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Speaker 3: to get on a GLP one, even though she was

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Speaker 3: only one hundred and twenty pounds, which probably does not

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Speaker 3: necesssitate needing a JLP one.

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Speaker 2: So that feels bad to.

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Speaker 1: Me, Yeah, that should feel bad. Just over fifty percent

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Speaker 1: of the sites asked about eating disorders at all in

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Speaker 1: their intake surveys, so there is some potential missed opportunities there.

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Speaker 1: And I should say that almost all the sites are

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Speaker 1: selling compounded GLP ones. They do this by making custom preparations.

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Speaker 1: They take bulk amounts of like ozembic or munjaro, dissolve

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Speaker 1: them in their own water, and then you have to

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Speaker 1: add something to personalize it to the patients. They usually

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Speaker 1: add like some B twelve or something so that it's

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Speaker 1: not exactly the same as the branded pharmaceutical. So it's

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Speaker 1: in this very regulatory gray zone. You got to be careful.

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Speaker 1: I mean, you know. Again, there's a flip side of this,

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Speaker 1: and I actually wrote about this this week, which is like,

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Speaker 1: if it's this easy, then should there be prescriptions at all?

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Speaker 1: Like this middle road of oh yeah, there are prescriptions,

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Speaker 1: but everyone can fake it seem sort of dumb. So

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Speaker 1: you either close these loopholes and you actually have to

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Speaker 1: see a doctor and discuss it, or you don't and

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Speaker 1: you just let people buy the things and the libertarians win.

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Speaker 2: Right, Yeah, and I think we have either.

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Speaker 3: Yeah, we haven't made that choice with most other medications.

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Speaker 3: And I think most people would not make the argument

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Speaker 3: that we should be allowing people to you know, take

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Speaker 3: statins whenever or you know, just get on different But

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Speaker 3: maybe maybe people would argue that.

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Speaker 1: All right, that's in for the health news of the

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Speaker 1: week after the break. What's the deal with cortisol?

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Speaker 3: All right, Perry, I am delighted to talk about cortisol,

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Speaker 3: something I've heard a lot about.

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Speaker 2: As a woman in her let's say, mid to late forties.

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Speaker 3: I'm aware that raising my cortisol too high will lead

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Speaker 3: to the dreaded belly fat. And I'm sure we'll get

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Speaker 3: later to the many ways in which my bones are

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Speaker 3: attorney to dust due to my high cortisol. Belly fat combo.

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Speaker 3: Oh it's terrible. But before we get into this just

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Speaker 3: for people who are getting all their information about cortisol

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Speaker 3: from the same Instagram that I'm getting it from. Let's

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Speaker 3: start by defining what is cortisol and what are we

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Speaker 3: actually talking about here overall.

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Speaker 2: So you're a doctor, tell.

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Speaker 1: Me, yeah, oh man, cortisol gets such a bad rap

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Speaker 1: online and it's such a critical hormone, it's so important.

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Speaker 1: So cortisol is a steroid hormone. We've talked about these

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Speaker 1: several times before and wellness. Actually, steroid hormones are really

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Speaker 1: interesting because the site that they act on is in

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Speaker 1: the nucleus, is with the DNA of a cell. So

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Speaker 1: all the steroid hormones, including things like testosterone and estrogen,

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Speaker 1: get into the nucleus and change how DNA is transcribed,

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Speaker 1: so it can fundamentally change what cells are doing, which

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Speaker 1: means all these things can do a million different things.

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Speaker 1: It's not like you know this one protein is responsible

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Speaker 1: for or you know, increasing your sugar level or decreasing

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Speaker 1: your sugar level. It does a million things. And I

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Speaker 1: think the best way to sort of think about cortisol

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Speaker 1: is that it is there primarily to save your life

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Speaker 1: in the next ten minutes at the expense of the

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Speaker 1: next ten years. So cortisol is a hormone that's present

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Speaker 1: to keep you moving and alive after something really bad

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Speaker 1: has happened to you, like you got mauled by a

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Speaker 1: saber toothed tiger, or you are, you know, running from

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Speaker 1: something that is trying to eat.

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Speaker 3: You can I'm gonna pause you there because I think

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Speaker 3: for most people the thing they think is driving that

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Speaker 3: is adrenaline.

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Speaker 2: So when you tell me you were chasing by a tiger,

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Speaker 2: I think adrenaline. Yeah, they're not the same.

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Speaker 1: They're not the same. And cortisol is secreted by the

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Speaker 1: adrenal glands, which is where adrenaline comes from. Two and

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Speaker 1: they are by all means related and evolutionarily followed kind

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Speaker 1: of similar. But adrenaline is much more cardiovascularly active in

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Speaker 1: terms of like flogging your heart and whatnot, whereas cortisol

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Speaker 1: is more focused on sugar levels. So when you're being

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Speaker 1: chased by a tiger, you want there to be plenty

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Speaker 1: of sugar in your blood for your muscles to use

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Speaker 1: and for your brain to use. And you really don't

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Speaker 1: care about whether there's energy for your gut or your

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Speaker 1: liver or like your bones, or for your immune system even,

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Speaker 1: which is a very energetic, energy intensive thing. So you're

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Speaker 1: kind of like shutting everything down and focusing all that

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Speaker 1: glucose into muscle and brain. And so when you give

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Speaker 1: someone cortisol or when they're indogenous, when their own cortisol

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Speaker 1: goes up, their blood sugar goes up, their immune system

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Speaker 1: ramps down. That's why glucocorticoids, which are cortisol derivatives, are immunosuppressants,

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Speaker 1: things like prednozone. Many people have used hydro cortizone cream

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Speaker 1: like for itches and stuff like that. So hydro cortizone

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Speaker 1: is cortisol, the exact same molecule. There's no difference between

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Speaker 1: hydro cortizone and the cortisol that you're adrenal land secretes.

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Speaker 1: I mean they put it in a cream obviously, But

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Speaker 1: that's what it is. The problem that people attribute to cortisol,

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Speaker 1: and sometimes incorrectly, as we'll go into, is like, what

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Speaker 1: if that stressor lasts longer than twenty minutes, Right, you're

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Speaker 1: running away from the tiger. Oh, you made it away

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Speaker 1: from the tiger. Great, you're good, everything's safe, everything can

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Speaker 1: go back to normal. What if your whole what if

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Speaker 1: your whole life is stressor what if you're constantly feeling

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Speaker 1: like you're being chased by a tiger and your cortisol

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Speaker 1: levels are high all the time, and it tells a

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Speaker 1: really nice story that like, ooh, that would do a

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Speaker 1: lot of bad things. But as I said, cortisol gets

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Speaker 1: a bad rap, and it might not be as bad

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Speaker 1: as you think.

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Speaker 3: So in terms of just sort of people thinking about

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Speaker 3: like the way that their quarter so moves throughout the day,

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Speaker 3: because cortisol is a it is a hormone, and it

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Speaker 3: would be a mistake to think of it as just

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Speaker 3: always flat except when you're chased by a tiger. It

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Speaker 3: is something which is fluctuating through the day. It's highest

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Speaker 3: in the morning, so when you sort of first wake

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Speaker 3: up in the morning, your cortisol tends to be tends

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Speaker 3: to be higher, and it's lowest sort of in the

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Speaker 3: middle of when you are asleep, is my sense, like

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Speaker 3: on average for most people, and then it will spike

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Speaker 3: at times during the day. This is something that's quite

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Speaker 3: hard to measure, but in principle it would spike when

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Speaker 3: you are doing either physically or emotionally stressful activities like

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Speaker 3: running from a tiger is that true.

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Speaker 1: Yeah, yeah, yeah. The morning cortisol spike is well described.

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Speaker 1: It is one of the reasons why heart attacks are

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Speaker 1: more common in the early hours of the morning, for example,

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Speaker 1: because your body's sort of revving up to get ready

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Speaker 1: to wake up the day. And we will get to

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Speaker 1: this is a circadian rhythm, like one of our fundamental

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Speaker 1: circadian rhythms. It's about five times higher in the morning

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Speaker 1: than it is at night. I mean, it's a real

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Speaker 1: it's a real shift over time. And if you really

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Speaker 1: dig into the data, you'll find that the level of

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Speaker 1: cortisol might not be as important as the circadian rhythm

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Speaker 1: of cortisol. So one of the things we see in

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Speaker 1: the truly chronically stressed are actually not high cortisol levels.

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Speaker 1: It's a loss of that fluctuation. It's flat cortisol levels. Yeah.

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Speaker 3: So I think that's a good that's a good pivot

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Speaker 3: into what I the first piece of what's tough about

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Speaker 3: this entire discussion is going to be really hard about

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Speaker 3: the data, which is like what are we measuring and

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Speaker 3: when are we measuring?

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Speaker 2: So this is not there are some things we measure in.

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Speaker 3: People where I think we can say, you know, maybe

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Speaker 3: you want to do some repeat measurements, but like we

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Speaker 3: have a good sense like something like you know like

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Speaker 3: a one C levels for like a diabetic. You know

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Speaker 3: you test me we you test it fasting not fasting.

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Speaker 3: But we have a good sense, we have a stable

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Speaker 3: sense of like how we test that, and we could

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Speaker 3: use to say, you know you're a diabetic, you're not

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Speaker 3: a diabetic. Measurements of cortisol which are done typically through

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Speaker 3: your blood, although actually they can also do saliva, you

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Speaker 3: can also do hair. You have many different ways to

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Speaker 3: test this. They don't all test the same thing.

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Speaker 2: And because there's this fluctuation, it's actually a really really

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Speaker 2: hard thing to hit.

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Speaker 3: If you wanted to say, what's the number that's going

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Speaker 3: to tell me I'm chronically stressed in some dangerous way,

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Speaker 3: there's sort of no number like that.

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Speaker 1: Yeah, and actually it's a lab test that's pretty bad.

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Speaker 1: So there's some lab tests like sodium level that's just

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Speaker 1: it's been figured out and we can do it really

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Speaker 1: quickly and it's highly accurate, and you test the same

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Speaker 1: blood sample twice and you get the same number, and

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Speaker 1: like it's really nice, and cortisol just isn't one of

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Speaker 1: those things. I mean One of the major issues is

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Speaker 1: that ninety five percent of cortisol in your blood is

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Speaker 1: bound to proteins and is inactive, so these are just

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Speaker 1: chaperone proteins that carry it around. And then the free fraction,

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Speaker 1: the five percent, is the thing that does stuff in

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Speaker 1: your cells. But almost all the lab tests out there

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Speaker 1: are measuring the total, so you know that's is it

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Speaker 1: correlated with the free Yeah, but not great and it's

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Speaker 1: hard to know. There's obviously the timing of measurement that's

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Speaker 1: really important, so you know, you really want to get

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Speaker 1: if you actually needed to measure cortisol, for example, to

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Speaker 1: tell if you have a disease of excessive cortisol production.

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Speaker 1: And these diseases exists called Cushing syndrome or Cushing's disease,

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Speaker 1: you get a test early in the morning when you've

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Speaker 1: got the best chance of capturing things high. The assays

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Speaker 1: that they use for cortisol have a lot of false positives,

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Speaker 1: so there's cross reactivity with a bunch of other hormones

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Speaker 1: and other substances that people are taking in It's just

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Speaker 1: like I mean, I'll say right now, like getting your

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Speaker 1: cortisol measured if you don't have symptoms of a cortisol

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Speaker 1: excess disease is you're unlikely to get any useful information.

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Speaker 3: So I think, okay, So when we talk about the

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Speaker 3: way to measure cortisol, actually measuring blood has both the

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Speaker 3: total and free fraction issue. It also has the issue

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Speaker 3: that when you take someone's blood, it raises their cortisol.

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Speaker 1: Yeah, because stressful.

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Speaker 3: It's like, it's stressful, like somebody's sticking a needle in

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Speaker 3: your arm and you're like, and it's a tiger, Like

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Speaker 3: I better get ready to run away.

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Speaker 2: It's not a tiger. You ask for that.

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Speaker 3: But as a result, like saliva is in some sense

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Speaker 3: the sort of best metric of this at a moment,

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Speaker 3: because it's not stressful to take someone's saliva. But the

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Speaker 3: thing that I wonder is why, you know we have

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Speaker 3: continuous glucose monitors. Why has someone not made something that

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Speaker 3: I stick in my You could put it on his

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Speaker 3: zin pouch, something I stick in my mouth and leave

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Speaker 3: in my mouth all the time, on like the side

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Speaker 3: of my cheek, and then it constantly measures my quarter cel.

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Speaker 3: Don't you think Brian Johnson would buy that in like

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Speaker 3: one hot second, Like why is the market not delivering

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Speaker 3: that Perry.

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Speaker 1: What's the problem, No doubt people are pitching that in

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Speaker 1: Silicon Valley right now.

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Speaker 3: Call me, call me VC funds. We're gonna measure the

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Speaker 3: cortisol with our mouths stick stick.

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Speaker 1: I think two things. One, cortisol is complicated to measure.

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Speaker 1: It's you know, it's a it's a hormone. It's it's

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Speaker 1: it's a bigger molecule than something like glucose, which is

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Speaker 1: small and easy to measure. And then the second thing

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Speaker 1: is that nobody knows what to do with the answer.

437
00:23:17,080 --> 00:23:18,639
Speaker 1: I could tell you what your cortisol is.

438
00:23:18,800 --> 00:23:20,680
Speaker 3: That's not the answer. I'm sorry, that's not the answer

439
00:23:20,720 --> 00:23:22,880
Speaker 3: to why they're constantly met. People love to measure stuff

440
00:23:22,960 --> 00:23:24,760
Speaker 3: or something to do it. The first answer was right, Scott,

441
00:23:24,760 --> 00:23:25,760
Speaker 3: you should have stopped at that one.

442
00:23:26,359 --> 00:23:28,920
Speaker 1: Okay, we will erase the second. Now it's fine. I

443
00:23:28,960 --> 00:23:29,800
Speaker 1: can be wrong sometimes.

444
00:23:30,160 --> 00:23:33,400
Speaker 3: Okay, So this is very hard to measure, and we'll

445
00:23:33,440 --> 00:23:36,200
Speaker 3: get into like why that probably means you shouldn't you

446
00:23:36,240 --> 00:23:39,840
Speaker 3: shouldn't measure it. But despite its difficulty in measuring, there

447
00:23:40,160 --> 00:23:44,399
Speaker 3: is actually a fair amount of research on the relationship

448
00:23:44,480 --> 00:23:47,359
Speaker 3: between cortisol measured in some way. We will get to

449
00:23:47,600 --> 00:23:52,200
Speaker 3: and various health outcomes, and I will just like spoiler,

450
00:23:52,680 --> 00:23:55,840
Speaker 3: I think most of this literature is really bad and

451
00:23:56,119 --> 00:23:58,680
Speaker 3: it is observational and not causal, and I have a

452
00:23:58,760 --> 00:24:01,800
Speaker 3: lot of complaints about it, and I've been practicing my complaints.

453
00:24:01,920 --> 00:24:05,720
Speaker 3: But before we get into them, I do think it's

454
00:24:05,760 --> 00:24:07,879
Speaker 3: worth talking like a little bit more. You alluded to

455
00:24:08,480 --> 00:24:13,480
Speaker 3: Cushings disease, but a little bit more about the places

456
00:24:13,560 --> 00:24:18,240
Speaker 3: where high cortisol can actually be very damaging.

457
00:24:17,920 --> 00:24:20,119
Speaker 2: Or we know that this is a this is a problem.

458
00:24:20,440 --> 00:24:23,200
Speaker 1: Yeah, we should talk about Cushing's disease because actually a

459
00:24:23,280 --> 00:24:28,920
Speaker 1: lot of the influencer work is taking what people see

460
00:24:28,920 --> 00:24:31,680
Speaker 1: in Cushions disease where cortisol levels are through the roof

461
00:24:32,160 --> 00:24:36,840
Speaker 1: and saying therefore, mildly elevated cortisol levels and normal people

462
00:24:36,920 --> 00:24:39,320
Speaker 1: also do this thing. And so so what Cushing's disease

463
00:24:39,440 --> 00:24:43,399
Speaker 1: is is a benign tumor, typically on the adrenal gland

464
00:24:43,920 --> 00:24:48,800
Speaker 1: that secretes cortisol. It is unregulated, so it's sitting there

465
00:24:48,960 --> 00:24:51,760
Speaker 1: and it's just secreting cortisols, secreting cortisols, secreting cortisol, and

466
00:24:51,760 --> 00:24:55,040
Speaker 1: that is quite bad for you. The syndrome of Cushing

467
00:24:55,080 --> 00:24:59,159
Speaker 1: syndrome is characterized by pretty dramatic moon faces. What they

468
00:24:59,240 --> 00:25:01,440
Speaker 1: call it the very round face that you may be

469
00:25:01,520 --> 00:25:03,480
Speaker 1: familiar with if you see people on very high dose

470
00:25:03,640 --> 00:25:07,440
Speaker 1: of other cotquot steroids like predmozone. Sorry about these terms,

471
00:25:07,480 --> 00:25:09,800
Speaker 1: but this is what the medical terms are. A buffalo hump,

472
00:25:09,880 --> 00:25:12,520
Speaker 1: which is like a collection of fat on the upper

473
00:25:12,600 --> 00:25:14,600
Speaker 1: part of the back at the bottom of the neck,

474
00:25:15,600 --> 00:25:20,879
Speaker 1: strea which are really violacious, like deep purple stretch marks

475
00:25:21,119 --> 00:25:26,080
Speaker 1: in the abdomen, a lot of accumulation of visceral fat, diabetes,

476
00:25:26,600 --> 00:25:29,720
Speaker 1: high blood sugar, and so on and so forth. The

477
00:25:29,840 --> 00:25:34,199
Speaker 1: treatment is removal of the cortisol secreting tumor, and.

478
00:25:34,280 --> 00:25:36,159
Speaker 3: I think it is it's actually very important to note

479
00:25:36,200 --> 00:25:37,880
Speaker 3: because some of the things we see in the sort

480
00:25:37,880 --> 00:25:41,240
Speaker 3: of wellness influencer claim space are things that seem like, well,

481
00:25:41,480 --> 00:25:44,440
Speaker 3: if you have this cushions disease, you will have this,

482
00:25:45,320 --> 00:25:50,240
Speaker 3: and therefore, if you have a mildly elevated level of

483
00:25:50,640 --> 00:25:54,520
Speaker 3: cortisol in the normal range, you also get less maybe less.

484
00:25:54,359 --> 00:25:57,760
Speaker 1: Belly fat, but still some belly fat, right right, And

485
00:25:57,840 --> 00:26:01,440
Speaker 1: that has that nice sort of like step by step

486
00:26:01,520 --> 00:26:03,960
Speaker 1: ring to it. But if you've been listening to Onelm's actually,

487
00:26:03,960 --> 00:26:06,280
Speaker 1: you know, you actually have to prove these things with data.

488
00:26:07,000 --> 00:26:09,440
Speaker 1: So let's talk about data. I mean, I you know,

489
00:26:09,880 --> 00:26:15,160
Speaker 1: there are clearly cases where cortisol high cortisol levels are

490
00:26:15,760 --> 00:26:17,840
Speaker 1: bad for you. I mean maybe the most dramatic one

491
00:26:17,960 --> 00:26:21,560
Speaker 1: is in sepsis in septic shock, where it is fairly

492
00:26:21,640 --> 00:26:24,399
Speaker 1: well established that if people are coming in with very

493
00:26:24,480 --> 00:26:26,639
Speaker 1: high cortisol levels in the setting of sepsis, they're more

494
00:26:26,760 --> 00:26:29,439
Speaker 1: likely to die. It's a nice study in PLUS one

495
00:26:29,520 --> 00:26:32,359
Speaker 1: in twenty nineteen that took one hundred and thirty nine

496
00:26:32,440 --> 00:26:36,679
Speaker 1: patients with severe sepsis or septic shock, and those who

497
00:26:36,760 --> 00:26:41,320
Speaker 1: had cortisol levels that were high by their definition had

498
00:26:41,359 --> 00:26:47,560
Speaker 1: a tenfold higher mortality risk. It's a pretty large effects size. Now, Emily,

499
00:26:47,960 --> 00:26:51,000
Speaker 1: that's not a causal step, as you said, that's observational.

500
00:26:51,359 --> 00:26:53,720
Speaker 1: So walk me through like why, yeah, is it the

501
00:26:53,760 --> 00:26:55,399
Speaker 1: cortisol that's bad or what are you thinking when you

502
00:26:55,520 --> 00:26:58,800
Speaker 1: hear Okay, high cortisol tenfold risk of death in septic shock.

503
00:26:58,920 --> 00:27:01,720
Speaker 3: Yeah, So I I think sort of two things in

504
00:27:01,800 --> 00:27:05,240
Speaker 3: that case, which will come up again later. So one

505
00:27:05,400 --> 00:27:08,840
Speaker 3: is that, yeah, this is not a randomized the cortisol

506
00:27:09,440 --> 00:27:11,560
Speaker 3: some people came in with a higher level of cortisol

507
00:27:11,600 --> 00:27:15,159
Speaker 3: than others. It seems plausible to me that that is

508
00:27:15,280 --> 00:27:19,119
Speaker 3: measuring something else about, you know, how stressful, like what

509
00:27:19,240 --> 00:27:22,200
Speaker 3: else is going on in your life? Or even like

510
00:27:22,400 --> 00:27:25,080
Speaker 3: how bad is this sepsis? I realize all sepsis is bad.

511
00:27:25,880 --> 00:27:28,840
Speaker 3: Sepsis is not good, but sort of like, could you

512
00:27:29,040 --> 00:27:31,480
Speaker 3: read this as this is is kind of a metric

513
00:27:31,560 --> 00:27:34,679
Speaker 3: itself of how much is the body struggling in other ways?

514
00:27:35,119 --> 00:27:36,760
Speaker 2: And this is just one measure of that.

515
00:27:37,560 --> 00:27:39,680
Speaker 3: I will say in this particular case, the fact that

516
00:27:39,720 --> 00:27:42,520
Speaker 3: the odds ratio is ten, which means like the mortality

517
00:27:42,640 --> 00:27:44,680
Speaker 3: risk is ten times as high, that's actually a quite

518
00:27:45,400 --> 00:27:48,640
Speaker 3: that's a very big effect. It is Therefore, the kinds

519
00:27:48,680 --> 00:27:51,560
Speaker 3: of biases I have in my mind, like differences in

520
00:27:51,760 --> 00:27:54,240
Speaker 3: other things that could be going on in people's lives

521
00:27:54,280 --> 00:27:57,960
Speaker 3: and so on, probably aren't driving a tenfold increase in mortality.

522
00:27:58,119 --> 00:28:03,920
Speaker 3: So the comp nation here of the particular outcome which

523
00:28:04,000 --> 00:28:06,800
Speaker 3: is so extreme and how large the effect size is,

524
00:28:07,000 --> 00:28:09,919
Speaker 3: would makes me more confident in that result, even though

525
00:28:09,960 --> 00:28:11,680
Speaker 3: I think it would be better to have a randomization.

526
00:28:11,720 --> 00:28:13,800
Speaker 3: Although this is a case in which I cannot imagine

527
00:28:14,119 --> 00:28:17,720
Speaker 3: how you would randomize people to different cortosol levels. That's

528
00:28:17,760 --> 00:28:20,159
Speaker 3: not really an available randomization, which is why we're going

529
00:28:20,240 --> 00:28:23,320
Speaker 3: to generally nature rely on observational data.

530
00:28:24,160 --> 00:28:27,760
Speaker 1: Yeah. Yeah. And for the medical people listening who trained

531
00:28:27,800 --> 00:28:29,520
Speaker 1: back when I did, there was a time when we

532
00:28:29,640 --> 00:28:32,840
Speaker 1: gave people cortisol or other gluca cortoicoids when they had

533
00:28:32,880 --> 00:28:36,119
Speaker 1: sepsis because we thought, oh, all this inflammation is the

534
00:28:36,200 --> 00:28:38,960
Speaker 1: bat like, their immune system's going crazy. We need to

535
00:28:39,000 --> 00:28:41,200
Speaker 1: suppress their immune system a little bit. That was standard

536
00:28:41,240 --> 00:28:43,880
Speaker 1: of care for a while. No longer really do that

537
00:28:43,920 --> 00:28:47,000
Speaker 1: except in rare circumstances, and so it is quite complicated.

538
00:28:47,080 --> 00:28:49,640
Speaker 1: And I think, you know, it's certainly possible that a

539
00:28:49,720 --> 00:28:52,080
Speaker 1: large amount of that observed effects size is just due

540
00:28:52,080 --> 00:28:54,120
Speaker 1: to the fact that really sick people have really high

541
00:28:54,160 --> 00:28:58,120
Speaker 1: cortosol potentially, but most people who are listening to us

542
00:28:58,240 --> 00:29:00,320
Speaker 1: are not current lead.

543
00:29:01,760 --> 00:29:04,840
Speaker 2: Shop. Yeah, stop listening. If that's you are hanging.

544
00:29:04,640 --> 00:29:05,160
Speaker 4: There, and.

545
00:29:07,480 --> 00:29:09,520
Speaker 1: Maybe we're the one thing keeping them, you know, seeing

546
00:29:09,600 --> 00:29:12,720
Speaker 1: in the hospital bed. We're not all right, we believe

547
00:29:12,760 --> 00:29:12,920
Speaker 1: in you.

548
00:29:13,360 --> 00:29:19,440
Speaker 3: Most people are worried about the idea that a chronically

549
00:29:19,560 --> 00:29:23,240
Speaker 3: elevated or frequently elevated level of cortisol or just having

550
00:29:23,320 --> 00:29:26,280
Speaker 3: high cortisol whatever people seem to mean by that, is

551
00:29:26,440 --> 00:29:30,600
Speaker 3: bad for some health outcome, like heart disease being the

552
00:29:30,720 --> 00:29:32,120
Speaker 3: sort of the one you should start with.

553
00:29:32,120 --> 00:29:34,240
Speaker 2: It's the one that comes up the most. And so

554
00:29:34,800 --> 00:29:36,560
Speaker 2: this is a place where there is some.

555
00:29:36,720 --> 00:29:38,640
Speaker 3: Data, and i want you to describe the data, and

556
00:29:38,720 --> 00:29:40,560
Speaker 3: then I'm going to tell you my feelings on it,

557
00:29:41,280 --> 00:29:41,920
Speaker 3: why it's wrong.

558
00:29:42,560 --> 00:29:45,360
Speaker 1: I'll set you up in the best way I know how. Okay,

559
00:29:46,280 --> 00:29:50,320
Speaker 1: I'm going to give you two studies here. One is

560
00:29:50,400 --> 00:29:52,600
Speaker 1: sort of a prototypical. There's other studies in this space

561
00:29:53,000 --> 00:29:55,960
Speaker 1: looking at urinary cortisol. Gosh, we didn't even mention that's

562
00:29:56,080 --> 00:29:58,680
Speaker 1: there's yet another place you can measure cortisol. You can

563
00:29:58,720 --> 00:30:00,880
Speaker 1: measure it in the urine and then the risk of

564
00:30:01,280 --> 00:30:04,720
Speaker 1: cardiovascular mortality. This was from the Journal of Clinical Endocritinology

565
00:30:04,760 --> 00:30:07,880
Speaker 1: and Metabolism. That's a good journal. Twenty ten, eight hundred

566
00:30:07,880 --> 00:30:10,520
Speaker 1: and sixty one participants above age sixty five. They got

567
00:30:10,600 --> 00:30:13,800
Speaker 1: twenty four hour urine cortisol levels at baseline, followed them

568
00:30:13,840 --> 00:30:17,120
Speaker 1: for six years. Over the course of that time, people

569
00:30:17,400 --> 00:30:21,120
Speaker 1: in the highest turtile, so the highest third of urinary

570
00:30:21,160 --> 00:30:23,520
Speaker 1: cortisol levels had five times the risk of dying in

571
00:30:23,560 --> 00:30:29,600
Speaker 1: cardiovascular disease, but there's no difference in depths from other causes.

572
00:30:29,640 --> 00:30:34,600
Speaker 1: So there's a big effect size fivefold from higher cortisol levels.

573
00:30:35,320 --> 00:30:38,000
Speaker 1: I told you I'd give you one other study just

574
00:30:38,080 --> 00:30:42,440
Speaker 1: to give you something to talk about. So nope, I'm not.

575
00:30:42,560 --> 00:30:45,400
Speaker 1: I'm going to wait on the Mendelian randomization because it's

576
00:30:45,440 --> 00:30:47,640
Speaker 1: going to require some explanations. So let's start with this.

577
00:30:47,920 --> 00:30:50,120
Speaker 1: My urinary cortisol is in the top third of people's

578
00:30:50,160 --> 00:30:52,239
Speaker 1: urinary cortisol. I have fivefold the risk of dying from

579
00:30:52,280 --> 00:30:54,960
Speaker 1: cardiovascular disease in the next six years. Sounds pretty bad.

580
00:30:55,560 --> 00:30:58,160
Speaker 1: Got to get my cortisol down, okay, I mean.

581
00:30:58,320 --> 00:31:03,240
Speaker 3: Look, here are some things that raise people's cortisol. Being poor,

582
00:31:04,000 --> 00:31:08,840
Speaker 3: working at night, having few resources, having a stressful family life,

583
00:31:09,520 --> 00:31:13,880
Speaker 3: having other diseases, things like that. All of those things

584
00:31:14,120 --> 00:31:19,280
Speaker 3: are independently associated with death from heart disease. We know

585
00:31:19,440 --> 00:31:23,880
Speaker 3: that like a million different ways, exercise causes you to

586
00:31:23,960 --> 00:31:28,320
Speaker 3: be less dying rate lowers your cortisol. Overall, all of

587
00:31:28,440 --> 00:31:31,640
Speaker 3: these things are going on in the background. And if

588
00:31:31,680 --> 00:31:33,480
Speaker 3: you look at the people in this study and you

589
00:31:33,600 --> 00:31:36,160
Speaker 3: look at the tersiles, they differ in a bunch of

590
00:31:36,320 --> 00:31:42,240
Speaker 3: different ways from each other, and it is therefore extremely

591
00:31:42,360 --> 00:31:48,200
Speaker 3: difficult to imagine that we are attributing this difference in

592
00:31:48,320 --> 00:31:53,120
Speaker 3: the risk of death to these levels of cortisol as

593
00:31:53,160 --> 00:31:56,200
Speaker 3: opposed to attributing them to these other things. Now, this

594
00:31:56,400 --> 00:31:58,040
Speaker 3: is a case in which actually the whole thing is

595
00:31:58,200 --> 00:32:00,920
Speaker 3: very complicated, because, well, maybe it's these other things raising

596
00:32:00,960 --> 00:32:03,600
Speaker 3: your cortisol, which is then causing you to you know,

597
00:32:04,160 --> 00:32:05,560
Speaker 3: have a higher risk of death.

598
00:32:05,640 --> 00:32:07,040
Speaker 2: That's an interesting mechanism.

599
00:32:07,160 --> 00:32:09,280
Speaker 3: But if you ask, like, what's the act like, what's

600
00:32:09,320 --> 00:32:12,320
Speaker 3: the action item here, what's the like thing that would

601
00:32:12,520 --> 00:32:13,760
Speaker 3: it's changing these other things.

602
00:32:13,800 --> 00:32:15,320
Speaker 2: It's not like if you gave someone.

603
00:32:15,120 --> 00:32:17,720
Speaker 3: A shot that magically lowered their cortisol that would have

604
00:32:18,360 --> 00:32:21,680
Speaker 3: this positive impact on them. These results are also this

605
00:32:21,760 --> 00:32:25,280
Speaker 3: sample is quite small, not that many people died, which

606
00:32:25,360 --> 00:32:29,360
Speaker 3: is good, and the therefore this sort of hazard ratio

607
00:32:29,480 --> 00:32:32,880
Speaker 3: of five is like incredibly noisy. It's consistent with an

608
00:32:32,880 --> 00:32:35,800
Speaker 3: effect that's two, it's consistent with an effect of thirteen times,

609
00:32:35,840 --> 00:32:38,000
Speaker 3: which is definitely not true. It's just this is a

610
00:32:38,080 --> 00:32:43,280
Speaker 3: statistically noisy, very potentially biased effect.

611
00:32:44,160 --> 00:32:48,040
Speaker 2: I just I don't think we learn anything from studies

612
00:32:48,120 --> 00:32:50,000
Speaker 2: like this. I just think we learned nothing.

613
00:32:50,400 --> 00:32:55,080
Speaker 1: So I completely agree that there's all this stuff that

614
00:32:55,120 --> 00:32:58,680
Speaker 1: can affect your cortisol that might also independently affect your

615
00:32:58,760 --> 00:33:01,480
Speaker 1: risk of death. Right we know in America at least

616
00:33:01,560 --> 00:33:04,520
Speaker 1: being poor dramatically increases your risk of dying from Christ and.

617
00:33:04,520 --> 00:33:07,400
Speaker 2: Also dramatically increases so yeah.

618
00:33:07,720 --> 00:33:11,480
Speaker 1: So so okay, that's classic confounding. The problem is, you know,

619
00:33:11,600 --> 00:33:13,520
Speaker 1: we all love a randomized trial, but no one's going

620
00:33:13,560 --> 00:33:16,160
Speaker 1: to do a randomized trial of like supplemental cortisol on

621
00:33:16,280 --> 00:33:20,000
Speaker 1: people that's not going to happen. Probably would be considered unethical.

622
00:33:20,440 --> 00:33:23,800
Speaker 1: So we're left with some other options, and I think

623
00:33:24,160 --> 00:33:27,440
Speaker 1: I think we need to talk about Mendelian randomization. Okay,

624
00:33:27,920 --> 00:33:31,120
Speaker 1: so let's put on our genetic hats for a second.

625
00:33:31,440 --> 00:33:35,160
Speaker 1: I sort of believe in Mendelian randomization as an approach,

626
00:33:35,240 --> 00:33:37,520
Speaker 1: and Emily, I think you are more skeptical of it.

627
00:33:37,640 --> 00:33:40,160
Speaker 1: So I'm gonna let me tell you how I view it,

628
00:33:40,480 --> 00:33:42,560
Speaker 1: and then you tell me why I'm wrong. Okay, here's

629
00:33:42,600 --> 00:33:48,200
Speaker 1: the idea. There are certain genes that increase the amount

630
00:33:48,200 --> 00:33:51,920
Speaker 1: of cortisol you make independent of other things. Genes that

631
00:33:52,120 --> 00:33:54,720
Speaker 1: have to do with hormone synthesis and stuff, and everyone

632
00:33:54,800 --> 00:33:57,000
Speaker 1: has little variations in their genes, and some are just

633
00:33:57,120 --> 00:33:59,680
Speaker 1: a bit more active than others, and so all else

634
00:33:59,760 --> 00:34:03,920
Speaker 1: being equal, there are people who genetically live at a

635
00:34:04,040 --> 00:34:08,000
Speaker 1: higher cortisol level than a similar person who had a

636
00:34:08,080 --> 00:34:11,960
Speaker 1: different genetic background, so you know, and this is true

637
00:34:11,960 --> 00:34:13,879
Speaker 1: of everything, not just cortisol. Right, Like, there's some people

638
00:34:13,960 --> 00:34:16,360
Speaker 1: just genetically have a higher LDL than other people, and

639
00:34:16,400 --> 00:34:20,280
Speaker 1: some people have genetically lower LDL. Okay, because your genetics

640
00:34:20,280 --> 00:34:28,440
Speaker 1: are assigned at birth, not no, at conception. That exposure

641
00:34:28,560 --> 00:34:33,000
Speaker 1: happens before you know that you're poor, before you know

642
00:34:33,440 --> 00:34:35,880
Speaker 1: you have stress in your life, before anything else, it

643
00:34:35,960 --> 00:34:38,840
Speaker 1: cannot be related to that. The genetics are not related

644
00:34:38,920 --> 00:34:42,480
Speaker 1: to those things. Being poor doesn't change your DNA, right,

645
00:34:43,320 --> 00:34:46,799
Speaker 1: And therefore we can use those genetic signals and say, Okay,

646
00:34:46,880 --> 00:34:50,120
Speaker 1: here's a person whose genes have them exposed to a

647
00:34:50,239 --> 00:34:53,239
Speaker 1: higher level of cortisol than they otherwise would have been

648
00:34:54,080 --> 00:34:56,359
Speaker 1: given everything that's going on in their life. And here's

649
00:34:56,400 --> 00:34:59,440
Speaker 1: a person whose genes have their cortisol lower than they

650
00:34:59,480 --> 00:35:02,080
Speaker 1: otherwise would have been, giving everything that's going on in

651
00:35:02,160 --> 00:35:04,680
Speaker 1: our life. And if the person with the genes that

652
00:35:04,880 --> 00:35:07,200
Speaker 1: predispose them to high cortisol has a higher risk of

653
00:35:07,280 --> 00:35:10,239
Speaker 1: cardiovascular disease. Then the person whose genes predisposed them to

654
00:35:10,360 --> 00:35:14,840
Speaker 1: low cortisol. I conclude, therefore, there is a causal link

655
00:35:15,040 --> 00:35:18,640
Speaker 1: between cortisol level and cardiovascular disease.

656
00:35:19,440 --> 00:35:25,440
Speaker 3: The term Mendilion randomization implies that something is being randomized,

657
00:35:25,640 --> 00:35:27,880
Speaker 3: and so I think when we think about this technique,

658
00:35:28,560 --> 00:35:34,080
Speaker 3: we want to think about the word random. So what

659
00:35:34,239 --> 00:35:39,040
Speaker 3: you are suggesting is that the genes are allocated randomly,

660
00:35:39,480 --> 00:35:42,839
Speaker 3: that when you are given genes are there's a piece

661
00:35:42,880 --> 00:35:47,960
Speaker 3: of the genetics that are coming randomly to you. That

662
00:35:48,200 --> 00:35:52,320
Speaker 3: is not true when comparing across people in the population overall.

663
00:35:52,520 --> 00:35:55,360
Speaker 3: So let me give you a more like direct example

664
00:35:55,440 --> 00:35:58,520
Speaker 3: of this. Imagine that instead of cortisol, we were thinking

665
00:35:58,719 --> 00:36:02,120
Speaker 3: about eye color and you said, there's a gene that

666
00:36:02,280 --> 00:36:04,480
Speaker 3: determines your that determines your eye color. In fact, there

667
00:36:04,560 --> 00:36:06,279
Speaker 3: is a gene that determines your eye color. There's a

668
00:36:06,320 --> 00:36:10,600
Speaker 3: set of genes. We understand about how those work, but

669
00:36:10,880 --> 00:36:14,319
Speaker 3: it is not when we look across the population, those

670
00:36:14,400 --> 00:36:17,640
Speaker 3: genes are not randomly distributed. It's not like randomly when

671
00:36:17,680 --> 00:36:21,160
Speaker 3: you're conceived you are given one of the eye color genes.

672
00:36:21,239 --> 00:36:24,040
Speaker 3: It's random only conditional on the genes.

673
00:36:23,719 --> 00:36:24,600
Speaker 2: That your parents have.

674
00:36:25,440 --> 00:36:28,279
Speaker 3: So you have a set of parents, and you have

675
00:36:28,600 --> 00:36:31,520
Speaker 3: your mom has a set of twenty three chromosomes. She

676
00:36:31,600 --> 00:36:35,640
Speaker 3: has two copies of each, and at conception in the egg,

677
00:36:36,040 --> 00:36:38,439
Speaker 3: you get one of those and which one you get

678
00:36:38,719 --> 00:36:42,880
Speaker 3: is random. But who your mother is, the genetics that

679
00:36:43,000 --> 00:36:47,000
Speaker 3: she starts with is not random. So when we talk

680
00:36:47,040 --> 00:36:51,080
Speaker 3: about Mendolian randomization, there's something cool, a cool idea in here.

681
00:36:51,680 --> 00:36:54,880
Speaker 3: I want you to imagine two children born to the

682
00:36:54,960 --> 00:36:58,800
Speaker 3: same set of parents, and mom has two copies of

683
00:36:59,000 --> 00:37:01,839
Speaker 3: each chromosome, and on one of those chromosomes she's got

684
00:37:01,880 --> 00:37:05,080
Speaker 3: like the high cortisol gene, and on the other copy

685
00:37:05,200 --> 00:37:09,960
Speaker 3: she's got the low cortisol gene. And her children, let's

686
00:37:09,960 --> 00:37:12,440
Speaker 3: say one of them gets the high cortisol, one of

687
00:37:12,480 --> 00:37:15,759
Speaker 3: them gets the low cortisol. That's random, and so then

688
00:37:15,840 --> 00:37:20,600
Speaker 3: we have two siblings who are effectively everything is, you know,

689
00:37:20,880 --> 00:37:23,680
Speaker 3: the same, except that in this case this particular thing

690
00:37:23,800 --> 00:37:28,359
Speaker 3: is randomly allocated. Wait, and so you could then get

691
00:37:28,480 --> 00:37:32,280
Speaker 3: many sibling pairs like that, and say, conditional on your family,

692
00:37:32,480 --> 00:37:38,520
Speaker 3: controlling for your parentage. Comparing you to your siblings. We're

693
00:37:38,560 --> 00:37:41,759
Speaker 3: going to see whether the sibling who was randomly allocated

694
00:37:41,800 --> 00:37:45,520
Speaker 3: the high cortisol gene has worse outcomes than the sibling

695
00:37:45,600 --> 00:37:48,920
Speaker 3: that was not randomly allocated. That's a really cool idea

696
00:37:49,400 --> 00:37:52,200
Speaker 3: that uses genetics and randomizes.

697
00:37:52,960 --> 00:37:55,320
Speaker 1: Do you agree? Yeah? All I wanted to say was

698
00:37:55,360 --> 00:37:57,840
Speaker 1: that in my mind, one of these kids is named

699
00:37:58,000 --> 00:38:00,000
Speaker 1: Gene and the other is named.

700
00:38:01,880 --> 00:38:05,479
Speaker 2: I love that so much. Okay, but what okay?

701
00:38:05,560 --> 00:38:10,879
Speaker 3: So that technique, that technique works like, that works sort

702
00:38:10,920 --> 00:38:12,719
Speaker 3: of in concept the way I've described it, and there

703
00:38:12,719 --> 00:38:15,880
Speaker 3: are some actually some issues with using that technique in practice,

704
00:38:15,920 --> 00:38:20,359
Speaker 3: but at least in principle, there is a real randomization there.

705
00:38:21,120 --> 00:38:21,960
Speaker 2: Here is the problem.

706
00:38:22,480 --> 00:38:25,759
Speaker 3: The studies that are being done that are using a

707
00:38:25,880 --> 00:38:29,640
Speaker 3: technique they are referring to as Mendillion randomization do not

708
00:38:29,880 --> 00:38:33,600
Speaker 3: actually do what I just described. Instead, what they do

709
00:38:33,960 --> 00:38:37,000
Speaker 3: is they don't look within sibling pairs. They look just

710
00:38:37,200 --> 00:38:42,440
Speaker 3: across people in the population. And that is ridiculous because

711
00:38:42,760 --> 00:38:46,560
Speaker 3: genetics are not randomly allocated across people in the population.

712
00:38:46,719 --> 00:38:49,200
Speaker 3: I mean, an equivalent thing is if you said, well,

713
00:38:49,600 --> 00:38:52,560
Speaker 3: I'm interested in the impact of race on something, and

714
00:38:52,680 --> 00:38:54,719
Speaker 3: I don't think I can just look at people's race,

715
00:38:54,800 --> 00:38:56,759
Speaker 3: because that's confounded with all kinds of other things. But

716
00:38:56,800 --> 00:38:58,520
Speaker 3: I'm going to look at a gene for skin color

717
00:38:58,520 --> 00:39:00,920
Speaker 3: and I'm going to relate that to the out Well,

718
00:39:00,960 --> 00:39:02,160
Speaker 3: that's stupid, that's not like.

719
00:39:02,200 --> 00:39:04,200
Speaker 2: Doesn't make any sense. It doesn't work.

720
00:39:04,719 --> 00:39:07,560
Speaker 3: And so this this technique is not being it's not

721
00:39:07,680 --> 00:39:10,640
Speaker 3: that it's conceptually poor, it's being used in a way

722
00:39:10,719 --> 00:39:11,520
Speaker 3: that makes no sense.

723
00:39:12,160 --> 00:39:15,799
Speaker 1: Well, so the there is a caveat to Mendelian randomization.

724
00:39:16,040 --> 00:39:18,400
Speaker 1: So to take your skin color example, which says that

725
00:39:18,719 --> 00:39:21,160
Speaker 1: in order to use this technique, you have to show

726
00:39:21,200 --> 00:39:24,680
Speaker 1: that the gene is associated with the phenotype. Right, So

727
00:39:24,760 --> 00:39:27,800
Speaker 1: the gene is associated with skin color, let's say, and

728
00:39:28,480 --> 00:39:31,800
Speaker 1: the gene is associated with the outcome, but the gene

729
00:39:32,800 --> 00:39:37,160
Speaker 1: is not associated with the outcome through any plausible path

730
00:39:37,440 --> 00:39:42,520
Speaker 1: outside of the phenotype. So there is like some statistical

731
00:39:42,640 --> 00:39:43,520
Speaker 1: testing you can may for that.

732
00:39:43,640 --> 00:39:45,200
Speaker 2: Yeah, that's called the exclusion restriction.

733
00:39:45,920 --> 00:39:48,880
Speaker 3: And in the cases that you've described, where we're comparing,

734
00:39:49,480 --> 00:39:53,399
Speaker 3: say to people with different genetics across different families, where

735
00:39:53,840 --> 00:39:56,319
Speaker 3: for example, one of them is born to a set

736
00:39:56,360 --> 00:39:58,960
Speaker 3: of parents who have high cortisol and one of them

737
00:39:59,000 --> 00:40:00,719
Speaker 3: is born to a set of parents with low cortisol.

738
00:40:01,239 --> 00:40:03,800
Speaker 3: Now your exclusion restriction is failed, and so that just

739
00:40:03,880 --> 00:40:06,759
Speaker 3: doesn't work. So I think you're right, there is a

740
00:40:07,000 --> 00:40:09,600
Speaker 3: thing and it's totally failing, and these guys don't seem

741
00:40:09,600 --> 00:40:10,200
Speaker 3: to understand that.

742
00:40:11,520 --> 00:40:13,839
Speaker 2: I just don't understand. I fundamentally perry.

743
00:40:13,920 --> 00:40:17,200
Speaker 3: This is like drives me crazy because people in medicine

744
00:40:17,320 --> 00:40:19,359
Speaker 3: use this technique all the time, and I just think

745
00:40:19,400 --> 00:40:21,600
Speaker 3: they don't understand what they're doing, and I can't understand

746
00:40:21,600 --> 00:40:22,560
Speaker 3: why they don't understand.

747
00:40:23,239 --> 00:40:25,880
Speaker 1: Let me give you the results of the cortisol Mendelian

748
00:40:25,960 --> 00:40:28,960
Speaker 1: randomization because maybe this is a moot point. Okay, So

749
00:40:29,160 --> 00:40:33,359
Speaker 1: in the observational framework, we've seen that a high level

750
00:40:33,360 --> 00:40:35,960
Speaker 1: of cortisol increases your risk of cardiovascular death by five

751
00:40:36,120 --> 00:40:41,600
Speaker 1: hundred percent. Okay. In the Mendelian randomization analysis, genes predisposing

752
00:40:41,719 --> 00:40:45,960
Speaker 1: high cortisol increase the risk of cardiovascular death by eight percent.

753
00:40:46,480 --> 00:40:48,160
Speaker 2: Right, I mean, okay.

754
00:40:48,440 --> 00:40:52,360
Speaker 3: So one thing is if you think what Mendelian randomization

755
00:40:52,520 --> 00:40:56,719
Speaker 3: is doing is fixing your causality problem, then I think

756
00:40:56,760 --> 00:40:59,000
Speaker 3: what you would say, Okay, now we've got a better result,

757
00:40:59,040 --> 00:41:02,480
Speaker 3: and it's basically zero like it's it does basically doesn't.

758
00:41:02,200 --> 00:41:03,840
Speaker 1: Matter, does not suggest causality.

759
00:41:03,920 --> 00:41:08,479
Speaker 3: I will say, I think counter counter example, as I've noted,

760
00:41:08,520 --> 00:41:11,399
Speaker 3: I don't think the Mendelian randomization really makes any sense

761
00:41:11,400 --> 00:41:11,680
Speaker 3: at all.

762
00:41:12,400 --> 00:41:15,080
Speaker 2: And part of the reason that the effect I think

763
00:41:15,160 --> 00:41:15,600
Speaker 2: is much.

764
00:41:15,560 --> 00:41:20,640
Speaker 3: Smaller is because the genes are identifying have very little

765
00:41:20,719 --> 00:41:25,239
Speaker 3: predictive power on actually having high cortisol, and so like

766
00:41:25,719 --> 00:41:28,080
Speaker 3: just these these genes are not have very high penetrants,

767
00:41:28,600 --> 00:41:32,160
Speaker 3: and so this may be failing and giving you a

768
00:41:32,280 --> 00:41:34,719
Speaker 3: very small number for reasons that kind of have nothing

769
00:41:34,760 --> 00:41:36,960
Speaker 3: to do with getting rid of bias. They may just

770
00:41:37,120 --> 00:41:39,800
Speaker 3: be generating noise. I hate this technique.

771
00:41:39,800 --> 00:41:44,439
Speaker 2: I understand that I'm being like and talking about I hate.

772
00:41:45,440 --> 00:41:49,600
Speaker 1: I just that's fine. We can't randomize people to high cortisol.

773
00:41:49,719 --> 00:41:53,080
Speaker 1: We can't supplement them with cortisol or placebo, so we're stuck.

774
00:41:53,239 --> 00:41:55,799
Speaker 1: We have to make some inferences. But I will say

775
00:41:56,160 --> 00:41:59,080
Speaker 1: that based on this data, it's there's not a compelling

776
00:41:59,360 --> 00:42:02,480
Speaker 1: argument high cortisol level in and of itself is causal

777
00:42:02,640 --> 00:42:03,840
Speaker 1: of cardiovascular disease.

778
00:42:04,360 --> 00:42:06,600
Speaker 2: I totally that. I think we totally agree.

779
00:42:07,120 --> 00:42:09,240
Speaker 3: I think your question about give me a better technique

780
00:42:09,239 --> 00:42:11,960
Speaker 3: is an interesting one. I mean, I do think a

781
00:42:12,120 --> 00:42:15,839
Speaker 3: true Mendelian randomization with a sort of a sibling pairastudy

782
00:42:16,239 --> 00:42:18,960
Speaker 3: would be an interesting thing to explore. It could have

783
00:42:19,040 --> 00:42:20,839
Speaker 3: some other problems, but I think that would be something

784
00:42:20,920 --> 00:42:25,320
Speaker 3: interesting to explore. I agree this is a very difficult problem.

785
00:42:25,760 --> 00:42:28,480
Speaker 3: I think one thing you could imagine randomizing if you

786
00:42:28,600 --> 00:42:31,800
Speaker 3: sort of at least in a short term way, is

787
00:42:32,000 --> 00:42:35,080
Speaker 3: you know, some of the kind of like behavioral techniques

788
00:42:35,120 --> 00:42:39,160
Speaker 3: that might lower people's cortisol, like meditation. You can imagine

789
00:42:39,239 --> 00:42:41,640
Speaker 3: running a study where you're like one group gets like

790
00:42:41,640 --> 00:42:44,279
Speaker 3: a lot of meditation support or some other you know,

791
00:42:44,480 --> 00:42:46,600
Speaker 3: therapy something that would lower their cortisol.

792
00:42:47,719 --> 00:42:48,960
Speaker 2: It probably have other effects, so.

793
00:42:48,960 --> 00:42:50,680
Speaker 3: It's not like a great study, but I you know,

794
00:42:51,200 --> 00:42:54,400
Speaker 3: like it's something like that to try to affect people's cortisol.

795
00:42:54,440 --> 00:42:56,640
Speaker 2: I agree, we're not going to find anything, but doesn't

796
00:42:56,640 --> 00:42:57,719
Speaker 2: mean it's not interesting to.

797
00:42:58,120 --> 00:42:59,200
Speaker 1: Try to at least.

798
00:42:59,239 --> 00:43:02,239
Speaker 3: Luck. All right, let's get so sorry, I got so

799
00:43:02,320 --> 00:43:04,360
Speaker 3: exercise guy. I feel like people are going to be like,

800
00:43:04,520 --> 00:43:07,080
Speaker 3: why are you so exercised about this? But it's like,

801
00:43:07,160 --> 00:43:09,320
Speaker 3: this is my job, This is like a thing, this

802
00:43:09,480 --> 00:43:12,000
Speaker 3: is like the core of my of my like professional

803
00:43:12,080 --> 00:43:15,560
Speaker 3: life other than parenting. Writing is like statistical methods.

804
00:43:15,880 --> 00:43:20,560
Speaker 1: What you guys don't know is that Emily, Emily's first

805
00:43:20,640 --> 00:43:23,280
Speaker 1: boyfriend was a Mendelian randomization study.

806
00:43:23,640 --> 00:43:29,600
Speaker 4: So okay, I want to move rather quickly through the

807
00:43:29,760 --> 00:43:34,799
Speaker 4: other basically true stuff that the other stuff.

808
00:43:34,560 --> 00:43:36,440
Speaker 1: That people say that high cortisol does. If we're going

809
00:43:36,520 --> 00:43:39,800
Speaker 1: to write off cardiovascular disease, and again, guys, we're not

810
00:43:39,880 --> 00:43:42,840
Speaker 1: saying that there's no association between higher cortisol levels and

811
00:43:42,880 --> 00:43:45,360
Speaker 1: these things. We're asking is it the cortisol not the

812
00:43:45,520 --> 00:43:48,279
Speaker 1: like life stress and the other stuff. So I think

813
00:43:48,640 --> 00:43:52,080
Speaker 1: you know a big one is diabetes metabolic disease, right, Like,

814
00:43:52,360 --> 00:43:55,719
Speaker 1: we we certainly know that people with cushions syndrome much

815
00:43:55,800 --> 00:43:57,879
Speaker 1: high risk of diabetes. We know that when you put

816
00:43:57,920 --> 00:44:01,319
Speaker 1: people on steroids like prednozone or hyd you courtizona, their

817
00:44:01,360 --> 00:44:04,880
Speaker 1: blood sugar goes up. I was surprised here, Emily, Like,

818
00:44:05,239 --> 00:44:08,400
Speaker 1: there's a nice meta analysis of twenty one studies. This

819
00:44:08,960 --> 00:44:14,360
Speaker 1: is appearing in psycho Neeuroendrochronology. In twenty eighteen, eleven thousand

820
00:44:14,440 --> 00:44:17,560
Speaker 1: people or almost twelve thousand people, no significant difference in

821
00:44:17,640 --> 00:44:21,520
Speaker 1: basil cortisol levels between subjects with and without the metabolic syndrome,

822
00:44:21,840 --> 00:44:23,840
Speaker 1: which I just wouldn't have. And that's like, that's not

823
00:44:23,920 --> 00:44:26,000
Speaker 1: even a causal study. It's just I mean, I think

824
00:44:26,400 --> 00:44:27,080
Speaker 1: there's no link.

825
00:44:27,640 --> 00:44:28,759
Speaker 2: What's so interesting there is?

826
00:44:28,880 --> 00:44:32,080
Speaker 3: I might have I would have thought that that we

827
00:44:32,320 --> 00:44:34,799
Speaker 3: would see an association there just because of all these

828
00:44:34,840 --> 00:44:35,520
Speaker 3: other factors.

829
00:44:35,680 --> 00:44:38,080
Speaker 2: Totally, But it seems like even you know.

830
00:44:38,680 --> 00:44:41,400
Speaker 1: Even the confounding can't and the confounding can't.

831
00:44:41,160 --> 00:44:43,920
Speaker 2: Get you there somehow. Yeah, maybe that's that's hard to measure.

832
00:44:45,160 --> 00:44:47,880
Speaker 1: Let's do stubborn belly fat?

833
00:44:48,480 --> 00:44:52,080
Speaker 2: Yes, so much of it? Okay, how do I.

834
00:44:52,160 --> 00:44:54,160
Speaker 1: Have so much stubborn belly fat? I don't think you too.

835
00:44:54,360 --> 00:44:57,160
Speaker 2: It's so stubborn. I am always arguing with it. It's

836
00:44:57,200 --> 00:44:59,600
Speaker 2: always making these terrible points.

837
00:44:59,760 --> 00:45:03,560
Speaker 1: Are Producer Tamar just rolled her eyes like Emily's saying

838
00:45:03,640 --> 00:45:04,760
Speaker 1: she has belly fat.

839
00:45:04,840 --> 00:45:10,479
Speaker 3: Enoise describe stubborn Well, okay, anyway, I as a middle

840
00:45:10,520 --> 00:45:12,560
Speaker 3: aged man, stubborn belly fat is I get it.

841
00:45:12,640 --> 00:45:14,600
Speaker 1: It's stubborn because it's like I work out, I try

842
00:45:14,640 --> 00:45:16,560
Speaker 1: to eat right, and it's still there and that's annoying.

843
00:45:17,080 --> 00:45:21,319
Speaker 1: So I did look into this for us once again

844
00:45:21,600 --> 00:45:24,960
Speaker 1: in Cushing syndrome and Cushing's disease, there is a substantial

845
00:45:25,040 --> 00:45:28,560
Speaker 1: increase in visceral outipost tissue. That's what belly fat is,

846
00:45:29,080 --> 00:45:31,960
Speaker 1: as opposed to subcutaneous fat, which is kind of all

847
00:45:32,000 --> 00:45:34,600
Speaker 1: over your body. Belly fat is visceral fat, and it's

848
00:45:35,040 --> 00:45:38,000
Speaker 1: not good for you. Higher amounts of visceral fat are

849
00:45:38,120 --> 00:45:45,719
Speaker 1: associated and potentially causally with cardiovascular disease. But in a

850
00:45:46,640 --> 00:45:50,399
Speaker 1: study pering clinical endochronology in twenty twenty four, they looked

851
00:45:50,440 --> 00:45:54,160
Speaker 1: at visceral fat and subcutaneous fat among people just regular

852
00:45:54,320 --> 00:45:57,520
Speaker 1: joes with varying cortisol levels, and there was no association

853
00:45:57,760 --> 00:46:01,920
Speaker 1: between higher cortisol level in the non pathologic range, in

854
00:46:01,960 --> 00:46:05,120
Speaker 1: the non Cushing's disease range, and belly fat. So that's

855
00:46:05,200 --> 00:46:05,800
Speaker 1: not it, folks.

856
00:46:06,600 --> 00:46:09,319
Speaker 3: I also think it's worth saying, like when people are

857
00:46:09,440 --> 00:46:11,480
Speaker 3: chronically stressed, it actually isn't.

858
00:46:12,120 --> 00:46:13,120
Speaker 2: We said this at the topics.

859
00:46:13,200 --> 00:46:15,680
Speaker 3: We're saying again, it's not that chronic stress means you

860
00:46:15,800 --> 00:46:18,160
Speaker 3: always have a high cortisol level. It actually means your

861
00:46:18,239 --> 00:46:21,160
Speaker 3: cortisol is very flat, as opposed to moving up and

862
00:46:21,239 --> 00:46:23,880
Speaker 3: down like it's sort of supposed to typically, And so

863
00:46:24,360 --> 00:46:26,560
Speaker 3: like your cortisol is supposed to be responsive to like

864
00:46:26,719 --> 00:46:29,839
Speaker 3: events and to the day, which of course is evolutionary

865
00:46:29,920 --> 00:46:32,440
Speaker 3: valuable because you want to really be able to respond

866
00:46:32,480 --> 00:46:33,080
Speaker 3: when the tiger.

867
00:46:33,400 --> 00:46:34,359
Speaker 2: When the tiger comes.

868
00:46:34,840 --> 00:46:38,040
Speaker 3: When people are chronically stressed, they can get a sort

869
00:46:38,040 --> 00:46:40,560
Speaker 3: of flattening of the cortosol, but it's not that it's higher,

870
00:46:40,680 --> 00:46:43,000
Speaker 3: and so this sort of whole narrative is kind of

871
00:46:43,040 --> 00:46:43,719
Speaker 3: con Yeah, it.

872
00:46:43,719 --> 00:46:46,480
Speaker 1: Can even burn out. So there's some nice studies in PTSD,

873
00:46:46,719 --> 00:46:49,440
Speaker 1: in patients with PTSD that actually shows your typical patient

874
00:46:49,480 --> 00:46:54,680
Speaker 1: with PTSD has lower cortisol levels than controls who don't

875
00:46:54,760 --> 00:46:57,600
Speaker 1: have trauma. So yeah, this whole idea that like, your

876
00:46:57,680 --> 00:47:01,080
Speaker 1: cortisol is so high and because you're so stressed, if anything,

877
00:47:01,400 --> 00:47:04,919
Speaker 1: it's blunting the cortisol response, or your cortosol might even

878
00:47:04,960 --> 00:47:05,279
Speaker 1: be low.

879
00:47:06,320 --> 00:47:08,759
Speaker 3: So you don't need to detox your cortisol, not that

880
00:47:08,960 --> 00:47:11,040
Speaker 3: we have any Like people will sell you a lot

881
00:47:11,080 --> 00:47:12,279
Speaker 3: of stuff gum ease.

882
00:47:12,400 --> 00:47:15,080
Speaker 1: Yeah, n well, yeah, I mean I did, I did

883
00:47:15,320 --> 00:47:17,960
Speaker 1: look into it in case people want to make their cortisol.

884
00:47:18,360 --> 00:47:19,600
Speaker 1: You know what, there are some things that will make

885
00:47:19,640 --> 00:47:21,800
Speaker 1: your cortisol lower that I think are good for you anyway,

886
00:47:22,320 --> 00:47:26,439
Speaker 1: So there's a pretty large meta analysis of randomized control

887
00:47:26,520 --> 00:47:30,080
Speaker 1: trials you talked about, you know, randomizing people to interventions

888
00:47:30,120 --> 00:47:33,440
Speaker 1: to lower cortisol, which of course have off target effects.

889
00:47:33,680 --> 00:47:36,640
Speaker 1: This is once again psycho Neeurontochronology twenty twenty four or

890
00:47:36,640 --> 00:47:39,280
Speaker 1: fifty eight randomized trials just about thirty five hundred patients

891
00:47:39,320 --> 00:47:43,440
Speaker 1: looking at different ways to reduce cortisol levels, and mindfulness,

892
00:47:43,520 --> 00:47:50,279
Speaker 1: meditation relaxation techniques both reduce cortisol levels by about a

893
00:47:51,120 --> 00:47:56,480
Speaker 1: third or so, not bad. Interestingly, the studies of yoga

894
00:47:56,560 --> 00:47:58,960
Speaker 1: and tai chiet didn't have a significant effect, and the

895
00:47:59,040 --> 00:48:01,840
Speaker 1: talk therapies like cognitive behavioral therapy and counseling did not

896
00:48:01,920 --> 00:48:02,920
Speaker 1: have a significant effect.

897
00:48:03,080 --> 00:48:09,640
Speaker 3: So meditation, Yeah, exercise is good for your cortisol lowers

898
00:48:09,640 --> 00:48:10,280
Speaker 3: your cortisol.

899
00:48:10,400 --> 00:48:13,160
Speaker 2: We also see that in randomized control trials.

900
00:48:13,360 --> 00:48:16,839
Speaker 1: Yep, absolutely exercise and we've hit on the several times.

901
00:48:16,880 --> 00:48:20,080
Speaker 1: But sleep, you guys, especially especially if you want to

902
00:48:20,120 --> 00:48:23,239
Speaker 1: maintain that diurnal variation, which does appear to be an

903
00:48:23,280 --> 00:48:27,600
Speaker 1: important thing for your overall health. Getting adequate amounts of

904
00:48:27,640 --> 00:48:30,960
Speaker 1: sleep gets the cortisol into the right place at the

905
00:48:31,040 --> 00:48:31,359
Speaker 1: right time.

906
00:48:31,840 --> 00:48:34,320
Speaker 3: So is it worth I think an interesting question is

907
00:48:34,360 --> 00:48:37,080
Speaker 3: it worth measuring your cortisol at all? So we just

908
00:48:37,200 --> 00:48:40,320
Speaker 3: gave you know there are these are recommendations too that

909
00:48:40,520 --> 00:48:44,040
Speaker 3: will reduce your cortisol, but also things which you should

910
00:48:44,239 --> 00:48:48,920
Speaker 3: probably be doing for a general like health maintenance regardless.

911
00:48:49,520 --> 00:48:52,000
Speaker 3: Would you recommend someone measure their cortisol.

912
00:48:52,640 --> 00:48:55,480
Speaker 1: If they had moon faces, a buffalo hump, or a

913
00:48:55,560 --> 00:48:59,680
Speaker 1: violaceous strea, I would recommend that they have cortisol levels measured.

914
00:49:00,239 --> 00:49:01,800
Speaker 2: Do you want to know what my cortosol level is?

915
00:49:01,880 --> 00:49:04,120
Speaker 3: Because I looked it up while we were here, because

916
00:49:04,160 --> 00:49:05,799
Speaker 3: I had it measured in the last time I had

917
00:49:05,840 --> 00:49:06,439
Speaker 3: a blood test.

918
00:49:06,880 --> 00:49:08,080
Speaker 1: What time of day was it.

919
00:49:09,239 --> 00:49:10,040
Speaker 2: It was in the morning.

920
00:49:11,840 --> 00:49:15,720
Speaker 1: It was fifteen micrograms pertest leader nineteen.

921
00:49:16,880 --> 00:49:21,080
Speaker 2: It only got in in the sufficient range for.

922
00:49:22,640 --> 00:49:26,360
Speaker 1: We should say, I can't believe yeah, sufficient, You know

923
00:49:26,480 --> 00:49:29,359
Speaker 1: you die without enough cortisol, right, Like that's the other

924
00:49:29,800 --> 00:49:32,320
Speaker 1: The flip side of this is that your adrenal glands

925
00:49:32,400 --> 00:49:35,799
Speaker 1: can stop producing cortisol. This is called Addison's disease, which

926
00:49:35,840 --> 00:49:41,839
Speaker 1: JFK had, and it causes like severe hypotension, sodium wasting death.

927
00:49:41,920 --> 00:49:44,600
Speaker 1: You need to supplement that's bad too. So I think

928
00:49:44,880 --> 00:49:47,200
Speaker 1: the cortisol is just like not something if you're into

929
00:49:47,560 --> 00:49:49,520
Speaker 1: interested in your health and wellness, it's just not worth

930
00:49:49,560 --> 00:49:52,359
Speaker 1: your time. It's like, don't you're not going to change

931
00:49:52,400 --> 00:49:55,320
Speaker 1: your life based on it. And yes you should destress,

932
00:49:55,400 --> 00:49:56,400
Speaker 1: but not because of cortisol.

933
00:49:57,760 --> 00:50:00,920
Speaker 3: Look, I think every time we talk about hormones, I

934
00:50:01,080 --> 00:50:05,000
Speaker 3: am more and more impressed with the endocrine system. I

935
00:50:05,080 --> 00:50:08,120
Speaker 3: feel like, you know, the human endocrine system is so

936
00:50:09,560 --> 00:50:14,279
Speaker 3: like tight, and it's so well thought out, and there's

937
00:50:14,400 --> 00:50:17,279
Speaker 3: so much of the wellness space that's about like give

938
00:50:17,320 --> 00:50:19,120
Speaker 3: yourself more of this hormone and more of that homer

939
00:50:19,160 --> 00:50:21,719
Speaker 3: and do this, and most of the time, like your endocrinsism,

940
00:50:21,800 --> 00:50:23,680
Speaker 3: like it's thinking about that, like it thought about when

941
00:50:23,719 --> 00:50:25,279
Speaker 3: the cord sho should be, when it should be low,

942
00:50:25,360 --> 00:50:28,440
Speaker 3: like how much you need. It's like estrogen, Like we're

943
00:50:28,480 --> 00:50:31,680
Speaker 3: all kind of moving moving together, and I just I

944
00:50:31,719 --> 00:50:33,720
Speaker 3: don't think it's a system we want to be messing

945
00:50:33,800 --> 00:50:34,319
Speaker 3: with too much.

946
00:50:35,239 --> 00:50:38,480
Speaker 1: With the exception of hormone replacement therapy and with the exceptional.

947
00:50:38,200 --> 00:50:41,440
Speaker 3: Yeah, yeah, okay, there are some things, but like like

948
00:50:42,200 --> 00:50:45,760
Speaker 3: our tendency to want to get inside the endocrine system

949
00:50:45,800 --> 00:50:48,400
Speaker 3: and mess around with it, I think is over. I

950
00:50:48,480 --> 00:50:50,960
Speaker 3: think we're doing we're doing too much of that outside

951
00:50:51,000 --> 00:50:52,360
Speaker 3: of I agree hormone replacement.

952
00:50:52,840 --> 00:50:55,520
Speaker 1: Yeah yeah. Cortisolt too high is bad, Cortisol too low

953
00:50:55,640 --> 00:50:58,000
Speaker 1: is bad. It needs to have a specific pattern. You're

954
00:50:58,040 --> 00:51:00,399
Speaker 1: not going to get this right with like ashwaganda, which

955
00:51:00,440 --> 00:51:02,160
Speaker 1: does lower your cortisol a little bit, by the way,

956
00:51:02,239 --> 00:51:05,000
Speaker 1: but like this is one. Trust your body a little

957
00:51:05,000 --> 00:51:06,200
Speaker 1: bit and be zen.

958
00:51:06,840 --> 00:51:11,600
Speaker 3: Trust your body, but don't trust Mendelian randomization because it's stupid.

959
00:51:14,520 --> 00:51:15,920
Speaker 1: It can be done very well.

960
00:51:16,640 --> 00:51:18,840
Speaker 2: It can be, but it's not okay. Enough of that

961
00:51:19,000 --> 00:51:21,920
Speaker 2: for me, all right, Perry, smash your pass cortisol.

962
00:51:23,160 --> 00:51:26,000
Speaker 1: I mean I'm a pass in terms of cortisol as

963
00:51:26,040 --> 00:51:29,440
Speaker 1: a wellness metric. Obviously I love the hormone. I die

964
00:51:29,520 --> 00:51:31,920
Speaker 1: without it, so do you. But I'm a past Emily

965
00:51:32,000 --> 00:51:32,640
Speaker 1: Smasher pass.

966
00:51:33,320 --> 00:51:37,480
Speaker 3: I am a pass on anything that involves detoxing, retoxing,

967
00:51:38,239 --> 00:51:43,360
Speaker 3: changing gummies adapt to this and that. Just trust your

968
00:51:43,440 --> 00:51:47,040
Speaker 3: endocrine system unless you have a buffalo and then get

969
00:51:47,080 --> 00:51:47,480
Speaker 3: it looked at.

970
00:51:48,239 --> 00:51:50,439
Speaker 1: All Right, that's it for cortisol. Your mail bag question

971
00:51:50,520 --> 00:51:51,920
Speaker 1: of the Week after the break.

972
00:51:57,440 --> 00:52:00,600
Speaker 2: Hi, Emily and Perry. This is celestin Detroit. My question

973
00:52:00,719 --> 00:52:01,840
Speaker 2: is more personal to both of you.

974
00:52:02,520 --> 00:52:05,480
Speaker 3: Is there anything that you felt certain about like ten

975
00:52:05,600 --> 00:52:07,840
Speaker 3: years ago that now you look back on and cringe.

976
00:52:08,719 --> 00:52:12,440
Speaker 2: We all have them, and I'm dying to know yours. Thanks.

977
00:52:13,160 --> 00:52:17,040
Speaker 1: Oh, this is such a good question. I'm sure there

978
00:52:17,080 --> 00:52:21,200
Speaker 1: are many things that I've suppressed, and I have convinced

979
00:52:21,239 --> 00:52:23,800
Speaker 1: myself that I never believed that really I did. But

980
00:52:24,040 --> 00:52:27,440
Speaker 1: the one I am quite sure I believed strongly. And

981
00:52:27,680 --> 00:52:29,359
Speaker 1: I think I'm going to just cheat a little bit

982
00:52:29,360 --> 00:52:31,839
Speaker 1: and say this was more like fifteen years ago, maybe

983
00:52:31,880 --> 00:52:37,000
Speaker 1: even pushing twenty years ago. But I was a hardcore

984
00:52:37,160 --> 00:52:41,759
Speaker 1: fluid resuscitation vigilante when I was in medical training. So

985
00:52:41,840 --> 00:52:44,440
Speaker 1: when someone came into the ICU with sepsis, I was

986
00:52:44,600 --> 00:52:47,320
Speaker 1: it was like a contest, like how much IVY fluid

987
00:52:47,360 --> 00:52:49,720
Speaker 1: can I put into this person in the next twelve hours?

988
00:52:50,560 --> 00:52:54,160
Speaker 1: And back then, we thought this was the right thing

989
00:52:54,200 --> 00:52:56,919
Speaker 1: to do. This totally makes me cringe now, like there's

990
00:52:56,920 --> 00:52:59,120
Speaker 1: been a lot of evidence in the past twenty years

991
00:52:59,160 --> 00:53:03,520
Speaker 1: that suggests that overly aggressive fluid resuscitation can cause major

992
00:53:03,560 --> 00:53:05,880
Speaker 1: problems down the road, and you know, people get volume

993
00:53:05,920 --> 00:53:08,160
Speaker 1: overloaded and their lungs don't work anymore and stuff like that.

994
00:53:08,280 --> 00:53:10,000
Speaker 1: But it was like it used to be a contest

995
00:53:10,080 --> 00:53:13,040
Speaker 1: among the residents, like I gave that guy fifteen liders

996
00:53:13,120 --> 00:53:15,480
Speaker 1: last night and like high five, like, yeah, that's how

997
00:53:15,520 --> 00:53:18,120
Speaker 1: you treat sepsis. And I cringe a little bit thinking

998
00:53:18,120 --> 00:53:19,719
Speaker 1: about that. Now, why you am.

999
00:53:22,000 --> 00:53:22,960
Speaker 2: I that's amazing.

1000
00:53:23,239 --> 00:53:27,040
Speaker 3: Mine is more Mine is more personal. It actually vaguely

1001
00:53:27,120 --> 00:53:31,000
Speaker 3: relates to to cortosol. So I used to be very

1002
00:53:31,160 --> 00:53:34,120
Speaker 3: sure that you should exercise in the morning before you eat,

1003
00:53:34,640 --> 00:53:36,560
Speaker 3: and that you should like not eat anything before you

1004
00:53:36,719 --> 00:53:40,399
Speaker 3: you should like exercise fasted. But it turns out that's

1005
00:53:40,520 --> 00:53:45,279
Speaker 3: really stupid and it's really bad for your cortisol. I

1006
00:53:45,400 --> 00:53:50,040
Speaker 3: think it raises your cortisol a lot to exercise fasted,

1007
00:53:50,239 --> 00:53:54,160
Speaker 3: and I don't do that anymore. And I think it

1008
00:53:54,320 --> 00:53:57,360
Speaker 3: was part of this space of like, you know, like

1009
00:53:57,560 --> 00:54:00,800
Speaker 3: diet culture that I find now very cringey.

1010
00:54:00,920 --> 00:54:02,719
Speaker 1: It's okay, we're all entitled to change.

1011
00:54:03,080 --> 00:54:06,279
Speaker 3: I can't believe you guys were high fiving. That's like,

1012
00:54:06,560 --> 00:54:11,800
Speaker 3: that's so nerdy and weird. Oh yeah, it makes me Yeah, okay,

1013
00:54:14,280 --> 00:54:15,600
Speaker 3: I have feelings. I'm not going to comment.

1014
00:54:17,719 --> 00:54:18,040
Speaker 1: Thanks.

1015
00:54:20,960 --> 00:54:22,720
Speaker 2: All right, that's it for us today.

1016
00:54:23,040 --> 00:54:25,080
Speaker 3: Stick with us next week when we'll ask what's the

1017
00:54:25,120 --> 00:54:28,200
Speaker 3: deal with pregnancy brain and we'll have a special guest.

1018
00:54:29,200 --> 00:54:33,600
Speaker 3: Wellness Actually is produced in association with iHeartMedia. Our senior

1019
00:54:33,640 --> 00:54:37,360
Speaker 3: producer is Tamar Avisheid. Our executive producer at iHeart is

1020
00:54:37,440 --> 00:54:40,960
Speaker 3: Jennifer Bassett. Our theme music is by Eric Deutsch, and

1021
00:54:41,080 --> 00:54:43,120
Speaker 3: our content is for educational purposes only.

1022
00:54:43,840 --> 00:54:46,040
Speaker 1: If you like the show, help other people find us.

1023
00:54:46,440 --> 00:54:49,200
Speaker 1: Leave a rating and review on Apple Podcasts or your

1024
00:54:49,320 --> 00:54:52,040
Speaker 1: podcatcher of choice and help us spread the word about

1025
00:54:52,080 --> 00:54:55,080
Speaker 1: the show. You can follow us on Instagram at Wellness

1026
00:54:55,120 --> 00:54:58,160
Speaker 1: Actually pod and don't forget. We want to hear from you.

1027
00:54:58,760 --> 00:55:01,600
Speaker 1: Head over to Wellness Action and leave us a question

1028
00:55:01,680 --> 00:55:04,560
Speaker 1: from our mailbag or suggest a topic for a future show.

1029
00:55:05,360 --> 00:55:07,160
Speaker 2: We'll let the influencers have the last word.

1030
00:55:07,400 --> 00:55:09,440
Speaker 5: When your cortisol levels are elevated, you can hang on

1031
00:55:09,480 --> 00:55:10,759
Speaker 5: to a lot of fat around your middle and this

1032
00:55:10,880 --> 00:55:13,120
Speaker 5: can be really frustrating because it seems like you're doing

1033
00:55:13,200 --> 00:55:15,520
Speaker 5: everything right, but it's not budging. The first thing I

1034
00:55:15,600 --> 00:55:17,160
Speaker 5: want you to do is get rid of the high

1035
00:55:17,160 --> 00:55:20,640
Speaker 5: intensity interval training. The second thing is intermittent fasting.

1036
00:55:20,800 --> 00:55:21,360
Speaker 2: Get rid of it.

1037
00:55:21,480 --> 00:55:24,000
Speaker 5: Eat thirty grams of protein within thirty minutes of waking up.

1038
00:55:24,520 --> 00:55:27,160
Speaker 5: And the third one is the least fun, and that

1039
00:55:27,360 --> 00:55:29,560
Speaker 5: is to stop drinking coffee first thing in the morning

1040
00:55:29,640 --> 00:55:30,600
Speaker 5: on an empty stomach.

1041
00:55:31,080 --> 00:55:32,440
Speaker 2: This third one might piss you off.